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Undernutrition-induced growth restriction in the early stages of life increases the risk of chronic disease in adulthood. Although metabolic impairments have been observed, few studies have characterized the gut microbiome and gut-liver metabolome profiles of growth-restricted animals during early-to-mid-life development. To induce growth restriction, mouse offspring were either born to gestational undernutrition (GUN) or suckled from postnatal undernutrition (PUN) dams fed a protein-restricted diet (8% protein) or control diet (CON; 20% protein) until weaning at postnatal age of 21 days (PN21). At PN21, all mice were fed the CON diet until adulthood (PN80). Livers were collected at PN21 and PN80, and fecal samples were collected weekly starting at PN21 (

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<<

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.

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 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.

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...

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

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.

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.

Background The acute respiratory distress syndrome (ARDS) is a serious disease in critically ill patients that is characterized by pulmonary dysfunctions, hypoxemia and significant mortality. Patients with immunodeficiency (e.g. SCID with T and B cell deficiency) are particularly susceptible to the development of severe ARDS. However, the role of T cells on pulmonary dysfunctions in immune-competent patients with ARDS is only incompletely understood. Methods Wild-type (wt) and RAG2−/− mice (lymphocyte deficient) received intratracheal instillations of LPS (4 mg/kg) or saline. On day 1, 4 and 10 lung mechanics and bronchial hyperresponsiveness towards acetylcholine were measured with the flexiVent ventilation set-up. The bronchoalveolar lavage fluid (BALF) was examined for leukocytes (FACS analysis) and pro-inflammatory cytokines (ELISA). Results In wt mice, lung mechanics, body weight and body temperature deteriorated in the LPS-group during the early phase (up to d4); these alterations were accompanied by increased leukocyte numbers and inflammatory cytokine levels in the BALF. During the late phase (day 10), both lung mechanics and the cell/cytokine homeostasis recovered in LPS-treated wt mice. RAG2−/− mice experienced changes in body weight, lung mechanics, BAL neutrophil numbers, BAL inflammatory cytokines levels that were comparable to wt mice. Conclusion Following LPS instillation, lung mechanics deteriorate within the first 4 days and recover towards day 10. This response is not altered by the lack of T lymphocytes suggesting that T cells play only a minor role for the initiation, propagation or recovery of LPS-induced lung dysfunctions or function of T lymphocytes can be compensated by other immune cells, such as alveolar macrophages. Electronic supplementary material The online version of this article (10.1186/s12890-018-0741-2) contains supplementary material, which is available to authorized users.

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 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.

Cells : open access journal 10(5), 1210 (2021). doi:10.3390/cells10051210 special issue: "Topical collection "The endothelial cell in lung inflammation" / editor: Konstantin G. Birukov, collection editor", Published by MDPI, Basel

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.

Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Nav1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain.SIGNIFICANCE STATEMENT In OA patients pain poorly correlates with joint tissue changes indicating mechanisms other than only tissue damage that cause pain in OA. We identified that DRG containing the somata of sensory neurons innervating the damaged knee are infiltrated with macrophages that are shaped into an M1-like phenotype by sensory neurons. We show that these DRG macrophages actively maintain OA pain remotely and independent of joint damage. The phenotype of these macrophages is crucial for a pain-promoting role. Targeting the phenotype of DRG macrophages with either M2-like macrophages or a cytokine fusion protein that skews macrophages into an M2-like phenotype resolves OA pain. Our work reveals a mechanism that contributes to the maintenance of OA pain distant from the affected knee joint and suggests that dorsal root ganglia macrophages are a target to treat osteoarthritis chronic pain.

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.

Tumor necrosis factor (TNF) is a well-known mediator of sepsis. In many cases, sepsis results in multiple organ injury including the lung with acute respiratory distress syndrome (ARDS). More than 20-year-old studies have suggested that TNF may be directly responsible for organ injury during sepsis. However, these old studies are inconclusive, because they relied on human rather than conspecific TNF, which was contaminated with endotoxin in most studies. In this study, we characterized the direct effects of intravenous murine endotoxin-free TNF on cardiovascular functions and organ injury in mice with a particular focus on the lungs. Because of the relevance of the acid sphingomyelinase in sepsis, ARDS, and caspase-independent cell death, we also included acid sphingomyelinase-deficient (ASM-/-) mice. ASM-/- and wild-type (WT) mice received 50 μg endotoxin-free murine TNF intravenously alone or in combination with the pan-caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (zVAD) and were ventilated at low tidal volume while lung mechanics were followed. Blood pressure was stabilized by intra-arterial fluid support, and body temperature was kept at 37°C to delay lethal shock and to allow investigation of blood gases, lung histopathology, proinflammatory mediators, and microvascular permeability 6 hours after TNF application. Besides the lungs, also the kidneys and liver were examined. TNF elicited the release of inflammatory mediators and a high mortality rate, but failed to injure the lungs, kidneys, or liver of healthy mice significantly within 6 hours. Mortality in WT mice was most likely due to sepsis-like shock, as indicated by metabolic acidosis, high procalcitonin levels, and cardiovascular failure. ASM-/- mice were protected from TNF-induced hypotension and reflex tachycardia and also from mortality. In WT mice, intravenous exogenous TNF does not cause organ injury but induces a systemic inflammatory response with cardiovascular failure, in which the ASM plays a role.

