Early Convalescent Plasma for High-Risk Outpatients with Covid-19.

BACKGROUND: Early administration of convalescent plasma obtained from blood donors who have recovered from coronavirus disease 2019 (Covid-19) may prevent disease progression in acutely ill, high-risk patients with Covid-19. METHODS: In this randomized, multicenter, single-blind trial, we assigned patients who were being treated in an emergency department for Covid-19 symptoms to receive either one unit of convalescent plasma with a high titer of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or placebo. All the patients were either 50 years of age or older or had one or more risk factors for disease progression. In addition, all the patients presented to the emergency department within 7 days after symptom onset and were in stable condition for outpatient management. The primary outcome was disease progression within 15 days after randomization, which was a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included the worst severity of illness on an 8-category ordinal scale, hospital-free days within 30 days after randomization, and death from any cause. RESULTS: A total of 511 patients were enrolled in the trial (257 in the convalescent-plasma group and 254 in the placebo group). The median age of the patients was 54 years; the median symptom duration was 4 days. In the donor plasma samples, the median titer of SARS-CoV-2 neutralizing antibodies was 1:641. Disease progression occurred in 77 patients (30.0%) in the convalescent-plasma group and in 81 patients (31.9%) in the placebo group (risk difference, 1.9 percentage points; 95% credible interval, -6.0 to 9.8; posterior probability of superiority of convalescent plasma, 0.68). Five patients in the plasma group and 1 patient in the placebo group died. Outcomes regarding worst illness severity and hospital-free days were similar in the two groups. CONCLUSIONS: The administration of Covid-19 convalescent plasma to high-risk outpatients within 1 week after the onset of symptoms of Covid-19 did not prevent disease progression. (SIREN-C3PO ClinicalTrials.gov number, NCT04355767.).

Improved mortality analysis in early-phase dose-ranging clinical trials for emergency medical diseases using Bayesian time-to-event models with active comparators.

Emergency medical diseases (EMDs) are the leading cause of death worldwide. A time-to-death analysis is needed to accurately identify the risks and describe the pattern of an EMD because the mortality rate can peak early and then decline. Dose-ranging Phase II clinical trials are essential for developing new therapies for EMDs. However, most dose-finding trials do not analyze mortality as a time-to-event endpoint. We propose three Bayesian dose-response time-to-event models for a secondary mortality analysis of a clinical trial: a two-group (active treatment vs control) model, a three-parameter sigmoid EMAX model, and a hierarchical EMAX model. The study also incorporates one specific active treatment as an active comparator in constructing three new models. We evaluated the performance of these six models and a very popular independent model using simulated data motivated by a randomized Phase II clinical trial focused on identifying the most effective hyperbaric oxygen dose to achieve favorable functional outcomes in patients with severe traumatic brain injury. The results show that the three-group, EMAX, and EMAX model with an active comparator produce the smallest averaged mean squared errors and smallest mean absolute biases. We provide a new approach for time-to-event analysis in early-phase dose-ranging clinical trials for EMDs. The EMAX model with an active comparator can provide valuable insights into the mortality analysis of new EMDs or other conditions that have changing risks over time. The restricted mean survival time, a function of the model's hazards, is recommended for displaying treatment effects for EMD research.

Coronavirus Disease 2019 Convalescent Plasma Outpatient Therapy to Prevent Outpatient Hospitalization: A Meta-Analysis of Individual Participant Data From 5 Randomized Trials.

