ACRT‐SCTS Scholar Abstracts

doi:10.1111/j.1752-8062.2010.00181_2.x

. 2010 Mar 25;3(2):S8–S55. doi: 10.1111/j.1752-8062.2010.00181_2.x

ACRT‐SCTS Scholar Abstracts

PMCID: PMC5350643

CLINICAL EPIDEMIOLOGY

A‐001

SERUM ALKALINE PHOSPHATASE AND RISK OF MORTALITY AND HOSPITALIZATION

Abramowitz M ¹, Muntner P², Coco M¹, Southern W¹, Lotwin I¹, Hostetter T¹, Melamed M¹  ¹Albert Einstein College of Medicine/Montefiore Medical Center, Bronx, NY, United States, ²University of Alabama at Birmingham, Birmingham, AL, United States

OBJECTIVES: Elevated alkaline phosphatase (AlkP) levels have been associated with mortality and vascular calcification in patients with ESRD. We conducted a retrospective cohort study to test whether higher levels of serum AlkP are associated with mortality and hospitalization in an outpatient population without CKD. METHODS AND POPULATION: Patients without a history of cancer, liver disease, HIV or transplantation with an eGFR ≥60 ml/min/1.73m² who had serum AlkP level measured between 2000 and 2002 (n = 10,743) at Montefiore Medical Center (MMC) clinics were followed through 9/11/08 (median 6.8 yrs). Mortality data were obtained via linkage to the Social Security Administration (n = 949 deaths). Hospitalization data were obtained from MMC records. Cox proportional hazards models were constructed to compare mortality and hospitalizations at different levels of AlkP. RESULTS: The mean age of the participants was 51 years, 64% were female, 26% were non‐Hispanic black, 16% were Hispanic, 13% had a diagnosis of hypertension, 9% had diabetes mellitus, and 8% had cardiovascular disease. Compared to the lowest quartile of AlkP (≤66 U/L), the relative hazard (RH) for mortality for patients in the highest quartile (≥104 U/L) after multivariable adjustment was 1.67 (95% CI 1.37‐2.03) (p‐trend across AlkP quartiles <0.001). High AlkP levels were also associated with all‐cause, infection‐related, and fracture‐related hospitalization. SIGNIFICANCE OF STUDY: Higher levels of serum AlkP are associated with mortality and risk for cardiovascular, fracture, and infection‐related hospitalization in an inner‐city clinic population. Studies are needed to further delineate mechanisms underlying these associations, including the role of AlkP inhibition in the prevention of human disease.

A‐002

BMI AND WC AS PREDICTORS OF 14‐YEAR ALL‐CAUSE, CARDIOVASCULAR, AND CANCER MORTALITY AMONG OLDER MEXICAN AMERICANS

Al Snih S ¹, Markides KS¹, Ottenbacher KJ¹, Goodwin JS¹  ¹University of Texas Medical Branch, Galveston, TX, United States

OBJECTIVES: To examine the effect of body mass index (BMI) and waist circumference (WC) on all‐cause, cardiovascular (CV), and cancer mortality among older Mexican Americans. METHODS AND POPULATION: A 14‐year prospective cohort study of 2575 non‐institutionalized men and women aged 65 and older from the Hispanic Established Population for the Epidemiological Study of the Elderly (1993‐94 to 2007). Measures included socio‐de‐mographic, smoking, medical conditions, BMI, and WC. Cox proportional regression analysis was used to estimate the hazard ratio for mortality over time by gender. RESULTS: At baseline, the mean BMI (Kg/m2) for men and women was 27.1 and 28.4, respectively, and the mean WC (cm) was 101.7 and 99.4, respectively. When BMI and WC were examined simultaneously, high BMI was associated with lower risk of all‐cause mortality in women, and WC was associated with high risk of all‐cause mortality in men and women. High WC was associated with high risk of CV mortality only in women. High BMI and high WC were not associated with all‐cancer mortality in either men or women. SIGNIFICANCE OF STUDY: Obesity measured by waist circumference is more predictive of mortality, especially among women, in older Mexican Americans than is obesity measured by the BMI.