Airway device placement and maintenance are of utmost importance when managing critically ill patients. The best method to secure airway devices is currently unknown.We sought to determine the force required to dislodge 4 types of airways with and without airway securing devices.We performed a prospective study using 4 commonly used airway devices (endotracheal tube [ETT], laryngeal mask airway [LMA], King laryngeal tube [King], and iGel) performed on 5 different mannequin models. All devices were removed twice per mannequin in random order, once unsecured and once secured as per manufacturers' recommendations; Thomas Tube Holder (Laerdal, Stavanger, Norway) for ETT, LMA, and King; custom tube holder for iGel. A digital force measuring device was attached to the exposed end of the airway device and gradually pulled vertically and perpendicular to the mannequin until the tube had been dislodged, defined as at least 4 cm of movement. Dislodgement force was reported as the maximum force recorded during dislodgement. We compared the relative difference in the secured and unsecured force for each device and between devices using a random-effects regression model accounting for variability in the manikins.The median dislodgment forces (interquartile range [IQR]) in pounds for each secured device were: ETT 13.3 (11.6, 14.1), LMA 16.6 (13.9, 18.3), King 21.7 (16.9, 25.1), and iGel 8 (6.8, 8.3). The median dislodgement forces for each unsecured device were: ETT 4.5 (4.3, 5), LMA 8.4 (6.8, 10.7), King 10.6 (8.2, 11.5), and iGel 3.9 (3.2, 4.2). The relative difference in dislodgement forces (95% confidence intervals) were higher for each device when secured: ETT 8.6 (6.2 to 11), LMA 8.8 (4.6 to 13), King 12.1 (7.2 to 16.6), iGel 4 (1.1 to 6.9). When compared to secured ETT, the King required greater dislodgement force (relative difference 8.6 [4.5-12.7]). The secured iGel required less force than the secured ETT (relative difference -4.8 [-8.9 to -0.8]).Compared with a secured device, an unsecured airway device requires only half the force to cause airway dislodgement. The secured King had the highest dislodgement force relative to the other studied devices.

Prehospital ultrasound is not yet widely implemented. Most studies report on convenience samples and trauma patients, often by prehospital physicians or critical care clinicians. We assessed the feasibility of paramedic performed prehospital lung ultrasound in medical patients with respiratory distress.Paramedics at 2 ambulance stations in the city of Pittsburgh, Pennsylvania, USA underwent a 2-hour training session in prehospital lung ultrasound using the SonoSite iViz, a handheld ultrasound device. Emergency medical services (EMS) command center (EMS-CC) physicians were instructed in the interpretation of lung ultrasound images. Paramedics enrolled patients presenting with signs and symptoms of respiratory distress over a 3-month period. The ultrasound exam included anterior and lateral views from both sides of the chest. Images were transmitted wirelessly using a mobile hotspot device and uploaded into an online image archiving system. Images were interpreted remotely by the EMS-CC physicians, and 2 expert sonographers provided an overread. We assessed agreement between EMS-CC physicians and experts, as well as between chart-review derived ED diagnosis and both EMS-CC physician and expert interpretation. We defined four a priori hypotheses that would need to be met for the intervention to be considered "feasible."A total of 34 of 78 (43.6%) eligible patients had an ultrasound exam completed. Image transmission was successful in 25 (73.5%) of cases where ultrasound was performed. The primary reason for not enrolling an otherwise eligible patient was equipment failure (25.0%), followed by patient acuity and patient refusal (18.2% each). A total of 20 (58.8%) completed scans were deemed uninterpretable upon expert review. Agreement between EMS physicians and experts was poor. Agreement between EMS-CC physicians and ED diagnosis, as well as between experts and ED diagnosis, was fair. The predetermined thresholds for feasibility were not met.Paramedic performed prehospital lung ultrasound for patients with respiratory distress and remote interpretation by EMS physicians did not meet the predetermined thresholds to be considered "feasible" in a real-world environment with currently available technologies. This study identified important barriers to the implementation of prehospital lung ultrasound, which should be addressed in future studies.

