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Background Elexacaftor-Tezacaftor-Ivacaftor (ETI) therapy is showing promising efficacy for treatment of cystic fibrosis (CF) and is becoming more widely available since recent FDA approval. However, little is known about how these drugs will affect lung infections, which are the leading cause of morbidity and mortality among people with CF (pwCF). Methods We analyzed sputum microbiome and metabolome data from pwCF (n=24) before and after ETI therapy using 16S rRNA gene sequencing and untargeted metabolomics. Results The sputum microbiome diversity, particularly its evenness, was increased (p=0.036) and the microbiome profiles were different between individuals before and after therapy (PERMANOVA F=1.92, p=0.044). Despite these changes, the microbiomes remained more similar within an individual than across the sampled population. No specific microbial taxa differed in relative abundance before and after therapy, but the collective log-ratio of classic CF pathogens to anaerobes significantly decreased (p=0.013). The sputum metabolome also showed changes associated with ETI (PERMANOVA F=4.22, p=0.002) and was characterized by greater variation across subjects while on treatment. Changes in the metabolome were driven by a decrease in peptides, amino acids, and metabolites from the kynurenine pathway, which were associated with a decrease in CF pathogens. Metabolism of the three small molecules that make up ETI was extensive, including previously uncharacterized structural modifications. Conclusions ETI therapy is associated with a changing microbiome and metabolome in airway mucus. This effect was stronger on sputum biochemistry, which may reflect changing niche space for microbial residency in lung mucus as the drug's effects take hold. Funding This project was funded by a National Institute of Allergy and Infectious Disease Grant R01AI145925

Children with traumatic arrests represent almost one third of annual pediatric out-of-hospital cardiac arrests (OHCAs). However, traumatic arrests are often excluded from study populations because survival posttraumatic arrest is thought to be negligible. We hypothesized that children treated and transported by emergency medical services (EMS) personnel after traumatic OHCA would have lower survival compared with children treated after medical OHCA.We performed a secondary, observational study of children younger than 18 years treated and transported by 78 EMS agencies in southwestern Pennsylvania after OHCA from 2010 to 2014. Etiology was determined as trauma or medical by EMS services. We analyzed patient, cardiac arrest, and resuscitation characteristics and ascertained vital status using the National Death Index. We used multivariable logistic regression to test the association of etiology with mortality after covariate adjustment.Forty eight of 209 children (23%) had traumatic OHCA. Children with trauma were older than those with medical OHCA (13.2 [3.8-15.9] vs 0.5 [0.2-2.4] years, P0.001). Prehospital return of spontaneous circulation frequency for trauma versus medical etiology was similar (90% vs 87%, P = 0.84). Patients with trauma had higher mortality (69% vs 45% P = 0.004).More than 8 of 10 children with EMS treated and transported OHCA achieved return of spontaneous circulation. Despite lower survival rates than medical OHCA patients, almost one third of children with a traumatic etiology survived throughout the study period. Future research programs warrant inclusion of children with traumatic OHCA to improve outcomes.

This study aimed to compare statewide emergency medical services protocols for the management of pediatric respiratory distress.We performed a descriptive study of emergency medical services protocols for the management of pediatric respiratory distress in the United States, excluding those without model or mandatory protocols. We compared medication recommendations for specific disease processes, including asthma, croup, epiglottitis, anaphylaxis, generalized respiratory distress, intubation, and drug assisted intubation.Thirty-four state protocols were included. All had protocols to address the management of pediatric respiratory distress. There was high agreement in albuterol use for bronchospasm and epinephrine use in anaphylaxis. Epinephrine was recommended in all anaphylaxis protocols, 27 croup protocols (79%), and 3 epiglottitis protocols (9%). Six states (18%) called for albuterol in patients with generalized respiratory distress. Steroid recommendations and indications had variance among states; 26 states (76%) allowed steroid use in patients with asthma, 19 states (56%) recommended steroid use in anaphylaxis, and 11 (32%) recommended steroid use in croup protocols. The route for steroid administration also varied among protocols. Five states (15%) allowed continuous positive airway pressure application in pediatric patients, whereas endotracheal intubation and rapid sequence intubations had varying requirements as well as recommendations for use. Twelve (35%) listed impending or current respiratory failure as an indication, whereas other states had specific markers, such as Glasgow Coma Scale or oxygen saturation, as indications.All included states had specific recommendations for the management of pediatric respiratory distress. There was consistency in recommendations for albuterol use for wheezing and epinephrine use for anaphylaxis. However, there was wide variability in other uses for epinephrine, steroid administration, continuous positive airway pressure use, and specific treatments for croup and epiglottitis. The findings of this study provide a base for important future evidence-based protocol developments and changes in prehospital pediatric respiratory distress treatment.

Introduction Out of hospital cardiac arrest (OHCA) patients are often transported to the closest emergency department (ED) or cardiac center for initial stabilization and may be transferred for further care. We investigated the effects of delay to transfer on in hospital mortality at a receiving facility. Methods We included OHCA patients transported from the ED by a single critical care transport service to a quaternary care facility between 2010 and 2018. We calculated dwell time as time from arrest to critical care transport team contact. We abstracted demographics, arrest characteristics, and interventions started prior to transport arrival. For the primary analysis, we used logistic regression to determine the association of dwell time and in-hospital mortality. As secondary outcomes we investigated for associations of dwell time and mortality within 24 h of arrival, proximate cause of death among decedents, arterial pH and lactate on arrival, sum of worst SOFA subscales within 24 h of arrival, and rearrest during interfacility transport. Results We included 572 OHCA patients transported from an outside ED to our facility. Median dwell time was 113 (IQR = 85–159) minutes. Measured in 30 min epochs, increasing dwell time was not associated with in-hospital mortality, 24-h mortality, cause of death and initial pH, but was associated with lower 24-h SOFA score (p = 0.01) and lower initial lactate (p = 0.03). Rearrest during transport was rare (n = 29, 5%). Dwell time was associated with lower probability of rearrest during transport (OR = 0.847, (95% CI 0.68–1.01), p = 0.07). Conclusions Dwell time was not associated with in-hospital mortality. Rapid transport may be associated with risk of rearrest. Prospective data are needed to clarify optimal patient stabilization and transport strategies.

BACKGROUND: The 12-lead ECG plays an important role in triaging patients with symptomatic coronary artery disease, making automated ECG interpretation statements of “Acute MI” or “Acute Ischemia” crucial, especially during prehospital transport when access to physician interpretation of the ECG is limited. However, it remains unknown how automated interpretation statements correspond to adjudicated clinical outcomes during hospitalization. We sought to evaluate the diagnostic performance of prehospital automated interpretation statements to four well-defined clinical outcomes of interest: confirmed ST- segment elevation myocardial infarction (STEMI); presence of actionable coronary culprit lesions, myocardial necrosis, or any acute coronary syndrome (ACS). METHODS: An observational cohort study that enrolled consecutive patients with non-traumatic chest pain transported via ambulance. Prehospital ECGs were obtained with the Philips MRX monitor from the medical command center and re-processed using manufacturer-specific diagnostic algorithms to denote the likelihood of >>>Acute MI<<< or >>>Acute Ischemia<<