BACKGROUND: Outpatient monoclonal antibodies are no longer effective and antiviral treatments for coronavirus disease 2019 (COVID-19) disease remain largely unavailable in many countries worldwide. Although treatment with COVID-19 convalescent plasma (CCP) is promising, clinical trials among outpatients have shown mixed results. METHODS: We conducted an individual participant data meta-analysis from outpatient trials to assess the overall risk reduction for all-cause hospitalizations by day 28 in transfused participants. Relevant trials were identified by searching Medline, Embase, medRxiv, World Health Organization COVID-19 Research Database, Cochrane Library, and Web of Science from January 2020 to September 2022. RESULTS: Five included studies from 4 countries enrolled and transfused 2620 adult patients. Comorbidities were present in 1795 (69%). The virus neutralizing antibody dilutional titer levels ranged from 8 to 14 580 in diverse assays. One hundred sixty of 1315 (12.2%) control patients were hospitalized, versus 111 of 1305 (8.5%) CCP-treated patients, yielding a 3.7% (95% confidence interval [CI], 1.3%-6.0%; P = .001) absolute risk reduction and 30.1% relative risk reduction for all-cause hospitalization. The hospitalization reduction was greatest in those with both early transfusion and high titer with a 7.6% absolute risk reduction (95% CI, 4.0%-11.1%; P = .0001) accompanied by at 51.4% relative risk reduction. No significant reduction in hospitalization was seen with treatment >5 days after symptom onset or in those receiving CCP with antibody titers below the median titer. CONCLUSIONS: Among outpatients with COVID-19, treatment with CCP reduced the rate of all-cause hospitalization and may be most effective when given within 5 days of symptom onset and when antibody titer is higher.

Selection of a statistical analysis method for the Glasgow Outcome Scale-Extended endpoint for estimating the probability of favorable outcome in future severe TBI clinical trials.

The Glasgow outcome scale-extended (GOS-E), an ordinal scale measure, is often selected as the endpoint for clinical trials of traumatic brain injury (TBI). Traditionally, GOS-E is analyzed as a fixed dichotomy with favorable outcome defined as GOS-E ≥ 5 and unfavorable outcome as GOS-E < 5. More recent studies have defined favorable vs unfavorable outcome utilizing a sliding dichotomy of the GOS-E that defines a favorable outcome as better than a subject's predicted prognosis at baseline. Both dichotomous approaches result in loss of statistical and clinical information. To improve on power, Yeatts et al proposed a sliding scoring of the GOS-E as the distance from the cutoff for favorable/unfavorable outcomes, and therefore used more information found in the original GOS-E to estimate the probability of favorable outcome. We used data from a published TBI trial to explore the ramifications to trial operating characteristics by analyzing the sliding scoring of the GOS-E as either dichotomous, continuous, or ordinal. We illustrated a connection between the ordinal data and time-to-event (TTE) data to allow use of Bayesian software that utilizes TTE-based modeling. The simulation results showed that the continuous method with continuity correction offers higher power and lower mean squared error for estimating the probability of favorable outcome compared to the dichotomous method, and similar power but higher precision compared to the ordinal method. Therefore, we recommended that future severe TBI clinical trials consider analyzing the sliding scoring of the GOS-E endpoint as continuous with continuity correction.

The Two-Bag Method for Management of Adult Diabetic Ketoacidosis-Experience With 634 Patients.

PURPOSE: To compare key resource utilization and safety outcomes of adult emergency department (ED) patients in diabetic ketoacidosis (DKA) managed via the Two-Bag or traditional One-Bag method. MATERIALS AND METHODS: This is a retrospective review at an academic medical center ED. Patients were included if >18 years, met diagnostic criteria for DKA (pH ≤ 7.30, bicarbonate ≤ 18 mmol/L, anion gap ≥ 10), and were managed via a standardized order set (either Two-Bag or One-Bag Method). Comparisons used independent-groups t-tests for continuous variables and χ2 tests for binary variables. RESULTS: We identified 634 patients with DKA managed via the Two-Bag method, and 107 managed via the One-Bag method. Cohorts were similar in demographics and presenting laboratories. The Two-Bag Method was associated with 8.1 h shorter to first bicarbonate >18 mmol/L (11.9 vs 20.0, P < .001), and 24 fewer IV fluid bags (5.3 vs 29.7, P < .001). Incidence of hypokalemia (potassium <3.0 mmol/L) was 53% lower in the Two-Bag cohort (6.6 vs 14.0%, P = .03); incidence of hypoglycemia (glucose <70 mg/dL) was 5.8 versus 10.3%, P = .16. CONCLUSIONS: For adult ED patients in DKA, the Two-Bag Method was associated with faster resolution of acidosis, fewer IV fluid bags charged, lower incidence of hypokalemia, and trend toward lower incidence of hypoglycemia compared to the One-Bag Method.

