Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage.

BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.).

Association of Active Renin Content With Mortality in Critically Ill Patients: A Post hoc Analysis of the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) Trial.

OBJECTIVE: Sepsis is a leading cause of mortality. Predicting outcomes is challenging and few biomarkers perform well. Defects in the renin-angiotensin system (RAS) can predict clinical outcomes in sepsis and may outperform traditional biomarkers. We postulated that RAS dysfunction (elevated active renin, angiotensin 1-7 [Ang-(1-7)], and angiotensin-converting enzyme 2 (ACE2) activity with depressed Ang-II and ACE activity) would be associated with mortality in a cohort of septic patients. DESIGN: Post hoc analysis of patients enrolled in the Vitamin C, Thiamine, and Steroids in Sepsis (VICTAS) randomized controlled trial. SETTING: Forty-three hospitals across the United States. PATIENTS: Biorepository samples of 103 patients. INTERVENTIONS: We analyzed day 0 (within 24 hr of respiratory failure, septic shock, or both) and day 3 samples ( n = 103 and 95, respectively) for assessment of the RAS. The association of RAS values with 30-day mortality was determined using Cox proportional hazards regression with multivariable adjustments for age, sex, VICTAS treatment arm, systolic blood pressure, Sequential Organ Failure Assessment Score, and vasopressor use. MEASUREMENTS AND MAIN RESULTS: High baseline active renin values were associated with higher 30-day mortality when dichotomized to the median of 188.7 pg/mL (hazard ratio [HR] = 2.84 [95% CI, 1.10-7.33], p = 0.031) or stratified into quartiles (Q1 = ref, HR Q2 = 2.01 [0.37-11.04], HR Q3 = 3.22 [0.64-16.28], HR Q4 = 5.58 [1.18-26.32], p for linear trend = 0.023). A 1- sd (593.6 pg/mL) increase in renin from day 0 to day 3 was associated with increased mortality (HR = 3.75 [95% CI, 1.94-7.22], p < 0.001), and patients whose renin decreased had improved survival compared with those whose renin increased (HR 0.22 [95% CI, 0.08-0.60], p = 0.003). Ang-(1-7), ACE2 activity, Ang-II and ACE activity did not show this association. Mortality was attenuated in patients with renin over the median on day 0 who received the VICTAS intervention, but not on day 3 ( p interaction 0.020 and 0.137, respectively). There were no additional consistent patterns of mortality on the RAS from the VICTAS intervention. CONCLUSIONS: Baseline serum active renin levels were strongly associated with mortality in critically ill patients with sepsis. Furthermore, a greater relative activation in circulating renin from day 0 to day 3 was associated with a higher risk of death.

The Increasing Burden of Emergency Department and Inpatient Consultations for "Papilledema".

BACKGROUND: Increasing incidence of idiopathic intracranial hypertension (IIH), overreported radiologic signs of intracranial hypertension, difficult access to outpatient neuro-ophthalmology services, poor insurance coverage, and medicolegal concerns have lowered the threshold for emergency department (ED) visits for "papilledema." Our objective was to examine referral patterns and outcomes of neuro-ophthalmology ED and inpatient consultations for concern for papilledema. METHODS: At one university-based quaternary care center, all adults referred for "papilledema" over one year underwent a standardized ED "papilledema protocol." We collected patient demographics, final diagnoses, and referral patterns. RESULTS: Over 1 year, 153 consecutive patients were referred for concern for papilledema. After papilledema protocol, 89 of 153 patients (58%) had bilateral optic disc edema, among whom 89% (79/89) had papilledema (intracranial hypertension). Of the 38 of 153 (25%) consultations for suspected disorder of intracranial pressure without previous fundus examination (Group 1), 74% (28/38) did not have optic disc edema, 21% (8/38) had papilledema, and 5% (2/38) had other causes of bilateral disc edema. Of the 89 of 153 (58%) consultations for presumed papilledema seen on fundus examination (Group 2), 58% (66/89) had confirmed papilledema, 17% (15/89) had pseudopapilledema, and 9% (8/89) had other causes of bilateral optic disc edema. Of the 26 of 153 (17%) patients with known IIH (Group 3), 5 had papilledema and 4 required urgent intervention. The most common diagnosis was IIH (58/79). Compared with IIH, patients with secondary causes of intracranial hypertension were older (P = 0.002), men (P < 0.001), not obese (P < 0.001), and more likely to have neurologic symptoms (P = 0.002). CONCLUSION: Inpatient and ED consultations for "papilledema" are increasing. Of the 153 ED and inpatient neuro-ophthalmology consultations seen for "papilledema" over 1 year, one-third of patients with optic disc edema of unknown cause before presentation to our ED had new vision- or life-threatening disease, supporting the need for prompt identification and evaluation of optic disc edema in the ED. In the face of limited access to neuro-ophthalmologists, this study supports the need for emergency department access to expert eye-care evaluation or ocular fundus camera for prompt identification of optic disc edema and standardized evaluation for neurologic emergencies.