A‐003

CLASS II HUMAN LEUKOCYTE ANTIGEN ALLELES ASSOCIATED WITH ABNORMAL VAGINAL FLORA

Allsworth J ¹, Peipert J¹, Bowcock A¹  ¹Washington University in St. Louis, St. Louis, MO, United States

OBJECTIVES: Disruption of vaginal flora is common with one third of women having bacterial vaginosis (BV). BV has serious health consequences – it may increase STD risk and preterm birth. Vaginal bacterial colonization may be regulated, in part, by human leukocyte antigen (HLA) class II gene products. Prior studies have demonstrated that HLA alleles may be associated with susceptibility to BV. This study reports preliminary data examining whether abnormal vaginal flora is associated with HLA‐DR alleles. METHODS AND POPULATION: Data were collected as part of a survey of 399 women and included questionnaire, blood draw, and vaginal swabs. Vaginal flora was assessed by Nugent score. Genotyping was completed using a linear array assay PCR/Sequence‐Specific Oligonucleotide Probe methodology. Relative risk estimates were generated from Poisson regression with robust error variance and mean differences using linear regression. RESULTS: This analysis presents data on 215 African American women. We examined the association with continuous Nugent score or BV, considering candidate alleles to be those with a mean change in Nugent of 1 or larger and a p‐value < 0.20. Among these alleles we identified 4 potential susceptibility alleles (DRB‐0101, 0302, 0405, 0802) that were associated with a 1.0‐4.1 unit difference in Nugent score. These alleles were associated with a 40‐90% increase in the risk of bacterial vaginosis. Conversely, 2 alleles were associated with lower Nugent scores (DRB‐1102, 1303), a slight decrease in the risk of BV (RR 0.7‐0.8) and may be protective alleles. SIGNIFICANCE OF STUDY: This preliminary study sought to identify potential alleles that may be associated with increased or decreased susceptibility to abnormal vaginal flora. Additional research is needed to replicate these findings.

A‐004

SERUM URIC ACID IS A GFR‐INDEPENDENT LONG‐TERM PREDICTOR OF RENAL INSUFFICIENCY: A LIPID RESEARCH CLINIC FOLLOW‐UP STUDY

Ben‐Dov IZ ¹, Kark JD²  ¹The Rockefeller University, New York, NY, United States, ²Hadassah ‐ Hebrew University Medical Center, Jerusalem, Israel

OBJECTIVES: To assess the long term prediction of renal failure by serum uric acid levels in a longitudinal population study. METHODS AND POPULATION: At Visit 2 of the Jerusalem Lipid Research Clinic study, 2426 of 2544 participants (aged 35‐78 in 1976‐79, 40% women) with extensive sociodemographic, physical and laboratory characterization had an estimated GFR >60 ml/min/1.73m2. We obtained the 25‐year incidence of mortality (582 events) and hospital‐diagnosed kidney failure (132 events, 69% chronic renal failure) by data linkage. Cox proportional hazards modeling was applied. RESULTS: SUA was positively associated with age (women only), BMI, BP, serum creatinine, GOT, ALKP, globulins, plasma total cholesterol (women) and triglycerides, inversely with HDL‐cholesterol, smoking, diabetes and dietary protein, and positively with education in men and inversely in women. SUA was robustly associated with all‐cause mortality; adjusted HR=1.35 (1.11‐1.65) for the 5th quintile vs. quintiles 1‐4 (p=0.003). SUA was a robust predictor of renal failure with a multivariable‐adjusted (including creatinine) HR=1.44 (1.24‐1.67) per mg/dl SUA (p<0.0001). It predicted kidney failure in patients with either normal baseline eGFR (≥90 ml/min/1.73m2, 57 events; HR=1.66 (1.32‐2.09, p<0.0001) or subnormal eGFR (<90 ml/min/1.73m2, 75 events; HR=1.35 (1.10‐1.65, p=0.004). The renal HRs associated with SUA were not linear; the 5th sex‐specific quintile (SUA >6.5 mg/dl in men, and >5.2 mg/dl in women) had the greatest step‐up in risk, adjusted HR=2.59 (1.80‐3.74) vs. quintiles 1‐4 (p<0.0001). SIGNIFICANCE OF STUDY: SUA predicts mortality and renal failure incidence independent of its demographic and clinical correlates. Treating asymptomatic hyperuricemia might alter the risks.