Association of substance use with outcomes in mildly ill COVID-19 outpatients.

BACKGROUND: Smoking, alcohol use, and non-prescription drug use are associated with worsened COVID-19 outcomes in hospitalized patients. Whether there is an association between substance use and outcomes in patients with COVID-19 who visited the Emergency Department (ED) but did not require hospitalization has not been well established. We investigated whether smoking, alcohol, and non-prescription drug use were associated with worsened COVID-19 outcomes among such patients presenting to the ED. METHODS: We conducted a secondary analysis of a clinical trial which sought to determine the effect of early convalescent plasma administration in patients presenting to the ED within 7 days of onset of mild COVID-19 symptoms. The study recruited 511 participants who were aged 50 years or older or had one or more risk factors for severe COVID-19. The primary outcome was disease progression within 15 days after randomization, which was defined as a composite of hospital admission for any reason, seeking emergency or urgent care, or death without hospitalization. Secondary outcomes included: no hospitalization within 30 days post-randomization, symptom worsening on the 5-category COVID-19 outpatient ordinal scale within 15 days post-randomization, and all-cause mortality. Substance use was categorized into either use or never use based on participant self-report. Logistic regression models were used to determine the association between substance use and outcomes. RESULTS: The mean age of the 511 patients enrolled was 52 years and the majority were females (274, 54%). Approximately 213 (42%) were non-Hispanic Whites, 156 (30%) Hispanics, 100 (20%) non-Hispanic Blacks, 18 (4%) non-Hispanic Asian, 8 (1%) American Indian Alaskan, and 16 (3%) unknown race. Tobacco 152 (30%) was the most common substance use reported. Alcohol use 36 (7%) and non-prescription drug use 33 (6%) were less common. Tobacco use and non-prescription drug use were associated with an increased risk for meeting the primary outcome ((tobacco: adjusted odds ratio [aOR] =2.08; 95% confidence interval [CI]: 1.37-3.15) and (drug: aOR =2.41; 95%CI: 1.17-5.00)) and increased risk for symptom worsening on the 5-category COVID-19 outpatient scale ((tobacco: aOR = 1.62; 95%CI: 1.09-2.42) and (drug: aOR = 2.32 95% CI: 1.10-4.87)) compared to non-use after adjusting for age, sex, plasma administration, and comorbidity. CONCLUSION: Tobacco and non-prescription drug use but not alcohol use were associated with worsened COVID-19 outcomes in patients who did not require hospitalization on their initial presentation. Future studies should determine the quantity, duration, and type of drug/tobacco use that may worsen COVID-19.

Longitudinal Trajectories of Post-Concussive Symptoms Following Mild Traumatic Brain Injury.

BACKGROUND: Individuals recovering from mild traumatic brain injury (TBI) represent a heterogenous population that requires distinct treatment approaches. Identification of recovery trajectories improves our ability to understand the natural history of mild TBI recovery and develop targeted interventions. OBJECTIVE: To utilize group-based trajectory modeling (GBTM) to identify distinct patterns of symptom recovery following mild TBI in the first 6 months after mild TBI. METHODS: This study is comprised of 253 adults who presented to the emergency department with mild TBI and completed assessments for six-months post-injury. Patients were recruited for the prospective observational cohort study, HeadSMART. The primary outcome measure was the Rivermead Postconcussion Symptom Questionnaire. GBTM was used to identify longitudinal trajectories of recovery following mild TBI using Rivermead scores at baseline, one, three, and six months following diagnosis. RESULTS: Findings identified four distinct trajectories of symptom recovery follwing mild TBI including 9% of participants who were categorized with minimal acute symptoms that decreased over time, 45% with mild acute symptoms that decreased over time, 33% with relatively higher acute symptoms that decreased over time, and 13% with relatively higher acute symptoms that increased over time. CONCLUSIONS: GBTM identified four distinct trajectories of recovery following mild TBI and GBTM may be useful for research interventions that can alter recovery trajectories.

Prevalence and Correlates of Depressive Symptoms Within 6 Months After First-Time Mild Traumatic Brain Injury.

