Management of high-risk pulmonary embolism in the emergency department: A narrative review.

BACKGROUND: High-risk pulmonary embolism (PE) is a complex, life-threatening condition, and emergency clinicians must be ready to resuscitate and rapidly pursue primary reperfusion therapy. The first-line reperfusion therapy for patients with high-risk PE is systemic thrombolytics (ST). Despite consensus guidelines, only a fraction of eligible patients receive ST for high-risk PE. OBJECTIVE: This review provides emergency clinicians with a comprehensive overview of the current evidence regarding the management of high-risk PE with an emphasis on ST and other reperfusion therapies to address the gap between practice and guideline recommendations. DISCUSSION: High-risk PE is defined as PE that causes hemodynamic instability. The high mortality rate and dynamic pathophysiology of high-risk PE make it challenging to manage. Initial stabilization of the decompensating patient includes vasopressor administration and supplemental oxygen or high-flow nasal cannula. Primary reperfusion therapy should be pursued for those with high-risk PE, and consensus guidelines recommend the use of ST for high-risk PE based on studies demonstrating benefit. Other options for reperfusion include surgical embolectomy and catheter directed interventions. CONCLUSIONS: Emergency clinicians must possess an understanding of high-risk PE including the clinical assessment, pathophysiology, management of hemodynamic instability and respiratory failure, and primary reperfusion therapies.

Disposition of emergency department patients with acute pulmonary embolism after ambulance arrival.

Objective: Most outpatients with pulmonary embolism (PE) are diagnosed in the emergency department (ED). The relationship between means of arrival, site of diagnosis, and disposition in ED patients with PE is unknown. We compared discharge home between patients arriving by emergency medical services (EMS) and those arriving by other means. Within the EMS cohort, we compared those with a recent PE diagnosis in the outpatient clinic setting to those who were diagnosed with PE in the ED. Methods: This study was a secondary analysis of a retrospective cohort that included all adult, non-pregnant ED patients treated for acute PE across 21 community EDs from January 2013 to April 2015. The primary outcome was discharge home within 24 h of ED registration; we also examined mortality. We described associations with patient arrival method and other patient characteristics. Results: Among 2996 ED patient encounters with acute PE, 644 (21.5%) arrived by EMS. This group had a lower frequency of discharge (9.2% vs 26.4%) and higher 30-day all-cause mortality (8.7% vs 3.1%) than their counterparts (p < 0.001 for both). These associations remained after adjusting for confounding variables. Among the EMS cohort, 14 patients (2.2%) arrived with a PE diagnosis recently made in the outpatient setting. Conclusion: Patients with PE who arrived at the ED by EMS were less likely to be discharged home within 24 h and more likely to die within 30 days than those who arrived by other means. Less than 3% of the EMS group had been diagnosed with PE before ED arrival.

Prevalence of and Eligibility for Surveillance Without Anticoagulation Among Adults With Lower-Risk Acute Subsegmental Pulmonary Embolism.

