Longitudinal Impact of Acute Spinal Cord Injury on Clinical Pharmacokinetics of Riluzole, a Potential Neuroprotective Agent.

Riluzole, a benzothiazole sodium channel blocker that received US Food and Drug Administration approval to attenuate neurodegeneration in amyotrophic lateral sclerosis in 1995, was found to be safe and potentially efficacious in a spinal cord injury (SCI) population, as evident in a phase I clinical trial. The acute and progressive nature of traumatic SCI and the complexity of secondary injury processes can alter the pharmacokinetics of therapeutics. A 1-compartment with first-order elimination population pharmacokinetic model for riluzole incorporating time-dependent clearance and volume of distribution was developed from combined data of the phase 1 and the ongoing phase 2/3 trials. This change in therapeutic exposure may lead to a biased estimate of the exposure-response relationship when evaluating therapeutic effects. With the developed model, a rational, optimal dosing scheme can be designed with time-dependent modification that preserves the required therapeutic exposure of riluzole.

Spine Injuries Sustained by U.S. Military Personnel in Combat are Different From Non-Combat Spine Injuries.

Spine injuries are more prevalent among Iraq and Afghanistan veterans than among veterans of previous conflicts. The purpose of this investigation was to characterize the context, mode, and clinical outcomes of spine injuries sustained by U.S. military personnel in theater. Injury and clinical data from patients who sustained a spine injury in Iraq or Afghanistan between 2003 and 2008 were extracted from the Joint Theater Trauma Registry. Fischer's exact test was used to compare demographic variables between battle and nonbattle spine injuries. Two-sided t tests and univariate analyses were performed to analyze the association between injury context, mechanism, and severity with clinical outcome. A total of 307 patients sustained spine injuries in theater during the study period, and 296 had adequate data for analysis. Most injuries occurred in battle (69.6%), and these injuries were more likely to have an Injury Severity Score considered severe (44.7% vs. 20.0%; p < 0.001) or critical (13.6% vs. 5.6%; p = 0.0458). Blast was the most common mechanism of injury (42.2%) and was more likely to be blunt (81.6%) than penetrating (18.4%; p < 0.0001). Battle-associated spine injuries were most commonly caused by blasts, were more severe, and more likely to involve multiple spinal levels.

A Bayesian multivariate joint frailty model for disease recurrences and survival.

Motivated by a study for soft tissue sarcoma, this article considers the analysis of diseases recurrence and survival. A multivariate frailty hazard model is established for joint modeling of three correlated time-to-event outcomes: local disease recurrence, distant disease recurrence (metastasis), and death. The goals are to find out (i) the effects of treatments on local and distant disease recurrences, and death, (ii) the effects of local and distant disease recurrences on death, and (iii) the correlation between local and distant recurrences. By our approach, all these three important questions, which are commonly asked in similar medical research studies, can be answered by a single model. We put the proposed joint frailty model in a Bayesian framework and use a hybrid Monte Carlo algorithm for the computation of posterior distributions. This hybrid algorithm relies on the evaluation of the gradient of target log density and a guided walk progress, and it combines these two strategies to suppress random walk behavior. A further distinction is that the hybrid algorithm can update all the components of a multivariate state vector simultaneously. Simulation studies are conducted to assess the proposed joint frailty model and the computation algorithm. The motivating soft tissue sarcoma data set is analyzed for illustration purpose. Copyright © 2016 John Wiley & Sons, Ltd.

Defining age-related differences in outcome after traumatic spinal cord injury: analysis of a combined, multicenter dataset.