OBJECTIVE: Depressive symptoms are among the most common neuropsychiatric sequelae of mild traumatic brain injury (mTBI). Very few studies have compared correlates of depressive symptoms within the first 6 months of injury in cohorts experiencing their first TBI. The authors investigated whether the correlates of depressive symptoms (being female, older, lower education, having brain lesions, experiencing worse postconcussive symptoms, and incomplete functional recovery) that have been established in populations with moderate to severe TBI were the same for individuals with first-time mTBI within the first 6 months of recovery. METHODS: Two hundred seventeen individuals with first-time mTBI were divided into subgroups-new-onset depressive symptoms, recurrent depressive symptoms, prior depression history only, and never depressed-and compared on clinical and demographic variables and the presence of postconcussive symptoms and functional recovery at 3 and 6 months. RESULTS: New-onset depressive symptoms developed in 12% of the cohort, whereas 11% of the cohort had recurrent depressive symptoms. Both depressive symptoms groups were more likely to comprise women and persons of color and were at higher risk for clinically significant postconcussive symptoms and incomplete functional recovery for the first 6 months postinjury. CONCLUSIONS: Presence of depressive symptoms after first-time mTBI was associated with persistent postconcussive symptoms and incomplete functional recovery in the first 6 months. Adding to the existing literature, these findings identified correlates of depressive symptom development and poor outcomes after mTBI, thus providing further evidence that mTBI may produce persistent symptoms and functional limitations that warrant clinical attention.

Association of Vasopressor Choice with Clinical and Functional Outcomes Following Moderate to Severe Traumatic Brain Injury: A TRACK-TBI Study.

BACKGROUND: Early hypotension following moderate to severe traumatic brain injury (TBI) is associated with increased mortality and poor long-term outcomes. Current guidelines suggest the use of intravenous vasopressors to support blood pressure following TBI; however, guidelines do not specify vasopressor type, resulting in variation in clinical practice. Minimal data are available to guide clinicians on optimal early vasopressor choice to support blood pressure following TBI. Therefore, we conducted a multicenter study to examine initial vasopressor choice for the support of blood pressure following TBI and its association with clinical and functional outcomes after injury. METHODS: We conducted a retrospective cohort study of patients enrolled in the transforming research and clinical knowledge in traumatic brain injury (TRACK-TBI) study, an 18-center prospective cohort study of patients with TBI evaluated in participating level I trauma centers. We examined adults with moderate to severe TBI (defined as Glasgow Coma Scale score < 13) who were admitted to the intensive care unit and received an intravenous vasopressor within 48 h of admission. The primary exposure was initial vasopressor choice (phenylephrine versus norepinephrine), and the primary outcome was 6-month Glasgow Outcomes Scale Extended (GOSE), with the following secondary outcomes: length of hospital stay, length of intensive care unit stay, in-hospital mortality, new requirement for dialysis, and 6-month Disability Rating Scale. Regression analysis was used to assess differences in outcomes between patients exposed to norepinephrine versus phenylephrine, with propensity weighting to address selection bias due to the nonrandom allocation of the treatment groups and patient dropout. RESULTS: The final study sample included 156 patients, of whom 79 (51%) received norepinephrine, 69 (44%) received phenylephrine, and 8 (5%) received an alternate drug as their initial vasopressor. 121 (77%) of patients were men, with a mean age of 43.1 years. Of patients receiving norepinephrine as their initial vasopressor, 32% had a favorable outcome (GOSE 5-8), whereas 40% of patients receiving phenylephrine as their initial vasopressor had a favorable outcome. Compared with phenylephrine, exposure to norepinephrine was not significantly associated with improved 6-month GOSE (weighted odds ratio 1.40, 95% confidence interval 0.66-2.96, p = 0.37) or any secondary outcome. CONCLUSIONS: The majority of patients with moderate to severe TBI received either phenylephrine or norepinephrine as first-line agents for blood pressure support following brain injury. Initial choice of norepinephrine, compared with phenylephrine, was not associated with improved clinical or functional outcomes.

Loss of Consciousness and Altered Mental State as Predictors of Functional Recovery Within 6 Months Following Mild Traumatic Brain Injury.

