A Shorter Door-In-Door-Out Time Is Associated with Improved Outcome in Large Vessel Occlusion Stroke.

Introduction: Endovascular thrombectomy (EVT) significantly improves outcomes in large vessel occlusion stroke (LVOS). When a patient with a LVOS arrives at a hospital that does not perform EVT, emergent transfer to an endovascular stroke center (ESC) is required. Our objective was to determine the association between door-in-door-out time (DIDO) and 90-day outcomes in patients undergoing EVT. Methods: We conducted an analysis of the Optimizing Prehospital Stroke Systems of Care-Reacting to Changing Paradigms (OPUS-REACH) registry of 2,400 LVOS patients treated at nine ESCs in the United States. We examined the association between DIDO times and 90-day outcomes as measured by the modified Rankin scale. Results: A total of 435 patients were included in the final analysis. The mean DIDO time for patients with good outcomes was 17 minute shorter than patients with poor outcomes (122 minutes [min] vs 139 min, P = 0.04). Absolute DIDO cutoff times of ≤60 min, ≤90 min, or ≤120 min were not associated with improved functional outcomes (46.4 vs 32.3%, P = 0.12; 38.6 vs 30.6%, P = 0.10; and 36.4 vs 28.9%, P = 0.10, respectively). This held true for patients with hyperacute strokes of less than four-hour onset. Lower baseline National Institutes of Health Stroke Scale (NIHSS) score (11.9 vs 18.2, P = \u3c.001) and younger age (62.5 vs 74.9 years (P \u3c .001) were associated with improved outcomes. On multiple regression analysis, age (odds ratio [OR] 1.71, 95% confidence interval [CI] 1.45-2.02) and baseline NIHSS score (OR 1.67, 95% CI 1.42-1.98) were associated with improved outcomes while DIDO time was not associated with better outcome (OR 1.13, 95% CI 0.99-1.30). Conclusion: Although the DIDO time was shorter for patients with a good outcome, this was non-significant in multiple regression analysis. Receipt of intravenous thrombolysis and time to EVT were not associated with better outcomes, while male gender, lower age, arrival by private vehicle, and lower NIHSS score portended better outcomes. No absolute DIDO-time cutoff or modifiable factor was associated with improved outcomes for LVOS. This study underscores the need to streamline DIDO times but not to set an artificial DIDO time benchmark to meet

Cross-Platform Array Screening Identifies COL1A2, THBS1, TNFRSF10D and UCHL1 as Genes Frequently Silenced by Methylation in Melanoma

Epigenetic regulation of tumor suppressor genes (TSGs) has been shown to play a central role in melanomagenesis. By integrating gene expression and methylation array analysis we identified novel candidate genes frequently methylated in melanoma. We validated the methylation status of the most promising genes using highly sensitive Sequenom Epityper assays in a large panel of melanoma cell lines and resected melanomas, and compared the findings with those from cultured melanocytes. We found transcript levels of UCHL1, COL1A2, THBS1 and TNFRSF10D were inversely correlated with promoter methylation. For THBS1 and UCHL1 the effect of this methylation on expression was confirmed at the protein level. Identification of these candidate TSGs and future research designed to understand how their silencing is related to melanoma development will increase our understanding of the etiology of this cancer and may provide tools for its early diagnosis

Resolution of inflammation: a new therapeutic frontier

Dysregulated inflammation is a central pathological process in diverse disease states. Traditionally, therapeutic approaches have sought to modulate the pro- or anti-inflammatory limbs of inflammation, with mixed success. However, insight into the pathways by which inflammation is resolved has highlighted novel opportunities to pharmacologically manipulate these processes — a strategy that might represent a complementary (and perhaps even superior) therapeutic approach. This Review discusses the state of the art in the biology of resolution of inflammation, highlighting the opportunities and challenges for translational research in this field

Case Reports1. A Late Presentation of Loeys-Dietz Syndrome: Beware of TGFβ Receptor Mutations in Benign Joint Hypermobility