A‐005

THE RISK OF SERIOUS INFECTION IN JUVENILE IDIOPATHIC ARTHRITIS

Beukelman T ¹, Delzell E¹, Saag KG¹  ¹University of Alabama at Birmingham, Birmingham, AL, United States

OBJECTIVES: To determine the clinical risk factors for serious infection among children with juvenile idiopathic arthritis (JIA) using Medicaid administrative claims data. METHODS AND POPULATION: The study data source will be national Medicaid Analytic eXtract (MAX) files from 1999 – 2005. Subject cohorts will be identified using a combination of physician diagnosis codes and pharmacy claims. The serious infection outcome will be defined by physician hospital discharge diagnosis codes. Control for potential confounding will be attempted using multi‐variable adjustment, propensity score methods, and instrumental variable analysis. Comparisons between JIA subjects and control subjects will be analyzed using Poisson regression. Comparisons between JIA subjects with different medication exposures will be analyzed using a new user design and Cox proportional hazards models. RESULTS: We hypothesize that children with JIA have an increased risk of serious infection compared to children without autoimmune disease, but not significantly increased from children with psoriasis. We hypothesize that among children with JIA, treatment with TNF inhibitors is an independent risk factor for an increased rate of serious infections, controlled for JIA disease severity. SIGNIFICANCE OF STUDY: Establishing the incidence of serious infection among children with JIA will provide a standard of comparison for future prospective studies of new therapeutic agents. Defining the risk factors for serious infection, including TNF inhibitor treatment, will allow for greatly improved informed decision making and patient care.

A‐006

ETHNIC GROUP DIFFERENCES IN INSULIN RESISTANCE‐ASSOCIATED PARAMETERS DUE TO SUGAR‐SWEETENED BEVERAGE INTAKE AND PHYSICAL ACTIVITY LEVELS

Bremer AA ¹, Byrd RS¹, Auinger P²  ¹UC Davis, Sacramento, CA, United States, ²University of Rochester, Rochester, NY, United States

OBJECTIVES: Given that sugar‐sweetened beverage (SSB) intake and physical activity (PA) levels are associated with insulin resistance‐associated parameters in adolescents at a population level, we sought to determine whether differences exist among ethnic groups and between the sexes. METHODS AND POPULATION: Data from 6,967 individuals aged 12‐19 years from the National Health and Nutrition Examination Survey (NHANES) during the years 1999‐2004 were analyzed. SSB intake and PA levels were studied, and the outcome measures included a homeostasis model assessment of insulin resistance (HOMA‐IR), total cholesterol (TC) levels, HDL‐cholesterol (HDL‐C) levels, LDL‐cholesterol (LDL‐C) levels, triglyceride (TG) levels, systolic blood pressure (SBP), diastolic blood pressure (DBP), waist circumference (WC), and body mass index (BMI) percentile for age‐sex. RESULTS: Controlling for SSB intake and PA levels, adolescents from ethnic minorities had an increased HOMA‐IR, SBP, WC, and BMI percentile for age‐sex compared to non‐Hispanic whites. Furthermore, adolescents from ethnic minorities (especially non‐Hispanic blacks) had higher HDL‐C and lower TG levels than their Caucasian counterparts. Many sex‐specific differences among the various ethnic groups were also observed. SIGNIFICANCE OF STUDY: The relationship between insulin resistance‐associated parameters and SSB intake and PA levels varies among ethnic groups and between the sexes. These findings illustrate the importance of race and sex in the investigation of disease processes and may have important implications for the diagnosis, prevention, and treatment of metabolic syndrome among individuals of different ethnicities.

A‐007

VITAMIN D IN ETHNICALLY DIVERSE POPULATION WITH LUPUS (SLE) AND TYPE 2 DIABETES (DM2)

Broder A ¹, Putterman C¹  ¹Albert Einstein College of Med/Montefiore Medical Center, Bronx, NY, United States