To evaluate the association between total medical contact, prehospital, and emergency department delays in antibiotic administration and in-hospital mortality among patient encounters with community-acquired sepsis.Retrospective cohort study.Nine hospitals served by 21 emergency medical services agencies in southwestern Pennsylvania from 2010 through 2012.All emergency medical services encounters with community acquired sepsis transported to the hospital.Among 58,934 prehospital encounters, 2,683 had community-acquired sepsis, with an in-hospital mortality of 11%. Median time from first medical contact to antibiotic administration (total medical contact delay) was 4.2 hours (interquartile range, 2.7-8.0 hr), divided into a median prehospital delay of 0.52 hours (interquartile range, 0.40-0.66 hr) and a median emergency department delay of 3.6 hours (interquartile range, 2.1-7.5 hr). In a multivariable analysis controlling for other risk factors, total medical contact delay was associated with increased in-hospital mortality (adjusted odds ratio for death, 1.03 [95% CI, 1.00-1.05] per 1-hr delay; p0.01), as was emergency department delay (p = 0.04) but not prehospital delay (p = 0.61).Both total medical contact and emergency department delay in antibiotic administration are associated with in-hospital mortality in community-acquired sepsis.

Clinical heart failure (HF) occurs frequently after ST-segment elevation myocardial infarction (STEMI), and is associated with increased mortality. We assessed the impact of remote ischemic peri-conditioning (RIPC) during inter-facility air medical transport of STEMI patients on clinical HF following primary percutaneous coronary intervention (pPCI).Data from Acute Coronary Treatment and Intervention Outcomes Network Registry®-Get With the Guidelines™ (ACTION Registry-GWTG) from two PCI-hospitals that are utilizing RIPC during inter-facility helicopter transport of STEMI patients for pPCI between March, 2013 and September, 2015 were used for this study. The analyses were limited to inter-facility STEMI patients transported by helicopter with LVEF55% after pPCI. The outcome measures were occurrence of clinical HF and serum level of brain-type natriuretic peptide (BNP).Out of the 150 STEMI patients in this analysis, 92 patients received RIPC and 58 did not. The RIPC and non-RIPC groups were generally similar in demographic and clinical characteristics except for lower incidence of cardiac arrest in the RIPC group (3/92 [3.3%] versus 13/58 [22.4%], p=0.002). STEMI patients who received RIPC were less likely to have in-hospital clinical HF compared to patients who did not receive RIPC (3/92 [3.3%] versus 7/58 [12.1%]; adjusted OR=0.22, 95% CI 0.05-0.92, p=0.038) after adjusting for baseline differences. In subgroup analysis, RIPC was associated with lower BNP (123 [interquartile range, 17.0-310] versus 319 [interquartile range, 106-552], p=0.029).RIPC applied during inter-facility air transport of STEMI patients for pPCI is associated with reduced incidence of clinical HF and serum BNP.

Background: Patients with acute illness who receive intravenous (IV) fluids prior to hospital arrival may have a lower in-hospital mortality. To better understand whether this is a direct treatment effect or epiphenomenon of downstream care, we tested the association between a prehospital fluid bolus and the change in inflammatory cytokines measured at prehospital and emergency department timepoints in a sample of non-trauma, non-cardiac arrest patients at risk for critical illness. Methods: In a prospective cohort study, we screened 4,013 non-trauma, non-cardiac arrest encounters transported by City of Pittsburgh Emergency Medical Services (EMS) to 2 hospitals from August 2013 to February 2014. In 345 patients, we measured prehospital biomarkers (IL-6, IL-10, and TNF) at 2 time points: the time of prehospital IV access placement by EMS and at ED arrival. We determined the relative change for marker X as: ([XED – XEMS]/XEMS). We determined the risk-adjusted association between prehospital IV fluid bolus and relative change for each marker using multivariable linear regression. Results: Among 345 patients, 88 (26%) received a prehospital IV fluid bolus and 257 (74%) did not. Compared to patients who did not receive prehospital fluids, median prehospital IL-6 was greater initially in subjects receiving a prehospital IV fluid bolus (22.3 [IQR 6.4–113] vs. 11.5 [IQR 5.5–47.6]). Prehospital IL-10 and TNF were similar in both groups (IL-10: 3.5 [IQR 2.2–25.6] vs. 3.0 [IQR 1.9–9.0]; TNF: 7.5 [IQR 6.4–10.4] vs. 6.9 [IQR 6.0–8.3]). After adjustment for demographics, illness severity, and prehospital transport time, we observed a relative decrease in IL-6 at hospital arrival in those receiving a prehospital fluid bolus (adjusted β = −10.0, 95% CI: −19.4, −0.6, p = 0.04), but we did not detect a significant change in IL-10 (p = 0.34) or TNF (p = 0.53). Conclusions: Among non-trauma, non-cardiac arrest patients at risk for critical illness, a prehospital IV fluid bolus was associated with a relative decrease in IL-6, but not IL-10 or TNF.

