Inhaled Fluticasone Furoate for Outpatient Treatment of Covid-19.

BACKGROUND: The effectiveness of inhaled glucocorticoids in shortening the time to symptom resolution or preventing hospitalization or death among outpatients with mild-to-moderate coronavirus disease 2019 (Covid-19) is unclear. METHODS: We conducted a decentralized, double-blind, randomized, placebo-controlled platform trial in the United States to assess the use of repurposed medications in outpatients with confirmed coronavirus disease 2019 (Covid-19). Nonhospitalized adults 30 years of age or older who had at least two symptoms of acute infection that had been present for no more than 7 days before enrollment were randomly assigned to receive inhaled fluticasone furoate at a dose of 200 µg once daily for 14 days or placebo. The primary outcome was the time to sustained recovery, defined as the third of 3 consecutive days without symptoms. Key secondary outcomes included hospitalization or death by day 28 and a composite outcome of the need for an urgent-care or emergency department visit or hospitalization or death through day 28. RESULTS: Of the 1407 enrolled participants who underwent randomization, 715 were assigned to receive inhaled fluticasone furoate and 692 to receive placebo, and 656 and 621, respectively, were included in the analysis. There was no evidence that the use of fluticasone furoate resulted in a shorter time to recovery than placebo (hazard ratio, 1.01; 95% credible interval, 0.91 to 1.12; posterior probability of benefit [defined as a hazard ratio >1], 0.56). A total of 24 participants (3.7%) in the fluticasone furoate group had urgent-care or emergency department visits or were hospitalized, as compared with 13 participants (2.1%) in the placebo group (hazard ratio, 1.9; 95% credible interval, 0.8 to 3.5). Three participants in each group were hospitalized, and no deaths occurred. Adverse events were uncommon in both groups. CONCLUSIONS: Treatment with inhaled fluticasone furoate for 14 days did not result in a shorter time to recovery than placebo among outpatients with Covid-19 in the United States. (Funded by the National Center for Advancing Translational Sciences and others; ACTIV-6 ClinicalTrials.gov number, NCT04885530.).

Sex-dependent differences in vulnerability to early risk factors for posttraumatic stress disorder: results from the AURORA study.

BACKGROUND: Knowledge of sex differences in risk factors for posttraumatic stress disorder (PTSD) can contribute to the development of refined preventive interventions. Therefore, the aim of this study was to examine if women and men differ in their vulnerability to risk factors for PTSD. METHODS: As part of the longitudinal AURORA study, 2924 patients seeking emergency department (ED) treatment in the acute aftermath of trauma provided self-report assessments of pre- peri- and post-traumatic risk factors, as well as 3-month PTSD severity. We systematically examined sex-dependent effects of 16 risk factors that have previously been hypothesized to show different associations with PTSD severity in women and men. RESULTS: Women reported higher PTSD severity at 3-months post-trauma. Z-score comparisons indicated that for five of the 16 examined risk factors the association with 3-month PTSD severity was stronger in men than in women. In multivariable models, interaction effects with sex were observed for pre-traumatic anxiety symptoms, and acute dissociative symptoms; both showed stronger associations with PTSD in men than in women. Subgroup analyses suggested trauma type-conditional effects. CONCLUSIONS: Our findings indicate mechanisms to which men might be particularly vulnerable, demonstrating that known PTSD risk factors might behave differently in women and men. Analyses did not identify any risk factors to which women were more vulnerable than men, pointing toward further mechanisms to explain women's higher PTSD risk. Our study illustrates the need for a more systematic examination of sex differences in contributors to PTSD severity after trauma, which may inform refined preventive interventions.

Factors associated with door-in-door-out times in large vessel occlusion stroke patients undergoing endovascular therapy.

INTRODUCTION: In the management of large vessel occlusion stroke (LVOS), patients are frequently evaluated first at a non-endovascular stroke center and later transferred to an endovascular stroke center (ESC) for endovascular treatment (EVT). The door-in-door-out time (DIDO) is frequently used as a benchmark for transferring hospitals though there is no universally accepted nor evidenced-based DIDO time. The goal of this study was to identify factors affecting DIDO times in LVOS patients who ultimately underwent EVT. METHODS: The Optimizing Prehospital Use of Stroke Systems of Care-Reacting to Changing Paradigms (OPUS-REACH) registry is comprised of all LVOS patients who underwent EVT at one of nine endovascular centers in the Northeast United States between 2015 and 2020. We queried the registry for all patients who were transferred from a non-ESC to one of the nine ESCs for EVT. Univariate analysis was performed using t-tests to obtain a p value. A priori, we defined a p value of <0.05 as significant. Multiple logistic regression was conducted to determine the association of variables to estimate an odds ratio. RESULTS: 511 patients were included in the final analysis. The mean DIDO times for all patients was 137.8 min. Vascular imaging and treatment at a non-certified stroke center were associated with longer DIDO times by 23 and 14 min, respectively. On multivariate analyses, the acquisition of vascular imaging was associated with 16 additional minutes spent at the non-ESC while presentation to a non-stroke certified hospital was associated with 20 additional minutes spent at the transferring hospital. The administration of intravenous thrombolysis (IVT) was associated with 15 min less spent at the non-ESC. DISCUSSION: Vascular imaging and non-stroke certified stroke centers were associated with longer DIDO times. Non-ESCs should integrate vascular imaging into their workflow as feasible to reduce DIDO times. Further work examining other details regarding the transfer process such as transfer via ground or air, could help further identify opportunities to improve DIDO times.