Background: Research networks need access to EMS data to conduct pilot studies and determine feasibility of prospective studies. Combining data across EMS agencies is complicated and costly. Leveraging the National EMS Information System (NEMSIS) to extract select agencies’ data may be an efficient and cost-effective method of providing network-level data. Objective: Describe the process of creating a Pediatric Emergency Care Applied Research Network (PECARN) specific NEMSIS data set and determine if these data were nationally representative. Methods: We established data use agreements (DUAs) with EMS agencies participating in PECARN to allow for agency identification through NEMSIS. Using 2019 NEMSIS version 3.4.0 data for EMS events with patients 18 years old and younger, we compared PECARN NEMSIS data to national NEMSIS data. Analyzed variables were selected for their ability to characterize events. No statistical analyses were utilized due to the large sample, instead, differences of ±5% were deemed clinically meaningful. Results: DUAs were established for 19 EMS agencies, creating a PECARN data set with 305,188 EMS activations of which 17,478 (5.7%) were pediatric. Of the pediatric activations, 17,140 (98.1%) were initiated through 9-1-1 and 9,487 (55.4%) resulted in transport by the documenting agency. The national data included 36,288,405 EMS activations of which 2,152,849 (5.9%) were pediatric. Of the pediatric activations 1,704,141 (79.2%) were initiated through 9-1-1 and 1,055,504 (61.9%) were transported by the documenting agency. Age and gender distributions were similar between the two groups, but the PECARN-specific data under-represents Black and Latinx patients. Comparison of EMS provider primary impressions revealed that three of the five most common were similar with injury being the most prevalent for both data sets along with mental/behavioral health and seizure. Conclusion: We demonstrated that NEMSIS can be leveraged to create network specific data sets. PECARN’s EMS data were similar to the national data, though racial/ethnic minorities and some primary impressions may be under-represented. Additionally, more EMS activations in PECARN study areas originated through 9-1-1 but fewer were transported by the documenting agency. This is likely related to the type of participating agencies, their ALS response level, and the diversity of the communities they serve.

Background Emergency medical services (EMS) response volume has been linked to weather and temporal factors in a regional EMS system. We aimed to identify if models of EMS utilization incorporating these data are generalizable through geographically disparate areas in the United States. Methods We performed a retrospective analysis of EMS dispatch data from four regions: New York City, San Francisco, Cincinnati, and Marin County for years 2016–2019. For each model, we used local weather data summarized from the prior 6 h into hourly bins. Our outcome for each model was EMS dispatches as count data. We fit and optimized a negative binomial regression model for each region, to estimate incidence rate ratios. We compared findings to a prior study performed in Western Pennsylvania. Results We included 5,940,637 EMS dispatches from New York City, 809,405 from San Francisco, 260,412 from Cincinnati, and 77,461 from Marin County. Models demonstrated consistency with the Western Pennsylvania model with respect to temperature, season, wind speed, dew point, and time of day; both in terms of direction and effect size when expressed as incidence rate ratios. Precipitation was associated with increasing dispatches in the New York City, Cincinnati, and Marin County models, but not the San Francisco model. Conclusion With minor differences, regional models demonstrated consistent associations between dispatches and time and weather variables. Findings demonstrate the generalizability of associations between these variables with respect to EMS use. Weather and temporal factors should be considered in predictive modeling to optimize EMS staffing and resource allocation.

Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder affecting 0.5-2% of pregnancies. The majority of cases present in the third trimester with pruritus, elevated serum bile acids and abnormal serum liver tests. ICP is associated with an increased risk of adverse outcomes, including spontaneous preterm birth and stillbirth. Whilst rare mutations affecting hepatobiliary transporters contribute to the aetiology of ICP, the role of common genetic variation in ICP has not been systematically characterised to date. Here, we perform genome-wide association studies (GWAS) and meta-analyses for ICP across three studies including 1138 cases and 153,642 controls. Eleven loci achieve genome-wide significance and have been further investigated and fine-mapped using functional genomics approaches. Our results pinpoint common sequence variation in liver-enriched genes and liver-specific cis-regulatory elements as contributing mechanisms to ICP susceptibility. ispartof: NATURE COMMUNICATIONS vol:13 issue:1 ispartof: location:England status: published

Introduction The COVID-19 pandemic may affect both use of 9–1-1 systems and prehospital treatment and transport practices. We evaluated EMS responses in an EMS region when it experienced low to moderate burden of COVID-19 disease to assess overall trends, response and management characteristics, and non-transport rates. Our goal is to inform current and future pandemic response in similar regions. Methods We performed a retrospective review of prehospital EMS responses from 22 urban, suburban, and rural EMS agencies in Western Pennsylvania. To account for seasonal variation, we compared demographic, response, and management characteristics for the 2-month period of March 15 to May 15, 2020 with the corresponding 2-month periods in 2016–2019. We then tested for an association between study period (pandemic vs historical control) and incidence of non-transport in unadjusted and adjusted regression. Finally, we described the continuous trends in responses and non-transports that occurred during the year before and initial phase of the COVID-19 pandemic from January 1, 2019 to May 31, 2020. Results Among 103,607 EMS responses in the 2-month comparative periods of March 15 to May 15, 2016–2020, we found a 26.5% [95% CI 26.9%, 27.1%] decrease in responses in 2020 compared to the same months from the four prior years. There was a small increase in respiratory cases (0.6% [95%CI 0.1%, 1.1%]) and greater frequency of abnormal vital signs suggesting a sicker patient cohort. There was a relative increase (46.6%) in non-transports between periods. The pandemic period was independently associated with an increase in non-transport (adjusted OR 1.68; 95%CI 1.59, 1.78). Among 177,194 EMS responses occurring in the year before and during the early period of the pandemic, between January 1, 2019, and May 31, 2020, we identified a 31% decrease in responses and a 48% relative increase in non-transports for April 2020 compared to the previous year's monthly averages. Conclusion Despite a low to moderate burden of infection during the initial period of the COVID-19 pandemic, we found a decline in overall EMS response volumes and an increase in the rate of non-transports independent of patient demographics and other response characteristics.

To describe the epidemiology of emergency department (ED) visits by pediatric patients transported from the out-of-hospital setting (ie, scene) by emergency medical services (EMS), and identify factors associated with EMS transport.We performed a cross-sectional study of ED visits from 2014 to 2017 utilizing a nationally representative probability sample survey of visits to US EDs. We included pediatric patients (18 years old) and compared encounters transported from the scene by EMS to those who arrived to the ED by all other means. We performed multivariable logistic regression to identify factors associated with scene EMS transport.Of 130.2 million pediatric ED encounters, 4.7 million (3.8%) arrived by EMS. Most patients were White (61.1%), non-Hispanic (77.5%), and publicly insured (52.2%). Multivariable analysis demonstrated associations with EMS transport: Black (vs White) race (adjusted odds ratio [aOR], 1.48; 95% confidence interval [CI], 1.16-1.89), ages 1 to younger than 5 years (aOR, 0.52; 95% CI, 0.37-0.72) and 5 to younger than 12 years (aOR, 0.56; 95% CI, 0.40-0.80) (vs adolescents), pediatric (aOR, 0.60; 95% CI, 0.42-0.85) and nonmetropolitan hospital status (aOR, 0.52; 95% CI, 0.35-0.78), blood testing (aOR, 2.34; 95% CI, 1.71-3.19), time to evaluation (31-60 minutes [aOR, 0.56; 95% CI, 0.39-0.80] and60 minutes [aOR, 0.51; 95% CI, 0.33-0.77] compared with 0-30 minutes), admission (aOR, 3.20; 95% CI, 2.33-4.38), and trauma (1.80; 95% CI, 1.43-2.28).Four percent of pediatric ED patients are transported to the ED by EMS from the scene. These patients receive a rapid and resource intense diagnostic evaluation, suggesting that higher acuity. Black patients, adolescents, and those with trauma were more likely to be transported by EMS.