OBJECTIVES: Over 60% of SLE patients are VitD deficient. Only a few studies compared vitD in SLE and other chronic diseases. VitD deficiency may be multifactorial and may reflect chronic disease state. We compared vitD (25OHD) levels in 2 chronic disease, SLE and DM2. We also compared the rates of vitD deficiency in our patients with the rates reported from the most recent NHANES (The National Health and Nutrition Examination Survey) data 2001‐2004. METHODS AND POPULATION: We identified patients followed at Montefiore Medical Center (Bronx, NY) with confirmed diagnoses of SLE or DM2 who had 25OHD measured between 2000 and 2009. Patients with both diseases, or with coexisting diagnoses of other autoimmune diseases, were excluded. RESULTS: We included 123 SLE and 3691 DM2 patients with confirmed diagnoses in our final analysis. Almost 70% were African‐American (AA) or Hispanic (H). Compared with SLE patients, the odd ratio of having low 25OHD was 2.0, 95%CI (1.3, 3.1) in the DM2 group, p = 0.003. However, based on the results of the most recent NHANES survey, the prevalence of 25OHD deficiency was lower in our DM2 and SLE patients than in the general population. In the multivariate analysis, in 1132 AA, younger age, low serum calcium, high serum creatinine, and season (October ‐ March) were associated with 25OHD < 20 ng/ml. In 927 non‐AA/non‐H, DM2, younger age, and low serum calcium were associated with 25OHD levels < 20 ng/ml. In 1030 H, only younger age and low serum calcium were associated with the higher odds of vitamin D deficiency. SIGNIFICANCE OF STUDY: The prevalence of 25OHD deficiency in SLE and DM2 patients was not higher than in the general population in the NHANES 2001 – 2004. SLE patients were less likely than DM2 patients to be 25OHD deficient. Disease‐specific and ethnicity‐specific definitions may need to be established.

A‐008

THE PREVALENCE OF PEDIATRIC HOSPITALIZATION FOR PYELONEPHRITIS IN CALIFORNIA INCREASES: RESULTS FROM A STATEWIDE HOSPITAL DISCHARGE DATABASE

Halpern MS², MaldonadoY², Shortliffe LD², Copp HL ¹  ¹University of California at San Francisco, San Francisco, CA, United States, ²Stanford University, Stanford, CA, United States

OBJECTIVES: Evidence supports that outpatient management of pyelonephritis (PN) is safe and effective. However, studies indicate that hospitalization adjusted for population growth for this diagnosis have not decreased, but remained stable. METHODS AND POPULATION: We evaluated trends in admission for PN for all children <18yrs from 1985‐2006 using the Office of Statewide Health Planning and Development database, a database that captures all discharges from acute care facilities in California (CA). Multivariate analysis was done to identify factors associated with PN admission. RESULTS: 46,300 children were hospitalized for PN in CA from 1985‐2006. The odds of hospitalization for PN increased by 4% per year. Males (OR 10.6) and females (OR 2.7) <1yr were more likely to be admitted than males and females 1‐<2yrs. Black, Hispanic, and Asian males had an increased odds of hospitalization compared to Whites whereas females had a decreased odds of hospitalization in Blacks, Hispanics, and Asians versus Whites. Males with private insurance were less likely to be hospitalized compared to Medicare/Medi‐Cal patients. SIGNIFICANCE OF STUDY: Despite data supporting outpatient management of PN, a large number of children receive inpatient care. Increased PN admissions may be related to a general increase in the prevalence of PN, more severe disease in minority boys and younger patients, and/or unequal access to healthcare.

A‐009

CHANGE IN ROTAVIRUS EPIDEMIOLOGY IN NORTHEAST FLORIDA AFTER THE INTRODUCTION OF ROTAVIRUS VACCINE

Custodio H ¹, Masnita‐Iusan C², Wludyka P², Rathore M¹  ¹University of Florida‐Jacksonville, Jacksonville, FL, United States, ²University of North Florida, Jacksonville, FL, United States

OBJECTIVES: National reports show decreased number and severity of rotavirus infections as well as delayed onset and shorter season after the introduction of the pentavalent rotavirus vaccine (RV5) in 2006. The objective of the study was to determine the epidemiology of rotavirus infections and hospitalizations in northeast Florida pre‐ and post‐licensure of RV5. METHODS AND POPULATION: A retrospective analysis was performed to compare rotavirus infections and hospitalizations in children less than 18 years of age in the pre‐vaccine period (January 1, 2004 to December 31, 2006) and vaccine period (January 1, 2007 to December 31, 2009). The number of RV5 doses distributed in northeast Florida was obtained. Season pattern in terms of onset, peak and end was determined. RESULTS: The proportion of positive tests decreased significantly from 27.3% to 13.1% in the pre‐vaccine and vaccine periods, respectively (P < 0.0001). Among those who had rotavirus infections, there was significant decrease in the proportion of hospitalization: from 30.6% in the pre‐vaccine period to 20.6% (P = 0.0024) in the vaccine period. The rotavirus season was delayed in onset by 8 months and duration prolonged by 2‐3 months in 2008 and did not occur in 2009. SIGNIFICANCE OF STUDY: There was a decrease in infections and hospitalizations due to rotavirus in northeast Florida after the introduction of RV5. The rotavirus season seems to be evolving. Continued surveillance over the next several years is critical to determine if these changes are sustained over time.