Effect of Fluvoxamine vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of fluvoxamine to shorten symptom duration or prevent hospitalization among outpatients with mild to moderate symptomatic COVID-19 is unclear. Objective: To evaluate the efficacy of low-dose fluvoxamine (50 mg twice daily) for 10 days compared with placebo for the treatment of mild to moderate COVID-19 in the US. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV-6) platform randomized clinical trial was designed to test repurposed medications in outpatients with mild to moderate COVID-19. A total of 1288 participants aged 30 years or older with test-confirmed SARS-CoV-2 infection and experiencing 2 or more symptoms of acute COVID-19 for 7 days or less were enrolled between August 6, 2021, and May 27, 2022, at 91 sites in the US. Interventions: Participants were randomized to receive 50 mg of fluvoxamine twice daily for 10 days or placebo. Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as the third day of 3 consecutive days without symptoms). There were 7 secondary outcomes, including a composite outcome of hospitalization, urgent care visit, emergency department visit, or death through day 28. Results: Among 1331 participants who were randomized (median age, 47 years [IQR, 38-57 years]; 57% were women; and 67% reported receiving ≥2 doses of a SARS-CoV-2 vaccine), 1288 completed the trial (674 in the fluvoxamine group and 614 in the placebo group). The median time to sustained recovery was 12 days (IQR, 11-14 days) in the fluvoxamine group and 13 days (IQR, 12-13 days) in the placebo group (hazard ratio [HR], 0.96 [95% credible interval, 0.86-1.06], posterior P = .21 for the probability of benefit [determined by an HR >1]). For the composite outcome, 26 participants (3.9%) in the fluvoxamine group were hospitalized, had an urgent care visit, had an emergency department visit, or died compared with 23 participants (3.8%) in the placebo group (HR, 1.1 [95% credible interval, 0.5-1.8], posterior P = .35 for the probability of benefit [determined by an HR <1]). One participant in the fluvoxamine group and 2 participants in the placebo group were hospitalized; no deaths occurred in either group. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with 50 mg of fluvoxamine twice daily for 10 days, compared with placebo, did not improve time to sustained recovery. These findings do not support the use of fluvoxamine at this dose and duration in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Effect of Higher-Dose Ivermectin for 6 Days vs Placebo on Time to Sustained Recovery in Outpatients With COVID-19: A Randomized Clinical Trial.

Importance: It is unknown whether ivermectin, with a maximum targeted dose of 600 µg/kg, shortens symptom duration or prevents hospitalization among outpatients with mild to moderate COVID-19. Objective: To evaluate the effectiveness of ivermectin at a maximum targeted dose of 600 µg/kg daily for 6 days, compared with placebo, for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: The ongoing Accelerating COVID-19 Therapeutic Interventions and Vaccines 6 (ACTIV-6) platform randomized clinical trial was designed to evaluate repurposed therapies among outpatients with mild to moderate COVID-19. A total of 1206 participants older than 30 years with confirmed COVID-19 experiencing at least 2 symptoms of acute infection for less than or equal to 7 days were enrolled at 93 sites in the US from February 16, 2022, through July 22, 2022, with follow-up data through November 10, 2022. Interventions: Participants were randomly assigned to receive ivermectin, with a maximum targeted dose of 600 µg/kg (n = 602) daily, or placebo (n = 604) for 6 days. Main Outcomes and Measures: The primary outcome was time to sustained recovery, defined as at least 3 consecutive days without symptoms. The 7 secondary outcomes included a composite of hospitalization, death, or urgent/emergent care utilization by day 28. Results: Among 1206 randomized participants who received study medication or placebo, the median (IQR) age was 48 (38-58) years, 713 (59.1%) were women, and 1008 (83.5%) reported receiving at least 2 SARS-CoV-2 vaccine doses. The median (IQR) time to sustained recovery was 11 (11-12) days in the ivermectin group and 11 (11-12) days in the placebo group. The hazard ratio (posterior probability of benefit) for improvement in time to recovery was 1.02 (95% credible interval, 0.92-1.13; P = .68). Among those receiving ivermectin, 34 (5.7%) were hospitalized, died, or had urgent or emergency care visits compared with 36 (6.0%) receiving placebo (hazard ratio, 1.0 [95% credible interval, 0.6-1.5]; P = .53). In the ivermectin group, 1 participant died and 4 were hospitalized (0.8%); 2 participants (0.3%) were hospitalized in the placebo group and there were no deaths. Adverse events were uncommon in both groups. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, with a maximum targeted dose of 600 µg/kg daily for 6 days, compared with placebo did not improve time to sustained recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Higher-Dose Fluvoxamine and Time to Sustained Recovery in Outpatients With COVID-19: The ACTIV-6 Randomized Clinical Trial.