OBJECTIVE: The authors tested the hypothesis that a combination of loss of consciousness (LOC) and altered mental state (AMS) predicts the highest risk of incomplete functional recovery within 6 months after mild traumatic brain injury (mTBI), compared with either condition alone, and that LOC alone is more strongly associated with incomplete recovery, compared with AMS alone. METHODS: Data were analyzed from 407 patients with mTBI from Head injury Serum Markers for Assessing Response to Trauma (HeadSMART), a prospective cohort study of TBI patients presenting to two urban emergency departments. Four patient subgroups were constructed based on information documented at the time of injury: neither LOC nor AMS, LOC only, AMS only, and both. Logistic regression models assessed LOC and AMS as predictors of functional recovery at 1, 3, and 6 months. RESULTS: A gradient of risk of incomplete functional recovery at 1, 3, and 6 months postinjury was noted, moving from neither LOC nor AMS, to LOC or AMS alone, to both. LOC was associated with incomplete functional recovery at 1 and 3 months (odds ratio=2.17, SE=0.46, p<0.001; and odds ratio=1.80, SE=0.40, p=0.008, respectively). AMS was associated with incomplete functional recovery at 1 month only (odds ratio=1.77, SE=0.37 p=0.007). No association was found between AMS and functional recovery in patients with no LOC. Neither LOC nor AMS was predictive of functional recovery at later times. CONCLUSIONS: These findings highlight the need to include symptom-focused clinical variables that pertain to the injury itself when assessing who might be at highest risk of incomplete functional recovery post-mTBI.

Age differences in outcome after mild traumatic brain injury: results from the HeadSMART study.

This study longitudinally examined age differences across multiple outcome domains in individuals diagnosed with acute mild traumatic brain injury (mTBI). A sample of 447 adults meeting VA/DoD criteria for mTBI was dichotomized by age into older (≥65 years; n = 88) and younger (<65 years; n = 359) sub-groups. All participants presented to the emergency department within 24 hours of sustaining a head injury, and outcomes were assessed at 1-, 3-, and 6-month intervals. Depressive symptoms were assessed using the Patient Health Questionnaire-9 (PHQ-9), post-concussive symptoms (PCS) were ascertained with the Rivermead Post-Concussion Questionnaire (RPQ), and functional recovery from the Extended Glasgow Outcome Scale (GOSE). Mixed effects logistic regression models showed that the rate of change over time in odds of functional improvement and symptom alleviation did not significantly differ between age groups (p = 0.200-0.088). Contrary to expectation, older adults showed equivalent outcome trajectories to younger persons across time. This is a compelling finding when viewed in light of the majority opinion that older adults are at risk for significantly worse outcomes. Future work is needed to identify the protective factors inherent to sub-groups of older individuals such as this.

Serum NfL (Neurofilament Light Chain) Levels and Incident Stroke in Adults With Diabetes Mellitus.

Background and Purpose- Effective stroke prevention depends on accurate stroke risk prediction. We determined the discriminative ability of NfL (neurofilament light chain) levels for distinguishing between adults with diabetes mellitus who develop incident stroke and those who remain stroke free during a 7-year follow-up period. Methods- We performed a case-control study of participants selected from the previously completed ACCORD trial (Action to Control Cardiovascular Risk in Diabetes). Cases were all ACCORD subjects who were stroke free at enrollment and developed incident stroke during follow-up (n=113). Control subjects (n=250) were randomly selected ACCORD subjects who had no stroke events either before or after randomization. NfL was measured in baseline samples using Single Molecule Array technology (Quanterix). Results- Baseline NfL levels were higher in stroke subjects, compared to controls, after adjusting for age, race, blood pressure, weight, and the Framingham Stroke Risk Score. Relative to the subjects in the lowest quintile of NfL levels, the hazard ratios of incident stroke for subjects in the second to fifth quintiles were 3.91 (1.45-10.53), 4.05 (1.52-10.79), 5.63 (2.16-14.66), and 9.75 (3.84-27.71), respectively, after adjusting for race and Framingham Stroke Risk Score. Incorporating NfL levels into a predictive score that already included race and Framingham Stroke Risk Score increased the score's C statistic from 0.71 (95% CI, 0.66-0.77) to 0.78 (95% CI, 0.73-0.83), P<0.001. Older age, nonwhite race, higher systolic blood pressure, glomerular filtration rate <60, and higher hemoglobin A1C were independent predictors of serum NfL in this cohort but diastolic blood pressure, durations of hypertension or diabetes mellitus, and lipid levels were not. In total, cardiovascular disease risk factors explained 19.2% of the variability in baseline NfL levels. Conclusions- Serum NfL levels predict incident stroke and add considerably to the discriminatory power of the Framingham Stroke Risk Score in a cohort of middle-aged and older adults with diabetes mellitus.