BACKGROUND CONTEXT: The existing evidence suggests that, although older spinal cord injury (SCI) patients experience a similar degree of neurologic recovery to younger patients, older patients experience diminished functional outcomes at follow-up. However, all studies have assumed that the impact of age on functional outcome is the same across the spectrum of injury severity. PURPOSE: To test this assumption, we evaluated age as a potential effect moderator governing the relationship between acute neurologic status and long-term functional outcome. STUDY DESIGN/SETTING: Combined analysis of two prospective SCI datasets enrolling patients from North American trauma centers over the last decade. PATIENT SAMPLE: Adult patients (≥16 years old) with traumatic SCI and a standardized American Spinal Injury Association (ASIA) neurologic examination performed within 3 days of injury. OUTCOME MEASURES: Functional independence measure (FIM) motor score at the 1-year follow-up was the primary outcome of interest. METHODS: To define older and younger age groups, age was dichotomized at a threshold of 65 years old. A sensitivity analysis was also performed by dichotomizing age at 60 years. Multivariable linear regression was used to investigate the moderating effects of age on the relationship between acute ASIA Impairment Scale (AIS) grade and follow-up FIM motor score. An interaction plot was generated to understand how the effect of age on functional outcome changed depending on the acute AIS grade. A second linear regression model investigating the moderating effects of age was produced that adjusted for additional relevant predictor variables. RESULTS: Of 729 patients, 376 met the eligibility criteria. The mean age was 43.2 (±16.9), with a total of 41 patients (10.9%) older than 65 years. In the univariable analysis there was no age-related difference in motor recovery or AIS grade conversion at follow-up; however, there was a significantly lower mean FIM motor score observed among the older group at 1 year (p=.03). In the multivariable analysis, age was found to have a significant moderating effect on the relationship between acute AIS grade and future functional status (p<.05). The interaction plot revealed that, although older patients had decreased follow-up FIM motor scores overall, this effect was greatest for AIS B and AIS C patients and lesser for AIS A and AIS D patients. After adjustment for additional covariates in the second linear model, these results remained unchanged. CONCLUSIONS: Overall, advanced age is associated with worse functional outcome after SCI; however, this effect varies across the spectrum of injury severity. These results will help to facilitate enhanced clinical communication as well as potentially aid in the development of customized treatment and rehabilitation protocols.

A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.

North American Clinical Trials Network for the Treatment of Spinal Cord Injury: goals and progress.

The North American Clinical Trials Network (NACTN) for the Treatment of Spinal Cord Injury is a consortium of 10 neurosurgery departments, a data management center, and a pharmacological center. The NACTN was established with the goal of bringing recent molecular and cell-based discoveries in neuroprotection and regeneration from the laboratory into clinical trials that optimize meaningful data outcomes and maximum safety to patients. The requirements of planning and executing clinical trials in spinal cord injury (SCI) and the steps that the NACTN has taken to address these requirements are discussed and illustrated in articles in this issue of the Journal of Neurosurgery: Spine. The progress that the NACTN has made in meeting these goals can be summarized as organizing a network of hospitals capable of enrolling a sufficient number of patients for conducting Phase I and II trials; creating a Data Management Center and a database of the natural history of recovery after SCI (at the time of this writing 485 patients were enrolled in the database); creating a database of the incidence and severity of complications that occur during acute and subacute treatment after SCI; developing a Pharmacological Center capable of performing pharmacokinetic and pharmacodynamic studies of therapeutic drugs; completing enrollment of 36 patients in NACTN's first clinical trial, a Phase I study of riluzole, a neuroprotective drug; and performing pharmacokinetic and pharmacodynamic studies of riluzole in acute SCI.

Predictors of pulmonary complications in blunt traumatic spinal cord injury.