Importance: The effect of higher-dose fluvoxamine in reducing symptom duration among outpatients with mild to moderate COVID-19 remains uncertain. Objective: To assess the effectiveness of fluvoxamine, 100 mg twice daily, compared with placebo, for treating mild to moderate COVID-19. Design, Setting, and Participants: The ACTIV-6 platform randomized clinical trial aims to evaluate repurposed medications for mild to moderate COVID-19. Between August 25, 2022, and January 20, 2023, a total of 1175 participants were enrolled at 103 US sites for evaluating fluvoxamine; participants were 30 years or older with confirmed SARS-CoV-2 infection and at least 2 acute COVID-19 symptoms for 7 days or less. Interventions: Participants were randomized to receive fluvoxamine, 50 mg twice daily on day 1 followed by 100 mg twice daily for 12 additional days (n = 601), or placebo (n = 607). Main Outcomes and Measures: The primary outcome was time to sustained recovery (defined as at least 3 consecutive days without symptoms). Secondary outcomes included time to death; time to hospitalization or death; a composite of hospitalization, urgent care visit, emergency department visit, or death; COVID-19 clinical progression scale score; and difference in mean time unwell. Follow-up occurred through day 28. Results: Among 1208 participants who were randomized and received the study drug, the median (IQR) age was 50 (40-60) years, 65.8% were women, 45.5% identified as Hispanic/Latino, and 76.8% reported receiving at least 2 doses of a SARS-CoV-2 vaccine. Among 589 participants who received fluvoxamine and 586 who received placebo included in the primary analysis, differences in time to sustained recovery were not observed (adjusted hazard ratio [HR], 0.99 [95% credible interval, 0.89-1.09]; P for efficacy = .40]). Additionally, unadjusted median time to sustained recovery was 10 (95% CI, 10-11) days in both the intervention and placebo groups. No deaths were reported. Thirty-five participants reported health care use events (a priori defined as death, hospitalization, or emergency department/urgent care visit): 14 in the fluvoxamine group compared with 21 in the placebo group (HR, 0.69 [95% credible interval, 0.27-1.21]; P for efficacy = .86) There were 7 serious adverse events in 6 participants (2 with fluvoxamine and 4 with placebo) but no deaths. Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with fluvoxamine does not reduce duration of COVID-19 symptoms. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

Renin-Angiotensin System Modulation With Synthetic Angiotensin (1-7) and Angiotensin II Type 1 Receptor-Biased Ligand in Adults With COVID-19: Two Randomized Clinical Trials.

Importance: Preclinical models suggest dysregulation of the renin-angiotensin system (RAS) caused by SARS-CoV-2 infection may increase the relative activity of angiotensin II compared with angiotensin (1-7) and may be an important contributor to COVID-19 pathophysiology. Objective: To evaluate the efficacy and safety of RAS modulation using 2 investigational RAS agents, TXA-127 (synthetic angiotensin [1-7]) and TRV-027 (an angiotensin II type 1 receptor-biased ligand), that are hypothesized to potentiate the action of angiotensin (1-7) and mitigate the action of the angiotensin II. Design, Setting, and Participants: Two randomized clinical trials including adults hospitalized with acute COVID-19 and new-onset hypoxemia were conducted at 35 sites in the US between July 22, 2021, and April 20, 2022; last follow-up visit: July 26, 2022. Interventions: A 0.5-mg/kg intravenous infusion of TXA-127 once daily for 5 days or placebo. A 12-mg/h continuous intravenous infusion of TRV-027 for 5 days or placebo. Main Outcomes and Measures: The primary outcome was oxygen-free days, an ordinal outcome that classifies a patient's status at day 28 based on mortality and duration of supplemental oxygen use; an adjusted odds ratio (OR) greater than 1.0 indicated superiority of the RAS agent vs placebo. A key secondary outcome was 28-day all-cause mortality. Safety outcomes included allergic reaction, new kidney replacement therapy, and hypotension. Results: Both trials met prespecified early stopping criteria for a low probability of efficacy. Of 343 patients in the TXA-127 trial (226 [65.9%] aged 31-64 years, 200 [58.3%] men, 225 [65.6%] White, and 274 [79.9%] not Hispanic), 170 received TXA-127 and 173 received placebo. Of 290 patients in the TRV-027 trial (199 [68.6%] aged 31-64 years, 168 [57.9%] men, 195 [67.2%] White, and 225 [77.6%] not Hispanic), 145 received TRV-027 and 145 received placebo. Compared with placebo, both TXA-127 (unadjusted mean difference, -2.3 [95% CrI, -4.8 to 0.2]; adjusted OR, 0.88 [95% CrI, 0.59 to 1.30]) and TRV-027 (unadjusted mean difference, -2.4 [95% CrI, -5.1 to 0.3]; adjusted OR, 0.74 [95% CrI, 0.48 to 1.13]) resulted in no difference in oxygen-free days. In the TXA-127 trial, 28-day all-cause mortality occurred in 22 of 163 patients (13.5%) in the TXA-127 group vs 22 of 166 patients (13.3%) in the placebo group (adjusted OR, 0.83 [95% CrI, 0.41 to 1.66]). In the TRV-027 trial, 28-day all-cause mortality occurred in 29 of 141 patients (20.6%) in the TRV-027 group vs 18 of 140 patients (12.9%) in the placebo group (adjusted OR, 1.52 [95% CrI, 0.75 to 3.08]). The frequency of the safety outcomes was similar with either TXA-127 or TRV-027 vs placebo. Conclusions and Relevance: In adults with severe COVID-19, RAS modulation (TXA-127 or TRV-027) did not improve oxygen-free days vs placebo. These results do not support the hypotheses that pharmacological interventions that selectively block the angiotensin II type 1 receptor or increase angiotensin (1-7) improve outcomes for patients with severe COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04924660.

