Post-Traumatic Stress Symptoms after Pediatric Injury: Relation to Pre-Frontal Limbic Circuitry.

Pre-frontal limbic circuitry is vulnerable to effects of stress and injury. We examined microstructure of pre-frontal limbic circuitry after traumatic brain injury (TBI) or extracranial injury (EI) and its relation to post-traumatic stress symptoms (PTSS). Participants aged 8 to 15 years who sustained mild to severe TBI (n = 53) or EI (n = 26) in motor vehicle incidents were compared with healthy children (n = 38) in a prospective longitudinal study. At the seven-week follow-up, diffusion tensor imaging was obtained in all groups; injured children completed PTSS ratings using a validated scale. Using probabilistic diffusion tensor tractography, pathways were seeded from bilateral amygdalae and hippocampi to estimate the trajectory of white matter connecting them to each other and to targeted pre-frontal cortical (PFC) regions. Microstructure was estimated using fractional anisotropy (FA) in white matter and mean diffusivity (MD) in gray matter. Pre-frontal limbic microstructure was similar across groups, except for reduced FA in the right hippocampus to orbital PFC pathway in the injured versus healthy group. We examined microstructure of components of pre-frontal limbic circuitry with concurrently obtained PTSS cluster scores in the injured children. Neither microstructure nor PTSS scores differed significantly in the TBI and EI groups. Across PTSS factors, specific symptom clusters were related positively to higher FA and MD. Higher hyperarousal, avoidance, and re-experiencing symptoms were associated with higher FA in amygdala to pre-frontal and hippocampus to amygdala pathways. Higher hippocampal MD had a central role in hyperarousal and emotional numbing symptoms. Age moderated the relation of white and gray matter microstructure with hyperarousal scores. Our findings are consistent with models of traumatic stress that implicate disrupted top-down PFC and hippocampal moderation of overreactive subcortical threat arousal systems. Alterations in limbic pre-frontal circuitry and PTSS place children with either brain or body injuries at elevated risk for both current and future psychological health problems.

Sleep disturbances and internalizing behavior problems following pediatric traumatic injury.

OBJECTIVE: This prospective longitudinal study investigated sleep disturbance (SD) and internalizing problems after traumatic injury, including traumatic brain injury (TBI) or extracranial/bodily injury (EI) in children and adolescents, relative to typically developing (TD) children. We also examined longitudinal relations between SD and internalizing problems postinjury. METHOD: Participants (N = 87) ages 8-15 included youth with TBI, EI, and TD children. Injury groups were recruited from a Level 1 trauma center after sustaining vehicle-related injuries. Parent-reported SD and internalizing problems were assessed at preinjury/baseline, and 6 and 12 months postinjury. Linear mixed models evaluated the relation of group and time of assessment on outcomes. RESULTS: Controlling for age, the combined traumatic injury group experienced significantly higher postinjury levels of SD (p = .042) and internalizing problems (p = .024) than TD children; however, TBI and EI injury groups did not differ from each other. Injury severity was positively associated with SD in the EI group only, but in both groups SD was associated with additional postinjury sequelae, including fatigue and externalizing behavior problems. Internalizing problems predicted subsequent development of SD but not vice versa. The relation between injury and SD 1 year later was consistent with mediation by internalizing problems at 6 months postinjury. CONCLUSIONS: Children with both types of traumatic injury demonstrated higher SD and internalizing problems than healthy children. Internalizing problems occurring either prior to or following pediatric injury may be a risk factor for posttraumatic SD. Consequently, internalizing problems may be a promising target of intervention to improve both SD and related adjustment concerns. (PsycINFO Database Record

General and Ethnic-Biased Bullying Among Latino Students: Exploring Risks of Depression, Suicidal Ideation, and Substance Use.