OBJECT: Pulmonary complications are the most common acute systemic adverse events following spinal cord injury (SCI), and contribute to morbidity, mortality, and increased length of hospital stay (LOS). Identification of factors associated with pulmonary complications would be of value in prevention and acute care management. Predictors of pulmonary complications after SCI and their effect on neurological recovery were prospectively studied between 2005 and 2009 at the 9 hospitals in the North American Clinical Trials Network (NACTN). METHODS: The authors sought to address 2 specific aims: 1) define and analyze the predictors of moderate and severe pulmonary complications following SCI; and 2) investigate whether pulmonary complications negatively affected the American Spinal Injury Association (ASIA) Impairment Scale conversion rate of patients with SCI. The NACTN registry of the demographic data, neurological findings, imaging studies, and acute hospitalization duration of patients with SCI was used to analyze the incidence and severity of pulmonary complications in 109 patients with early MR imaging and long-term follow-up (mean 9.5 months). Univariate and Bayesian logistic regression analyses were used to analyze the data. RESULTS: In this study, 86 patients were male, and the mean age was 43 years. The causes of injury were motor vehicle accidents and falls in 80 patients. The SCI segmental level was in the cervical, thoracic, and conus medullaris regions in 87, 14, and 8 patients, respectively. Sixty-four patients were neurologically motor complete at the time of admission. The authors encountered 87 complications in 51 patients: ventilator-dependent respiratory failure (26); pneumonia (25); pleural effusion (17); acute lung injury (6); lobar collapse (4); pneumothorax (4); pulmonary embolism (2); hemothorax (2), and mucus plug (1). Univariate analysis indicated associations between pulmonary complications and younger age, sports injuries, ASIA Impairment Scale grade, ascending neurological level, and lesion length on the MRI studies at admission. Bayesian logistic regression indicated a significant relationship between pulmonary complications and ASIA Impairment Scale Grades A (p = 0.0002) and B (p = 0.04) at admission. Pulmonary complications did not affect long-term conversion of ASIA Impairment Scale grades. CONCLUSIONS: The ASIA Impairment Scale grade was the fundamental clinical entity predicting pulmonary complications. Although pulmonary complications significantly increased LOS, they did not increase mortality rates and did not adversely affect the rate of conversion to a better ASIA Impairment Scale grade in patients with SCI. Maximum canal compromise, maximum spinal cord compression, and Acute Physiology and Chronic Health Evaluation-II score had no relationship to pulmonary complications.

Incidence and severity of acute complications after spinal cord injury.

OBJECT: The aim of this multicenter, prospective study was to determine the spectrum, incidence, and severity of complications during the initial hospitalization of patients with spinal cord injury. METHODS: The study was conducted at 9 university-affiliated hospitals that comprise the clinical centers of the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The study population comprised 315 patients admitted to NACTN clinical centers between June 25, 2005, and November 2, 2010, who had American Spinal Injury Association (ASIA) Impairment Scale grades of A-D and were 18 years of age or older. Patients were managed according to a standardized protocol. RESULTS: The study population was 79% male with a median age of 44 years. The leading causes of injury were falls (37%) and motor vehicle accidents (28%). The distribution of initial ASIA grades were A (40%), B (16%), C (15%), and D (29%). Fifty-eight percent of patients sustained 1 or more severe, moderate, or mild complications. Complications were associated with more severe ASIA grade: 84% of patients with Grade A and 25% of patients with Grade D had at least 1 complication. Seventy-eight percent of complications occurred within 14 days of injury. The most frequent types of severe and moderate complications were respiratory failure, pneumonia, pleural effusion, anemia, cardiac dysrhythmia, and severe bradycardia. The mortality rate was 3.5% and was associated with increased age and preexisting morbidity. CONCLUSIONS: Knowledge of the type, frequency, time of occurrence, and severity of specific complications that occur after spinal cord injury can aid in their early detection, treatment, and prevention. The data are of importance in evaluating and selecting therapy for clinical trials.

Pharmacology of riluzole in acute spinal cord injury.