Background: Thoracic aortic aneurysms (TAA) and dissections are not uncommon causes of sudden death in young adults. Loeys-Dietz syndrome (LDS) is a rare, recently described, autosomal dominant, connective tissue disease characterized by aggressive arterial aneurysms, resulting from mutations in the transforming growth factor beta (TGFβ) receptor genes TGFBR1 and TGFBR2. Mean age at death is 26.1 years, most often due to aortic dissection. We report an unusually late presentation of LDS, diagnosed following elective surgery in a female with a long history of joint hypermobility. Methods: A 51-year-old Caucasian lady complained of chest pain and headache following a dural leak from spinal anaesthesia for an elective ankle arthroscopy. CT scan and echocardiography demonstrated a dilated aortic root and significant aortic regurgitation. MRA demonstrated aortic tortuosity, an infrarenal aortic aneurysm and aneurysms in the left renal and right internal mammary arteries. She underwent aortic root repair and aortic valve replacement. She had a background of long-standing joint pains secondary to hypermobility, easy bruising, unusual fracture susceptibility and mild bronchiectasis. She had one healthy child age 32, after which she suffered a uterine prolapse. Examination revealed mild Marfanoid features. Uvula, skin and ophthalmological examination was normal. Results: Fibrillin-1 testing for Marfan syndrome (MFS) was negative. Detection of a c.1270G > C (p.Gly424Arg) TGFBR2 mutation confirmed the diagnosis of LDS. Losartan was started for vascular protection. Conclusions: LDS is a severe inherited vasculopathy that usually presents in childhood. It is characterized by aortic root dilatation and ascending aneurysms. There is a higher risk of aortic dissection compared with MFS. Clinical features overlap with MFS and Ehlers Danlos syndrome Type IV, but differentiating dysmorphogenic features include ocular hypertelorism, bifid uvula and cleft palate. Echocardiography and MRA or CT scanning from head to pelvis is recommended to establish the extent of vascular involvement. Management involves early surgical intervention, including early valve-sparing aortic root replacement, genetic counselling and close monitoring in pregnancy. Despite being caused by loss of function mutations in either TGFβ receptor, paradoxical activation of TGFβ signalling is seen, suggesting that TGFβ antagonism may confer disease modifying effects similar to those observed in MFS. TGFβ antagonism can be achieved with angiotensin antagonists, such as Losartan, which is able to delay aortic aneurysm development in preclinical models and in patients with MFS. Our case emphasizes the importance of timely recognition of vasculopathy syndromes in patients with hypermobility and the need for early surgical intervention. It also highlights their heterogeneity and the potential for late presentation. Disclosures: The authors have declared no conflicts of interes

Simple Changes to Emergency Department Workflow Improve Analgesia in Mechanically Ventilated Patients

Introduction: In 2013 the Society for Critical Care Medicine (SCCM) published guidelines for the management of pain and agitation in the intensive care unit (ICU). These guidelines recommend using an analgesia-first strategy in mechanically ventilated patients as well as reducing the use of benzodiazepines. Benzodiazepines increase delirium in ICU patients thereby increasing ICU length of stay. We sought to determine whether a simple educational intervention for emergency department (ED) staff, as well as two simple changes in workflow, would improve adherence to the SCCM guidelines.Methods: This was a cohort study that took place from 2014-2016. All patients who were intubated in the ED by an emergency physician (EP) during this time were eligible for inclusion in this study. In January 2015, we began an educational campaign with the ED staff consisting of a series of presentations and online trainings. The impetus for our educational campaign was to have best practices in place for our new emergency medicine residency program starting in July 2016. We made two minor changes in our ED workflow to support this educational objective. First, fentanyl infusions were stocked in the ED. Second, we instituted a medication order set for mechanically ventilated patients. This order set nudged EPs to choose medications consistent with the SCCM guidelines. We then evaluated the use of opioids and benzodiazepines in mechanically ventilated patients from 2014 through 2016 using Fisher’s exact test. All analyses were conducted in the overall sample (n=509) as well as in subgroups after excluding patients with seizures/status epilepticus as their primary admission diagnosis (n=461).Results: In 2014 prior to the interventions, 41% of mechanically ventilated patients received an opioid, either as an intravenous (IV) push or IV infusion. In 2015 immediately after the intervention, 71% of patients received an opioid and 64% received an opioid in 2016. The use of benzodiazepine infusions decreased from 22% in 2014 to 7% in 2015 to 1% in 2016.Conclusion: A brief educational intervention along with two simple changes in ED workflow can improve compliance with the SCCM guidelines for the management of pain and agitation in mechanically ventilated patients

Assessing Disparities in Access to Advanced Stroke Care in 4 Northeastern States Using the Social Vulnerability Index