Neuro-ophthalmology Emergency Department and Inpatient Consultations at a Large Academic Referral Center.

PURPOSE: Prompt neuro-ophthalmology consultation prevents diagnostic errors and improves patient outcomes. The scarcity of neuro-ophthalmologists means that the increasing outpatient demand cannot be met, prompting many emergency department (ED) referrals by non-neuro-ophthalmologists. We describe our quaternary care institution's ED and inpatient neuro-ophthalmology consultation patterns and patient outcomes. DESIGN: Prospective observational study. PARTICIPANTS: Consecutive neuro-ophthalmology ED and inpatient consultation requests over 1 year. METHODS: We collected patient demographics, distance traveled, insurance status, referring provider details, consultation question, final diagnosis, complexity of consultation, time of consultation, and need for outpatient follow-up. MAIN OUTCOME MEASURES: Consultation patterns and diagnoses, complexity, and follow-up. RESULTS: Of 494 consecutive adult ED and inpatient neuro-ophthalmology consultations requested over 1 year, 241 of 494 consultations (49%) occurred at night or during weekends. Of ED consultations (322 of 494 [65%]), 127 of 322 consultations (39%) occurred during weekdays, 126 of 322 consultations (39%) occurred on weeknights, and 69 of 322 consultations (22%) occurred on weekends or holidays. Of 322 ED consultations, 225 of 322 consultations (70%) were patients who initially sought treatment in the ED with a neuro-ophthalmic chief symptom. Of the 196 patients sent to the ED by a health care professional, 148 patients (148/196 [76%]) were referred by eye care specialists (74 optometrists and 74 ophthalmologists). The most common ED referral questions were for papilledema (75 of 322 [23%]) and vision loss (72 of 322 [22%]). A total of 219 of 322 patients (68%) received a final active neuro-ophthalmic diagnosis, 222 of 322 patients (69%) were cases of high or very high complexity, and 143 of 322 patients (44%) required admission. Inpatient consultations (n = 172) were requested most frequently by hospitalists, including neurologists (71 of 172 [41%]) and oncologists (20 of 172 [12%]) for vision loss (43 of 172 [25%]) and eye movement disorders (36 of 172 [21%]) and by neurosurgeons (58 of 172 [33%]) for examination for mass or a preoperative evaluation (19 of 172 [11%]). An active neuro-ophthalmic diagnosis was confirmed in 67% of patients (116 of 172). Outpatient neuro-ophthalmology follow-up was required for 291 of 494 patients (59%). CONCLUSIONS: Neuro-ophthalmology consultations are critical to the diagnosis and management in the hospital setting. In the face of a critical shortage of neuro-ophthalmologists, this study highlights the need for technological and diagnostic aids for greater outpatient access. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Ensemble Simulations and Experimental Free Energy Distributions: Evaluation and Characterization of Isoxazole Amides as SMYD3 Inhibitors.

Optimization of binding affinities for ligands to their target protein is a primary objective in rational drug discovery. Herein, we report on a collaborative study that evaluates various compounds designed to bind to the SET and MYND domain-containing protein 3 (SMYD3). SMYD3 is a histone methyltransferase and plays an important role in transcriptional regulation in cell proliferation, cell cycle, and human carcinogenesis. Experimental measurements using the scintillation proximity assay show that the distributions of binding free energies from a large number of independent measurements exhibit non-normal properties. We use ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) and TIES (thermodynamic integration with enhanced sampling) protocols to predict the binding free energies and to provide a detailed chemical insight into the nature of ligand-protein binding. Our results show that the 1-trajectory ESMACS protocol works well for the set of ligands studied here. Although one unexplained outlier exists, we obtain excellent statistical ranking across the set of compounds from the ESMACS protocol and good agreement between calculations and experiments for the relative binding free energies from the TIES protocol. ESMACS and TIES are again found to be powerful protocols for the accurate comparison of the binding free energies.

