Faculty Bibliography

OBJECTIVE:To compare the efficacy of a regimen combining mental practice (MP) with overground training (OT) with the efficacy of a regimen consisting of OT only on gait velocity and lower extremity motor outcomes in individuals with chronic (>12mo postinjury), incomplete spinal cord injury (SCI). DESIGN/METHODS:Randomized, controlled, single-blinded study. SETTING/METHODS:Outpatient rehabilitation laboratories. PARTICIPANTS/METHODS:Subjects with chronic, incomplete SCI (N=18). INTERVENTIONS/METHODS:Subjects were randomly assigned to receive (1) OT only, occurring 3d/wk for 8 weeks; or (2) OT augmented by MP (MP + OT), during which randomly assigned subjects listened to an MP audio recording directly after OT sessions. MAIN OUTCOME MEASURES/METHODS:Subjects were administered a test of gait velocity as well as the Tinetti Performance Oriented Mobility Assessment, Spinal Cord Injury Independence Measure, and Satisfaction With Life Scale on 2 occasions before intervention, 1 week after intervention, and 12 weeks after intervention. RESULTS:A significant increase in gait velocity was exhibited across subjects at both 1 week posttherapy (P=.005) and at 12 weeks posttherapy (P=.006). However, no differences were seen in intervention response at either 1 or 12 weeks postintervention among subjects in the MP + OT group versus the OT-only group. CONCLUSIONS:OT was associated with significant gains in gait velocity, and these gains were not augmented by further addition of MP.

The use of propensity score methods to adjust for selection bias in observational studies has become increasingly popular in public health and medical research. A substantial portion of studies using propensity score adjustment treat the propensity score as a conventional regression predictor. Through a Monte Carlo simulation study, Austin and colleagues. investigated the bias associated with treatment effect estimation when the propensity score is used as a covariate in nonlinear regression models, such as logistic regression and Cox proportional hazards models. We show that the bias exists even in a linear regression model when the estimated propensity score is used and derive the explicit form of the bias. We also conduct an extensive simulation study to compare the performance of such covariate adjustment with propensity score stratification, propensity score matching, inverse probability of treatment weighted method, and nonparametric functional estimation using splines. The simulation scenarios are designed to reflect real data analysis practice. Instead of specifying a known parametric propensity score model, we generate the data by considering various degrees of overlap of the covariate distributions between treated and control groups. Propensity score matching excels when the treated group is contained within a larger control pool, while the model-based adjustment may have an edge when treated and control groups do not have too much overlap. Overall, adjusting for the propensity score through stratification or matching followed by regression or using splines, appears to be a good practical strategy.

The possibility that cytokine administration could enhance the antitumor effects of proteasome inhibition was explored. It was found that coadministration of bortezomib and interferon-α (IFN-α) induced synergistic apoptosis in human melanoma cell lines and prolonged survival in a murine model of melanoma. A phase I study was conducted to determine the tolerability and the maximum tolerated dose of bortezomib when administered in combination with IFN-α-2b to patients with metastatic melanoma. Patients were treated on a 5-week cycle. In week 1 of cycle 1, patients received 5 million U/m(2) IFN-α subcutaneously thrice weekly. During weeks 2-4 of cycle 1, bortezomib was administered intravenously weekly along with IFN-α thrice weekly. There was a treatment break during week 5. After cycle 1, bortezomib was administered in combination with IFN-α. Bortezomib was administered in escalating doses (1.0, 1.3, or 1.6 mg/m) to cohorts of 3 patients. Sixteen patients were treated (8 women, 8 men; median age 59 y). Common grade 3 toxicities included fatigue (5), vomiting (3), and diarrhea (3). Grade 4 toxicities included fatigue (3) and lymphopenia (1). The maximum tolerated dose for bortezomib was 1.3 mg/m(2). One patient had a partial response, and 7 had stable disease. Progression-free survival was 2.5 months, and overall survival was 10.3 months. Bortezomib administration did not augment the ability of IFN-α to induce phosphorylation of STAT1 in circulating immune cells; however, it did lead to reduced plasma levels of proangiogenic cytokines. The combination of bortezomib and IFN-α can be safely administered to melanoma patients.