OBJECT: The aim of this paper was to characterize individual and population pharmacokinetics of enterally administered riluzole in a Phase 1 clinical trial of riluzole as a neuroprotective agent in adults 18-70 years old with acute spinal cord injury (SCI). METHODS: Thirty-five individuals with acute SCI, American Spinal Injury Association Impairment Scale Grades A-C, neurological levels from C-4 to T-12, who were enrolled in the Phase 1 clinical trial sponsored by the North American Clinical Trials Network for Treatment of Spinal Cord Injury, received 50 mg riluzole twice daily for 28 doses. The first dose was administered at a mean of 8.7 ± 2.2 hours postinjury. Trough plasma samples were collected within 1 hour predose, and peak plasma samples were collected 2 hours postdose on Days 3 and 14 of treatment. Riluzole concentrations were quantified by high-performance liquid chromatography assay. The data were analyzed for individual and population pharmacokinetics using basic structural and covariate models. The pharmacokinetic measures studied were the peak concentration (C(max)), trough concentration (C(min)), systemic exposure (AUC(0-12)), clearance (CL/F), and volume of distribution (V_F) normalized by the bioavailability (F). RESULTS: The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher CL and larger V. The pharmacokinetics of riluzole (C(max), C(min), AUC(0-12), CL, and V) changed during the acute and subacute phases of SCI during the 14 days of therapy. It was consistently observed in patients at all clinical sites that C(max), C(min), and AUC(0-12) (128.9 ng/ml, 45.6 ng/ml, and 982.0 ng × hr/ml, respectively) were significantly higher on Day 3 than on Day 14 (76.5 ng/ml, 19.1 ng/ml, and 521.0 ng × hr/ml, respectively). These changes resulted from lower CL (49.5 vs 106.2 L/hour) and smaller V (557.1 vs 1297.9/L) on Day 3. No fluid imbalance or cytochrome P 1A2 induction due to concomitant medications was identified during the treatment course to account for such increases in V and CL, respectively. Possible mechanisms underlying these changes are discussed. CONCLUSIONS: This is the first report of clinical pharmacokinetics of riluzole in patients with SCI. The C(max) and AUC(0-12) achieved in SCI patients were lower than those in ALS patients on the same dose basis, due to a higher clearance and larger volume of distribution in SCI patients. The finding in SCI patients of an increase in the clearance and distribution of riluzole between the 3rd and 14th days after SCI, with a lower plasma concentration of riluzole on the 14th day, stresses the importance of monitoring changes in drug metabolism after SCI in interpreting the safety and efficacy of therapeutic drugs that are used in clinical trials in SCI. Clinical trial registration no.: NCT00876889.

Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial.

In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889.

A clinical prediction model for long-term functional outcome after traumatic spinal cord injury based on acute clinical and imaging factors.

To improve clinicians' ability to predict outcome after spinal cord injury (SCI) and to help classify patients within clinical trials, we have created a novel prediction model relating acute clinical and imaging information to functional outcome at 1 year. Data were obtained from two large prospective SCI datasets. Functional independence measure (FIM) motor score at 1 year follow-up was the primary outcome, and functional independence (score ≥ 6 for each FIM motor item) was the secondary outcome. A linear regression model was created with the primary outcome modeled relative to clinical and imaging predictors obtained within 3 days of injury. A logistic model was then created using the dichotomized secondary outcome and the same predictor variables. Model validation was performed using a bootstrap resampling procedure. Of 729 patients, 376 met the inclusion criteria. The mean FIM motor score at 1 year was 62.9 (±28.6). Better functional status was predicted by less severe initial American Spinal Injury Association (ASIA) Impairment Scale grade, and by an ASIA motor score >50 at admission. In contrast, older age and magnetic resonance imaging (MRI) signal characteristics consistent with spinal cord edema or hemorrhage predicted worse functional outcome. The linear model predicting FIM motor score demonstrated an R-square of 0.52 in the original dataset, and 0.52 (95% CI 0.52,0.53) across the 200 bootstraps. Functional independence was achieved by 148 patients (39.4%). For the logistic model, the area under the curve was 0.93 in the original dataset, and 0.92 (95% CI 0.92,0.93) across the bootstraps, indicating excellent predictive discrimination. These models will have important clinical impact to guide decision making and to counsel patients and families.

Ethnic differences in drinking outcomes following a brief alcohol intervention in the trauma care setting.