Background Access to endovascular stroke centers (ESCs) is crucial for patients to receive optimal care for large‐vessel occlusion strokes. Disparities in stroke care are well documented, including differences in patients who receive intravenous thrombolysis and endovascular therapy. Here, we describe racial, ethnic, sex, and social disparities in access to ESCs using the Social Vulnerability Index (SVI), a composite measure of a community\u27s health. Methods This is a population‐based study of 4 Northeastern states. We geocoded all ESCs in New York, New Jersey, Pennsylvania, and Delaware and calculated the distance from the centroid of each census tract to the nearest ESC. We then used the US Centers for Disease Control\u27s Social Vulnerability Index and its 4 subcomponents to calculate the health of that census tract. Results are presented as mean drive times by quartile of SVI (quartile 1=least vulnerable, quartile 4=most vulnerable) and the mean SVI dichotomized to census tracts located less than and greater than 60 minutes to the nearest ESC. Results A total of 42 000 000 people and 10 000 census tracts were included in our data. There were no significant differences in the mean SVI for census with drive times of \u3c60 minutes versus \u3e60 minutes to the nearest ESC. However, there were significant differences in 2 subcomponents of the SVI: Minority Status & Language and Household Composition & Disability. In the Minority Status subcomponent of the SVI, those in the most vulnerable census tracts (quartile 4) were located closest to ESCs compared with the least vulnerable census tracts (quartile 1), while for the Household Composition subcomponent, the most vulnerable census tracts were located farthest from the ESCs. Conclusion The SVI is a valuable tool for assessing disparities in access to advanced stroke care and predicting where additional ESCs should be added to benefit the population as a whole

Simple Changes to Emergency Department Workflow Improve Analgesia in Mechanically Ventilated Patients

Introduction: In 2013 the Society for Critical Care Medicine (SCCM) published guidelines for the management of pain and agitation in the intensive care unit (ICU). These guidelines recommend using an analgesia-first strategy in mechanically ventilated patients as well as reducing the use of benzodiazepines. Benzodiazepines increase delirium in ICU patients thereby increasing ICU length of stay. We sought to determine whether a simple educational intervention for emergency department (ED) staff, as well as two simple changes in workflow, would improve adherence to the SCCM guidelines.Methods: This was a cohort study that took place from 2014-2016. All patients who were intubated in the ED by an emergency physician (EP) during this time were eligible for inclusion in this study. In January 2015, we began an educational campaign with the ED staff consisting of a series of presentations and online trainings. The impetus for our educational campaign was to have best practices in place for our new emergency medicine residency program starting in July 2016. We made two minor changes in our ED workflow to support this educational objective. First, fentanyl infusions were stocked in the ED. Second, we instituted a medication order set for mechanically ventilated patients. This order set nudged EPs to choose medications consistent with the SCCM guidelines. We then evaluated the use of opioids and benzodiazepines in mechanically ventilated patients from 2014 through 2016 using Fisher’s exact test. All analyses were conducted in the overall sample (n=509) as well as in subgroups after excluding patients with seizures/status epilepticus as their primary admission diagnosis (n=461).Results: In 2014 prior to the interventions, 41% of mechanically ventilated patients received an opioid, either as an intravenous (IV) push or IV infusion. In 2015 immediately after the intervention, 71% of patients received an opioid and 64% received an opioid in 2016. The use of benzodiazepine infusions decreased from 22% in 2014 to 7% in 2015 to 1% in 2016.Conclusion: A brief educational intervention along with two simple changes in ED workflow can improve compliance with the SCCM guidelines for the management of pain and agitation in mechanically ventilated patients

Males Receive Low-Tidal Volume Component of Lung Protective Ventilation More Frequently than Females in the Emergency Department

Introduction: Mechanical ventilation is a commonly performed procedure in the emergency department (ED). Approximately 240,000 patients per year receive mechanical ventilation in the ED representing 0.23% of ED visits. An ED-based trial published in 2017 showed that a bundle of interventions in mechanically ventilated patients, including low tidal volume ventilation, reduced the development of acute respiratory distress syndrome by nearly 50%. Prior literature has shown that as many as 40% of ED patients do not receive lung protective ventilation. Our goal was to determine whether differences exist between the percent of males vs females who are ventilated at ≥ 8 milliliters per kilogram (mL/kg) of predicted body weight.Methods: We conducted this study at Temple University Hospital, a tertiary care center located in Philadelphia, Pennsylvania. This was a planned subgroup analysis of study looking at interventions to improve adherence to recommended tidal volume settings. We used a convenience sample of mechanically ventilated patients in our ED between September 1, 2017, and September 30, 2018. All adult patient > 18 years old were eligible for inclusion in the study. Our primary outcome measure was the number of patients who had initial tidal volumes set at > 8 mL/kg of predicted body weight. Our secondary outcome was the number of patients who had tidal volumes set at ≥ 8 mL/kg at 60 minutes after initiation of mechanical ventilation.Results: A total of 130 patients were included in the final analysis. We found that significantly more females were initially ventilated with tidal volumes ≥ 8 mL/kg compared to men: 56% of females vs 9% of males (p=<0.001). Data was available for 107 patients (82%) who were in the ED at 60 minutes after initiation of mechanical ventilation. Again, a significantly larger percentage of females were ventilated with tidal volumes ≥ 8 mL/kg at 60 minutes: 56% of females vs 10% of males (p<0.001).Conclusion: The vast majority of tidal volumes ≥ 8 mL/kg during mechanical ventilation occurs in females. We suggest that objective measurements, such as a tape measure and tidal volume card, be used when setting tidal volumes for all patients, especially females