Importance: Approximately 8% of acute pulmonary emboli are confined to the subsegmental arteries. The 2016 and 2021 American College of Chest Physicians (CHEST) guidelines and expert panel reports suggest the use of structured surveillance without anticoagulation for select ambulatory patients with subsegmental pulmonary embolism who do not have active cancer, deep vein thrombosis, impaired cardiopulmonary reserve, marked symptoms, or increased risk of recurrent venous thromboembolism; however, guideline uptake in community practice is unknown, as is the proportion of outpatients eligible for surveillance. Objective: To describe the prevalence of surveillance among outpatients with acute subsegmental pulmonary embolism and to estimate the proportion of patients eligible for structured surveillance using modified CHEST criteria. Design, Setting, and Participants: This retrospective cohort study was conducted across 21 US community hospitals in the Kaiser Permanente Northern California integrated health system from January 1, 2017, to December 31, 2021. Adult outpatients with acute subsegmental pulmonary embolism were included. Patients with the following higher-risk characteristics were excluded: codiagnoses requiring hospitalization, non-low-risk vital signs (ie, systolic blood pressure <90 mm Hg, pulse ≥110 bpm, or peripheral cutaneous pulse oximetry ≤92%), prediagnosis anticoagulant use, or hospice care. Data analysis was performed from November 2022 to February 2023. Main Outcomes and Measures: The main outcomes were the (1) prevalence of surveillance and (2) eligibility for surveillance using 2 sets of criteria: the CHEST criteria modified by excluding patients with higher-risk characteristics or right ventricular dysfunction and a stricter set of criteria requiring age younger than 65 years and no more than 1 embolus. The prevalence of structured surveillance was calculated and the proportion of patients eligible for surveillance was estimated. Results: Of the 666 outpatients with acute subsegmental pulmonary embolism included in this study, 229 with lower-risk characteristics were examined. Their median age was 58 (IQR, 42-68) years; more than half were men (120 [52.4%]) and self-identified as non-Hispanic White (128 [55.9%]). Six patients (2.6%) were initially not treated with anticoagulants. Among the lower-risk cohort, only 1 patient (0.4% [95% CI, 0.01%-2.4%]) underwent structured surveillance, without 90-day sequelae. Thirty-five patients (15.3% of the lower-risk group and 5.3% of the full cohort) were surveillance eligible using modified CHEST criteria. Fifteen patients (6.6% of the lower-risk group and 2.3% of the full cohort) were surveillance eligible using stricter criteria. Conclusions and Relevance: In this cohort study of lower-risk outpatients with subsegmental pulmonary embolism, few were eligible for structured surveillance, and only a small proportion of eligible patients underwent surveillance despite the CHEST guideline. If forthcoming trials find surveillance safe and effective, substantial uptake into clinical practice may require more than passive diffusion.

Tension Pneumomediastinum and Coronary Artery Thrombosis Following a Motorcycle Accident: A Case Report.

INTRODUCTION: Tension pneumomediastinum and coronary artery thrombosis (CAT) secondary to blunt polytrauma are, rare yet have the potential for serious complication. CASE REPORT: A 40-year-old man presented to the emergency department following a motorcycle accident. He was found to have multiple orthopedic injuries, pneumothorax, and pneumomediastinum. An electrocardiogram showed myocardial infarction. He developed obstructive shock physiology that resolved with mediastinal percutaneous needle drainage. Subsequent coronary angiography revealed acute thrombosis of the left circumflex artery. CONCLUSION: This is a rare case of traumatic tension pneumomediastinum associated with coronary artery thrombosis requiring coronary stenting. Emergency physicians should be mindful of CAT in the setting of blunt chest injury.

Universal HIV screening in the emergency department: an interrupted time series analysis.

We performed a calendar-matched, 12-month, before (November 27, 2017 to November 26, 2018) and after (November 27, 2018 to November 26, 2019) study, to assess the utility of an emergency department-based HIV screening program. There were 710 and 14 335 patients screened for HIV during the pre and post-best practice alert (BPA) periods, respectively, representing more than a 20-fold increase in HIV screening following BPA implementation. Total HIV positive tests increased 5-fold following BPA implementation.

The presentation of spontaneous coronary artery dissection in the emergency department: Signs and symptoms in an unsuspecting population.