A Wearable Multimodal Sensing System for Tracking Changes in Pulmonary Fluid Status, Lung Sounds, and Respiratory Markers.

Heart failure (HF) exacerbations, characterized by pulmonary congestion and breathlessness, require frequent hospitalizations, often resulting in poor outcomes. Current methods for tracking lung fluid and respiratory distress are unable to produce continuous, holistic measures of cardiopulmonary health. We present a multimodal sensing system that captures bioimpedance spectroscopy (BIS), multi-channel lung sounds from four contact microphones, multi-frequency impedance pneumography (IP), temperature, and kinematics to track changes in cardiopulmonary status. We first validated the system on healthy subjects (n = 10) and then conducted a feasibility study on patients (n = 14) with HF in clinical settings. Three measurements were taken throughout the course of hospitalization, and parameters relevant to lung fluid status-the ratio of the resistances at 5 kHz to those at 150 kHz (K)-and respiratory timings (e.g., respiratory rate) were extracted. We found a statistically significant increase in K (p < 0.05) from admission to discharge and observed respiratory timings in physiologically plausible ranges. The IP-derived respiratory signals and lung sounds were sensitive enough to detect abnormal respiratory patterns (Cheyne-Stokes) and inspiratory crackles from patient recordings, respectively. We demonstrated that the proposed system is suitable for detecting changes in pulmonary fluid status and capturing high-quality respiratory signals and lung sounds in a clinical setting.

Predictors at Admission of Mechanical Ventilation and Death in an Observational Cohort of Adults Hospitalized With Coronavirus Disease 2019.

BACKGROUND: Coronavirus disease (COVID-19) can cause severe illness and death. Predictors of poor outcome collected on hospital admission may inform clinical and public health decisions. METHODS: We conducted a retrospective observational cohort investigation of 297 adults admitted to 8 academic and community hospitals in Georgia, United States, during March 2020. Using standardized medical record abstraction, we collected data on predictors including admission demographics, underlying medical conditions, outpatient antihypertensive medications, recorded symptoms, vital signs, radiographic findings, and laboratory values. We used random forest models to calculate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for predictors of invasive mechanical ventilation (IMV) and death. RESULTS: Compared with age <45 years, ages 65-74 years and ≥75 years were predictors of IMV (aORs, 3.12 [95% CI, 1.47-6.60] and 2.79 [95% CI, 1.23-6.33], respectively) and the strongest predictors for death (aORs, 12.92 [95% CI, 3.26-51.25] and 18.06 [95% CI, 4.43-73.63], respectively). Comorbidities associated with death (aORs, 2.4-3.8; P < .05) included end-stage renal disease, coronary artery disease, and neurologic disorders, but not pulmonary disease, immunocompromise, or hypertension. Prehospital use vs nonuse of angiotensin receptor blockers (aOR, 2.02 [95% CI, 1.03-3.96]) and dihydropyridine calcium channel blockers (aOR, 1.91 [95% CI, 1.03-3.55]) were associated with death. CONCLUSIONS: After adjustment for patient and clinical characteristics, older age was the strongest predictor of death, exceeding comorbidities, abnormal vital signs, and laboratory test abnormalities. That coronary artery disease, but not chronic lung disease, was associated with death among hospitalized patients warrants further investigation, as do associations between certain antihypertensive medications and death.

An antibody-free dual-biomarker rapid enrichment workflow (AnDREW) improves the sensitivity of malaria rapid diagnostic tests.