Evolution of endovascular stroke centers and disparities in access to stroke care in four Northeastern states: 2015-2019.

OBJECTIVES: Disparities exist throughout our healthcare system, especially related to access to care. Advanced stroke care for strokes is only available at selected endovascular centers (ESCs) in the United States. Although the number of ESCs increase each year, this does not necessarily reflect increased access to care. Here, we look at the evolution of ESC in four states and disparities in access to advanced stroke care. MATERIALS AND METHODS: This is a descriptive study of access to ESCs in four Northeastern states between 2015-2019. Using data from the United States Census Bureau and spatial analysis, we examined the proportion of the population with drive times of less than 60 minutes stratified by income, race/ethnicity, population density, and insurance. We also calculated the mean drive time for each of these socioeconomic groups from their census tracts to the nearest ESC. RESULTS: Between 2015 and 2019, the number of ESCs increased from 15 to 48. The proportion of patients within a 60-minute drive of an ESC increased from 77% to 88%. However, only 66% of the least densely populated quartile lived within 60 min of an ESC. By income, access to ESCs in the wealthiest quartile was 96.6% compared to 83.7% in the lowest quartile. Hispanics and non-Hispanic Blacks had the largest proportions of populations within 60 minutes of an ESC while Non-Hispanic Whites had the smallest. CONCLUSIONS: This study underscores the need to evaluate the placement of new ESCs to assure that these hospitals decrease disparities and increase access to advanced stroke care.

Intensive Versus Standard Treatment of Hyperglycemia in Acute Ischemic Stroke Patient: A Randomized Clinical Trial Subgroups Analysis.

BACKGROUND: Benefit from blood glucose (BG) control during acute ischemic stroke may depend on glycemic parameters. We evaluated for associations between the SHINE (Stroke Hyperglycemia Insulin Network Effort) randomized treatment group and the SHINE predefined 90-day functional outcome, within-patient subgroups defined by various glycemic parameters. METHODS: The SHINE Trial randomized 1151 patients within 12 hours with acute ischemic stroke and hyperglycemia to standard (target BG 80-179 mg/dL) or intensive (target BG 80-130 mg/dL) BG control for 72 hours. We predefined 6 glycemic parameters: acute BG level, absence versus presence of diagnosed and undiagnosed diabetes, hemoglobin A1c, glycemic gap (acute BG-average daily hemoglobin A1c based BG), stress hyperglycemia ratio (acute BG/average daily hemoglobin A1c based BG), and BG variability (SD). Favorable functional outcome was defined by the SHINE Trial and based on the modified Rankin Scale score at 90 days, adjusted for stroke severity. We computed relative risks adjusted for baseline stroke severity and thrombolysis use. RESULTS: Likelihood for favorable outcome was lowest among patients with undiagnosed diabetes compared to patients with true nondiabetes (adjusted relative risk, 0.42 [99% CI, 0.19-0.94]). We did not find any relationship between the favorable outcome rate and baseline BG or any of the glycemic parameters. No differences between SHINE treatment groups were identified among any of these patient subgroups. CONCLUSIONS: In this exploratory subgroup analysis, intensive versus standard insulin treatment of hyperglycemia in acute ischemic stroke patient subgroups, did not influence the 90-day functional outcomes, nor did we identify associations between these glycemic parameters and 90-day functional outcomes.