Using a cross-sectional sample of 534 Latino students from middle and high schools in a large North Carolina school district, we examined the relation of general and ethnic-biased bullying to depression and the indirect pathways through depression to suicidal ideation and substance use outcomes. A structural equation model tested the direct and indirect paths. The final model fit was excellent, χ2(90) = 127.6, p = .0056, RMSEA = 0.028, CFI = 0.974, TLI = 0.961. Ethnic-biased and verbal or relational bullying had a direct effect on depression, but general and physical bullying did not. Indirect effects through depression were found for ethnic-biased and verbal or relational bullying in relation to suicidal ideation, alcohol, and illicit drug use. Child nativity was marginally associated with ethnic-biased bullying, indicating foreign-born students may experience greater ethnic-biased bullying. Implications for future research and bullying prevention are discussed.

Altered stress system reactivity after pediatric injury: Relation with post-traumatic stress symptoms.

Injury is the leading cause of death and disability in childhood. Injured children are at high risk for developing alterations in stress response systems and post-traumatic stress symptoms (PTSS) that may compromise long-term physical and psychological health. In a prospective, observational cohort study, we examined individual differences in, and correlates of, stress-reactivity of the hypothalamic-pituitary-adrenal axis (HPA; salivary cortisol) and autonomic nervous system (ANS; salivary alpha amylase, sAA) following pediatric injury. Participants were 8-15 years of age and hospitalized for traumatic brain injury (TBI; n=55; M age=13.9 yrs; 40 males) or extracranial injury (EI; n=29; M age 12.3 yrs, 20 males) following vehicular accidents. Six months post-injury, saliva was collected before and after the Trier Social Stress Test and later assayed for cortisol and sAA. Relative to a healthy non-injured comparison group (n=33; M age=12.5 yrs, 16 males), injured children (ages 8-12 years), but not adolescents (ages 13-15 yrs), had higher cortisol levels; regardless of age, injured participants showed dampened cortisol reactivity to social evaluative threat. Compared to participants with EI, children with TBI had elevated cortisol and adolescents had elevated sAA. With respect to PTSS, individual differences in sAA were negatively correlated with avoidance in the TBI group and positively correlated with emotional numbing within the EI group. Importantly, psychological and neurobiological sequelae were weakly related to injury severity. Given the high prevalence of pediatric injury, these sequelae affect many children and represent a significant public health concern. Consequently, surveillance of post-traumatic sequelae should include the full spectrum of injury severity. Monitoring the activity, reactivity, and regulation of biological systems sensitive to environmental insults may advance our understanding of individual differences in sequelae and adaptation following traumatic pediatric injury.

Recovery of Working Memory Following Pediatric Traumatic Brain Injury: A Longitudinal Analysis.

In a prospective longitudinal study, the trajectory of verbal and visual-spatial working memory (WM) development was examined 2-, 6-, 12-, and 24-months following complicated-mild to severe pediatric traumatic brain injury (TBI; n = 55) relative to an orthopedic injury comparison group (n = 47). Individual growth curve modeling revealed an interaction of age, severity, and time for verbal, but not visual-spatial WM. The youngest children with severe TBI had the lowest scores and slowest verbal WM growth. WM outcome is best understood in light of age at injury and TBI severity. Findings support the early vulnerability hypothesis and highlight the need for long-term follow-up.

Relations between mental health diagnoses, mental health treatment, and substance use in homeless youth.

BACKGROUND: Youth experiencing homelessness have elevated rates of mental illness and substance use compared to the general population. However, the extent to which underlying mental health issues may contribute to substance use as a way to manage symptoms and whether mental health treatment may reduce risk for substance use is unclear. This paper investigated these relations in a community sample of homeless youth. METHODS: Youth ages 13-24 (N=416) were interviewed as part of a community count and survey of homeless youth in Houston, Texas. A path analysis examined relations among lifetime diagnoses of ADHD, bipolar disorder, and depression; past-month marijuana, alcohol, and synthetic marijuana use, and hypothesized mediators of past-year mental health treatment and perceived unmet need for treatment. RESULTS: Rates of prior mental disorder diagnoses were high, with extensive comorbidity across the three diagnoses (n=114, 27.3% had all three diagnoses). Relations varied by diagnoses and substances. ADHD was positively related to current marijuana use (ß=0.55 (0.16), p<0.001), a relation that mental health treatment did not mediate. Depression was positively related to synthetic marijuana use through unmet need (ß=0.25 (0.09), p=0.004) and to alcohol use through unmet need (ß=0.20 (0.10), p=0.04) CONCLUSIONS: This study provides new information about relations between prior mental health diagnoses and substance use in homeless youth. Findings support the need to consider prior mental disorder diagnoses in relation to current substance use and to assess for whether youth perceive they have unmet needs for mental health treatment.