Rapid diagnostic tests (RDTs) are critical to the success of malaria elimination campaigns. These tests are rapid, user-friendly, and field-deployable to resource-limited regions. However, RDTs demonstrate poor sensitivity because they can only tolerate a small (5 µL) volume of blood, which limits the amount of protein biomarker delivered to the test. We have developed the Antibody-free Dual-biomarker Rapid Enrichment Workflow (AnDREW) for purifying histidine-rich protein 2 (HRP2) and Plasmodium lactate dehydrogenase (PLDH) from large volume (150 µL) blood samples. We used Zn(II)NTA and aptamer-conjugated magnetic beads to capture HRP2 and PLDH, respectively. Both biomarkers were then eluted into RDT-compatible volumes using ethylene diamine tetraacetic acid (EDTA). We optimized both bead conjugates individually by enzyme-linked immunosorbent assays (ELISAs) and then combined the optimized capture and elution assays for both biomarkers to produce the AnDREW. The AnDREW-enhanced RDTs exhibited a 11-fold and 9-fold improvement in analytical sensitivity for detection of HRP2 and PLDH, respectively, when compared to unenhanced RDTs. Moreover, the limit of detection for PLDH was improved 11-fold for the AnDREW-enhanced RDTs (3.80 parasites/µL) compared to unenhanced RDTs (42.31 parasites/µL). Importantly, the AnDREW utilizes a pan-specific PLDH aptamer and improves upon existing methods by eluting both biomarkers without complexed antibodies.

The cyanobacterial lectin, microvirin-N, enhances the specificity and sensitivity of lipoarabinomannan-based TB diagnostic tests.

Tuberculosis (TB) is one of the top ten causes of death globally, despite being treatable. The eradication of TB disease requires, amongst others, diagnostic tests with high specificity and sensitivity that will work at the point of care (POC) in low-resource settings. The TB surface glycolipid antigen, mannose-capped lipoarabinomannan (ManLAM) currently serves as the only POC molecular diagnostic biomarker suitable for use in low cost immunoassays. Here, we demonstrate the high affinity and exceptional specificity of microvirin-N (MVN), a 14.3 kDa cyanobacterial lectin, toward H37Rv TB ManLAM and utilize it to develop a novel on-bead ELISA. MVN binds to ManLAM with sub-picomolar binding affinity, but does not bind to other variants of LAM expressed by non-pathogenic mycobacteria - a level of binding specificity and affinity that current commercially available anti-LAM antibodies cannot achieve. An on-bead ELISA was subsequently developed using MVN-functionalized magnetic beads which allows for the specific capture of ManLAM from human urine with a limit of detection (LOD) of 1.14 ng mL-1 and no cross-reactivity when tested with PILAM, a variant of LAM found on non-pathogenic mycobacteria.

Inorganic Complexes and Metal-Based Nanomaterials for Infectious Disease Diagnostics.

Infectious diseases claim millions of lives each year. Robust and accurate diagnostics are essential tools for identifying those who are at risk and in need of treatment in low-resource settings. Inorganic complexes and metal-based nanomaterials continue to drive the development of diagnostic platforms and strategies that enable infectious disease detection in low-resource settings. In this review, we highlight works from the past 20 years in which inorganic chemistry and nanotechnology were implemented in each of the core components that make up a diagnostic test. First, we present how inorganic biomarkers and their properties are leveraged for infectious disease detection. In the following section, we detail metal-based technologies that have been employed for sample preparation and biomarker isolation from sample matrices. We then describe how inorganic- and nanomaterial-based probes have been utilized in point-of-care diagnostics for signal generation. The following section discusses instrumentation for signal readout in resource-limited settings. Next, we highlight the detection of nucleic acids at the point of care as an emerging application of inorganic chemistry. Lastly, we consider the challenges that remain for translation of the aforementioned diagnostic platforms to low-resource settings.

Regional Variations in Rehabilitation Outcomes of Adult Patients With Traumatic Brain Injury: A Uniform Data System for Medical Rehabilitation Investigation.

OBJECTIVES: To examine regional differences in rehabilitation outcomes among adult patients with moderate-to-severe traumatic brain injury (TBI) who received care at an inpatient rehabilitation facility (IRF). DESIGN: We conducted a secondary analysis of a large, multi-center dataset from the Uniform Data System for Medical Rehabilitation. SETTING: More than 70% of all IRFs in the United States. PARTICIPANTS: Adult TBI patients (N=175,358) aged 18 years or older who were admitted and discharged from an IRF in the United States between 2004 and 2014. Qualifying etiology included traumatic brain dysfunction Impairment Group codes 02.21 (traumatic, open injury) and 02.22 (traumatic, closed injury). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Discharge functional status (total, cognitive, motor), length of stay, and discharge to home. RESULTS: Patient and clinical characteristics varied significantly by geographic location, as did median functional status, length of stay, and percentage of patients discharged home. The region where IRF care was received, race and ethnicity, age, occurrence of 1 or more falls during the IRF stay, case mix group, and insurance status were associated with discharge functional status, length of stay, and discharge to home. CONCLUSIONS: Our findings provide evidence of geographic differences in outcomes and potential disparities in care of TBI patients who received IRF care. More research is needed to identify TBI patients at risk for poor discharge outcomes to inform development and testing of interventions to reduce disparities in outcomes for these patients.