Bayesian hierarchical EMAX model for dose-response in early phase efficacy clinical trials.

A primary goal of a phase II dose-ranging trial is to identify a correct dose before moving forward to a phase III confirmatory trial. A correct dose is one that is actually better than control. A popular model in phase II is an independent model that puts no structure on the dose-response relationship. Unfortunately, the independent model does not efficiently use information from related doses. One very successful alternate model improves power using a pre-specified dose-response structure. Past research indicates that EMAX models are broadly successful and therefore attractive for designing dose-response trials. However, there may be instances of slight risk of nonmonotone trends that need to be addressed when planning a clinical trial design. We propose to add hierarchical parameters to the EMAX model. The added layer allows information about the treatment effect in one dose to be "borrowed" when estimating the treatment effect in another dose. This is referred to as the hierarchical EMAX model. Our paper compares three different models (independent, EMAX, and hierarchical EMAX) and two different design strategies. The first design considered is Bayesian with a fixed trial design, and it has a fixed schedule for randomization. The second design is Bayesian but adaptive, and it uses response adaptive randomization. In this article, a randomized trial of patients with severe traumatic brain injury is provided as a motivating example.

Influence of study population definition on the effect of age on outcomes after blunt head trauma.

OBJECTIVES: The purpose of this study was to assess whether study population definition influences the effect of age on outcomes after blunt head trauma. We hypothesized that examining 'all comers' receiving head computerized tomography after blunt head trauma, fewer older individuals would meet Veterans Administration and Department of Defense (VA/DoD) criteria for traumatic brain injury (TBI), and would, therefore, display better outcomes than younger cohorts. However, restricting to participants meeting VA/DoD criteria for TBI, we hypothesized that older individuals would have worse outcomes. METHODS: Data from a recently completed prospective cohort study were analysed with age dichotomized at 65 years. Logistic regression modelling, controlled for potential confounders including head trauma severity, was estimated to measure the effect of age on functional recovery, post-concussion symptoms (PCS), and depressive symptoms at 1-month post-TBI. RESULTS: Fewer older than younger individuals met VA/DoD criteria for TBI. Older individuals had better functional, PCS, and depressive outcomes at 1 month. Restricting to those meeting VA/DoD criteria for TBI, older individuals continued to have better functional and PCS outcomes but had outcomes comparable to younger on depressive symptoms. CONCLUSIONS: Contrary to our hypothesis, there was a tendency for older adults to have better outcomes than younger, independent of the diagnostic criteria applied.

DRD2 C957T polymorphism is associated with improved 6-month verbal learning following traumatic brain injury.