Enhancing the Career Planning Self-Determination of Young Adults with Mental Health Challenges.

The impact of an intervention on the self-determination and career planning engagement of young adults with mental health challenges was studied. Sixty-seven young adults, 20 to 30 years of age, with mental health diagnoses (e.g., depression, bipolar disorder) were randomly assigned to intervention and control groups. Statistically significant greater increases were made by the intervention group versus the control group for self-determination and career planning engagement, and self-determination at least partially mediated increases in career planning engagement. With career planning self-determination interventions, young adults with mental health challenges might be able to achieve better career and life outcomes than is typical for this population.

Long-Term School Outcomes of Children and Adolescents With Traumatic Brain Injury.

OBJECTIVE: To better understand the impact of age at injury, severity of injury, and time since injury on long-term school outcomes of children with traumatic brain injury (TBI). PARTICIPANTS: Four groups of children: complicated mild/moderate TBI (n = 23), severe TBI (n = 56), orthopedic injury (n = 35), and healthy controls (n = 42). Children with TBI were either 2 years postinjury or 6 years postinjury. DESIGN: Cross-sectional design. MEASURES: School records as well as parental ratings of functional academic skills and school competency. RESULTS: Children with severe TBI had consistently high usage of school services and low school competency ratings than children with orthopedic injuries and healthy controls. In contrast, children with complicated-mild/moderate TBI were significantly more likely to receive school support services and have lower competence ratings at 6 years than at 2 years postinjury. Students injured at younger ages had lower functional academic skill ratings than those injured at older ages. CONCLUSIONS: These findings highlight the increasing academic challenges faced over time by students with complicated-mild/moderate TBI and the vulnerability of younger children to poorer development of functional academic skills.

Phase II Clinical Trial of Atorvastatin in Mild Traumatic Brain Injury.

Statins constitute a class of medications commonly used in the treatment of elevated cholesterol. However, in experimental studies, statins also have other non-cholesterol-mediated mechanisms of action, which may have neuroprotective effects. The aim of this study was to determine whether administration of atorvastatin for 7 days post-injury would improve neurological recovery in patients with mild traumatic brain injury (mTBI). The hypothesis was that atorvastatin administration would reduce post-concussion symptoms and also that atorvastatin administration for 1 week post-injury would be safe. One hundred forty patients with mTBI were planned to be enrolled and randomly assigned to receive atorvastatin 1 mg/kg (up to 80 mg/kg) per day or placebo for 7 days starting within 24 h of injury. Assessments of post-concussion syndrome, post-traumatic stress and depressive symptoms, cognition, memory, verbal fluency, functional, and work status were performed at baseline, 1 week, and 1 and 3 months. The result on the Rivermead Post-Concussion Symptoms Questionnaire at 3 months was the primary outcome. Enrollment in the trial was stopped early because of difficulty in recruiting sufficient numbers of subjects. Fifty-two patients with mTBI were enrolled; 28 patients received atorvastatin and 24 received placebo. The median Rivermead score was 2 for the atorvastatin group, compared to 3.5 for the placebo group, at 3 months post-injury (χ2(1) = 0.0976; p = 0.7547). The change in the Rivermead score between baseline and 3 months was also analyzed. The median decrease in score was 4 for the atorvastatin group and 10.5 for the placebo group (χ2(1) = 0.8750; p = 0.3496). No serious adverse events occurred, and there was no significant difference in the incidence of adverse events in the two treatment groups. Atorvastatin administration for 7 days post-injury was safe, but there were no significant differences in neurological recovery post-mTBI with atorvastatin.