BACKGROUND: Evidence suggests that brief interventions in the trauma care setting reduce drinking, subsequent injury and driving under the influence (DUI) arrest. However, evidence on the effectiveness of these interventions in ethnic minority groups is lacking. The current study evaluates the efficacy of brief intervention among whites, blacks and Hispanics in the United States. METHODS: We conducted a two-group parallel randomized trial comparing brief motivational intervention (BMI) and treatment as usual with assessment (TAU+) to evaluate treatment differences in drinking patterns by ethnicity. Patients were recruited from a level 1 urban trauma center over a 2-year period. The study included 1493 trauma patients, including 668 whites, 288 blacks and 537 Hispanics. Hierarchical linear modeling was used to evaluate ethnic differences in drinking outcomes including volume per week, maximum amount consumed in 1 day, percentage days abstinent and percentage days heavy drinking at 6- and 12-month follow-up. Analyses controlled for age, gender, employment status, marital status, prior alcohol treatment, type of injury and injury severity. Special emphasis was given to potential ethnic differences by testing the interaction between ethnicity and BMI. RESULTS: At 6- and 12-month follow-up, BMI significantly reduced maximum amount consumed in 1 day (P < 0.001; P < 0.001, respectively) and percentage days heavy drinking (P < 0.05; P < 0.05, respectively) among Hispanics. Hispanics in the BMI group also reduced average volume per week at 12-month follow-up (chi(2) = 6.8, df = 1, P < 0.01). In addition, Hispanics in TAU+ reduced maximum amount consumed at 6- and 12-month follow-up (P < 0.001; P < 0.001) and volume per week at 12-month follow-up (P < 0.001). Whites and blacks in both BMI and TAU+ reduced volume per week and percentage days heavy drinking at 12-month follow-up (P < 0.001; P < 0.01, respectively) and decreased maximum amount at 6- (P < 0.001) and 12-month follow-up (P < 0.001). All three ethnic groups In both BMI and TAU+ reduced volume per week at 6-month follow-up (P < 0.001) and percentage days abstinent at 6- (P < 0.001) and 12-month follow-up (P < 0.001). CONCLUSIONS: All three ethnic groups evidenced reductions in drinking at 6- and 12-month follow-up independent of treatment assignment. Among Hispanics, BMI reduced alcohol intake significantly as measured by average volume per week, percentage days heavy drinking and maximum amount consumed in 1 day.

Changes in the regional prevalence of child obesity in 4th, 8th, and 11th grade students in Texas from 2000-2002 to 2004-2005.

Although national and state estimates of child obesity are available, data at these levels are insufficient to monitor effects of local obesity prevention initiatives. The purpose of this study was to examine regional changes in the prevalence of obesity due to statewide policies and programs among children in grades 4, 8, and 11 in Texas Health Services Regions (HSRs) between 2000-2002 and 2004-2005, and nine selected counties in 2004-2005. A cross-sectional, probability-based sample of 23,190 Texas students in grades 4, 8, and 11 were weighed and measured to obtain BMI. Obesity was >95th percentile for BMI by age/sex using Centers for Disease Control and Prevention growth charts. Child obesity prevalence significantly decreased between 2000-2002 and 2004-2005 for 4th grade students in the El Paso HSR (-7.0%, P = 0.005). A leveling off in the prevalence of obesity was noted for all other regions for grades 4, 8, and 11. County-level data supported the statistically significant decreases noted in the El Paso region. The reduction of child obesity levels observed in the El Paso area is one of the few examples of effective programs and policies based on a population-wide survey: in this region, a local foundation funded extensive regional implementation of community programs for obesity prevention, including an evidence-based elementary school-based health promotion program, adult nutrition and physical activity programs, and a radio and television advertising campaign. Results emphasize the need for sustained school, community, and policy efforts, and that these efforts can result in decreases in child obesity at the population level.

Cognitive susceptibility to smoking: Two paths to experimenting among Mexican origin youth.