Socio-demographic and trauma-related predictors of PTSD within 8 weeks of a motor vehicle collision in the AURORA study.

This is the initial report of results from the AURORA multisite longitudinal study of adverse post-traumatic neuropsychiatric sequelae (APNS) among participants seeking emergency department (ED) treatment in the aftermath of a traumatic life experience. We focus on n = 666 participants presenting to EDs following a motor vehicle collision (MVC) and examine associations of participant socio-demographic and participant-reported MVC characteristics with 8-week posttraumatic stress disorder (PTSD) adjusting for pre-MVC PTSD and mediated by peritraumatic symptoms and 2-week acute stress disorder (ASD). Peritraumatic Symptoms, ASD, and PTSD were assessed with self-report scales. Eight-week PTSD prevalence was relatively high (42.0%) and positively associated with participant sex (female), low socioeconomic status (education and income), and several self-report indicators of MVC severity. Most of these associations were entirely mediated by peritraumatic symptoms and, to a lesser degree, ASD, suggesting that the first 2 weeks after trauma may be a uniquely important time period for intervening to prevent and reduce risk of PTSD. This observation, coupled with substantial variation in the relative strength of mediating pathways across predictors, raises the possibility of diverse and potentially complex underlying biological and psychological processes that remain to be elucidated with more in-depth analyses of the rich and evolving AURORA data.

Optimizing Prehospital Stroke Systems of Care-Reacting to Changing Paradigms (OPUS-REACH): a pragmatic registry of large vessel occlusion stroke patients to create evidence-based stroke systems of care and eliminate disparities in access to stroke care.

BACKGROUND: Large vessel occlusion (LVO) strokes are best treated with rapid endovascular therapy (EVT). There are two routes that LVO stroke patients can take to EVT therapy when transported by EMS: primary transport (ambulance transports directly to an endovascular stroke center (ESC) or secondary transport (EMS transports to a non-ESC then transfers for EVT). There is no clear evidence which path to care results in better functional outcomes for LVO stroke patients. To find this answer, an analysis of a large, real-world population of LVO stroke patients must be performed. METHODS: A pragmatic registry of LVO stroke patients from nine health systems across the United States. The nine health systems span urban and rural populations as well as the spectrum of socioeconomic statuses. We will use univariate and multivariate analysis to explore the relationships between type of EMS transport, socioeconomic factors, and LVO stroke outcomes. We will use geographic information systems and spatial analysis to examine the complex movements of patients in time and space. To detect an 8% difference between groups, with a 3:1 patient ratio of primary to secondary transports, 95% confidence and 80% power, we will need approximately 1600 patients. The primary outcome is the patients with modified Rankin Scale (mRS) ≤ 2 at 90 days. Subgroup analyses include patients who receive intravenous thrombolysis and duration of stroke systems. Secondary analyses include socioeconomic factors associated with poor outcomes after LVO stroke. DISCUSSION: Using the data obtained from the OPUS-REACH registry, we will develop evidence based algorithms for prehospital transport of LVO stroke patients. Unlike prior research, the OPUS-REACH registry contains patient-level data spanning from EMS dispatch to ninety day functional outcomes. We expect that we will find modifiable factors and socioeconomic disparities associated with poor outcomes in LVO stroke. OPUS-REACH with its breadth of locations, detailed patient records, and multidisciplinary researchers will design the optimal prehospital stroke system of care for LVO stroke patients.

Examining Associations between Adverse Childhood Experiences and Posttraumatic Stress Disorder Symptoms among Young Survivors of Urban Violence.

Our study examines the association between Adverse Childhood Experience (ACE) exposure and posttraumatic stress disorder (PTSD) symptoms among survivors of violence. In this cross-sectional study, an ACE questionnaire and PTSD Checklist for DSM-5 (PCL-5) were completed by 147 participants ≤ 3 months after presenting to a Philadelphia, PA emergency department between 2014 and 2019 with a violent injury. This study treated ACEs, both separate and cumulative, as exposures and PTSD symptom severity as the outcome. Most participants (63.3%) met criteria for provisional PTSD, 90% reported experiencing ≥ 1 ACE, and 39% reported experiencing ≥ 6 ACEs. Specific ACEs were associated with increasing PCL-5 scores and increased risk for provisional PTSD. Additionally, as participants' cumulative ACE scores increased, their PCL-5 scores worsened (b = 0.16; p < 0.05), and incremental ACE score increases predicted increased odds for a positive provisional PTSD screen. Results provide further evidence that ACEs exacerbate the development of PTSD in young survivors of violence. Future research should explore targeted interventions to treat PTSD among survivors of interpersonal violence.

The LIMIT clinical decision instrument reduces neuroimaging compared to unstructured clinician judgement in recurrent seizures.