Pre- to post-immigration sexual risk behaviour and alcohol use among recent Latino immigrants in Miami.

Retrospective pre-immigration data on sexual risk and alcohol use behaviours was collected from 527 recent Latino immigrants to the USA, aged 18-34. Two follow-up assessments (12 months apart) reported on post-immigration behaviours. Using a mixed model growth curve analysis, a six-level sexual risk change variable was constructed combining measures of sexual partners and condom use. The mixed model growth curve was also used to examine associations between changes in sexual risk behaviour and changes in alcohol use and for testing interaction effects of gender and documentation status. Results suggest that individuals with high sexual risk behaviour at pre-immigration converge to low/moderate risk post-immigration, and that those who were sexually inactive or had low sexual risk at pre-immigration increased their risk post-immigration. Individuals with moderately higher initial but decreasing sexual risk behaviour showed the steepest decline in alcohol use, but their drinking at Time 3 was still higher than individuals reporting low sexual risk at Time 1. On average, men drank more than women, except women in one of the highest sexual risk categories at Time 1 - who seemed to drink as much, if not more, than men. Undocumented men reported more frequent drinking than documented men. In contrast, undocumented women reported lower alcohol use than documented women.

Longitudinal diffusion tensor imaging after pediatric traumatic brain injury: Impact of age at injury and time since injury on pathway integrity.

Following pediatric traumatic brain injury (TBI), longitudinal diffusion tensor imaging may characterize alterations in initial recovery and subsequent trajectory of white matter development. Our primary aim examined effects of age at injury and time since injury on pathway microstructure in children ages 6-15 scanned 3 and 24 months after TBI. Microstructural values generated using tract-based spatial statistics extracted from core association, limbic, and projection pathways were analyzed using general linear mixed models. Relative to children with orthopedic injury, the TBI group had lower fractional anisotropy (FA) bilaterally in all seven pathways. In left-hemisphere association pathways, school-aged children with TBI had the lowest initial pathway integrity and showed the greatest increase in FA over time suggesting continued development despite incomplete recovery. Adolescents showed limited change in FA and radial diffusivity and had the greatest residual deficit suggesting relatively arrested development. Radial diffusivity was persistently elevated in the TBI group, implicating dysmyelination as a core contributor to chronic post-traumatic neurodegenerative changes. The secondary aim compared FA values over time in the total sample, including participants contributing either one or two scans to the analysis, to the longitudinal cases contributing two scans. For each pathway, FA values and effect sizes were very similar and indicated extremely small differences in measurement of change over time in the total and longitudinal samples. Statistical approaches incorporating missing data may reliably estimate the effects of TBI and provide increased power to identify whether pathways show neurodegeneration, arrested development, or continued growth following pediatric TBI. Hum Brain Mapp 37:3929-3945, 2016. © 2016 Wiley Periodicals, Inc.

Psychometric Analysis of the Three-Factor Eating Questionnaire-R18V2 in Adolescent and Young Adult-Aged Central Nervous System Tumor Survivors.

PURPOSE: Adolescent and young adult (AYA)-aged central nervous system (CNS) tumor survivors are an understudied population that is at risk of developing adverse health outcomes, such as obesity. Long-term follow-up guidelines recommend monitoring those at risk of obesity, thus motivating the need for an eating behavior questionnaire. An abbreviated online version of the Three-Factor Eating Questionnaire (TFEQ-R18v2) has been developed, but its applicability to this population is not yet known. This study investigated the instrument's factor structure and reliability in this population. METHODS: AYA-aged CNS tumor survivors (n = 114) aged 15-39 years completed the TFEQ-R18V2 questionnaire online. Confirmatory factor analysis was used to examine the fit of the three-factor structure (uncontrollable eating, cognitive restraint, and emotional eating [EE]) and reliability (internal consistency of the TFEQ-R18v2). Associations between the three factors and body mass index (BMI) were assessed by linear regression. RESULTS: The theorized three-factor structure was supported in our population (RMSEA = 0.056 and CFI = 0.98) and demonstrated good reliability (α of 0.81-0.93). EE (ß = 0.07, 95% CI 0.02-0.13) was positively associated with BMI, whereas the other two subscale scores were not. CONCLUSION: The TFEQ-R18v2 instrument holds promise for research and clinical use among AYA-aged CNS tumor survivors. The instrument may be a useful tool for researchers to develop tailored weight management strategies. It also may be a valuable tool for clinicians to monitor survivors who are at risk of obesity and to facilitate referral. Our results also suggest that EE in this population should be further investigated as a potential target for intervention.