A‐010

COMMON GENETIC RISK FACTORS FOR ISCHEMIC STROKE AND CORONARY ARTERY DISEASE

Dahabreh IJ ¹, Kitsios G¹, Trikalinos TA¹, Kent DM¹  ¹Tufts Medical Center, Boston, MA, United States

OBJECTIVES: We hypothesized that polymorphisms associated with coronary artery disease (CAD) in large meta‐analyses may also be implicated in ischemic stroke (IS). We thus assessed the credibility of validated CAD polymorphisms in IS. METHODS AND POPULATION: We reviewed meta‐analyses indexed by the Human Genome Epidemiology Network (HuGENet) to identify validated CAD polymorphisms, i.e. those with statistically significant summary odds ratio and >30 studies. We then searched HuGENet and PubMed (through 07/31/2009) for meta‐analyses on the same polymorphisms in IS. For polymorphisms without a published meta‐analysis we performed one de novo, using allele‐based random effects models. For significant associations (p<0.05) we calculated the False Positive Report Probability (FPRP). RESULTS: We found 9 validated variants for CAD: F2‐rs1799963, SERPINE1‐rs1799889, AGT‐rs699, F5‐rs6025, MTHFR‐rs1801133, APOE‐e4, ACE‐rs4646994, CETP‐rs708272 and PON1‐rs662. For the first 7 there were published meta‐analyses on associations with IS. Five were significant, with the exception of rs699 and rs1799889. We performed de novo meta‐analyses for rs662 and rs708272 and IS. Summary odds ratios were 1.10 (95% CI, 1.04‐1.17) for rs662 (22 studies, 7384 cases/11074 controls, per G‐allele) and 1.3 (95% CI, 1.05‐1.63) for rs708272, (2 studies, 311 cases/336 controls, per B1‐allele). FPRP was <20% for a wide range of prior probabilities of a true association only for rs4646994. SIGNIFICANCE OF STUDY: Overall, seven of nine polymorphisms identified as risk factors for CAD appear to also be potential risk factors for IS. Genetic convergence between CAD and IS may reflect true genetic effects on common aspects of the pathophysiology of these diseases, correlations between phenotypes, biases, or interplay of all these factors. Genetic associations in IS have limited credibility.

A‐011

INTRADIALYTIC HYPERTENSION AND MORTALITY IN HEMODIALYSIS PATIENTS

Dalrymple L ¹, Chin A¹, Kaysen G¹, Nguyen D¹  ¹University of California, Davis, Sacramento, CA, United States

OBJECTIVES: Intradialytic hypertension (ID‐HTN), an increase in blood pressure during hemodialysis, occurs in a select portion of dialysis patients. We examined whether ID‐HTN was associated with an increased risk of mortality. METHODS AND POPULATION: We conducted a retrospective cohort study of adult patients who started dialysis between January 1,1996 and June 1,2005 at four outpatient dialysis centers in Sacramento, CA. Mean change in intradialytic systolic blood pressure (SBP) was classified into categories: < ‐ 10, ≤ 10 & ≥ ‐10, or > 10 mmHg. ID‐HTN was defined as a SBP change > 10 mmHg. In a sensitivity analysis, SBP change was also examined as a continuous variable. Cox proportional hazards models were used to examine the association between ID‐HTN and mortality. The adjusted model included demographics, comorbidities, dialysis factors and baseline SBP. RESULTS: Of the 679 patients included, 59 had ID‐HTN. In the unadjusted analysis, ID‐HTN was associated with a 90% increase in mortality (HR 1.92, 95% CI 1.29, 2.84). However, in the adjusted model, ID‐HTN was not associated with an increase in mortality (HR 1.07, 95% CI 0.67, 1.69). In contrast, when SBP change was modeled as a continuous variable, a 1 mmHg increase in SBP was associated with a 1% increase in mortality (HR 1.01; 95% CI 1.001 to 1.019), corresponding to a 10% increase in risk for each 10 mmHg rise in SBP. SIGNIFICANCE OF STUDY: Our study found ID‐HTN, defined as a more than 10 mmHg rise in SBP, was not associated with mortality. However, when SBP was examined as a continuous exposure, an increase in SBP was associated with an increased risk of death. A rise in SBP during dialysis may be associated with an increased risk of death, however, the threshold at which a clinically significant rise in mortality occurs remains to be defined.