Cognitive susceptibility to smoking, defined as the lack of a firm commitment not to smoke in the future or if offered a cigarette by a friend, begins in childhood and is an early phase in the transition from never to ever smoking. Our objectives were to examine susceptibility to smoking and other psychosocial risk factors for experimentation with cigarettes among Mexican origin adolescents and to determine whether susceptibility status moderates the relationship between established risk factors for experimentation with cigarettes and future experimentation. We examined susceptibility and several psychosocial factors associated with susceptibility as baseline predictors of experimentation after 3 years of follow-up among 964 Mexican origin girls and boys between 11 and 13 years of age from the Houston metropolitan area. Participants were recruited between May 2005 and October 2006 and reported that they had never experimented with cigarettes at baseline. Baseline susceptibility and experimentation rates were 23% and 9%, respectively, whereas the follow-up experimentation rate, among those who had not experimented at baseline, was 22%. Susceptible adolescents at baseline were 2.6 times more likely to have experimented with cigarettes by follow-up. Baseline susceptibility moderated the relationship between experimentation at follow-up and the psychosocial risk factors assessed at baseline. Susceptibility is a valid and strong marker for the transition to experimentation for Mexican origin adolescents. Our results suggest that tailoring primary prevention programs by a youth's susceptibility status may increase the efficacy of prevention efforts among Mexican origin youth.

Management and outcomes of anorectal infection in the cancer patient.

BACKGROUND: The objective of this retrospective cohort study is to examine the presentation and outcomes for a contemporary series of cancer patients with anorectal infection. In addition, we seek to identify factors which are associated with surgical intervention. METHODS: The study cohort was identified from International Classification of Disease (ICD)-9 codes for diagnosis of infection of the anal and rectal region and patients who underwent a surgical oncology consultation at The University of Texas M.D. Anderson Cancer Center between 1/2000 and 12/2006. Clinical presentation, treatment rendered, and outcomes were retrospectively recorded. RESULTS: Of the 100 patients evaluated by the surgical oncology service for anorectal infection, 42 were treated nonoperatively and 58 underwent surgical intervention. Factors associated with surgical intervention based on logistic multivariable analysis included diagnosis of an abscess [odds ratio (OR) 10.5, 95% confidence interval (CI) 2.9-38.5] and documentation of erythema on physical examination (OR 3.1, 95% CI 1.1-8.4). Thrombocytopenia (platelets <50,000) was associated with nonoperative management (OR 0.3, 95% CI 0.1-0.7). Incision and drainage was the most common surgical procedure (79%) while a wide debridement for a necrotizing soft tissue infection was required in two patients. Infection-specific 90-day mortality was 1% (n = 1), attributable to a necrotizing infection. However, median overall survival for the entire cohort was only 14.4 months (95% CI 7.9-19.5 months). CONCLUSIONS: Identification of an abscess, erythema on physical exam, and thrombocytopenia were associated with management strategy. Although rare, necrotizing soft tissue infections are associated with significant mortality.

A modified forward multiple regression in high-density genome-wide association studies for complex traits.

Genome-wide association studies (GWAS) have been widely used to identify genetic effects on complex diseases or traits. Most currently used methods are based on separate single-nucleotide polymorphism (SNP) analyses. Because this approach requires correction for multiple testing to avoid excessive false-positive results, it suffers from reduced power to detect weak genetic effects under limited sample size. To increase the power to detect multiple weak genetic factors and reduce false-positive results caused by multiple tests and dependence among test statistics, a modified forward multiple regression (MFMR) approach is proposed. Simulation studies show that MFMR has higher power than the Bonferroni and false discovery rate procedures for detecting moderate and weak genetic effects, and MFMR retains an acceptable-false positive rate even if causal SNPs are correlated with many SNPs due to population stratification or other unknown reasons.

Do minority or white patients respond to brief alcohol intervention in trauma centers? A randomized trial.