Loss of Consciousness Is Related to White Matter Injury in Mild Traumatic Brain Injury.

To study the relation of loss of consciousness (LOC) to white matter integrity after mild traumatic brain injury (mTBI), we acquired diffusion tensor imaging (DTI) at 3 Tesla in 79 participants with mTBI and normal computed tomography (age 18 to 50 years) whom we imaged after a mean post-injury interval of 25.9 h (standard deviation = 12.3) and at 3 months. For comparison, 64 participants with orthopedic injury (OI) underwent DTI at similar intervals. Quantitative tractography was used to measure fractional anisotropy (FA) and mean diffusivity (MD) in the left and right uncinate fasciculus (UF), left and right inferior frontal occipital fasciculus (IFOF), and the genu of the corpus callosum. Generalized estimating equation models assessed the association between LOC and both MD and FA across time after mTBI and compared their DTI metrics with the OI group. LOC was significantly related to MD in UF and IFOF (p values ranged from p < 0.0001 to 0.0270) and to FA in left UF (p = 0.0104) and right UF (p = 0.0404). Between-group differences in MD were significant for left UF, left and right IFOF, and the genu of the corpus callosum on initial DTI, but not at 3 months post-injury, and these differences were specific to the mTBI subgroup with LOC. Groups did not differ in FA at either occasion. Early DTI may provide a biomarker for mTBI with LOC, even in patients whose consciousness recovers by arrival in the emergency department. MD better differentiates mTBI from OI than FA on early DTI, but this is specific to mTBI with LOC. DTI findings support a continuum of white matter injury in early mTBI.

Stress and Multiple Substance Use Behaviors Among Hispanic Adolescents.

Hispanic adolescents reported a higher annual prevalence of use of nearly all major drugs compared to non-Hispanic White and African American adolescents. Cultural or minority stressors, such as those related to the acculturation process, discrimination, immigration, poverty, and community violence, have been implicated in these outcomes. Unfortunately, few studies have examined how these stressors may have a differential or additive effect when considered simultaneously. The current study examined the relation between stress and multiple substance use behaviors in a sample of Hispanic adolescents (n = 1036), age 11-19 years old. Latent class analysis identified subgroups of Hispanic adolescents based on combinations of substance use behaviors. General linear models were used to examine mean differences by class among the eight domains of stress. Fit statistics revealed a six-class structure: no substance use risk, predominately alcohol use, low polysubstance use, high polysubstance use, illicit drug use, and predominately marijuana use. Differences in stress across the six classes were identified for four of the eight domains: family economic, acculturation gap, community and gang, and family and drug stress. The effect sizes revealed the largest mean differences in stress between the no substance use group and the two polysubstance use groups and between the no risk group and alcohol use group. The findings from this study support the use of interventions that target stress to affect multiple substance use behaviors in Hispanic adolescents.

Does processing speed mediate the effect of pediatric traumatic brain injury on working memory?