INTRODUCTION: Given the many causes of seizures, emergency physicians often utilize brain computed tomography (CT) to evaluate for intracranial pathology. Previously, we have validated the LIMIT (Let's Image Malignancy, Intracranial Hemorrhage, and Trauma) clinical decision instrument (CDI) study to determine which patients with recurrent seizures require emergent neuroimaging. The LIMIT CDI had a negative predictive value (NPV) of 99.9%. Here, we seek to compare the LIMIT CDI to unstructured physician judgement. METHODS: This was an observational study of patients who presented with a complaint of seizure. A research assistant reviewed the electronic medical record (EMR) for each patient and applied the LIMIT CDI. Brain CT was used as a proxy for physician judgement. If no brain CT was ordered and the patient was discharged from the emergency department (ED), the EMR was searched to determine whether patient had any medical visits within one year of the index visit. If the patient had no new neurological findings on follow up or abnormalities on follow up neuroimaging, this was considered a patient who did not require a brain CT in the ED. Patients who did not have a CT on their ED visit and had no follow up visits were excluded. RESULTS: 1739 patients were screened and 1108 patients were in the final analysis. 24 patients who did not have a brain CT and no follow up visits were excluded. 10 patients (0.9%) had positive CTs. 9/10 of the patients were identified by the CDI resulting in a sensitivity of 90%, specificity of 81.1% and a negative predictive value (NPV) of 99.9%, and a negative likelihood ratio (LR) of 0.12. Clinician judgement identified all 10 patients with a positive brain CT for a sensitivity of 100%, specificity of 67.8%, and a NPV and negative LR of 100% and 0, respectively. Using unstructured clinical judgement, EPs ordered 364 brain CTs while only 217 brain CTs would have been ordered using the CDI, a reduction of 13.3%. DISCUSSION: When compared to unstructured physician judgement, the LIMIT CDI would have reduced brain CT usage by more than 13%. Although the LIMIT CDI needs to be validated in a larger set of patients, it performed better than unstructured physician judgement for evaluating need for emergent neuroimaging after recurrent seizures.

Effect of Ivermectin vs Placebo on Time to Sustained Recovery in Outpatients With Mild to Moderate COVID-19: A Randomized Clinical Trial.

Importance: The effectiveness of ivermectin to shorten symptom duration or prevent hospitalization among outpatients in the US with mild to moderate symptomatic COVID-19 is unknown. Objective: To evaluate the efficacy of ivermectin, 400 µg/kg, daily for 3 days compared with placebo for the treatment of early mild to moderate COVID-19. Design, Setting, and Participants: ACTIV-6, an ongoing, decentralized, double-blind, randomized, placebo-controlled platform trial, was designed to evaluate repurposed therapies in outpatients with mild to moderate COVID-19. A total of 1591 participants aged 30 years and older with confirmed COVID-19, experiencing 2 or more symptoms of acute infection for 7 days or less, were enrolled from June 23, 2021, through February 4, 2022, with follow-up data through May 31, 2022, at 93 sites in the US. Interventions: Participants were randomized to receive ivermectin, 400 µg/kg (n = 817), daily for 3 days or placebo (n = 774). Main Outcomes and Measures: Time to sustained recovery, defined as at least 3 consecutive days without symptoms. There were 7 secondary outcomes, including a composite of hospitalization or death by day 28. Results: Among 1800 participants who were randomized (mean [SD] age, 48 [12] years; 932 women [58.6%]; 753 [47.3%] reported receiving at least 2 doses of a SARS-CoV-2 vaccine), 1591 completed the trial. The hazard ratio (HR) for improvement in time to recovery was 1.07 (95% credible interval [CrI], 0.96-1.17; posterior P value [HR >1] = .91). The median time to recovery was 12 days (IQR, 11-13) in the ivermectin group and 13 days (IQR, 12-14) in the placebo group. There were 10 hospitalizations or deaths in the ivermectin group and 9 in the placebo group (1.2% vs 1.2%; HR, 1.1 [95% CrI, 0.4-2.6]). The most common serious adverse events were COVID-19 pneumonia (ivermectin [n = 5]; placebo [n = 7]) and venous thromboembolism (ivermectin [n = 1]; placebo [n = 5]). Conclusions and Relevance: Among outpatients with mild to moderate COVID-19, treatment with ivermectin, compared with placebo, did not significantly improve time to recovery. These findings do not support the use of ivermectin in patients with mild to moderate COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04885530.

The AURORA Study: a longitudinal, multimodal library of brain biology and function after traumatic stress exposure.