A prospective cross-sectional study examining the documented evaluation of patients at high risk for mild traumatic brain injury.

OBJECTIVES: Annually, the CDC reports that 2.5 million Emergency Department (ED) visits occur due to Traumatic Brain Injuries (TBI) with nearly 75% classified as mild TBI (mTBI). Generally, these injuries are thought to be under recognized. This study was done to determine the proportion of patients, who were considered high risk for an mTBI, that had documentation of an mTBI evaluation. METHODS: A prospective cross-section of patients was identified using a 3-question screen at the time of triage: did an injury occur; was the mechanism consistent with mTBI; and was there a period of altered mental status. Chart review was completed for these patients who were thought to meet a minimum threshold warranting an evaluation for mTBI. RESULTS: 38,621 patients were screened over 16 weeks, of whom 441 (1.14%) were identified as being high risk for having an mTBI and met inclusion criteria. Recommended portions of an mTBI evaluation occurred in fewer than 50% of patients. In total, 98 subjects were diagnosed with an mTBI, and 49 received mTBI discharge instructions. The odds ratio for the subgroup of patients who had documented criteria sufficient for diagnosis revealed that an isolated head injury increased a patient's odds of a documented diagnosis by 2.1 times (95%, 1.3-3.4). CONCLUSIONS: Many patients with a possible mTBI did not have significant portions of an mTBI evaluation documented, and roughly half of the patients with a documented mTBI diagnosis did not receive discharge education. Changes in clinicians' approach to mTBI must occur to ensure patients receive appropriate evaluations, management, and education.

Effect of Vitamin C, Thiamine, and Hydrocortisone on Ventilator- and Vasopressor-Free Days in Patients With Sepsis: The VICTAS Randomized Clinical Trial.

Importance: Sepsis is a common syndrome with substantial morbidity and mortality. A combination of vitamin C, thiamine, and corticosteroids has been proposed as a potential treatment for patients with sepsis. Objective: To determine whether a combination of vitamin C, thiamine, and hydrocortisone every 6 hours increases ventilator- and vasopressor-free days compared with placebo in patients with sepsis. Design, Setting, and Participants: Multicenter, randomized, double-blind, adaptive-sample-size, placebo-controlled trial conducted in adult patients with sepsis-induced respiratory and/or cardiovascular dysfunction. Participants were enrolled in the emergency departments or intensive care units at 43 hospitals in the United States between August 2018 and July 2019. After enrollment of 501 participants, funding was withheld, leading to an administrative termination of the trial. All study-related follow-up was completed by January 2020. Interventions: Participants were randomized to receive intravenous vitamin C (1.5 g), thiamine (100 mg), and hydrocortisone (50 mg) every 6 hours (n = 252) or matching placebo (n = 249) for 96 hours or until discharge from the intensive care unit or death. Participants could be treated with open-label corticosteroids by the clinical team, with study hydrocortisone or matching placebo withheld if the total daily dose was greater or equal to the equivalent of 200 mg of hydrocortisone. Main Outcomes and Measures: The primary outcome was the number of consecutive ventilator- and vasopressor-free days in the first 30 days following the day of randomization. The key secondary outcome was 30-day mortality. Results: Among 501 participants randomized (median age, 62 [interquartile range {IQR}, 50-70] years; 46% female; 30% Black; median Acute Physiology and Chronic Health Evaluation II score, 27 [IQR, 20.8-33.0]; median Sequential Organ Failure Assessment score, 9 [IQR, 7-12]), all completed the trial. Open-label corticosteroids were prescribed to 33% and 32% of the intervention and control groups, respectively. Ventilator- and vasopressor-free days were a median of 25 days (IQR, 0-29 days) in the intervention group and 26 days (IQR, 0-28 days) in the placebo group, with a median difference of -1 day (95% CI, -4 to 2 days; P = .85). Thirty-day mortality was 22% in the intervention group and 24% in the placebo group. Conclusions and Relevance: Among critically ill patients with sepsis, treatment with vitamin C, thiamine, and hydrocortisone, compared with placebo, did not significantly increase ventilator- and vasopressor-free days within 30 days. However, the trial was terminated early for administrative reasons and may have been underpowered to detect a clinically important difference. Trial Registration: ClinicalTrials.gov Identifier: NCT03509350.