OBJECTIVES: Spontaneous coronary artery dissection (SCAD) has emerged as a common cause of acute coronary syndrome (ACS) in young women, although it is rarely discussed in the differential diagnosis for chest pain in the emergency department (ED). In a population otherwise considered low risk for myocardial infarction, there is a danger of incomplete workup and missed diagnosis. In this study, we aim to describe the clinical presentation of those who present to the ED with SCAD to increase awareness of this potentially fatal diagnosis among emergency practitioners. METHODS: Data were queried from the Mayo Clinic "Virtual" Multicenter SCAD Registry, a large multisite international disease registry. The registry includes demographic information as well as data from both medical records and surveys administered following the SCAD event. Symptom presentation was abstracted from survey narrative responses. Data analysis was performed using descriptive statistics. RESULTS: Of 1196 subjects included, chest pain was reported during initial SCAD event in 95.7%. Most common chest symptoms descriptors were pain, pressure/weight, and tightness, with radiation most often in one or both arms/shoulders. Other common symptoms included nausea, shortness of breath, and diaphoresis. Most common electrocardiogram (ECG) findings reported were ST elevation, T-wave abnormality, and normal ECG. Initial troponin values were within normal range in 20.1% of patients. CONCLUSION: With young healthy women often considered "low risk" for ACS, it is important to understand that SCAD is a cause of ACS, and familiarity with presentation can improve awareness among emergency physicians. Our data can provide insight in helping to identify young women who present with chest pain due to SCAD so they can be appropriately evaluated.

Immune checkpoint inhibitor-induced hypophysitis: lessons learnt from a large cancer cohort.

Immune checkpoint inhibitors (ICIs) can cause pituitary dysfunction due to hypophysitis. We aimed to characterize ICI-induced hypophysitis and examine its association with overall survival in this single-center retrospective cohort study of adult patients with cancer who received an ICI from January 1, 2012 through December 31, 2016. A total of 896 patients were identified who received ipilimumab alone (n=120); ipilimumab and nivolumab (n=50); ipilimumab before or after pembrolizumab (n=70); pembrolizumab alone (n=406); and nivolumab alone (n=250). Twenty-six patients (2.9%) developed hypophysitis after a median of 2.3 months. Median age at the start of ICI was 57.9 years and 54% were men. Hypophysitis occurred in 7.9% of patients receiving ipilimumab alone or in combination or sequence with a programmed cell death protein 1 inhibitor; 1.7% after pembrolizumab alone, never after nivolumab alone. Secondary adrenal insufficiency occurred in all hypophysitis cases. Use of ipilimumab alone or in combination was associated with pituitary enlargement on imaging and mass effects more frequently than pembrolizumab alone. Occurrence of hypophysitis was associated with improved overall survival by univariate analysis (median 50.7 vs 16.5 months; p=0.015) but this association was not observed in multivariable landmark survival analysis (HR for mortality 0.75; 95% CI 0.38 to 1.30; p=0.34) after adjusting for age, sex and malignancy type. To conclude, hypophysitis occurred most frequently after ipilimumab and manifested as anterior hypopituitarism affecting the corticotrophs more commonly than thyrotrophs and gonadotrophs. Mass effects and pituitary enlargement occurred more frequently in ipilimumab-induced hypophysitis. The association of hypophysitis with overall survival needs further investigation.

G-Quadruplexes influence pri-microRNA processing.

RNA G-Quadruplexes (G4) have been shown to possess many biological functions, including the regulation of microRNA (miRNA) biogenesis and function. However, their impact on pri-miRNA processing remains unknown. We identified G4 located near the Drosha cleavage site in three distinct pri-miRNAs: pri-mir200c, pri-mir451a, and pri-mir497. The folding of the potential G4 motifs was determined in solution. Subsequently, mutations disrupting G4 folding led to important changes in the mature miRNAs levels in cells. Moreover, using small antisense oligonucleotides binding to the pri-miRNA, it was possible to modulate, either positively or negatively, the mature miRNA levels. Together, these data demonstrate that G4 motifs could contribute to the regulation of pri-mRNA processing, a novel role for G4. Considering that bio-informatics screening indicates that between 9% and 50% of all pri-miRNAs contain a putative G4, these structures possess interesting potential as future therapeutic targets.

Aven recognition of RNA G-quadruplexes regulates translation of the mixed lineage leukemia protooncogenes.