A‐012

GENDER DIFFERENCES IN SARCOPENIA TRAJECTORY

Dam T ¹, Bettencourt R², Barrett‐Connor E²  ¹Columbia University, New York, NY, United States, ²University California San Diego, San Diego, CA, United States

OBJECTIVES: Sarcopenia is common among older adults and has serious consequences including increased risk of mobility disability, functional dependency and mortality. The factors involved in the development of sarcopenia is unclear. The development of sarcopenia is not fully attributed to reduced physical activity or a sedentary state. Few studies have repeated measures of muscle mass and strength. The objectives of this study is to examine the longitudinal association of age with body fat, muscle mass and grip strength (GS) and to determine whether these age‐derived slopes differ between men and women. METHODS AND POPULATION: The participants this study included 1184 (724 women, 464 men) community dwelling adults from the Rancho Bernardo cohort who had measures of GS, lean muscle mass and body fat obtained from whole body dual energy x‐ray absorptiometry scans. These measures were initially collected in 1992‐1996 and repeated approximately every 4 years for 3 additional visits. Sarcopenia trajectories were examined over a total of 12 years. RESULTS: At baseline, the mean age was 68.8 (10.8) and mean BMI was 25.5 (3.7). Women had lower grip strength, total lean mass, appendicular lean mass (ALM), but greater total body fat than men. At baseline, older adults had weaker grip strength, lower total lean mass, ALM, and body fat. Men and women aged >=72 had lower grip strength, lower ALM and lower total lean mass at baseline. Over 12 years, men and women >=72 had a steeper rate of decline with grip strength, ALM and total lean mass; but a slower increase in total body fat and truncal fat compared to adults <72 years old. SIGNIFICANCE OF STUDY: The trajectories of grip strength, lean mass and body fat differed by age and gender. Whether these different trajectory patterns predict clinical outcomes need further examination.

A‐013

EXECUTIVE DYSFUNCTION AND INSTRUMENTAL ACTIVITIES OF DAILY LIVING PERFORMANCE IN PARKINSON'S DISEASE WITHOUT DEMENTIA

Foster E¹  ¹Washington University School of Medicine, St. Louis, MO, United States

OBJECTIVES: Executive functions orchestrate instrumental activities of daily living (IADL), which are essential for productive and independent living. Non‐demented individuals with Parkinson disease (PD) reliably demonstrate executive function deficits on neuropsychological tests, but the impact of these deficits on real‐world functional performance is unclear. We are conducting a study to determine the relationship between executive dysfunction and IADL performance in PD. METHODS AND POPULATION: Eleven non‐demented individuals with PD (age: M=60.6, SD=4.6; MMSE: M=29.2, SD=1.3) have undergone executive function and IADL assessment using standardized performance‐based tests. The IADL test employs a graded cueing system if the participant cannot complete the task independently. A preliminary exploration of the data from one executive function test (attentional set shifting) and one IADL test (medication management) is reported here. Non‐parametric analyses were used. RESULTS: Six participants required verbal cues to complete the medication management task. Age, education, motor impairment, and MMSE were equivalent for participants who did and did not require cues (ps>0.23). Participants who required cues tended to perform worse on the executive function test than those who did not (p=0.07). Total number of cues was significantly correlated with total number of errors on the executive function test (rs=0.62, p=0.04). SIGNIFICANCE OF STUDY: Even in the absence of dementia, mild cognitive deficits may impair daily function in individuals with PD. A better understanding of the relationship between executive dysfunction and IADL performance in this population is warranted. Future results will guide development of more comprehensive occupational therapy programs to improve function and quality of life for individuals with PD.