Objective: Hypotension in the prehospital environment is common and linked to dose-dependent mortality. Bolus dose epinephrine (BDE) may reverse hypotension. We tested if BDE use to treat profound hypotension is associated with 24-hour survival. Methods: We performed a retrospective case-cohort study of critical care transport patients with systolic blood pressure (SBP)

ObjectivesChest pain is among the leading causes for emergency medical services (EMS) activation. Acute myocardial infarction (MI) is not only one of the most critical aetiologies of chest pain, but also one of few conditions encountered by EMS that has been shown to follow a circadian pattern. Understanding the diurnal relationship between the inflow of chest pain patients and the likelihood of acute MI may inform prehospital and emergency department (ED) healthcare providers regarding the prediction, and hence prevention, of dire outcomes.MethodsThis was a secondary analysis of previously collected data from an observational prospective study that enrolled consecutive chest pain patients transported by a large metropolitan EMS system in the USA. We used the time of EMS call to determine the time-of-day of the indexed encounter. Two independent reviewers examined available medical data to determine our primary outcome, the presence of MI, and our secondary outcomes, infarct size and 30-day major adverse cardiac events (MACE). We estimated infarct size using peak troponin level.ResultsWe enrolled 2065 patients (age 56±17, 53% males, 7.5% with MI). Chest pain encounters increased from 9:00 AM to 2:00 PM, with a peak at 1:00 PM and a nadir at 6:00 AM. Acute MI had a bimodal distribution with two peaks: 10 AM in ST-elevation MI, and 10 PM in non-ST-elevation MI. ST-elevation MI with afternoon onset was an independent predictor of infarct size. Acute MI with winter and early spring presentation was an independent predictor of 30-day MACE.ConclusionsEMS-attended chest pain calls follow a diurnal pattern, with the most vulnerable patients encountered during afternoons and winter/spring seasons. These data can inform prehospital and ED healthcare providers regarding the time of presentation where patients are more likely to have an underlying MI and subsequently worse outcomes.

Background: Fluctuations in emergency medical services (EMS) responses can have a substantial impact on the ability of agencies to meet resource needs within an EMS system. We aimed to identify weather characteristics as potentially predictable factors associated with EMS responses. Methods: We reviewed hourly counts of scene responses documented by 24 EMS agencies in Western Pennsylvania from January 1, 2014 to December 31, 2017 and compared rates of responses to weather characteristics. Responses to counties nonadjacent to the studied weather reporting station and interfacility/scheduled transports were excluded. We identified the mean temperature, meters visibility, dew point, wind speed, total millimeters of precipitation, and presence of rain or snow in 6-hour windows prior to dispatch, in addition to temporal factors of time of day and weekend vs. weekday. Analysis was performed using multivariable linear regression of a negative binomial distribution, reporting incidence rate ratios (IRR) with 95% confidence intervals (CI). Secondary analyses were performed for transports to the hospital and cases involving transports for traumatic complaints and pediatric patients (age Results: We included 529,058 responses (54.8% female, mean age 57.2 ± SD 24.7 years). In our multivariable model, responses were associated with (IRR, 95% CI) rain (1.10, 1.08–1.11) snow (1.07, 1.05–1.09), and both rain and snow (1.15, 1.11–1.19). A lower incidence of responses occurred on weekends (0.84, 0.83–0.85) and at night (0.62, 0.61–0.62). Increasing temperature in 5 °C increments was associated with an increase in responses across seasons with an effect that varied between 1.16 (1.15–1.17) in winter to 1.31 (1.28–1.33) in summer. Windy weather was associated with increased responses from light breeze (1.10, 1.09–1.11) to fresh breeze or greater (1.23, 1.16–1.30). Transports occurred in a similar pattern to responses. Trauma transports (n = 64,235) occurred more during weekends (1.04, 1.02–1.06). Pediatric transports (n = 21,880) were not significantly associated with precipitation or season. Conclusion: EMS responses increased with rising temperature and following rain and snow. These findings may assist in planning by EMS agencies and emergency departments to identify periods of greatest resource utilization.