SummaryThe current paradigm is that inflammatory pain passively resolves following the cessation of inflammation. Yet, in a substantial proportion of patients with inflammatory diseases, resolution of inflammation is not sufficient to resolve pain, resulting in chronic pain. Mechanistic insight how inflammatory pain is resolved is lacking. Here we show that macrophages actively control resolution of inflammatory pain remotely from the site of inflammation by transferring mitochondria to sensory neurons. During resolution of inflammatory pain in mice, M2-like macrophages infiltrate the dorsal root ganglia that contain the somata of sensory neurons, concurrent with the recovery of oxidative phosphorylation in sensory neurons. The resolution of pain and the transfer of mitochondria requires expression of CD200 Receptor (CD200R) on macrophages and the non-canonical CD200R-ligand iSec1 on sensory neurons. Our data reveal a novel mechanism for active resolution of inflammatory pain.Graphical Abstract

Respiratory diseases represent a global health burden. Because research on therapeutic strategies of airway diseases is essential, the technique of precision-cut lung slices (PCLS) has been developed and widely studied. PCLS are an alternative ex vivo model and have the potential to replace and reduce in vivo animal models. So far, the majority of studies was conducted with short-term cultivated PCLS (≤ 72 h). As there is large interest in research of chronic diseases and chronic toxicity, feasibility of cultivating human PCLS long-term over 2 weeks and recently over 4 weeks was investigated by another research group with successful results. Our aim was to establish a model of long-term cultivated rat PCLS over a period of 29 days.Rat PCLS were cultured for 29 days and analysed regarding viability, histopathology, reactivity and gene expression at different time points during cultivation.Cultivation of rat PCLS over a 29-day time period was successful with sustained viability. Furthermore, the ability of bronchoconstriction was maintained between 13 and 25 days, depending on the mediator. However, reduced relaxation, altered sensitivity and increased respiratory tone were observed. Regarding transcription, alteration in gene expression pattern of the investigated target genes was ascertained during long-term cultivation with mixed results. Furthermore, the preparation of PCLS seems to influence messenger ribonucleic acid (mRNA) expression of most target genes. Moreover, the addition of fetal bovine serum (FBS) to the culture medium did not improve viability of PCLS. In contrast to medium without FBS, FBS seems to affect measurements and resulted in marked cellular changes of metaplastic and/or regenerative origin.Overall, a model of long-term cultivated rat PCLS which stays viable for 29 days and reactive for at least 13 days could be established. Before long-term cultivated PCLS can be used for in-depth study of chronic diseases and chronic toxicity, further investigations have to be made.

Noninvasive ventilation (NIV), including bilevel positive airway pressure and continuous positive airway pressure, is a safe and important therapeutic option in the management of prehospital respiratory distress. NAEMSP recommends:NIV should be used in the management of prehospital patients with respiratory failure, such as those with chronic obstructive pulmonary disease, asthma, and pulmonary edema.NIV is a safe intervention for use by Emergency Medical Technicians.Medical directors must assure adequate training in NIV, including appropriate patient selection, NIV system operation, administration of adjunctive medications, and assessment of clinical response.Medical directors must implement quality assessment and improvement programs to assure optimal application of and outcomes from NIV.Novel NIV methods such as high-flow nasal cannula and helmet ventilation may have a role in prehospital care.

Objectives Ventilator management in prehospital settings using end-tidal CO2 can lead to inappropriate ventilation in the absence of point of care blood gas (POCBG) measurements. Implementation of POCBG testing in helicopter Emergency Medical Services (HEMS) is limited in part because of concern for preanalytical and analytical errors due to altitude, vibration, and other associated environmental factors and due to insufficient documentation of implementation challenges. Methods We performed accuracy and precision verification studies using standard materials tested pre-, in-, and post-flight (n=10) in a large HEMS agency. Quality assurance error log data were extracted and summarized for common POCBG errors during the first 31 months of use and air medical transport personnel were surveyed regarding POCBG use (n=63). Results No clinically significant differences were found between pre-, in-, and post-flight blood gas measurements. Error log data demonstrated a reduction in device errors over time. Survey participants found troubleshooting device errors and learning new clinical processes to be the largest barriers to implementation. Continued challenges for participants coincided with error log data including temperature and sampling difficulties. Survey participants indicated that POCBG testing improved patient management. Conclusions POCBG testing does not appear to be compromised by the HEMS environment. Temperature excursions can be reduced by use of insulated transport bags with heating and cooling packs. Availability of POCBG results in air medical transport appeared to improve ventilator management, increase recognition of ventilation-perfusion mismatch, and improve patient tolerance of ventilation.

European journal of neurology ene.15356 (2022). doi:10.1111/ene.15356, Published by Blackwell Science, Oxford

Scientific reports 10, 14646 (2020). doi:10.1038/s41598-020-71500-1, Published by Macmillan Publishers Limited, part of Springer Nature, [London]

Prompt identification of acute coronary syndrome is a challenge in clinical practice. The 12-lead electrocardiogram (ECG) is readily available during initial patient evaluation, but current rule-based interpretation approaches lack sufficient accuracy. Here we report machine learning-based methods for the prediction of underlying acute myocardial ischemia in patients with chest pain. Using 554 temporal-spatial features of the 12-lead ECG, we train and test multiple classifiers on two independent prospective patient cohorts (n = 1244). While maintaining higher negative predictive value, our final fusion model achieves 52% gain in sensitivity compared to commercial interpretation software and 37% gain in sensitivity compared to experienced clinicians. Such an ultra-early, ECG-based clinical decision support tool, when combined with the judgment of trained emergency personnel, would help to improve clinical outcomes and reduce unnecessary costs in patients with chest pain., Diagnosing a heart attack requires excessive testing and prolonged observation, which frequently requires hospital admission. Here the authors report a machine learning-based system based exclusively on ECG data that can help clinicians identify 37% more heart attacks during initial screening.

Background: Compared to day workers, shift workers face an elevated risk of cardiovascular disease. We reviewed the evidence to address the research question: Does acute exposure to shift work impact (blunt) the natural drop (dip) in Blood Pressure (BP) occurring during sleep and/or nighttime hours? (PROSPERO CRD42018110847). Methods: We performed a systematic review of five databases. We compared pooled estimates of mean BP stratified by periods of shift work, rest/leisure, and sleep, and evaluated the quality of evidence with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework. Results: Our search covered 1/1/1980-10/24/2018 and yielded 1,636 records. Inter-rater agreement during screening was high (Kappa=0.87). We retained 44 studies described in 50 publications. We identified wide variation in shift worker type, shift schedules, and regularity of BP measurements. Most studies examined BP during one shift workday and one rest/leisure day. No study examined the impact of repeated exposure to shift work on the sleep-related dip in BP. Eighteen studies examined night shifts and one reported on BP during sleep post night shift. Compared to BP measured during shift work, BP measured during any sleep period separate from shift work was lower by 17.5 mmHg Systolic BP (95%CI 15.75, 19.27) and 15.4 mmHg lower for Diastolic BP (95%CI 14.38, 16.42) (p Conclusions: There is limited research exploring the acute and long-term impact of shift work on BP during sleep. The available evidence is heterogenous, low quality, and suggests that the mean dip in BP during sleep separate from shift work is not blunted.

OBJECTIVE Recent studies have shown an increase of C-reactive-protein (CRP) after exposure to zinc- and copper-containing welding fumes. The objective of this study was to determine the effects of exposure to zinc- and copper-containing welding fumes on leukocytes, their subtypes, and myeloperoxidase (MPO). METHODS Serum samples of male volunteers were examined after exposures to welding fumes in two settings: repeated exposure on 4 consecutive days for 6 hours and single exposures for different times (3, 4, 5 hours). RESULTS Neutrophil granulocyte and MPO levels showed increases 24 hours after single and repeated exposures for 6 hours similar to CRP increases reported in literature. Overall leukocyte levels and levels of monocytes and lymphocytes were not significantly affected. CONCLUSIONS This study indicates the involvement of neutrophil granulocytes in welding fume fever additional to mediator related effects.