A‐014

AERIAL PESTICIDE SPRAYING FOR WEST NILE VIRUS MOSQUITO CONTROL AND HEALTH COMPLAINTS

Geraghty EM ¹, Franks P¹, Margolis HG¹  ¹University of California, Davis, Sacramento, CA, United States

OBJECTIVES: In the summer of 2005, Sacramento County, California had the greatest number of human cases of West Nile virus in the country. Emergency measures were taken to quickly reduce mosquito populations. In particular, aerial spraying of pyrethrin pesticides was performed. However, there was widespread fear among county residents that exposure to the pesticide would lead to health problems. This research examines the relationship between aerial pyrethrin pesticide spraying and acute physiologic complaints. METHODS AND POPULATION: Geographic information systems were used to determine exposure status for all Sacramento County citizens by their residential zip code. Adding parcel and zoning data helped to further define those at risk for exposure to aerially sprayed pesticide. Zip code level exposures were then matched to Emergency Department (ED) visit data. Regression analyses examined the adjusted relationships between pesticide exposure and acute emergency room diagnoses. Sensitivity of the modeling technique to detect effects was assessed by using the approach to examine the relationship between ambient air pollutants and ED visits for asthma exacerbation, for which there is a large body of evidence. RESULTS: No significant difference was seen in any diagnostic codes for residents exposed to aerial pesticide spraying compared to those who were not exposed. The model sensitivity analysis is still in process. SIGNIFICANCE OF STUDY: This work has important public health implications. It will help to inform public health officials so that they may accurately represent risks posed by aerial pyrethrin pesticide spray programs, in the face of imminent risk of West Nile virus infection, a now endemic disease.

A‐015

ASSOCIATION BETWEEN SERUM 25‐HYDROXYVITAMIN D LEVEL AND UPPER RESPIRATORY TRACT INFECTIONS

Ginde AA ¹, Mansbach JM², Camargo CA²  ¹University of Colorado Denver, Aurora, CO, United States, ²Harvard Medical School, Boston, MA, United States

OBJECTIVES: Recent studies suggest a role for vitamin D in innate immunity, including the prevention of respiratory infections. We sought to examine the association between vitamin D status and recent upper respiratory tract infection (URTI) in a large, nationally representative population. METHODS AND POPULATION: We performed a secondary analysis of the Third National Health and Nutrition Examination Survey, a probability survey of the US population conducted from 1988 to 1994. We examined the association between serum 25‐hydroxyvitamin D (25OHD) level and recent URTI (defined as “past few days”) in 18,883 participants aged ≥12 years. The analysis adjusted for demographics and clinical factors (season, body mass index, smoking history, asthma, and chronic obstructive pulmonary disease). RESULTS: The median serum 25OHD level was 72 nmol/L (interquartile range, 53‐91 nmol/L), and 19% (95%CI, 18‐20%) of participants reported a recent URTI. Recent URTI was reported by 24% of participants with 25(OH)D levels <25 nmol/L (deficient), 20% for 25‐74 nmol/L, and 17% for ≥75 nmol/L (ptrend<0.001). Even after adjusting for demographic and clinical characteristics, lower 25OHD levels were independently associated with recent URTI (compared to ≥75 nmol/L group: OR 1.36 [95%CI, 1.01‐1.84] for <25 nmol/L and OR 1.24 [95%CI, 1.07‐1.43] for 25‐74 nmol/L groups). The association between 25OHD and URTI appeared stronger among individuals with asthma and chronic obstructive pulmonary disease (OR 5.67 and 2.26, respectively). SIGNIFICANCE OF STUDY: Serum 25OHD levels are inversely associated with recent URTI. This association may be stronger in those with obstructive lung diseases. Randomized controlled trials are warranted to explore the effect of vitamin D supplementation on respiratory infection.