Adverse posttraumatic neuropsychiatric sequelae (APNS) are common among civilian trauma survivors and military veterans. These APNS, as traditionally classified, include posttraumatic stress, postconcussion syndrome, depression, and regional or widespread pain. Traditional classifications have come to hamper scientific progress because they artificially fragment APNS into siloed, syndromic diagnoses unmoored to discrete components of brain functioning and studied in isolation. These limitations in classification and ontology slow the discovery of pathophysiologic mechanisms, biobehavioral markers, risk prediction tools, and preventive/treatment interventions. Progress in overcoming these limitations has been challenging because such progress would require studies that both evaluate a broad spectrum of posttraumatic sequelae (to overcome fragmentation) and also perform in-depth biobehavioral evaluation (to index sequelae to domains of brain function). This article summarizes the methods of the Advancing Understanding of RecOvery afteR traumA (AURORA) Study. AURORA conducts a large-scale (n = 5000 target sample) in-depth assessment of APNS development using a state-of-the-art battery of self-report, neurocognitive, physiologic, digital phenotyping, psychophysical, neuroimaging, and genomic assessments, beginning in the early aftermath of trauma and continuing for 1 year. The goals of AURORA are to achieve improved phenotypes, prediction tools, and understanding of molecular mechanisms to inform the future development and testing of preventive and treatment interventions.

Impact of a shelter-in-place order during the COVID-19 pandemic on the incidence of opioid overdoses.

INTRODUCTION: Since the beginning of the novel coronavirus (COVID-19) pandemic in the United States, there have been concerns about the potential impact of the pandemic on persons with opioid use disorder. Shelter-in-place (SIP) orders, which aimed to reduce the spread and scope of the virus, likely also impacted this patient population. This study aims to assess the role of the COVID-19 pandemic on the incidence of opioid overdose before and after a SIP order. METHODS: A retrospective review of the incidence of opioid overdoses in an urban three-hospital system was conducted. Comparisons were made between the first 100 days of a city-wide SIP order during the COVID-19 pandemic and the 100 days during the COVID-19 pandemic preceding the SIP order (Pre-SIP). Differences in observed incidence and expected incidence during the SIP period were evaluated using a Fisher's Exact test. RESULTS: Total patient visits decreased 22% from 46,078 during the Pre-SIP period to 35,971 during the SIP period. A total of 1551 opioid overdoses were evaluated during the SIP period, compared to 1665 opioid overdoses during the Pre-SIP period, consistent with a 6.8% decline. A Fisher's Exact Test demonstrated a p < 0.0001, with a corresponding Odds Ratio of 1.20 with a 95% confidence interval (1.12;1.29). CONCLUSION: The COVID-19 pandemic and the associated SIP order were associated with a statistically and clinically significant increase in the proportion of opioid overdoses in relation to the overall change in total ED visits.

Evaluating the utility of Rapid Response EEG in emergency care.

BACKGROUND: Timely management of non-convulsive status epilepticus (NCSE) is critical to improving patient outcomes. However, NCSE can only be confirmed using electroencephalography (EEG), which is either significantly delayed or entirely unavailable in emergency departments (EDs). We piloted the use of a new bedside EEG device, Rapid Response EEG (Rapid-EEG, Ceribell), in the ED and evaluated its impact on seizure management when used by emergency physicians. METHODS: Patients who underwent Rapid-EEG to rule out NCSE were prospectively enrolled in a pilot project conducted at two ED sites (an academic hospital and a community hospital). Physicians were surveyed on the perceived impact of the device on seizure treatment and patient disposition, and we calculated physicians' sensitivity and specificity (with 95% CI) for diagnosing NCSE using Rapid-EEG's Brain Stethoscope function. RESULTS: Of the 38 patients enrolled, the one patient with NCSE was successfully diagnosed and treated within minutes of evaluation. Physicians reported that Rapid-EEG changed clinical management for 20 patients (53%, 95% CI 37% to 68%), primarily by ruling out seizures and avoiding antiseizure treatment escalation, and expedited disposition for 8 patients (21%, 95% CI 11% to 36%). At the community site, physicians diagnosed seizures by their sound using Brain Stethoscope with 100% sensitivity (95% CI 5% to 100%) and 92% specificity (95% CI 62% to 100%). CONCLUSION: Rapid-EEG was successfully deployed by emergency physicians at academic and community hospitals, and the device changed management in a majority of cases. Widespread adoption of Rapid-EEG may lead to earlier diagnosis of NCSE, reduced unnecessary treatment and expedited disposition of seizure mimics.

Changes in Procoagulant Blood Biomarkers After Mechanical Thrombectomy.