Background The Emergency Severity Index (ESI) is a widely used tool to triage patients in emergency departments. The ESI tool is used to assess all complaints and has significant limitation for accurately triaging patients with suspected acute coronary syndrome (ACS). Objective We evaluated the accuracy of ESI in predicting serious outcomes in suspected ACS and aimed to assess the incremental reclassification performance if ESI is supplemented with a clinically validated tool used to risk-stratify suspected ACS. Methods We used existing data from an observational cohort study of patients with chest pain. We extracted ESI scores documented by triage nurses during routine medical care. Two independent reviewers adjudicated the primary outcome, incidence of 30-day major adverse cardiac events. We compared ESI with the well-established modified HEAR/T (patient History, Electrocardiogram, Age, Risk factors, but without Troponin) score. Results Our sample included 750 patients (age, 59 ± 17 years; 43% female; 40% black). A total of 145 patients (19%) experienced major adverse cardiac event. The area under the receiver operating characteristic curve for ESI score for predicting major adverse cardiac event was 0.656, compared with 0.796 for the modified HEAR/T score. Using the modified HEAR/T score, 181 of the 391 false positives (46%) and 16 of the 19 false negatives (84%) assigned by ESI could be reclassified correctly. Conclusion The ESI score is poorly associated with serious outcomes in patients with suspected ACS. Supplementing the ESI tool with input from other validated clinical tools can greatly improve the accuracy of triage in patients with suspected ACS.

Objective The objective of this study was to compare statewide prehospital protocols for the management of pediatric seizures. Methods We performed a descriptive analysis comparing statewide protocols for emergency medical services management of pediatric seizures within the United States, excluding states for which no statewide protocol/model was available. We compared antiepileptic drugs (AEDs), routes and doses of administration, and differences in febrile seizure management. Results Of 50 states, 34 had either statewide protocols or models and were included. All had a protocol for the management of seizures and provided specific recommendations for the management of pediatric seizures. Twelve states (35%) preferentially recommended midazolam over other benzodiazepines. Thirty-two (94%) of 34 allowed for use of midazolam, with variable use of other AEDs. All allowed for use of intramuscular AED. Twenty-six (77%) allowed for intranasal AED. Nine (27%) allowed emergency medical services to administer a patient's own abortive AED, and 6 (18%) allowed for use of a patient's vagal nerve stimulator, when present. There was a wide variability with respect to dosing ranges for medications. Thirty-two (94%) of 34 included blood glucose measurement within the protocol. Twenty-one protocols (62%) provided recommendations for febrile seizures, including recommending active/passive cooling (8/34, 24%) and antipyretic administration (9/34, 26%). Conclusions All statewide protocols carried specific guidelines for the prehospital management of pediatric seizures; however, there was wide variability with respect to specific AEDs, routes of administration, and drug dosages. In addition to broader availability of statewide guidance, areas of potential protocol improvement and research include AED dose optimization, reprioritization of blood glucose, and greater emphasis on intranasal or intramuscular medication dosing.

Background: Prehospital pediatric endotracheal intubation (ETI) is rarely performed. Previous research has suggested that pediatric prehospital ETI, when performed by ground advanced life support c...

Biofouling has long been a problem for biomaterials, so being able to control the fouling on the surface of a biomaterial would be ideal. In this study a copolymer system was designed comprising three moieties: an epoxy containing group, glycidyl methacrylate (GMA); a thermoresponsive segment, N-isopropylacrylamide (NIPAAm); and an antifouling zwitterionic unit, sulfobetaine methacrylate (SBMA). The copolymers (pGSN), synthesized via free radical polymerization with these 3 moieties, were then grafted onto polydimethylsiloxane (PDMS). The presence of a critical temperature for both the copolymers and the coated PDMS was evidenced by particle size and contact angle measurements. The coated PDMS exhibited controllable temperature-dependent antifouling behaviors and stimuli-responsive phase characteristics in the presence of salts. The interactions of the coated PDMS with biomolecules were tested via attachment of fibrinogen protein, platelets, human whole blood, and tumor cells (HT1080). The attachment and detachment of these biomolecules were studied at different temperatures. Exposed hydrophobic domains of thermoresponsive NIPAAm-rich pGSN containing NIPAAm at 56 mol% generally allows molecular and cellular attachment on the PDMS surface at 37 °C. On the other hand, the coated PDMS with a relatively high content of SBMA (>41 mol%) in the copolymer started to exhibit fouling resistance and lower the thermoresponsive properties. Interestingly, the incorporation of zwitterionic SBMA units into the copolymers was found to accelerate the hydration of the PDMS surfaces and resulted in biomolecular and cellular detachment at 25 °C, which is comparable to the detachment at 4 °C. This modified surface behavior is found to be consistent through all biofouling tests.

Background Delay in seeking medical treatment for suspected acute coronary syndrome can lead to negative patient outcomes. Objective Our aim was to evaluate the prevalence and predictors of delay in seeking care in high-risk chest pain patients with or without acute coronary syndrome (ACS). Methods This was a secondary analysis of an observational cohort study of patients transported by Emergency Medical Services for a chief complaint of chest pain. Important demographic and clinical characteristics were extracted from electronic health records. Two independent reviewers adjudicated the presence of ACS. Logistic regression was used to model the predictors of delay in seeking care. Results The final sample included 743 patients (99% non-Hispanic). Overall, 24% presented > 12 h from onset of symptoms. Among those with ACS (n = 115), 14% presented > 12 h after onset of symptoms. Race, smoking, diabetes, and related symptoms were associated with delayed seeking behavior. In multivariate analysis, non-Caucasian race (black or others) was the only independent predictor of > 12 h delay in seeking care (odds ratio 1.4; 95% confidence interval 1.0–1.9). Conclusions One in four patients with chest pain, including 14% of those with ACS, wait more than 12 h before seeking care. Compared to non-blacks, black patients are 40% more likely to delay seeking care > 12 h.

BACKGROUND Asthma is a common pediatric diagnosis for emergency medical services (EMS) transports, however there is a paucity of data on prehospital asthma management. The purpose of this study was to describe prehospital management of pediatric patients with suspected asthma exacerbation. METHODS We conducted a retrospective review of electronic medical records from 24 ground EMS agencies in Southwestern Pennsylvania between 1 January 2014 to 31 December 2017. We identified patients 2 to 17 years with documented wheezing, excluding those with suspected anaphylaxis. Patients with documented respiratory distress were classified as severe asthma. We report descriptive statistics of demographics, vital signs, and management including administration of medications and performance of procedures. RESULTS Of 19 246 pediatric transports, 1078 (5.6%) patients had wheezing. Of these, 532 (49%) met criteria for severe asthma. Patients with severe asthma were more likely to be adolescents compared to those with nonsevere asthma (49.6% vs 6%; P < .001). While rates of intravenous methylprednisolone administration were higher in patients with severe asthma (68/532, 12.8%) compared to those with nonsevere asthma (13/546, 2.4%; P < .001), overall use of steroids was low (7.5%). Other therapies provided included albuterol (n = 699, 64.8%), ipratropium bromide (n = 271, 25.1%), and oxygen (n = 280, 26.0%). One hundred eighty patients (16.7%) received a peripheral IV line. Two patients (0.4%) were given continuous positive airway pressure. CONCLUSION Approximately 6% of pediatric EMS transports are for asthma. Steroid usage was low in even those with severe asthma, representing an area of process improvement. These data provide a baseline to future research to identify interventions that may improve outcomes.