Argon exerts neuroprotection. Thus, it might improve patients’ neurological outcome after cerebral disorders or cardiopulmonary resuscitation. However, limited data are available concerning its effect on pulmonary vessel and airways. We used rat isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of rats and humans to assess this topic. IPL: Airway and perfusion parameters, oedema formation and the pulmonary capillary pressure (Pcap) were measured and the precapillary and postcapillary resistance (Rpost) was calculated. In IPLs and PCLS, the pulmonary vessel tone was enhanced with ET-1 or remained unchanged. IPLs were ventilated and PCLS were gassed with argon-mixture or room-air. IPL: Argon reduced the ET-1-induced increase of Pcap, Rpost and oedema formation (p B-receptors abolished argon-induced relaxation (p A-receptors only affected ET-1-pre-contracted PAs (p A/B-receptor agonists attenuated ET-1-induced contraction in PAs and baclofen (GABAB-agonist) even in pulmonary veins (p

Prehospital care of severe trauma patients often involves endotracheal intubation (ETI), which has complications. The frequency and predictors of post-ETI hypotension and cardiac arrest are not well defined in this population. We sought to derive and validate a scoring system that predicts post-ETI hypotension in prehospital patients and to describe the impact of hypotension on outcome. We performed an observational cohort study including normotensive adult trauma patients requiring ETI, treated from 2001 to 2018 by critical care transport providers in a regional air medical transport system. We divided eligible patients into a derivation cohort (2001–2010) and validation cohort (2011–2018) for analysis. We identified predictors of new systolic hypotension (

Background Tyrosine kinase inhibitors (TKIs) inhibit the platelet derived growth factor receptor (PDGFR) and gain increasing significance in the therapy of proliferative diseases, e.g. pulmonary arterial hypertension (PAH). Moreover, TKIs relax pulmonary vessels of rats and guinea pigs. So far, it is unknown, whether TKIs exert relaxation in human and murine pulmonary vessels. Thus, we studied the effects of TKIs and the PDGFR-agonist PDGF-BB in precision-cut lung slices (PCLS) from both species. Methods The vascular effects of imatinib (mice/human) or nilotinib (human) were studied in Endothelin-1 (ET-1) pre-constricted pulmonary arteries (PAs) or veins (PVs) by videomicroscopy. Baseline initial vessel area (IVA) was defined as 100%. With regard to TKI-induced relaxation, K+-channel activation was studied in human PAs (PCLS) and imatinib/nilotinib-related changes of cAMP and cGMP were analysed in human PAs/PVs (ELISA). Finally, the contractile potency of PDGF-BB was explored in PCLS (mice/human). Results Murine PCLS: Imatinib (10 μM) relaxed ET-1-pre-constricted PAs to 167% of IVA. Vice versa, 100 nM PDGF-BB contracted PAs to 60% of IVA and pre-treatment with imatinib or amlodipine prevented PDGF-BB-induced contraction. Murine PVs reacted only slightly to imatinib or PDGF-BB. Human PCLS: 100 μM imatinib or nilotinib relaxed ET-1-pre-constricted PAs to 166% or 145% of IVA, respectively, due to the activation of KATP-, BKCa 2+- or Kv-channels. In PVs, imatinib exerted only slight relaxation and nilotinib had no effect. Imatinib and nilotinib increased cAMP in human PAs, but not in PVs. In addition, PDGF-BB contracted human PAs/PVs, which was prevented by imatinib. Conclusions TKIs relax pre-constricted PAs/PVs from both, mice and humans. In human PAs, the activation of K+-channels and the generation of cAMP are relevant for TKI-induced relaxation. Vice versa, PDGF-BB contracts PAs/PVs (human/mice) due to PDGFR. In murine PAs, PDGF-BB-induced contraction depends on intracellular calcium. So, PDGFR regulates the tone of PAs/PVs. Since TKIs combine relaxant and antiproliferative effects, they may be promising in therapy of PAH.