Cardiac surgery associated acute kidney injury (CSA-AKI) is associated with poor outcomes including increased mortality, length of hospital stay (LOS) and cost. The incidence of acute kidney injury (AKI) is reported to be between 3 and 30% depending on the definition of AKI. We designed a multicenter randomized controlled trial to test our hypothesis that a perioperative infusion of sodium bicarbonate (SB) during cardiac surgery will attenuate the post-operative rise in creatinine indicating renal injury when compared to a perioperative infusion with normal saline. An interim analysis was performed after data was available on the first 120 participants. A similar number of patients in the two treatment groups developed AKI, defined as an increase in serum creatinine the first 48 h after surgery of 0.3 mg/dl or more. Specifically 14 patients (24%) who received sodium chloride (SC) and 17 patients (27%) who received SB were observed to develop AKI post-surgery, resulting in a relative risk of AKI of 1.1 (95% CI: 0.6-2.1, chi-square p-value = 0.68) for patients receiving SB compared to those who received SC. The data safety monitoring board for the trial recommended closing the study early as there was only a 12% probability that the null hypothesis would be rejected. We therefore concluded that a perioperative infusion of SB failed to attenuate the risk of CSA-AKI.

BACKGROUND:While tamoxifen activity is mainly due to endoxifen and the concentration of this active metabolite is, in part, controlled by CYP2D6 metabolic status, clinical correlative studies have produced mixed results. FINDINGS/RESULTS:In an exploratory study, we determined the CYP2D6 metabolic status and plasma concentrations of endoxifen among 224 Filipino and Vietnamese women participating in a clinical trial of adjuvant hormonal therapy for operable breast cancer. We further conducted a nested-case-control study among 48 women (half with recurrent disease, half without) investigating the relationship of endoxifen concentrations and recurrence of disease. We found a significant association of reduced endoxifen plasma concentrations with functionally important CYP2D6 genotypes. High endoxifen concentrations were associated with higher risk of recurrence; with a quadratic trend fitted to a stratified Cox proportional hazards regression model, the likelihood ratio p-value was 0.002. The trend also showed that in 8 out of 9 pairs with low endoxifen concentrations, the recurrent case had lower endoxifen levels than the matched control. CONCLUSIONS:This exploratory analysis suggests that there is an optimal range for endoxifen concentrations to achieve favorable effects as adjuvant therapy. In particular, at higher concentrations (>70 ng.ml), endoxifen may promote recurrence.

OBJECTIVES/OBJECTIVE:To examine prestroke lifestyle factors associated with poststroke mortality and recovery in older women. DESIGN/METHODS:Longitudinal prospective cohort study. SETTING/METHODS:The Women's Health Initiative (WHI, clinical trials and observational study), 40 clinical centers in the United States. PARTICIPANTS/METHODS:WHI participants, women aged 50 to 79, who were stroke-free at baseline (1993/98), with incident stroke before 2005. MEASUREMENTS/METHODS:Participants were followed for mortality through 2010. Prestroke characteristics were from the last examination before the stroke event. Annual follow-up for clinical events ascertained hospitalization for stroke that was subsequently physician adjudicated with medical records. Multivariable regression models were used to analyze factors associated with poststroke mortality and poststroke recovery at hospital discharge (poststroke Glasgow score), adjusting for stroke type. RESULTS:Of 3,173 women with incident stroke, 1,111 (35%) died. Individuals who were overweight or obese before stroke had lower poststroke mortality than those who were normal weight (obese: hazard ratio (HR) = 0.69, 95% confidence interval (CI) = 0.53-0.88; overweight: HR = 0.72, 95% CI = 0.58-0.90); individuals who were underweight before stroke had nonsignificantly greater poststroke mortality (HR = 2.02, 95% CI = 0.98-4.16, P = .06). Other prestroke factors associated with poststroke mortality included diabetes mellitus (HR = 1.28, 95% CI = 1.01-1.64), current smoking (vs nonsmoker, HR = 2.13, 95% CI = 1.53-3.00), physical inactivity (vs >150 min of exercise per week, HR = 1.39, 95% CI = 1.09-1.78), and lowest physical function quartile (vs highest, HR = 1.54, 95% CI = 1.18-2.02). Prestroke diabetes mellitus was associated with lower odds of good recovery after stroke (odds ratio (OR) = 0.60, 95% CI = 0.44-0.82). Current hormone use before stroke was associated with greater odds of moderate than of severe disability after stroke (OR = 1.29, 95% CI = 1.00-1.66). CONCLUSION/CONCLUSIONS:Potentially modifiable factors before stroke, including smoking, diabetes mellitus, and being underweight, were associated with greater poststroke mortality in older women. Being overweight or obese and physical activity before stroke were associated with lower poststroke mortality in older women.