Healthcare disparities in the initial management of patients with acute coronary syndrome (ACS) exist. Yet, the complexity of interactions between demographic, social, economic, and geospatial determinants of health hinders incorporating such predictors in existing risk stratification models. We sought to explore a machine-learning-based approach to study the complex interactions between the geospatial and social determinants of health to explain disparities in ACS likelihood in an urban community. This study identified consecutive patients transported by Pittsburgh emergency medical service for a chief complaint of chest pain or ACS-equivalent symptoms. We extracted demographics, clinical data, and location coordinates from electronic health records. Median income was based on US census data by zip code. A random forest (RF) classifier and a regularized logistic regression model were used to identify the most important predictors of ACS likelihood. Our final sample included 2400 patients (age 59 ± 17 years, 47% Females, 41% Blacks, 15.8% adjudicated ACS). In our RF model (area under the receiver operating characteristic curve of 0.71 ± 0.03) age, prior revascularization, income, distance from hospital, and residential neighborhood were the most important predictors of ACS likelihood. In regularized regression (akaike information criterion = 1843, bayesian information criterion = 1912, χ2 = 193, df = 10, p

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.

Haploidentical stem cell transplantation (haplo SCT) in Stage IV neuroblastoma relapsed patients has been proven efficacious, while immunotherapy utilizing the anti-GD2 antibody dinutuximab beta has become a standard treatment for neuroblastoma. The combinatorial therapy of haplo SCT and dinutuximab may potentiate the efficacy of the immunotherapy. To gain further understanding of the synergistic effects, functional immunomonitoring was assessed during the clinical trial CH14.18 1021 Antibody and IL2 After haplo SCT in Children with Relapsed Neuroblastoma (NCT02258815). Rapid immune reconstitution of the lymphoid compartment was confirmed, with clinically relevant dinutuximab serum levels found in all patients over the course of treatment. Only one patient developed human anti-chimeric antibodies (HACAs). In-patient monitoring revealed highly functional NK cell posttransplant capable of antibody-dependent cellular cytotoxicity (ADCC). Degranulation of NK cell subsets revealed a significant response increased by dinutuximab. This was irrespective of the KIR receptor–ligand constellation within the NK subsets, defined by the major KIR receptors CD158a, CD158b, and CD158e. Moreover, complement-dependent cytotoxicity (CDC) was shown to be an extremely potent effector-cell independent mechanism of tumor cell lysis, with a clear positive correlation to GD2 expression on the cancer cells as well as to the dinutuximab concentrations. The ex vivo testing of patient-derived effector cells and the sera collected during dinutuximab therapy demonstrated both high functionality of the newly established lymphoid immune compartment and provided confidence that the antibody dosing regimen was sufficient over the duration of the dinutuximab therapy (up to nine cycles in a 9-month period). During the course of the dinutuximab therapy, proinflammatory cytokines and markers (sIL2R, TNFa, IL6, and C reactive protein) were significantly elevated indicating a strong anti-GD2 immune response. No impact of FcGR polymorphism on event-free and overall survival was found. Collectively, this study has shown that in-patient functional immunomonitoring is feasible and valuable in contributing to the understanding of anti-cancer combinatorial treatments such as haplo SCT and antibody immunotherapy.

Background Mobile phone-based dispatch of volunteers to out-of-hospital cardiac arrests (OHCA) has been shown to increase the likelihood of early CPR and AED application. In the United States, limited characterization of patients encountered as a result of such systems exists. Aims Examine prehospital case characteristics and outcomes from a multi-year deployment of PulsePoint Respond in Pittsburgh, Pennsylvania. Methods PulsePoint event timing, location, and associated prehospital electronic health records (ePCRs) were obtained for EMS-encountered OHCA cases that did and did not generate PulsePoint alerts within the service area of Pittsburgh EMS from July 2016 to October 2020. ePCRs were reviewed and OHCA case characteristics were extracted according to the Utstein template. PulsePoint-associated OHCA and non-PulsePoint-associated OHCA were compared. Results Of 840 total PulsePoint dispatches, 64(7.6%) were for OHCA for which resuscitation was attempted. Forty-one (64.1%) were witnessed, 38(59.4%) received bystander CPR, and 13(20.0%) of these patients had an AED applied prior to EMS arrival. Twenty-seven (39.7%) had an initial shockable rhythm, and 31(48.4%) patients achieved ROSC in the field. In the city of Pittsburgh, there were 1229 total OHCA during the study period, with an estimated 29.6% occurring in public. When PulsePoint-associated and publicly occurring non-PulsePoint-associated OHCA were compared, baseline characteristics (age, sex, witnessed status) were similar, but PulsePoint-associated OHCA received more bystander CPR(p=0.008). Conclusions A minority of PulsePoint dispatches in Pittsburgh were triggered by true OHCA. The majority of OHCA during the study period occurred within private residences where PulsePoint responders are not currently dispatched. PulsePoint dispatches were associated with prognostically favorable OHCA characteristics and increased bystander CPR performance.

Background Novel temporal-spatial features of the 12‑lead ECG can conceptually optimize culprit lesions' detection beyond that of classical ST amplitude measurements. We sought to develop a data-driven approach for ECG feature selection to build a clinically relevant algorithm for real-time detection of culprit lesion. Methods This was a prospective observational cohort study of chest pain patients transported by emergency medical services to three tertiary care hospitals in the US. We obtained raw 10-s, 12‑lead ECGs (500 s/s, HeartStart MRx, Philips Healthcare) during prehospital transport and followed patients 30 days after the encounter to adjudicate clinical outcomes. A total of 557 global and lead-specific features of P-QRS-T waveform were harvested from the representative average beats. We used Recursive Feature Elimination and LASSO to identify 35/557, 29/557, and 51/557 most recurrent and important features for LAD, LCX, and RCA culprits, respectively. Using the union of these features, we built a random forest classifier with 10-fold cross-validation to predict the presence or absence of culprit lesions. We compared this model to the performance of a rule-based commercial proprietary software (Philips DXL ECG Algorithm). Results Our sample included 2400 patients (age 59 ± 16, 47% female, 41% Black, 10.7% culprit lesions). The area under the ROC curves of our random forest classifier was 0.85 ± 0.03 with sensitivity, specificity, and negative predictive value of 71.1%, 84.7%, and 96.1%. This outperformed the accuracy of the automated interpretation software of 37.2%, 95.6%, and 92.7%, respectively, and corresponded to a net reclassification improvement index of 23.6%. Metrics of ST80; Tpeak-Tend; spatial angle between QRS and T vectors; PCA ratio of STT waveform; T axis; and QRS waveform characteristics played a significant role in this incremental gain in performance. Conclusions Novel computational features of the 12‑lead ECG can be used to build clinically relevant machine learning-based classifiers to detect culprit lesions, which has important clinical implications.

PDGFR-inhibition by the tyrosine kinase inhibitor (TKI) nintedanib attenuates the progress of idiopathic pulmonary fibrosis (IPF). However, the effects of PDGF-BB on the airway tone are almost unknown. We studied this issue and the mechanisms beyond, using isolated perfused lungs (IPL) of guinea pigs (GPs) and precision-cut lung slices (PCLS) of GPs and humans.IPL: PDGF-BB was perfused after or without pre-treatment with the TKI imatinib (perfused/nebulised) and its effects on the tidal volume (TV), the dynamic compliance (Cdyn) and the resistance were studied.The bronchoconstrictive effects of PDGF-BB and the mechanisms beyond were evaluated. PCLS (human): The bronchoconstrictive effects of PDGF-BB and the bronchorelaxant effects of imatinib were studied. All changes of the airway tone were measured by videomicroscopy and indicated as changes of the initial airway area.PCLS (GP/human): PDGF-BB lead to a contraction of airways. IPL: PDGF-BB decreased TV and Cdyn, whereas the resistance did not increase significantly. In both models, inhibition of PDGFR-(β) (imatinib/SU6668) prevented the bronchoconstrictive effect of PDGF-BB. The mechanisms beyond PDGF-BB-induced bronchoconstriction include activation of MAP2K and TP-receptors, actin polymerisation and CaPDGFR regulates the airway tone. In PCLS from GPs, this regulatory mechanism depends on the β-subunit. Hence, PDGFR-inhibition may not only represent a target to improve chronic airway disease such as IPF, but may also provide acute bronchodilation in asthma. Since asthma therapy uses topical application. This is even more relevant, as nebulisation of imatinib also appears to be effective.