Retrograde lung vascular perfusion can appear in high-risk surgeries. The present report is the first to study long-term retrograde perfusion of isolated perfused mouse lungs (IPLs) and to use the tyrosine kinase ephB4 and its ligand ephrinB2 as potential markers for acute lung injury. Mouse lungs were subjected to anterograde or retrograde perfusion with normal-pressure ventilation (NV) or high-pressure ventilation (=overventilation, OV) for 4 hours. Outcome parameters were cytokine, ephrinB2 and ephB4 levels in perfusate samples and bronchoalveolar lavage (BAL), and the wet-to-dry ratio. Anterograde perfusion was feasible for 4 hours, while lungs receiving retrograde perfusion presented considerable collapse rates. Retrograde perfusion resulted in an increased wet-to-dry ratio when combined with high-pressure ventilation; other physiological parameters were not affected. Cytokine levels in BAL and perfusate, as well as levels of soluble ephB4 in BAL were increased in OV, while soluble ephrinB2 BAL levels were increased in retrograde perfusion. BAL levels of ephrinB2 and ephB4 were also determined in vivo, including mice ventilated for 7 hours with normal-volume ventilation (NVV) or high-volume ventilation (HVV) with increased levels of ephB4 in HVV BAL compared to NVV. Retrograde perfusion in IPL is limited as a routine method to investigate effects due to collapse for yet unclear reasons. If successful, retrograde perfusion has an influence on pulmonary oedema formation. In BAL, ephrinB2 seems to be up-regulated by flow reversal, while ephB4 is a marker for acute lung injury.

Smoking is the leading preventable cause of premature death in Germany. The network "Education Against Tobacco" (EAT) is an initiative that was founded in Germany in 2012, in which more than 3500 medical students and physicians engage in volunteer work in about 80 medical faculties in 14 countries. In this article, the concept, activities, objectives and associated research studies oft he EAT initiative are introduced.On the school level, the initiative addresses 10- to 15-year-old secondary school students. In addition to a multimodal approach, school visits use modern media such as facemorphing apps, which are not only used by students (45,000 per year in 14 countries), but by a total of over 500,000 other people as well. The effectiveness of the school-based intervention is currently being investigated in randomised long-term studies with 20,000 adolescents in Germany. A first long-term study demonstrated evidence of a protective effect regarding the onset of smoking, especially among female students, students having a low level of education and students with a migratory background.The programme educates several hundred prospective physicians at 13 (of 28 participating) German medical faculties each year in science-based elective courses for the well-established smoking cessation counselling of patients and sensitises them to the tobacco epidemic. The approved members engage in dialogue with local members of the German house of representatives as "Ärzteverband Tabakprävention".EAT motivates the prospective generation of physicians, initially through prevention in school settings, to face the challenge of national tobacco control at the university and federal level.

Civilian out-of-hospital transfusions have not been adequately studied. This study seeks to characterize patients receiving out-of-hospital blood product transfusion during critical care transport.We studied patients transported by a regional critical care air-medical service who received blood products during transport. This service carries two units of uncrossmatched packed Red Blood Cells (pRBCs) on every transport in addition to blood obtained from referring facilities. The pRBC are administered according to a protocol for the treatment of hemorrhagic shock or based on medical command physician order. Transfusion amount was categorized into three groups based on the volume transfused (350 mL, 350-700 mL,700 mL). The association between prehospital transfusion and in-hospital outcomes (mortality, subsequent blood transfusion and emergent surgery) was estimated using logistic regression models, controlling for age, first systolic blood pressure, first heart rate, Glasgow Coma Score, time of transfer, and length of hospital admission.Among the 1,440 critical care transports with transfusions examined, 81% were for medical patients, being gastrointestinal hemorrhage the most common indication (26%, CI 24-28%). pRBC transfusions were associated with emergent surgery (OR = 1.81, 95% CI = 1.31-2.52) and in-hospital transfusions (OR = 2.00, 95% CI = 1.46-2.76). Those with transfusions700 mL were associated with emergent surgery (OR = 1.79, 95% CI = 1.10-2.92) and mortality (OR = 2.11; 95% CI = 1.21-3.69).In this sample, the majority of patients receiving blood products during air-medical transport were transfused for medic conditions; gastrointestinal hemorrhage was the most common chief complaint. The pRBC transfusions were associated with emergent surgery and in-hospital transfusion. Transfusions of700 mL were associated with mortality.

Stroke is the leading cause of disability in the United States with most of these patients being transported by emergency medical services. These providers are the first medical point of contact and must be able to rapidly and accurately identify stroke and transport these patients to the appropriate facilities for treatment. There are many conditions that have similar presentations to stroke and can be mistakenly identified as potential strokes, thereby affecting the initial prehospital triage.A retrospective observational study examined patients with suspected strokes transported to a single comprehensive stroke center (CSC) by a helicopter emergency medical service (HEMS) agency from 2007 through 2013. Final diagnosis was extracted from the Get with the Guidelines (GWTG) database and hospital discharge diagnosis for those not included in the database. Frequencies of discharge diagnosis were calculated and then stratified into interfacility vs. scene transfers.In this study 6,243 patients were transported: 3,376 patients were screened as potential strokes, of which 2,527 had a final diagnosis of stroke (2,242 ischemic stroke and 285 transient ischemic attack), 166 had intracranial hemorrhage, and 655 were stroke mimics. Stroke mimics were more common among scene transfers (223, 32%) than among interfacility transfers (432, 16%).In our study approximately 20% of potential stroke patients transported via HEMS were mimics. Identifying the need for CSC resources can be an important factor in creating a prehospital triage tool to facilitate patient transport to an appropriate health care facility.