STUDY OBJECTIVE: The current study evaluates whether the effectiveness of brief alcohol intervention in reducing 6- and 12-month risk of injuries in a large Level I urban trauma center varies according to trauma patients' ethnicity. METHODS: Eligible white, Hispanic, and black trauma patients aged 18 years or older were randomized to brief alcohol intervention or treatment as usual. The intervention was a "non-confrontational, patient-centered conversation" focused on patients' drinking pattern, with the purpose of encouraging them to change risky drinking. Study outcomes were patient-reported 6- and 12-month incidence of all-type injuries, alcohol-related injuries, and serious injuries (ie, injuries requiring emergency department visit or hospital admission). RESULTS: A total of 1,493 trauma patients (668 whites, 537 Hispanics, 288 blacks) participated in this study. After 1 year of follow-up, we were not able to detect any important association between brief intervention and the risk of all-type injuries, alcohol-related injuries, or serious injuries among study participants. In addition, the association between brief intervention and the outcomes of interest was not modified by patients' ethnicity. CONCLUSION: Our study, congruent with some recent publications, implies that there are some patient- and provider-related impediments that could restrict the effectiveness of brief intervention programs in trauma centers, regardless of patient ethnicity. Unless those impediments are identified and eliminated, assuming that brief intervention will be an effective strategy for controlling future alcohol-related injuries among trauma patients and should be provided under any circumstances might not be reasonable.

Screening for traumatic brain injury in an offender sample: a first look at the reliability and validity of the Traumatic Brain Injury Questionnaire.

OBJECTIVE: To assess the reliability and validity of the Traumatic Brain Injury Questionnaire (TBIQ) for assessing history of traumatic brain injury (TBI) in an offender population. SETTING/PARTICIPANTS: Offenders (118 women and 107 men) from 6 federal prison facilities in 3 geographic regions. MEASURES: TBIQ and multiple measures of cognitive and behavioral functioning. RESULTS: Preliminary results indicated good test-retest reliability for lifetime history of head injury, good internal consistency for symptom severity and frequency scales, and good criterion validity for frequency of head injury and frequency and severity of symptoms. CONCLUSION: The TBIQ holds promise as an instrument for the assessment of TBI history in offender populations.

Response accuracy of hazard identification in migrant farm workers.

This study assessed potential biases introduced by using maternal proxies for reporting work hazards, illness symptoms, and acute agricultural injuries in studies of migrant farmworker families. A convenience sample of 79 mother/spouse and mother/oldest child pairs was obtained from a two-year cohort study of migrant farmworker families from Starr County, Texas. Pairs completed an interviewer-administered survey including 27 close-ended items describing work history, illness symptoms, and acute injuries during the 2001 migration season. Data analysis included prevalence, sensitivity, and specificity measures. Maternal proxy reports of subjective symptoms of a spouse or child were approximately 50% lower than spouse or child self-reports. Sensitivity and specificity of mothers' responses regarding hazard items were higher for spouses than for children. For items measuring illness symptoms, sensitivity of mothers' responses for spouses and oldest child pairs was generally less than 30%; however, specificity was generally above 90%. For acute agricultural injury, the mother/spouse sensitivity was 75%, the mother/child 40%, and specificities were 100% and 97%, respectively. Sensitivity and specificity for mother/ spouse pairs was generally higher than mother/child pairs for work hazards, illness symptoms and acute injuries. While mothers may be acceptable proxies for spouses in this population, efforts should be made to collect data directly from adolescent children in studies of agricultural injuries.

A cohort study of injuries in migrant farm worker families in South Texas.

PURPOSE: This cohort study estimated the frequency of and risk factors for work injuries among migrant farmworker families over a two-year period. METHODS: The cohort consisted of 267 families. Bilingual interviewers asked mothers to respond for their family soliciting demographic, psychosocial, employment, and work-related injury information. Cox regression was used to examine risk factors for first injury events. RESULTS: Of the 267 families, nearly 60% migrated and 96% of these completed the follow-up interviews. These families represented about 310 individuals each year who had participated in farmwork on average 6 days a week, 10 hours a day, for 2.7 months in the past year. Twenty-five work-related injuries were reported with an overall rate of 12.5/100 FTE (95% C.I., 8.6-19.0). Working for a contractor increased the hazard ratio, and use of car seat belts and working for more than one employer during the season decreased it. CONCLUSIONS: If person-time at risk for injuries is taken into account the reported injuries are substantial. Because the injuries were quite diverse, specific interventions may have to focus on improved working conditions (physical and economic), ergonomic modifications, and enhanced enforcement of existing regulations.