OBJECTIVE: Processing speed (PS) and working memory (WM), core abilities that support learning, are vulnerable to disruption following traumatic brain injury (TBI). Developmental increases in WM are related to age-related changes in PS. The purpose of this study was to investigate whether WM deficits in children with TBI are mediated by PS. METHOD: The performance of children with complicated mild, moderate, and severe TBI (n = 77) was examined relative to an orthopedic injury (n = 30) and a healthy comparison group (n = 40) an average of 4 years after injury (range 8 months to 12 years). Coding was utilized as a measure of PS, while the WM measures included complex verbal and visual-spatial span tasks with parallel processing requirements. Mediation analysis examined whether TBI might have an indirect effect on WM through PS. RESULTS: Children in the TBI group performed more poorly than the combined comparison groups on coding and visual-spatial WM. Verbal WM scores were lower in TBI and the healthy comparison relative to the orthopedic group. TBI severity group differences were found on coding, but not WM measures. The relation between coding and both the WM tasks was similar. Bootstrap regression analyses suggested that PS, as measured by coding, might partially mediate the effect of group performance on WM. CONCLUSIONS: TBI disrupts core PS and WM abilities that scaffold more complex abilities. Importantly, slowed PS was associated with WM deficits commonly identified following pediatric TBI. Implications of our findings regarding the relation between PS and WM may suggest interventions for children and adolescents following TBI.

Impacts of a Comprehensive School Readiness Curriculum for Preschool Children at Risk for Educational Difficulties.

This article reports findings from a cluster-randomized study of an integrated literacy- and math-focused preschool curriculum, comparing versions with and without an explicit socioemotional lesson component to a business-as-usual condition. Participants included 110 classroom teachers from randomized classrooms and approximately eight students from each classroom (N = 760) who averaged 4.48 (SD = 0.44) years of age at the start of the school year. There were positive impacts of the two versions of the curriculum on language, phonological awareness, math, and socioemotional outcomes, but there were no added benefits to academic or socioemotional outcomes for the children receiving explicit socioemotional instruction. Results are discussed with relevance to early childhood theory, policy, and goals of closing the school readiness gap.

Designing Normative Messages About Active Surveillance for Men With Localized Prostate Cancer.

Active surveillance is increasingly recognized as a reasonable option for men with low-risk, localized prostate cancer, yet few men who might benefit from conservative management receive it. The authors examined the acceptability of normative messages about active surveillance as a management option for patients with low-risk prostate cancer. Men with a diagnosis of localized prostate cancer who were recruited through prostate cancer support organizations completed a web-based survey (N = 331). They rated messages about active surveillance for believability, accuracy, and importance for men to hear when making treatment decisions. The message "You don't have to panic … you have time to think about your options" was perceived as believable, accurate, and important by more than 80% of the survivors. In contrast, messages about trust in the active surveillance protocol and "knowing in plenty of time" if treatment is needed were rated as accurate by only about 36% of respondents. For active surveillance to be viewed as a reasonable alternative, men will need reassurance that following an active surveillance protocol is likely to allow time for curative treatment if the cancer progresses.

White matter and reading deficits after pediatric traumatic brain injury: A diffusion tensor imaging study.

Pediatric traumatic brain injury often results in significant long-term deficits in mastery of reading ability. This study aimed to identify white matter pathways that, when damaged, predicted reading deficits in children. Based on the dual-route model of word reading, we predicted that integrity of the inferior fronto-occipital fasciculus would be related to performance in sight word identification while integrity of the superior longitudinal fasciculus would be related to performance in phonemic decoding. Reading fluency and comprehension were hypothesized to relate to the superior longitudinal fasciculus, inferior fronto-occipital fasciculus, and cingulum bundle. The connectivity of white matter pathways was used to predict reading deficits in children aged 6 to 16 years with traumatic brain injury (n = 29) and those with orthopedic injury (n = 27) using tract-based spatial statistics. Results showed that children with traumatic brain injury and reduced microstructural integrity of the superior longitudinal fasciculus demonstrated reduced word-reading ability on sight word and phonemic decoding tasks. Additionally, children with traumatic brain injury and microstructural changes involving the cingulum bundle demonstrated reduced reading fluency. Results support the association of a dorsal pathway via the superior longitudinal fasciculus with both sight word reading and phonemic decoding. No association was identified between the inferior fronto-occipital fasciculus and sight word reading or phonemic decoding. Reading fluency was associated with the integrity of the cingulum bundle. These findings support dissociable pathways predicting word reading and fluency using Diffusion Tensor Imaging and provide additional information for developing models of acquired reading deficits by specifying areas of brain damage which may predict reading deficits following recovery from the acute phase of TBI.