Background: Naloxone is widely available to bystanders and first responders to treat patients with suspected opioid overdose. In these patients, the prognostic factors and potential benefits associ...

Background Sleep deprivation is common in shift work occupations, including safety-sensitive occupations. While extending sleep prior to scheduled shifts (i.e., “banking sleep”) may be an intuitive strategy for fatigue mitigation, the evidence behind this strategy is unclear. Methods We performed a systematic review of literature retrieved in searches of four databases. We examined agreement between two independent screeners, abstracted key findings, reviewed and synthesized findings, and evaluated the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. The Cochrane Collaboration's risk of bias tool was used to evaluate bias of individual studies. We reported findings as prescribed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Results Of the 3007 records screened, five met inclusion criteria. The inter-rater agreement for inclusion/exclusion was high (κ = 0.87). One study addressed patient safety outcomes. Four studies assessed the impact of banking sleep on performance, five assessed measures of acute fatigue, and three evaluated banking sleep on indicators of health. All five studies presented a very serious risk of bias and the quality of evidence was very low. Given these caveats, the findings, in aggregate, support banking sleep as a strategy to improve indicators of performance and acute fatigue. Conclusions This systematic review identifies gaps in research of shift workers on the efficacy of banking sleep as a fatigue risk management strategy. The available evidence supports banking sleep prior to shiftwork as a strategy for improved patient safety, performance, and reducing acute fatigue.

BackgroundInhospital stroke (IHS) is associated with high morbidity and mortality, likely related to multiple factors, including delayed time to recognition, associated comorbidities, and initial care from non-stroke trained providers. We hypothesized that guided revision of a formalized ‘stroke code’ system can improve diagnosis and time to thrombolysis and thrombectomy.MethodsIHS activations occurring at a comprehensive stroke center between 2013 and 2016 were retrospectively analyzed to guide revisions of an established stroke code protocol to improve provider communication and time to imaging, reduce stroke mimic rate, and improve the use of parallel processing. After protocol implementation, we prospectively collected data between 2016 and 2017 for comparison with the pre-implementation group, including diagnostic accuracy and relevant time points (code call to examination, examination to imaging, and imaging to intervention). We report descriptive statistics for comparison of patient characteristics and time metrics (time to imaging and reperfusion after IHS activation). Multivariable regression analysis was performed to identify independent predictors of stroke mimics and time metrics.ResultsThere were 136 cases in the pre-implementation group and 69 in the post-implementation group. A reduction in stroke mimics (52% vs 33%, P=0.01) occurred after protocol initiation. Mean time to imaging after stroke code call was 7.6 min shorter (P=0.026) and mean time from imaging to acute reperfusion therapy was 45.7 vs 19.8 min (P=0.05) in the pre- versus the post-implementation group.ConclusionRevision of an existing IHS protocol was associated with a lower rate of stroke mimics, and a shorter time to intravenous and intra-arterial intervention.

BACKGROUND: Nonspecific ST-T repolarization (NST) abnormalities alter the ST-segment for reasons often unrelated to acute myocardial ischemia, which could contribute to misdiagnosis or inappropriate treatment. We sought to define the prevalence of NST patterns in patients with chest pain and evaluate how such patterns correlate with the eventual etiology of chest pain and course of hospitalization. METHODS: This was a prospective observational study that included consecutive prehospital chest pain patients from three tertiary care hospitals in the U.S. Two independent reviewers blinded from clinical data audited the prehospital 12-lead ECG for the presence or absence of NST patterns (i.e., right or left bundle branch block, left ventricular hypertrophy with strain pattern, ventricular pacing, ventricular rhythm, or coarse atrial fibrillation). The primary outcome was 30-day major adverse cardiac events (MACE) defined as cardiac arrest, acute heart failure, post-discharge infarction, or all-cause death. RESULTS: The final sample included 750 patients (age 59±17, 58% males). A total of 40 patients (5.3%) experienced 30-MACE and 131 (17.5%) had NST patterns. The presence of NST patterns was an independent multivariate predictor of 30-day MACE (9.9% vs. 4.4%, OR = 2.2 [95% CI = 1.1–4.5]. Patients with NST patterns had increased median length of stay (1.0 [IQR 0.5–3] vs. 2.0 [IQR 1–4] days, p

Introduction Appropriate prehospital (PH) triage of patients with chest pain can significantly improve outcomes in acute myocardial infarction (MI). We sought to explore how PH providers triage chest pain as high versus low risk and to evaluate the accuracy and predictors of their triage decision. Methods This was a prospective, observational cohort study that enrolled consecutive patients with chest pain transported by emergency medical services (EMS) to 3 tertiary care hospitals in the US. EMS triage decision (high risk versus low-risk) was defined based on the transmission of PH electrocardiogram (ECG) to a command center for medical consultation with or without catheter laboratory activation. Two independent reviewers examined in-hospital medical records to adjudicate the presence of acute MI and to audit the findings on the presenting ECG. Results We enrolled 2,065 patients (aged 56 ± 17, 53% male) of whom 768 (37%) were triaged as high risk. Those triaged as high risk were older, were more likely to be men or have significant cardiac history, and had a higher rate of acute MI events (14.2% versus 3.5%). The sensitivity and specificity for triaging MI events as high risk were 70% and 97%, respectively. A total of 46/155 (30%) MI events were misclassified as low risk. No previous coronary revascularization and ECG misinterpretation were strong independent predictors of such undertriage. Conclusions PH providers have moderate sensitivity in triaging high-risk patients; 1 in 3 MI events are undertriaged. Emergency nurses need to pay special attention to patients with benign past histories during transition of care and should always reinterpret ECGs for subtle ischemic changes.

Study objective It is unknown whether regionalization of postarrest care by interfacility transfer to cardiac arrest receiving centers reduces mortality. We seek to evaluate whether treatment at a cardiac arrest receiving center, whether by direct transport or early interfacility transfer, is independently associated with long-term outcome. Methods We performed a retrospective cohort study including adults resuscitated from out-of-hospital cardiac arrest in southwestern Pennsylvania and neighboring Ohio, West Virginia, and Maryland, which includes approximately 5.7 million residents in urban, suburban, and rural counties. Patients were treated by 1 of 78 ground emergency medical services agencies or 2 air medical transport agencies between January 1, 2010, and November 30, 2014. Our primary exposures of interest were interfacility transfer to a cardiac arrest receiving center within 24 hours of arrest or any treatment at a cardiac arrest receiving center regardless of transfer status. Our primary outcome was vital status, assessed through December 31, 2014, with National Death Index records. We used unadjusted and adjusted survival analyses to test the independent association of cardiac arrest receiving center care, whether through direct or interfacility transport, on mortality. Results Overall, 5,217 cases were observed for 3,629 person-years, with 3,865 total deaths. Most patients (82%) were treated at 42 non–cardiac arrest receiving centers with median annual volume of 17 cases (interquartile range 1 to 53 cases per center annually), whereas 18% were cared for at cardiac arrest receiving centers receiving at least 1 interfacility transfer per month. In adjusted models, treatment at a cardiac arrest receiving center was independently associated with reduced hazard of death compared with treatment at a non–cardiac arrest receiving center (adjusted hazard ratio 0.84; 95% confidence interval 0.74 to 0.94). These effects were unchanged when analysis was restricted to patients brought from the scene to the treating hospital. No other hospital characteristic, including total out-of-hospital cardiac arrest patient volume and cardiac catheterization capabilities, independently predicted outcome. Conclusion Both early interfacility transfer to a cardiac arrest receiving center and direct transport to a cardiac arrest receiving center from the scene are independently associated with reduced mortality.