Traumatic brain injury (TBI) often leads to heterogeneous clinical outcomes, which may be influenced by genetic variation. A single-nucleotide polymorphism (SNP) in the dopamine D2 receptor (DRD2) may influence cognitive deficits following TBI. However, part of the association with DRD2 has been attributed to genetic variability within the adjacent ankyrin repeat and kinase domain containing 1 protein (ANKK1). Here, we utilize the Transforming Research and Clinical Knowledge in Traumatic Brain Injury Pilot (TRACK-TBI Pilot) study to investigate whether a novel DRD2 C957T polymorphism (rs6277) influences outcome on a cognitive battery at 6 months following TBI-California Verbal Learning Test (CVLT-II), Wechsler Adult Intelligence Test Processing Speed Index Composite Score (WAIS-PSI), and Trail Making Test (TMT). Results in 128 Caucasian subjects show that the rs6277 T-allele associates with better verbal learning and recall on CVLT-II Trials 1-5 (T-allele carrier 52.8 ± 1.3 points, C/C 47.9 ± 1.7 points; mean increase 4.9 points, 95% confidence interval [0.9 to 8.8]; p = 0.018), Short-Delay Free Recall (T-carrier 10.9 ± 0.4 points, C/C 9.7 ± 0.5 points; mean increase 1.2 points [0.1 to 2.5]; p = 0.046), and Long-Delay Free Recall (T-carrier 11.5 ± 0.4 points, C/C 10.2 ± 0.5 points; mean increase 1.3 points [0.1 to 2.5]; p = 0.041) after adjusting for age, education years, Glasgow Coma Scale, presence of acute intracranial pathology on head computed tomography scan, and genotype of the ANKK1 SNP rs1800497 using multivariable regression. No association was found between DRD2 C947T and non-verbal processing speed (WAIS-PSI) or mental flexibility (TMT) at 6 months. Hence, DRD2 C947T (rs6277) may be associated with better performance on select cognitive domains independent of ANKK1 following TBI.

Prevalence and Prognostic Association of Circulating Troponin in the Acute Respiratory Distress Syndrome.

OBJECTIVE: Circulating cardiac troponin has been associated with adverse prognosis in the acute respiratory distress syndrome in small and single-center studies; however, comprehensive studies of myocardial injury in acute respiratory distress syndrome using modern high-sensitivity troponin assays, which can detect troponin at much lower circulating concentrations, have not been performed. DESIGN: We performed a prospective cohort study. SETTING: We included patients enrolled in previously completed trials of acute respiratory distress syndrome. PATIENTS: One thousand fifty-seven acute respiratory distress syndrome patients were included. INTERVENTIONS: To determine the association of circulating high-sensitivity troponin I (Abbott ARCHITECT), with acute respiratory distress syndrome outcomes, we measured high-sensitivity troponin I within 24 hours of intubation. The primary outcome was 60-day mortality. MEASUREMENTS AND MAIN RESULTS: Detectable high-sensitivity troponin I was present in 94% of patients; 38% of patients had detectable levels below the 99th percentile of a healthy reference population (26 ng/L), whereas 56% of patients had levels above the 99th percentile cut point. After multivariable adjustment, age, cause of acute respiratory distress syndrome, temperature, heart rate, vasopressor use, Sequential Organ Failure Assessment score, creatinine, and PCO2 were associated with higher high-sensitivity troponin I concentration. After adjustment for age, sex, and randomized trial assignment, the hazard ratio for 60-day mortality comparing the fifth to the first quintiles of high-sensitivity troponin I was 1.61 (95% CI, 1.11-2.32; p trend = 0.003). Adjusting for Sequential Organ Failure Assessment score suggested that this association was not independent of disease severity (hazard ratio, 0.95; 95% CI, 0.64-1.39; p = 0.93). CONCLUSIONS: Circulating troponin is detectable in over 90% of patients with acute respiratory distress syndrome and is associated with degree of critical illness. The magnitude of myocardial injury correlated with mortality.

Dynamic Changes in High-Sensitivity Cardiac Troponin I Are Associated with Dynamic Changes in Sum Absolute QRST Integral on Surface Electrocardiogram in Acute Decompensated Heart Failure.