G-quadruplexes (G4) are extremely stable secondary structures forming stacks of guanine tetrads. DNA G4 structures have been extensively studied, however, less is known about G4 motifs in mRNAs, especially in their coding sequences. Herein, we show that Aven stimulates the mRNA translation of the mixed lineage leukemia (MLL) proto-oncogene in an arginine methylation-dependent manner. The Aven RGG/RG motif bound G4 structures within the coding regions of the MLL1 and MLL4 mRNAs increasing their polysomal association and translation, resulting in the induction of transcription of leukemic genes. The DHX36 RNA helicase associated with the Aven complex and was required for optimal translation of G4 mRNAs. Depletion of Aven led to a decrease in synthesis of MLL1 and MLL4 proteins resulting in reduced proliferation of leukemic cells. These findings identify an Aven-centered complex that stimulates the translation of G4 harboring mRNAs, thereby promoting survival of leukemic cells.

Small antisense oligonucleotides against G-quadruplexes: specific mRNA translational switches.

G-quadruplexes (G4) are intricate RNA structures found throughout the transcriptome. Because they are associated with a variety of biological cellular mechanisms, these fascinating structural motifs are seen as potential therapeutic targets against many diseases. While screening of chemical compounds specific to G4 motifs has yielded interesting results, no single compound successfully discriminates between G4 motifs based on nucleotide sequences alone. This level of specificity is best attained using antisense oligonucleotides (ASO). Indeed, oligonucleotide-based strategies are already used to modulate DNA G4 folding in vitro. Here, we report that, in human cells, the use of short ASO to promote and inhibit RNA G4 folding affects the translation of specific mRNAs, including one from the 5'UTR of the H2AFY gene, a histone variant associated with cellular differentiation and cancer. These results suggest that the relatively high specificity of ASO-based strategies holds significant potential for applications aimed at modulating G4-motif folding.

Programming a highly structured ribozyme into complex allostery using RNA oligonucleotides.

RNA possesses great potential for expanding the toolbox currently available to synthetic biologists. Here, the modulation of the Hepatitis Delta Virus ribozyme's activity with a series of rationally designed aptamers and effector RNA oligonucleotides is described. The ribozyme was initially fused with an 18-nucleotide hairpin structure that abolished its self-cleaving activity. The binding of a 14-mer oligonucleotide to the hairpin rescued the self-cleavage in a concentration-dependent manner. This modified ribozyme was inserted into the 5' UTR of a reporter gene, and the resulting construct was used to demonstrate that it is possible to modulate the ribozyme activity in cellulo with the oligonucleotide. Subsequently, ribozymes possessing specialized aptamers respecting other logic gates were also successfully designed and found to be functional in vitro. To our knowledge, this is the first example of HDV ribozyme regulation by oligonucleotides, as well as the first allosteric regulation of HDV ribozyme in mammalian cells.

Selection of the most potent specific on/off adaptor-hepatitis delta virus ribozymes for use in gene targeting.

The Hepatitis Delta Virus (HDV) ribozyme, which is well adapted to the environment of the human cell, is an excellent candidate for the future development of gene-inactivation systems. On top of this, a new generation of HDV ribozymes now exists that benefits from the addition of a specific on/off adaptor (specifically the SOFA-HDV ribozymes) which greatly increases both the ribozyme's specificity and its cleavage activity. Unlike RNAi and hammerhead ribozymes, the designing of SOFA-HDV ribozymes to cleave, in trans, given RNA species has never been the object of a systematic optimization study, even with their recent use for the gene knockdown of various targets. This report aims at both improving and clarifying the design process of SOFA-HDV ribozymes. Both the ribozyme and the targeted RNA substrate were analyzed in order to provide new criteria that are useful in the selection of the most potent SOFA-HDV ribozymes. The crucial features present in both the ribozyme's biosensor and blocker, as well as at the target site, were identified and characterized. Simple rules were derived and tested using hepatitis C virus NS5B RNA as a model target. Overall, this method should promote the use of the SOFA-HDV ribozymes in a plethora of applications in both functional genomics and gene therapy.