Point-of-care ultrasound (POCUS) has been suggested as a useful tool to predict survival and guide interventions in out-of-hospital cardiac arrest (OHCA). While POCUS has been deployed in prehospital settings, a minimal amount of data exists on prehospital use, particularly by personnel with limited ultrasound experience. We aimed to characterize the feasibility and barriers to prehospital POCUS during OHCA by emergency medicine services (EMS) physicians in training.We deployed the SonoSite iViz portable ultrasound device for use by EMS physicians for OHCA in an urban EMS system. All physicians received POCUS education as part of their graduate medical training and were provided an instructional video on use of the SonoSite iViz device. POCUS use was limited to identifying cardiac motion during pulse checks, without interrupting resuscitation, and the results could be used to supplement management at the physicians' discretion. Data were recorded prospectively by saving images on the device and through a custom electronic form within the patient care report. The primary measure was the frequency of use of POCUS during OHCA. Secondarily, we characterized agreement by expert (ultrasound fellowship trained) faculty (using a kappa statistic) and identified reported barriers to the use of prehospital POCUS.From November 2016 to March 2017, 348 physician field responses were reviewed, including 127 cases of OHCA. There were 106 patients remaining in arrest on physician arrival, with 56 (52.8%) cases of POCUS use. Still or video images were recorded in 48 cases; video in 34 cases. From video images, agreement in identifying cardiac motion between the EMS physician and expert reviewer occurred in 91% of cases (K = 0.82). Reasons cited for not using POCUS included return of circulation soon before or after arrival, prioritizing clinical interventions, not having the ultrasound device, mechanical failure, and cessation of resuscitation per advanced directives.Use of POCUS by EMS physicians to detect cardiac activity in OHCA is feasible and correlates with expert interpretation. Several avoidable barriers were identified and should be considered in the future implementation of prehospital POCUS. Larger studies are needed to determine what role POCUS may play in prehospital cardiac arrest management.

Background There is an emerging body of evidence that links exposure to shift work to cardiovascular disease (CVD). The risk of coronary events, such as myocardial infarction, is greater among night shift workers compared to day workers. There is reason to believe that repeated exposure to shift work, especially night shift work, creates alterations in normal circadian patterns of blood pressure (BP) and heart rate variability (HRV) and that these alterations contribute to increased risk of CVD. Recent data suggest that allowing shift workers to nap during night shifts may help to normalize BP and HRV patterns and, over time, reduce the risk of CVD. The risk of CVD related to shift work is elevated for emergency medical services (EMS) shift workers due in part to long-duration shifts, frequent use of night shifts, and a high prevalence of multiple jobs. Methods We will use a randomized crossover trial study design with three study conditions. The targeted population is comprised of EMS clinician shift workers, and our goal enrollment is 35 total participants with an estimated 10 of the 35 enrolled not completing the study protocol or classified as lost to attrition. All three conditions will involve continuous monitoring over 72 h and will begin with a 36-h at-home period, followed by 24 total hours in the lab (including a 12-h simulated night shift), ending with 12 h at home. The key difference between the three conditions is the intra-shift nap. Condition 1 will involve a simulated 12-h night shift with total sleep deprivation. Condition 2 will involve a simulated 12-h night shift and a 30-min nap opportunity. Condition 3 will involve a simulated 12-h night shift with a 2-h nap opportunity. Our primary outcomes of interest include blunted BP dipping and reduced HRV as measured by the standard deviation of the inter-beat intervals of normal sinus beats. Non-dipping status will be defined as sleep hours BP dip of less than 10%. Discussion Our study will address two indicators of cardiovascular health and determine if shorter or longer duration naps during night shifts have a clinically meaningful impact. Trial registration ClinicalTrials.gov NCT04469803. Registered on 9 July 2020

Objective: Few areas of prehospital care are supported by evidence-based guidelines (EBGs). We aimed to identify gaps in clinical and operational prehospital EBGs to prioritize future EBG development and research funding. Methods: Using modified Delphi methodology, we sought consensus among experts in prehospital care and EBG development. Five rounds of surveys were administered between October 2019 and February 2020. Round 1 asked participants to list the top three gaps in prehospital clinical guidelines and top three gaps in operational guidelines that should be prioritized for guideline development and research funding. Based on responses, 3 reviewers performed thematic analysis to develop a list of prehospital EBG gaps, with participant feedback in Round 2. In Round 3, participants rated each gap's importance using a 5-point Likert scale, and participants' responses were averaged. In Round 4, participants rank-ordered 10 gaps with the highest mean scores identified in Round 3. In Round 5, participants indicated their agreement with sets of the highest ranked gaps. Results: Of 23 invited participants, 14 completed all 5 rounds. In Rounds 1 and 2, participants submitted 65 clinical and 58 operational gaps, and thematic analysis identified 23 unique clinical gaps and 28 unique operational gaps. The final prioritized list of clinical EBG gaps was: 1) airway management in adult and pediatric patients, 2) care of the pediatric patient, and 3) management of prehospital behavioral health emergencies, with 79% of participants agreeing. The final prioritized list of operational EBG gaps was: 1) define and measure the impact of EMS care on patient outcomes, 2) practitioner wellness, and 3) practitioner safety in the out-of-hospital environment, with 86% of participants agreeing. Conclusions: This modified Delphi study identifies gaps in prehospital EBGs that, if prioritized for development and research funding, would be expected to have the greatest impact on prehospital clinical care and operations.

Background Classical ST‐T waveform changes on standard 12‐lead ECG have limited sensitivity in detecting acute coronary syndrome (ACS) in the emergency department. Numerous novel ECG features have been previously proposed to augment clinicians' decision during patient evaluation, yet their clinical utility remains unclear. Methods and Results This was an observational study of consecutive patients evaluated for suspected ACS (Cohort 1 n=745, age 59±17, 42% female, 15% ACS; Cohort 2 n=499, age 59±16, 49% female, 18% ACS). Out of 554 temporal‐spatial ECG waveform features, we used domain knowledge to select a subset of 65 physiology‐driven features that are mechanistically linked to myocardial ischemia and compared their performance to a subset of 229 data‐driven features selected by multiple machine learning algorithms. We then used random forest to select a final subset of 73 most important ECG features that had both data‐ and physiology‐driven basis to ACS prediction and compared their performance to clinical experts. On testing set, a regularized logistic regression classifier based on the 73 hybrid features yielded a stable model that outperformed clinical experts in predicting ACS, with 10% to 29% of cases reclassified correctly. Metrics of nondipolar electrical dispersion (ie, circumferential ischemia), ventricular activation time (ie, transmural conduction delays), QRS and T axes and angles (ie, global remodeling), and principal component analysis ratio of ECG waveforms (ie, regional heterogeneity) played an important role in the improved reclassification performance. Conclusions We identified a subset of novel ECG features predictive of ACS with a fully interpretable model highly adaptable to clinical decision support applications. Registration URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT04237688.