Rate of Decompensation of Normoxic Emergency Department Patients with SARS-CoV-2

Introduction: As of October 30, 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 44 million people worldwide and killed over 1.1 million people. In the emergency department (ED), patients who need supplemental oxygen or respiratory support are admitted to the hospital, but the course of normoxic patients with SARS-CoV-2 infection is unknown. In our health system, the policy during the coronavirus 2019 (COVID-19) pandemic was to admit all patients with abnormal chest imaging (CXR) regardless of their oxygen level. We also admitted febrile patients with respiratory complaints who resided in congregate living. We describe the rate of decompensation among patients admitted with suspected SARS-CoV-2 infection but who were not hypoxemic in the ED.Methods: This is a retrospective observational study of patients admitted to our health system between March 1–May 5, 2020 with suspected SARS-CoV-2 infection. We queried our registry to find patients who were admitted to the hospital but had no recorded oxygen saturation of <92% in the ED and received no supplemental oxygen prior to admission. Our primary outcome was decompensation at 72 hours, defined by the need for respiratory support (oxygen, high-flow nasal cannula, non-invasive ventilation, or intubation).Results: A total of 840 patients met our inclusion criteria. Of those patients, 376 (45%) tested positive for SARS-CoV-2. Sixty patients (7.1%) with suspected COVID-19 required respiratory support at 72 hours including 27 (3%) of confirmed SARS-CoV-2 positive patients. Among the 376 patients who tested positive for SARS-CoV-2, 54 patients (14%) had normal CXR in the ED. One-third of patients with normal CXRs decompensated at 72 hours. Seven SARS-CoV-2 positive patients in our cohort died during their hospitalization, of whom five had normal CXRs on admission.Conclusion: Sixty (7.1%) of suspected COVID-19 patients hospitalized at 72 hours required respiratory support despite being normoxic in the ED. Further research should look to identify the normoxic SARS-CoV-2 patients at risk for decompensation

Rate of Decompensation of Normoxic Emergency Department Patients with SARS-CoV-2

Introduction: As of October 30, 2020, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 44 million people worldwide and killed over 1.1 million people. In the emergency department (ED), patients who need supplemental oxygen or respiratory support are admitted to the hospital, but the course of normoxic patients with SARS-CoV-2 infection is unknown. In our health system, the policy during the coronavirus 2019 (COVID-19) pandemic was to admit all patients with abnormal chest imaging (CXR) regardless of their oxygen level. We also admitted febrile patients with respiratory complaints who resided in congregate living. We describe the rate of decompensation among patients admitted with suspected SARS-CoV-2 infection but who were not hypoxemic in the ED.Methods: This is a retrospective observational study of patients admitted to our health system between March 1–May 5, 2020 with suspected SARS-CoV-2 infection. We queried our registry to find patients who were admitted to the hospital but had no recorded oxygen saturation of <92% in the ED and received no supplemental oxygen prior to admission. Our primary outcome was decompensation at 72 hours, defined by the need for respiratory support (oxygen, high-flow nasal cannula, non-invasive ventilation, or intubation).Results: A total of 840 patients met our inclusion criteria. Of those patients, 376 (45%) tested positive for SARS-CoV-2. Sixty patients (7.1%) with suspected COVID-19 required respiratory support at 72 hours including 27 (3%) of confirmed SARS-CoV-2 positive patients. Among the 376 patients who tested positive for SARS-CoV-2, 54 patients (14%) had normal CXR in the ED. One-third of patients with normal CXRs decompensated at 72 hours. Seven SARS-CoV-2 positive patients in our cohort died during their hospitalization, of whom five had normal CXRs on admission.Conclusion: Sixty (7.1%) of suspected COVID-19 patients hospitalized at 72 hours required respiratory support despite being normoxic in the ED. Further research should look to identify the normoxic SARS-CoV-2 patients at risk for decompensation