Substantial variation across states in the prevalence and trends in childhood overweight and obesity indicate a need for state-specific surveillance to make state comparisons to national estimates and identify high-risk populations. The purpose of this study was to examine body mass index (BMI) trends among third-grade children in Ohio between the 2004-2005 and 2009-2010 school years and examine changes in prevalence of obesity by specific demographic subgroups. Third-grade children (n=33,672) were directly weighed and measured throughout the school years by trained health care professionals. Trends in overweight/obesity (≥85th percentile of BMI by age/sex), obesity (≥95th percentile), and obesity level 2 (≥97th percentile) over five time periods (2004-2005, 2006-2007, 2007-2008, 2008-2009, 2009-2010) were modeled using logistic regression, accounting for the survey design and adjusting for sex, race/ethnicity, National School Lunch Program (NSLP) participation, and age. Differences in these BMI categories were also examined by these subgroups. BMI estimates did not demonstrate a statistically significant trend over the five time periods for overweight/obesity (34% to 36%), obesity (18% to 20%), or obesity level 2 (12% to 14%). However, increases in overweight/obesity prevalence were found in Hispanic children (37.8% vs 53.1%; P<0.01). Decreases in obesity (16.6% vs 14.1%; P=0.02) and obesity level 2 (11.3% vs 9.3%; P=0.02) were found among children not participating in NSLP and residing in suburban counties (obesity [17.3% vs 14.7%; P=0.03] and obesity level 2 [11.8% vs 9.8%; P=0.05]). Finally, decreases in overweight/obesity and obesity level 2 among boys were observed (15% vs 12.9%; P=0.02). Despite no significant overall trends in overweight/obesity, obesity, or obesity level 2 between 2004 and 2010, prevalence changed among specific subgroups. Obesity prevention efforts should be widespread and include special emphasis on groups experiencing increases or no change in prevalence.

BACKGROUND:Cervical cancer incidence and mortality rates are high among women from Appalachia, yet data do not exist on human papillomavirus (HPV) prevalence among these women. We examined the prevalence of genital HPV among Appalachian women and identified correlates of HPV detection. METHODS:We report data from a case-control study conducted between January 2006 and December 2008 as part of the Community Awareness, Resources, and Education (CARE) Project. We examined HPV prevalence among 1116 women (278 women with abnormal Pap tests at study entry [cases], 838 women with normal Pap tests [controls]) from Appalachian Ohio. Analyses used multivariable logistic regression to identify correlates of HPV detection. RESULTS:The prevalence of HPV was 43.1% for any HPV type, 33.5% for high-risk HPV types, 23.4% for low-risk HPV types, and 12.5% for vaccine-preventable HPV types. Detection of any HPV type was more common among women who were ages 18-26 (OR = 2.09, 95% CI: 1.26-3.50), current smokers (OR = 1.86, 95% CI: 1.26-2.73), had at least five male sexual partners during their lifetime (OR = 2.28, 95% CI: 1.56-3.33), or had multiple male sexual partners during the last year (OR = 1.98, 95% CI: 1.25-3.14). Similar correlates were identified for detection of a high-risk HPV type. CONCLUSIONS:HPV was prevalent among Appalachian women, with many women having a high-risk HPV type detected. Results may help explain the high cervical cancer rates observed among Appalachian women and can help inform future cervical cancer prevention efforts in this geographic region.

There is a need for time-efficient, valid measures of distal paretic upper extremity (UE) movement. The purposes of this study were to (1) determine the psychometric properties of the wrist stability and mobility and wrist/hand scale of the upper extremity Fugl-Meyer (w/h UE FM) as a "stand-alone" measure of distal UE movement; and (2) provide detailed instructions on w/h UE FM administration and scoring. The upper extremity Fugl Meyer (UE FM) and Action Research Arm Test (ARAT) were administered on 2 separate occasions to each of 29 subjects exhibiting stable, mild UE hemiparesis (23 men; mean age ± SD, 60.8±12.3 y; mean time since stroke onset for subjects in the sample, 36.0 mo). Fifty-eight observations were collected on each measure. w/h UE FM internal consistency levels (measured by Cronbach α) were high (.90 and .88 for first and second testing sessions, respectively). The intraclass correlation coefficient for the UE FM was .98, while the intraclass correlation coefficient for the w/h UE FM was .97. Concurrent validity measured by Spearman correlation was moderately high between the w/h UE FM and ARAT (.72, P<.001). From these data, it appears that the w/h UE FM is a promising tool to measure distal UE movement in minimally impaired stroke, although more research with a larger sample is needed. A standardized approach to UE test administration is critical to accurate score interpretation across patients and trials. Thus, the article also provides instructions and pictures for w/h UE FM administration and scoring.