Better futures: a randomized field test of a model for supporting young people in foster care with mental health challenges to participate in higher education.

The purpose of the study was to conduct a preliminary efficacy evaluation of the Better Futures model, which is focused on improving the postsecondary preparation and participation of youth in foster care with mental health challenges. Sixty-seven youth were randomized to either a control group that received typical services or an intervention group, which involved participation in a Summer Institute, individual peer coaching, and mentoring workshops. Findings indicate significant gains for the intervention group on measures of postsecondary participation, postsecondary and transition preparation, hope, self-determination, and mental health empowerment, as compared to the control group. Youth in the intervention group also showed positive trends in the areas of mental health recovery, quality of life, and high school completion. Implications for future research and practice are discussed, while emphasizing the capacities of youth in foster care with mental health conditions to successfully prepare for and participate fully in high education.

Effect of erythropoietin and transfusion threshold on neurological recovery after traumatic brain injury: a randomized clinical trial.

IMPORTANCE: There is limited information about the effect of erythropoietin or a high hemoglobin transfusion threshold after a traumatic brain injury. OBJECTIVE: To compare the effects of erythropoietin and 2 hemoglobin transfusion thresholds (7 and 10 g/dL) on neurological recovery after traumatic brain injury. DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial of 200 patients (erythropoietin, n = 102; placebo, n = 98) with closed head injury who were unable to follow commands and were enrolled within 6 hours of injury at neurosurgical intensive care units in 2 US level I trauma centers between May 2006 and August 2012. The study used a factorial design to test whether erythropoietin would fail to improve favorable outcomes by 20% and whether a hemoglobin transfusion threshold of greater than 10 g/dL would increase favorable outcomes without increasing complications. Erythropoietin or placebo was initially dosed daily for 3 days and then weekly for 2 more weeks (n = 74) and then the 24- and 48-hour doses were stopped for the remainder of the patients (n = 126). There were 99 patients assigned to a hemoglobin transfusion threshold of 7 g/dL and 101 patients assigned to 10 g/dL. INTERVENTIONS: Intravenous erythropoietin (500 IU/kg per dose) or saline. Transfusion threshold maintained with packed red blood cells. MAIN OUTCOMES AND MEASURES: Glasgow Outcome Scale score dichotomized as favorable (good recovery and moderate disability) or unfavorable (severe disability, vegetative, or dead) at 6 months postinjury. RESULTS: There was no interaction between erythropoietin and hemoglobin transfusion threshold. Compared with placebo (favorable outcome rate: 34/89 [38.2%; 95% CI, 28.1% to 49.1%]), both erythropoietin groups were futile (first dosing regimen: 17/35 [48.6%; 95% CI, 31.4% to 66.0%], P = .13; second dosing regimen: 17/57 [29.8%; 95% CI, 18.4% to 43.4%], P < .001). Favorable outcome rates were 37/87 (42.5%) for the hemoglobin transfusion threshold of 7 g/dL and 31/94 (33.0%) for 10 g/dL (95% CI for the difference, -0.06 to 0.25, P = .28). There was a higher incidence of thromboembolic events for the transfusion threshold of 10 g/dL (22/101 [21.8%] vs 8/99 [8.1%] for the threshold of 7 g/dL, odds ratio, 0.32 [95% CI, 0.12 to 0.79], P = .009). CONCLUSIONS AND RELEVANCE: In patients with closed head injury, neither the administration of erythropoietin nor maintaining hemoglobin concentration of greater than 10 g/dL resulted in improved neurological outcome at 6 months. The transfusion threshold of 10 g/dL was associated with a higher incidence of adverse events. These findings do not support either approach in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00313716.