BACKGROUND: A three-dimensional electrocardiographic (ECG) metric, the sum absolute QRST integral (SAI QRST), predicts ventricular arrhythmias in heart failure (HF) patients with implantable cardioverter defibrillator and mechanical response to cardiac resynchronization therapy. We hypothesized that there is an association between patient-specific changes in SAI QRST and myocardial injury as measured by high-sensitivity troponin I (hsTnI). METHODS: Sum absolute integral QRST on resting 12-lead ECG and hsTnI were measured simultaneously, every 3 hours, and during 12-hour observation period in a prospective cohort of emergency department patients (n = 398; mean age 57.8 ± 13.2 years; 54% female, 64% black), diagnosed with acute coronary syndrome (ACS, n = 28), acutely decompensated HF (acute decompensated heart failure, n = 35), cardiac non-ACS (n = 19), or noncardiac condition (n = 316). Random-effects linear regression analysis assessed the association of SAI QRST and myocardial injury, with adjustment for demographics (age, sex, race), prevalent cardiovascular disease (myocardial infarction, history of revascularization, stroke, and HF), risk factors (diabetes, smoking, hypercholesterolemia, hypertension, and cocaine use), and left bundle branch block. RESULTS: Within the entire cohort, SAI QRST decreased by 3 (95%CI -5 to -1) mV*ms every 3 hours. A 10-fold increase in hsTnI was associated with a 7.7 (0.6-14.9) mV*ms increase in SAI QRST. In the subgroup of acutely decompensated HF patients (n = 35), a 10-fold increase in hsTnI was associated with a 61.0 (5.9-116.1) mV*ms increase in SAI QRST. CONCLUSION: Patient-specific time-varying changes in the surface ECG scalar measure of global electrical heterogeneity, as measured by SAI QRST, and in myocardial injury as measured by hsTnI, are independently and directly associated with each other, likely reflecting a common underlying mechanism.

Hepatoma-derived Growth Factor Predicts Disease Severity and Survival in Pulmonary Arterial Hypertension.

RATIONALE: Pulmonary arterial hypertension (PAH) is a fatal disease, and pulmonary microvascular remodeling is an important contributor to PAH development. Therefore, we hypothesized that a circulating angiogenic factor could predict disease severity and survival. OBJECTIVES: We sought to assess the relationship of serum hepatoma-derived growth factor (HDGF) with PAH disease severity and survival. METHODS: Using a newly developed enzyme-linked immunosorbent assay, we evaluated circulating HDGF levels in two independent PAH cohorts and two different characterized control cohorts. Clinical and laboratory data were also used to assess the value of HDGF as a PAH prognostic biomarker. MEASUREMENTS AND MAIN RESULTS: Serum HDGF levels were significantly elevated in two independent PAH cohorts. Importantly, serum HDGF levels were not elevated in a noncardiac chronic disease cohort. Further, patients with elevated HDGF had significantly lower exercise tolerance, worse New York Heart Association functional class, and higher levels of N-terminal pro-brain natriuretic peptide. HDGF was a strong predictor of mortality, with an unadjusted hazard ratio of 4.5 (95% confidence interval, 1.9-10.3; P = 0.003 by log-rank test). In multivariable Cox proportional hazards models, elevated HDGF levels predicted decreased survival after being adjusted for age, PAH subtype, invasive hemodynamics, and N-terminal pro-brain natriuretic peptide. CONCLUSIONS: Elevated HDGF was associated with worse functional class, exertional intolerance, and increased mortality in PAH, suggesting HDGF as a potential biomarker for predicting mortality and as having possible diagnostic value for distinguishing PAH from non-PAH. HDGF may add additional value in PAH risk stratification in clinical trials and may represent a potential target for future PAH drug development.

Head injury serum markers for assessing response to trauma: Design of the HeadSMART study.

BACKGROUND: Accurate diagnosis and risk stratification of traumatic brain injury (TBI) at time of presentation remains a clinical challenge. The Head Injury Serum Markers for Assessing Response to Trauma study (HeadSMART) aims to examine blood-based biomarkers for diagnosing and determining prognosis in TBI. METHODS: HeadSMART is a 6-month prospective cohort study comparing emergency department patients evaluated for TBI (exposure group) to (1) emergency department patients evaluated for traumatic injury without head trauma and (2) healthy persons. Study methods and characteristics of the first 300 exposure participants are discussed. RESULTS: Of the first 300 participants in the exposure arm, 70% met the American Congress of Rehabilitation Medicine criteria for TBI, with the majority (80.1%) classified as mild TBI. The majority of subjects in the exposure arm had Glasgow Coma Scale scores of 13-15 (98.0%), normal head computed tomography (81.3%) and no prior history of concussion (71.7%). CONCLUSION: With systematic phenotyping, HeadSMART will facilitate diagnosis and risk-stratification of the heterogeneous group of individuals currently diagnosed with TBI.