OBJECTIVES: There is limited knowledge of the relationship between mechanical thrombectomy (MT) and endothelial inflammation in large-vessel occlusion (LVO) acute ischemic stroke (AIS). Intimal arterial damage releases tissue factor, a precipitant of the clotting cascade and thrombosis. We report changes in blood coagulation markers after MT treated with and without tissue plasminogen activator for AIS. MATERIALS AND METHODS: Cases of LVO-AIS treated with MT were included. Blood coagulation marker levels were measured within 10 h of stroke onset as a baseline and then 48 h later. Assayed biomarkers included: tissue factor procoagulant activity (TFPCA), factor VII (FVII), activated factor VII (FVIIa), factor VIII (FVIII), d-dimer, thrombin-antithrombin complex (TAT), plasminogen activator inhibitor-1 (PAI-1), and tissue factor pathway inhibitor (TFPI). Biomarker levels of MT with tissue plasminogen activator (TPA) or without (non-TPA) are reported. RESULTS: Biomarker levels from five patients with LVO-AIS treated with MT (three non-TPA, two TPA) were included. In non-TPA cases, TFPCA and PAI-1 increased while FVII, FVIIa, TAT, d-dimer, and TFPI decreased from baseline to 48 h. In TPA cases, TFPCA, FVIIa, d-dimer, TFPI, and PAI-1 decreased while FVIII increased from baseline to 48 h. CONCLUSIONS: TFPCA increased after MT in non-TPA but decreased in TPA treated patients. This finding suggests that MT is associated with elevated inflammation and procoagulation which may be reduced with TPA treatment. With further validation, the increase in TFPCA levels could help guide anticoagulant management of patients with MT without TPA.

Efficacy of Clopidogrel for Prevention of Stroke Based on CYP2C19 Allele Status in the POINT Trial.

BACKGROUND AND PURPOSE: Clopidogrel is an antiplatelet drug that is metabolized to its active form by the CYP2C19 enzyme. The CHANCE trial (Clopidogrel in High-Risk Patients With Acute Nondisabling Cerebrovascular Events) found a significant interaction between loss-of-function allele status for the CYP2C19 gene and the effect of dual antiplatelet therapy with aspirin and clopidogrel on the rate of early recurrent stroke following acute transient ischemic attack/minor stroke. The POINT (Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke Trial), similar in design to CHANCE but performed largely in North America and Europe, demonstrated a reduction in early recurrent stroke with dual antiplatelet therapy compared with aspirin alone. This substudy was done to evaluate a potential interaction between loss-of-function CYP2C19 alleles and outcome by treatment group in POINT. METHODS: Of the 269 sites in 10 countries that enrolled patients in POINT, 134 sites participated in this substudy. DNA samples were genotyped for CYP2C19 *2, *3, and *17 alleles and classified as being carriers or noncarriers of loss-of-function alleles. Major ischemia consisted of ischemic stroke, myocardial infarction, or ischemic vascular death. RESULTS: Nine hundred thirty-two patients provided analyzable DNA. The rates of major ischemia were 6.7% for the aspirin group versus 2.3% for the dual antiplatelet therapy group (hazard ratio, 0.33 [95% CI, 0.09-1.21]; P=0.09) among carriers of loss-of-function allele. The rates of major ischemia were 5.6% for the aspirin group versus 3.7% for the dual antiplatelet therapy group (hazard ratio, 0.65 [95% CI, 0.32-1.34]; P=0.25) among noncarriers. There was no significant interaction by genotype for major ischemia (P=0.36) or stroke (P=0.33). CONCLUSIONS: This substudy of POINT found no significant interaction with CYP2C19 loss-of-function carrier status and outcome by treatment group. Failure to confirm the findings from the CHANCE trial may be because the loss-of-function alleles tested are not clinically important in this context or because the 2 trials had differences in racial/ethnic composition. Additionally, differences between the 2 trials might be due to chance as our statistical power was limited to 50%. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00991029.

Derivation of a clinical decision instrument to identify patients with status epilepticus who require emergent brain CT.

BACKGROUND: Studies have shown the value of CT brain imaging in adults with first-time seizures, but there are no recommendations regarding emergent brain CTs in persons with an established seizure disorders. Our study aimed to derive a clinical decision instrument (CDI) to determine which patients with status epilepticus (SE) require emergent brain imaging. METHODS: This was a retrospective chart review of patients who presented to our emergency department with SE between 2010 and 2018. Patients with first-time seizures were excluded. A priori, we defined high risk criteria for emergent imaging as well as positive findings on brain CT. High risk criteria included known malignancy, trauma, and immunosuppression. Positive CT scans included findings such as intracranial hemorrhage (ICH) and mass. RESULTS: We identified 214 patients who met inclusion criteria Of the 181 patients without high risk criteria, 3% had positive CT scans. Of the 33 patients with high risk criteria, 10% had positive CT scans. The sensitivity, specificity, PPV, and NPV for our initial CDI were 38%, 85%, 9%, and 97%. Adding the criterion of prior ICH would have lowered our miss rate to 0.6%. Modifying our CDI to 1) History of ICH, 2) Malignancy, 3) Immunosuppression, and 4) Trauma would result in a CDI with sensitivity, specificity, PPV, and NPV of 87.5%, 87.4%, 21.2%, and 99.5%. CONCLUSIONS: By using four criteria to identify high risk patients, we can defer CT scanning in the vast majority of patients with SE and known seizure disorders. This CDI should be prospectively validated before adoption.