Introduction HEART score is widely used to stratify patients with chest pain in the emergency department but has never been validated for cocaine-associated chest pain (CACP). We sought to evaluate the performance of HEART score in risk stratifying patients with CACP compared to an age- and sex-matched cohort with non-CACP. Methods The parent study was an observational cohort study that enrolled consecutive patients with chest pain. We identified patients with CACP and age/sex matched them to patients with non-CACP in 1:2 fashion. HEART score was calculated retrospectively from charts. The primary outcome was major adverse cardiac events (MACE) within 30 days of indexed encounter. Results We included 156 patients with CACP and 312 age-and sex-matched patients with non-CACP (n = 468, mean age 51 ± 9, 22% females). There was no difference in rate of MACE between the groups (17.9% vs. 15.7%, p = 0.54). Compared to the non-CACP group, the HEART score had lower classification performance in those with CACP (AUC = 0.68 [0.56–0.80] vs. 0.84 [0.78–0.90], p = 0.022). In CACP group, Troponin score had the highest discriminatory value (AUC = 0.72 [0.60–0.85]) and Risk factors score had the lowest (AUC = 0.47 [0.34–0.59]). In patients deemed low-risk by the HEART score, those with CACP were more likely to experience MACE (14% vs. 4%, OR = 3.7 [1.3–10.7], p = 0.016). Conclusion In patients with CACP, HEART score performs poorly in stratifying risk and is not recommended as a rule out tool to identify those at low risk of MACE.

Emergency department (ED) nurses need to identify patients with potential acute coronary syndrome (ACS) rapidly because treatment delay could impact patient outcomes. Aims of this secondary analysis were to identify key patient factors that could be available at initial ED nurse triage that predict ACS. Consecutive patients with chest pain who called 9-1-1, received a 12-lead electrocardiogram in the prehospital setting, and were transported via emergency medical service were included in the study. A total of 750 patients were recruited. The sample had an average age of 59 years old, was 57% male, and 40% Black. One hundred and fifteen patients were diagnosed with ACS. Older age, non-Caucasian race, and faster respiratory rate were independent predictors of ACS. There was an interaction between heart rate by Type II diabetes receiving insulin in the context of ACS. Type II diabetics requiring insulin for better glycemic control manifested a faster heart rate. By identifying patient factors at ED nurse triage that could be predictive of ACS, accuracy rates of triage may improve, thus impacting patient outcomes.

Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1–3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans. © 2020, The Author(s), under exclusive licence to Springer Nature Limited., Wellcome Trust, WT: 104807/Z/14/Z University College London, UCL: 100140/Z/12/Z, 107212/Z/15/Z, MR/L019027, 203141/Z/16/Z, 091157/Z/10/Z Bundesministerium für Bildung und Forschung, BMBF: 01ZX1306A University of Cambridge 201250/Z/16/Z 01ZX1709 Seventh Framework Programme, FP7 NIHR Bristol Biomedical Research Centre Deutsche Forschungsgemeinschaft, DFG Deutsche Forschungsgemeinschaft, DFG: EXC 2167-390884018 Juvenile Diabetes Research Foundation United Kingdom, JDRF: 9-2011-253, 5-SRA-2015-130-A-N National Institute for Health Research, NIHR: RG65966 Medical Research Council, MRC: RG95376, MR/L006197/1 Great Ormond Street Hospital for Children, GOSH, Acknowledgements The NBR-RD PID Consortium is part of the NIHR BioResource, for which funding was provided by the NIHR (NIHR, grant number RG65966). We acknowledge the participation of all NIHR BioResource volunteers, and thank the NIHR BioResource centre and staff for their contribution. J.E.D.T. is supported by the Medical Research Council (MRC) (RG95376 and MR/L006197/1); A.J.T. is supported by the Wellcome Trust (104807/Z/14/Z) and the NIHR Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London; K.G.C.S. is supported by the MRC (programme grant MR/L019027) and is a Wellcome Investigator; A.J.C. was supported by the Wellcome Trust (091157/Z/10/Z, 107212/Z/15/Z, 100140/Z/12/Z, 203141/Z/16/Z), JDRF (9-2011-253, 5-SRA-2015-130-A-N), NIHR Oxford Biomedical Research Centre and NIHR Cambridge Biomedical Research Centre; E.E. has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND) under grant agreement number 609020-Scientia Fellows; E.R. is supported by the Wellcome Trust (201250/Z/16/Z); D.E. is supported by the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (SysInflame grant 01ZX1306A; GB-XMAP grant 01ZX1709) and funded by the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) under Germany’s Excellence Strategy (EXC 2167-390884018). The NIHR Cambridge Biomedical Research Centre (BRC) is a partnership between Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge, funded by the NIHR. This research was co-funded by the support listed above and the NIHR Cambridge BRC.

ObjectivesHigher 24-hour blood pressure (BP) and blunted BP dipping during sleep and night-time hours are associated with adverse health outcomes. Night shift work may affect 24-hour BP and dipping patterns, but empirical data in emergency medical services (EMS) clinician shift workers are sparse. We implemented ambulatory blood pressure monitoring (ABPM) in EMS workers to characterise BP during night shift work versus a non-workday, and sleep versus wake.MethodsParticipants worked night shifts. Hourly ABPM and wrist actigraphy (to measure sleep) were collected during two 24-hour periods, one scheduled night shift and one non-workday. Blunted BP dipping was defined as a BP decrease of ResultsOf 56 participants, 53 (53.6% female, mean age 26.5 (SD 7.5) years) completed the study. During daytime sleep on a workday, 49.1% of participants had blunted systolic BP (SBP) or diastolic BP (DBP) dipping. During night-time sleep on a non-workday, 25% had blunted SBP dipping and 3.9% blunted DBP dipping. Blunted SBP or DBP dipping occurred among all participants who did not nap during the night shift or who napped ConclusionsDuring night shift work, the BP dipping of EMS shift workers is blunted; however, most who nap for 60 min or longer experience a healthy dip in BP. The potential health consequences of these observations in EMS clinicians warrant further study.

Introduction Levosimendan is approved for acute heart failure. Within this context, pulmonary hypertension represents a frequent co-morbidity. Hence, the effects of levosimendan on segmental pulmonary vascular resistance (PVR) are relevant. So far, this issue has been not studied. Beyond that the relaxant effects of levosimendan in human pulmonary vessel are unknown. We addressed these topics in rats’ isolated perfused lungs (IPL) and human precision-cut lung slices (PCLS). Material and methods In IPL, levosimendan (10 μM) was perfused in untreated and endothelin-1 pre-contracted lungs. The pulmonary arterial pressure (PPA) was continuously recorded and the capillary pressure (Pcap) was determined by the double-occlusion method. Thereafter, segmental PVR, expressed as precapillary (Rpre) and postcapillary resistance (Rpost) and PVR were calculated. Human PCLS were prepared from patients undergoing lobectomy. Levosimendan-induced relaxation was studied in naive and endothelin-1 pre-contracted PAs and PVs. In endothelin-1 pre-contracted PAs, the role of K+-channels was studied by inhibition of KATP-channels (glibenclamide), BKCa2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine). All changes of the vascular tone were measured by videomicroscopy. In addition, the increase of cAMP/GMP due to levosimendan was measured by ELISA. Results Levosimendan did not relax untreated lungs or naive PAs and PVs. In IPL, levosimendan attenuated the endothelin-1 induced increase of PPA, PVR, Rpre and Rpost. In human PCLS, levosimendan relaxed pre-contracted PAs or PVs to 137% or 127%, respectively. In pre-contracted PAs, the relaxant effect of levosimendan was reduced, if KATP- and Kv-channels were inhibited. Further, levosimendan increased cGMP in PAs/PVs, but cAMP only in PVs. Discussion Levosimendan reduces rats’ segmental PVR and relaxes human PAs or PVs, if the pulmonary vascular tone is enhanced by endothelin-1. Regarding levosimendan-induced relaxation, the activation of KATP- and Kv-channels is of impact, as well as the formation of cAMP and cGMP. In conclusion, our results suggest that levosimendan improves pulmonary haemodynamics, if PVR is increased as it is the case in pulmonary hypertension.