Characteristics and Clinical Outcomes of Adult Patients Hospitalized with COVID-19 - Georgia, March 2020.

SARS-CoV-2, the novel coronavirus that causes coronavirus disease 2019 (COVID-19), was first detected in the United States during January 2020 (1). Since then, >980,000 cases have been reported in the United States, including >55,000 associated deaths as of April 28, 2020 (2). Detailed data on demographic characteristics, underlying medical conditions, and clinical outcomes for persons hospitalized with COVID-19 are needed to inform prevention strategies and community-specific intervention messages. For this report, CDC, the Georgia Department of Public Health, and eight Georgia hospitals (seven in metropolitan Atlanta and one in southern Georgia) summarized medical record-abstracted data for hospitalized adult patients with laboratory-confirmed* COVID-19 who were admitted during March 2020. Among 305 hospitalized patients with COVID-19, 61.6% were aged <65 years, 50.5% were female, and 83.2% with known race/ethnicity were non-Hispanic black (black). Over a quarter of patients (26.2%) did not have conditions thought to put them at higher risk for severe disease, including being aged ≥65 years. The proportion of hospitalized patients who were black was higher than expected based on overall hospital admissions. In an adjusted time-to-event analysis, black patients were not more likely than were nonblack patients to receive invasive mechanical ventilation† (IMV) or to die during hospitalization (hazard ratio [HR] = 0.63; 95% confidence interval [CI] = 0.35-1.13). Given the overrepresentation of black patients within this hospitalized cohort, it is important for public health officials to ensure that prevention activities prioritize communities and racial/ethnic groups most affected by COVID-19. Clinicians and public officials should be aware that all adults, regardless of underlying conditions or age, are at risk for serious illness from COVID-19.

Concussion Care in the Emergency Department: A Prospective Observational Brief Report.

STUDY OBJECTIVE: Emergency physicians are often the initial-and only-clinical providers for patients who have sustained a mild traumatic brain injury. This prospective observational study seeks to examine the practice patterns of clinicians in an academic Level I trauma center as they relate to the evaluation of patients who were presumed to be at high risk for mild traumatic brain injury. Specifically, we describe the frequency of a documented mild traumatic brain injury evaluation, diagnosis, and discharge education. METHODS: This pilot study took place in a single academic Level I trauma and emergency care center during a 4-week period. Patients were identified by triage nurses, who determined whether they responded affirmatively to 2 questions that indicated a potential risk for mild traumatic brain injury. Data were abstracted from emergency department clinician documentation on identified patients to describe the frequency of a documented mild traumatic brain injury evaluation (history and physical examination), diagnosis, and discharge education among those who were identified to be at risk for a mild traumatic brain injury. RESULTS: Ninety-eight subjects were included in the present study. Documentation of a mild traumatic brain injury evaluation was present for less than 50% of patients, a final diagnosis of mild traumatic brain injury was included for 36 (37%; 95% confidence interval 27.8% to 46.7%), and discharge education was provided to 15 (15%; 95% confidence interval 9.2% to 21.4%). Of the 36 patients who received a documented mild traumatic brain injury diagnosis, 15 (41.5%; 95% confidence interval 26.7% to 57.9%) received mild traumatic brain injury-specific discharge education. CONCLUSION: This study suggests that the majority of patients at high risk for mild traumatic brain injury have no documentation of an evaluation for one. Also, patients with a mild traumatic brain injury diagnosis were unlikely to receive appropriate discharge education about it. Education and standardization are needed to ensure that patients at risk for mild traumatic brain injury receive appropriate evaluation and care.

Patient and Surrogate Postenrollment Perspectives on Research Using the Exception From Informed Consent: An Integrated Survey.