Study objective We aim to determine whether administration of higher doses of naloxone for the treatment of opioid overdose is associated with increased pulmonary complications. Methods This was a retrospective, observational, cross-sectional study of 1,831 patients treated with naloxone by the City of Pittsburgh Bureau of Emergency Medical Services. Emergency medical services and hospital records were abstracted for data in regard to naloxone dosing, route of administration, and clinical outcomes, including the development of complications such as pulmonary edema, aspiration pneumonia, and aspiration pneumonitis. For the purposes of this investigation, we defined high-dose naloxone as total administration exceeding 4.4 mg. Multivariable analysis was used to attempt to account for confounders such as route of administration and pretreatment morbidity. Results Patients receiving out-of-hospital naloxone in doses exceeding 4.4 mg were 62% more likely to have a pulmonary complication after opioid overdose (42% versus 26% absolute risk; odds ratio 2.14; 95% confidence interval 1.44 to 3.18). This association remained statistically significant after multivariable analysis with logistic regression (odds ratio 1.85; 95% confidence interval 1.12 to 3.04). A secondary analysis showed an increased risk of 27% versus 13% (odds ratio 2.57; 95% confidence interval 1.45 to 4.54) when initial naloxone dosing exceeded 0.4 mg. Pulmonary edema occurred in 1.1% of patients. Conclusion Higher doses of naloxone in the out-of-hospital treatment of opioid overdose are associated with a higher rate of pulmonary complications. Furthermore, prospective study is needed to determine the causality of this relationship.

In this study, we present a method to experimentally quantify and numerically identify the constituent-specific material behavior of soft biological tissues. This allows the clear identification of the individual contributions of major load-bearing constituents and their interactions in the constitutive law. While the overall approach is applicable for many tissues, here it will be presented for the identification of a sophisticated constituent-specific material model of viable lung parenchyma. This material model will help to better model the effects of various lung diseases that feature altered fiber content in the lungs, such as emphysema or fibrosis. To experimentally quantify the mechanical properties of collagen, elastin, collagen–elastin–fiber interactions, and ground substance, we examined 18 collagenase and elastase treated rat lung parenchymal slices. The mechanical contributions of the collagen and elastin fibers in the living tissue were inferred from uniaxial tension tests comparing the behavior before and after the selective digestion of the respective fibers. In order to also obtain the mechanical influence of the ground substance, we consecutively treated the samples with both proteases. Collagen and elastin fibers are morphologically interconnected. Thus, a mechanical interaction between these fibers appears likely, but has not yet been experimentally verified. In this paper, we propose an experimental method to quantitatively assess the mechanical behavior of these collagen–elastin–fiber interactions. Based on our experiments, we have identified individual material models within a nonlinear continuum mechanics framework for each load-bearing component via an inverse analysis. The proposed constituent-specific material law can be incorporated into computational models of the respiratory system to simulate and even predict the behavior and alteration of the individual constituents and their effect on the whole respiratory system during normal and artificial breathing, in particular in the case of diseases that alter the fibers in the tissue.

BACKGROUND Pediatric patients attended to by emergency medical services (EMS) but not transported to the hospital are an at-risk population. We aimed to evaluate risk factors associated with nontransport by EMS in pediatric patients. METHODS We reviewed medical records of 24 agencies in a regional EMS system in Southwestern Pennsylvania between January 1, 2014, and December 31, 2017. We abstracted demographics (age, sex, medical complaint, median household income by zip code, race, ethnicity), clinical characteristics (abnormal vital signs by age, procedures done), and transport characteristics. We excluded patients ≥ 18 years, interfacility transfers, scene assists, cardiac arrest, and those without a patient encounter. We used unadjusted and adjusted logistic regression to identify factors associated with nontransport, reporting adjusted odds ratios (aOR) with 95% confidence intervals (CIs). RESULTS We included 30,663 pediatric patients (52.9% male, mean ± SD age = 8.5 ± 6.2 years), of whom 5,002 (16.3%) were nontransports. In adjusted analysis (aOR, 95% CI), nontransports were associated with medical categories of trauma (4.32, 3.57-5.23), respiratory (4.03, 3.09-5.26), toxicologic (2.53, 1.66-3.86), and syncope (5.97, 3.78-9.41). Nontransports were less likely for psychiatric (0.52, 0.34-0.79) complaints; for black patients compared to white (0.31, 0.26-0.37); and in patients 6 to

Background Platelet-derived growth factor (PDGF)-BB and its receptor PDGFR are highly expressed in pulmonary hypertension (PH) and mediate proliferation. Recently, we showed that PDGF-BB contracts pulmonary veins (PVs) and that this contraction is prevented by inhibition of PDGFR-β (imatinib/SU6668). Here, we studied PDGF-BB-induced contraction and downstream-signalling in isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of guinea pigs (GPs). Methods In IPLs, PDGF-BB was perfused after or without pre-treatment with imatinib (perfused/nebulised), the effects on the pulmonary arterial pressure (PPA), the left atrial pressure (PLA) and the capillary pressure (Pcap) were studied and the precapillary (Rpre) and postcapillary resistance (Rpost) were calculated. Perfusate samples were analysed (ELISA) to detect the PDGF-BB-induced release of prostaglandin metabolites (TXA2/PGI2). In PCLS, the contractile effect of PDGF-BB was evaluated in pulmonary arteries (PAs) and PVs. In PVs, PDGF-BB-induced contraction was studied after inhibition of PDGFR-α/β, L-Type Ca2+-channels, ROCK/PKC, prostaglandin receptors, MAP2K, p38-MAPK, PI3K-α/γ, AKT/PKB, actin polymerisation, adenyl cyclase and NO. Changes of the vascular tone were measured by videomicroscopy. In PVs, intracellular cAMP was measured by ELISA. Results In IPLs, PDGF-BB increased PPA, Pcap and Rpost. In contrast, PDGF-BB had no effect if lungs were pre-treated with imatinib (perfused/nebulised). In PCLS, PDGF-BB significantly contracted PVs/PAs which was blocked by the PDGFR-β antagonist SU6668. In PVs, inhibition of actin polymerisation and inhibition of L-Type Ca2+-channels reduced PDGF-BB-induced contraction, whereas inhibition of ROCK/PKC had no effect. Blocking of EP1/3- and TP-receptors or inhibition of MAP2K-, p38-MAPK-, PI3K-α/γ- and AKT/PKB-signalling prevented PDGF-BB-induced contraction, whereas inhibition of EP4 only slightly reduced it. Accordingly, PDGF-BB increased TXA2 in the perfusate, whereas PGI2 was increased in all groups after 120 min and inhibition of IP-receptors did not enhance PDGF-BB-induced contraction. Moreover, PDGF-BB increased cAMP in PVs and inhibition of adenyl cyclase enhanced PDGF-BB-induced contraction, whereas inhibition of NO-formation only slightly increased it. Conclusions PDGF-BB/PDGFR regulates the pulmonary vascular tone by the generation of prostaglandins, the increase of calcium, the activation of MAPK- or PI3K/AKT/mTOR signalling and actin remodelling. More insights in PDGF-BB downstream-signalling may contribute to develop new therapeutics for PH.

Background Many of the clinical risk scores routinely used for chest pain assessment have not been validated in patients at high risk for acute coronary syndrome (ACS). We performed an independent comparison of HEART, TIMI, GRACE, FRISC, and PURSUIT scores for identifying chest pain due to ACS and for predicting 30-day death or re-infarction in patients arriving through Emergency Medical Services (EMS). Methods and results We enrolled consecutive EMS patients evaluated for chest pain at three emergency departments. A reviewer blinded to outcome data retrospectively reviewed patient charts to compute each risk score. The primary outcome was ACS diagnosed during the primary admission, and the secondary outcome was death or re-infarction within 30-days of initial presentation. Our sample included 750 patients (aged 59 ± 17 years, 42% female), of whom 115 (15.3%) had ACS and 33 (4.4%) had 30-day death or re-infarction. The c-statistics of HEART, TIMI, GRACE, FRISC, and PURSUIT for identifying ACS were 0.87, 0.86, 0.73, 0.84, and 0.79, respectively, and for predicting 30-day death or re-infarction were 0.70, 0.73, 0.72, 0.72, and 0.62, respectively. Sensitivity/negative predictive value of HEART ≥ 4 and TIMI ≥ 3 for ACS detection were 0.94/0.98 and 0.87/0.97, respectively. Conclusions In chest pain patients admitted through EMS, HEART and TIMI outperform other scores for identifying chest pain due to ACS. Although both have similar negative predictive value, HEART has better sensitivity and lower rate of false negative results, thus it can be used preferentially over TIMI in the initial triage of this population.