STUDY OBJECTIVE: It is important for researchers interested in trials using the exception from informed consent to understand the views and experiences of enrolled individuals. Previous studies have shown that patient and surrogate attitudes are generally positive. These studies were small and did not include pediatric patients, and interviews were often conducted long after trial enrollment. This study sought to explore attitudes toward exception from informed consent in a larger sample and more contemporaneous setting. METHODS: A 10-item paper-and-pencil survey was integrated into the Established Status Epilepticus Treatment Trial, a randomized trial of 3 treatments for benzodiazepine-refractory status epilepticus in pediatric and adult patients. Primary domains included attitudes toward trial enrollment, exception from informed consent, and community consultation. Simple descriptive statistics, χ2, and Fisher's exact tests were conducted. RESULTS: Of 317 patients and surrogates, 90% agreed with or were neutral about the statement "I am glad that I/my family member was included in the Established Status Epilepticus Treatment Trial research study," whereas 10% disagreed. Twenty-seven percent disagreed with enrollment in the study without prospective consent. Black participants were more likely than white, other race, and unknown-race participants to disagree with enrollment without prospective consent (36% versus 23%, 14%, and 14%, respectively). Participants indicated that patients (81%), their families (65%), and those at risk for seizures (51%) were most important to include in community consultation. CONCLUSION: This study aimed to explore attitudes toward exception from informed consent enrollment among participants at all sites in a large, multicenter exception from informed consent trial. General acceptance of trial enrollment was high; acceptance of exception from informed consent specifically was somewhat lower, especially among black participants. Our findings provide further support for targeted community consultation focusing on individuals with connections to the disease under study. Future research should focus on communication in the postenrollment period, especially with individuals who may have concerns about exception from informed consent.

Recommendations for the Emergency Department Prevention of Sport-Related Concussion.

Sport-related concussion refers to the subset of concussive injuries occurring during sport activities. Similar to concussion from nonsport mechanisms, sport-related concussion is associated with significant morbidity, including migrainous headaches, disruption in normal daily activities, and long-term depression and cognitive deficits. Unlike nonsport concussions, sport-related concussion may be uniquely amenable to prevention efforts to mitigate these problems. The emergency department (ED) visit for sport-related concussion represents an opportunity to reduce morbidity by timely diagnosis and management using best practices, and through education and counseling to prevent a subsequent sport-related concussion. This article provides recommendations to reduce sport-related concussion disability through primary, secondary, and tertiary preventive strategies enacted during the ED visit. Although many recommendations have a solid evidence base, several research gaps remain. The overarching goal of improving sport-related concussion outcome through enactment of ED-based prevention strategies needs to be explicitly studied.

Atomistic Modeling of Scattering Curves for Human IgG1/4 Reveals New Structure-Function Insights.

Small angle x-ray and neutron scattering are techniques that give solution structures for large macromolecules. The creation of physically realistic atomistic models from known high-resolution structures to determine joint x-ray and neutron scattering best-fit structures offers a, to our knowledge, new method that significantly enhances the utility of scattering. To validate this approach, we determined scattering curves for two human antibody subclasses, immunoglobulin G (IgG) 1 and IgG4, on five different x-ray and neutron instruments to show that these were reproducible, then we modeled these by Monte Carlo simulations. The two antibodies have different hinge lengths that connect their antigen-binding Fab and effector-binding Fc regions. Starting from 231,492 and 190,437 acceptable conformations for IgG1 and IgG4, respectively, joint x-ray and neutron scattering curve fits gave low goodness-of-fit R factors for 28 IgG1 and 2748 IgG4 structures that satisfied the disulphide connectivity in their hinges. These joint best-fit structures showed that the best-fit IgG1 models had a greater separation between the centers of their Fab regions than those for IgG4, in agreement with their hinge lengths of 15 and 12 residues, respectively. The resulting asymmetric IgG1 solution structures resembled its crystal structure. Both symmetric and asymmetric solution structures were determined for IgG4. Docking simulations with our best-fit IgG4 structures showed greater steric clashes with its receptor to explain its weaker FcγRI receptor binding compared to our best-fit IgG1 structures with fewer clashes and stronger receptor binding. Compared to earlier approaches for fitting molecular antibody structures by solution scattering, we conclude that this joint fit approach based on x-ray and neutron scattering data, combined with Monte Carlo simulations, significantly improved our understanding of antibody solution structures. The atomistic nature of the output extended our understanding of known functional differences in Fc receptor binding between IgG1 and IgG4.

The Effect of Goal-Directed Therapy on Patient Morbidity and Mortality After Traumatic Brain Injury: Results From the Progesterone for the Treatment of Traumatic Brain Injury III Clinical Trial.

OBJECTIVES: To estimate the impact of goal-directed therapy on outcome after traumatic brain injury, our team applied goal-directed therapy to standardize care in patients with moderate to severe traumatic brain injury, who were enrolled in a large multicenter clinical trial. DESIGN: Planned secondary analysis of data from Progesterone for the Treatment of Traumatic Brain Injury III, a large, prospective, multicenter clinical trial. SETTING: Forty-two trauma centers within the Neurologic Emergencies Treatment Trials network. PATIENTS: Eight-hundred eighty-two patients were enrolled within 4 hours of injury after nonpenetrating traumatic brain injury characterized by Glasgow Coma Scale score of 4-12. MEASUREMENTS AND MAIN RESULTS: Physiologic goals were defined a priori in order to standardize care across 42 sites participating in Progesterone for the Treatment of Traumatic Brain Injury III. Physiologic data collection occurred hourly; laboratory data were collected according to local ICU protocols and at a minimum of once per day. Physiologic transgressions were predefined as substantial deviations from the normal range of goal-directed therapy. Each hour where goal-directed therapy was not achieved was classified as a "transgression." Data were adjudicated electronically and via expert review. Six-month outcomes included mortality and the stratified dichotomy of the Glasgow Outcome Scale-Extended. For each variable, the association between outcome and either: 1) the occurrence of a transgression or 2) the proportion of time spent in transgression was estimated via logistic regression model. RESULTS: For the 882 patients enrolled in Progesterone for the Treatment of Traumatic Brain Injury III, mortality was 12.5%. Prolonged time spent in transgression was associated with increased mortality in the full cohort for hemoglobin less than 8 gm/dL (p = 0.0006), international normalized ratio greater than 1.4 (p < 0.0001), glucose greater than 180 mg/dL (p = 0.0003), and systolic blood pressure less than 90 mm Hg (p < 0.0001). In the patient subgroup with intracranial pressure monitoring, prolonged time spent in transgression was associated with increased mortality for intracranial pressure greater than or equal to 20 mm Hg (p < 0.0001), glucose greater than 180 mg/dL (p = 0.0293), hemoglobin less than 8 gm/dL (p = 0.0220), or systolic blood pressure less than 90 mm Hg (p = 0.0114). Covariates inversely related to mortality included: a single occurrence of mean arterial pressure less than 65 mm Hg (p = 0.0051) or systolic blood pressure greater than 180 mm Hg (p = 0.0002). CONCLUSIONS: The Progesterone for the Treatment of Traumatic Brain Injury III clinical trial rigorously monitored compliance with goal-directed therapy after traumatic brain injury. Multiple significant associations between physiologic transgressions, morbidity, and mortality were observed. These data suggest that effective goal-directed therapy in traumatic brain injury may provide an opportunity to improve patient outcomes.

High-throughput binding affinity calculations at extreme scales.

BACKGROUND: Resistance to chemotherapy and molecularly targeted therapies is a major factor in limiting the effectiveness of cancer treatment. In many cases, resistance can be linked to genetic changes in target proteins, either pre-existing or evolutionarily selected during treatment. Key to overcoming this challenge is an understanding of the molecular determinants of drug binding. Using multi-stage pipelines of molecular simulations we can gain insights into the binding free energy and the residence time of a ligand, which can inform both stratified and personal treatment regimes and drug development. To support the scalable, adaptive and automated calculation of the binding free energy on high-performance computing resources, we introduce the High-throughput Binding Affinity Calculator (HTBAC). HTBAC uses a building block approach in order to attain both workflow flexibility and performance. RESULTS: We demonstrate close to perfect weak scaling to hundreds of concurrent multi-stage binding affinity calculation pipelines. This permits a rapid time-to-solution that is essentially invariant of the calculation protocol, size of candidate ligands and number of ensemble simulations. CONCLUSIONS: As such, HTBAC advances the state of the art of binding affinity calculations and protocols. HTBAC provides the platform to enable scientists to study a wide range of cancer drugs and candidate ligands in order to support personalized clinical decision making based on genome sequencing and drug discovery.