A‐016

METABOLIC SYNDROME PREVALENCE IN MENTALLY ILL TEENS

Gracious BL ¹, Cook SR¹, Finucane TL¹, Aulinger P¹  ¹University of Rochester Medical Center, Rochester, NY, United States

OBJECTIVES: The objective of this study was to determine the prevalence of metabolic syndrome in adolescents with severe mental illness. METHODS AND POPULATION: A retrospective chart review of 226 adolescents aged 12‐18 admitted to the Strong Behavioral Health Child and Adolescent Partial Hospital Program between August 2004 and November 2006 was conducted with approval of the University of Rochester Research Subject Review Board. Extracted information included demographics, BMI, resting blood pressures, and fasting lipid profile and glucose values. Data was compared with NHANES 99‐02 as a national reference, using the same definition of metabolic syndrome. RESULTS: Metabolic syndrome prevalence in our sample of seriously mentally ill adolescents was 10.2%, slightly more than 9.4% in NHANES 99‐02. Females with mental illness had twice the prevalence of metabolic syndrome as those nationally (9.9% vs. 5.3%). Mentally ill adolescents were more likely to have metabolic syndrome at a healthy weight (2.4% vs. 1.6%) as well as if overweight (9.1% vs. 7.8%). SIGNIFICANCE OF STUDY: Primary care and child psychopharmacology providers are encouraged to screen for and educate mentally ill adolescents and their families about health risks of adverse metabolic and cardiovascular parameters. Research efforts should be directed toward better understanding the heightened risk for females (consistent with the adult literature) and to better understand the contribution that mental illness may play in raising metabolic risk. Developing screening and prevention/intervention programs that are appropriate to a mentally ill population will be important to reduce their long‐term risk of earlier morbidity and mortality from diabetes and cardiovascular disease.

A‐017

ANTIDEPRESSANT PRESCRIBING IN U.S. NURSING HOMES BETWEEN 1996‐2006

Hanlon JT¹, Handler SM ¹, Castle NG¹  ¹University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: To describe the change in antidepressant prescribing for nursing home residents between 1996‐2006. An additional objective was to examine the association between antidepressant prescribing and staffing patterns or co‐prescribing of other psychotropic medications in the same cohort. METHODS AND POPULATION: Settings: 12,556 U.S. Nursing homes in 1996 and 2006. Data Sources: On‐line Survey Certification and Reporting data and the Area Resource File. Measurements: Increasing prescribing of antidepressants analyzed using multivariable multinomial generalized estimating equations (GEE). RESULTS: Antidepressant prescribing increased (p<0.05) from 21.9% in 1996 to 47.5% in 2006. After controlling for resident, organizational and market factors, increased antidepressant prescribing was associated with more time spent by physician extenders (Adjusted odds ratio [AOR] 2.21; 95% confidence interval [CI] 1.96‐2.51), registered nurses (AOR 1.06, 95% CI 1.02‐1.10), or nurses aides (AOR 1.08; 95%CI 1.04‐1.12) in a facility, as well as the co‐prescribing of sedative/hypnotics (AOR 1.12; 95% CI 1.08‐1.16). Factors found to be protective of increasing antidepressant prescribing (i.e., decrease antidepressant prescribing) included having medical directors and physicians spend more time in the facility (AOR 0.60; 95% CI 0.53‐0.69 and AOR 0.62; 95% CI 0.54‐0.71, respectively), or co‐prescribing of antianxiety or antipsychotic agents (AOR 0.70; 95% CI 0.68‐0.72 and AOR 0.74; 95% CI 0.72‐0.77, respectively). SIGNIFICANCE OF STUDY: Prescribing of antidepressants has increased dramatically in the past decade in older nursing home residents and seems to be associated with certain staffing characteristics and the co‐prescribing of psychotropic medications.

A‐018

METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS (MRSA) CARRIAGE AND INFECTION IN CHILDREN FROM AN EMERGENCY DEPARTMENT(ED)

Immergluck LC ^1,3, Jain S^2,3, Satola S², Quarshie A¹, Jerris RC^3,2  ¹Morehouse School of Medicine, Atlanta, GA, United States, ²Emory University, Atlanta, GA, United States, ³Children's Healthcare of Atlanta, Atlanta, GA, United States

OBJECTIVES: To determine rates of and risks for MRSA carriage in children seen in the ED for skin and soft tissue infections (SSTI) compared with those seen for other conditions; to characterize the S. aureus (SA); and to observe SSTI outcomes. METHODS AND POPULATION: We performed nasal and axilla swabs for SA from Nov 2006‐Apr 2008 on randomly selected children presenting to the ED (SURVgroup) and on children with SSTI (SSTIgroup). For the SSTIgroup, clinical outcomes was determined by chart review and phone follow‐up. Antibiograms and molecular testing were performed on all SA. RESULTS: MRSA carriage rates were 17% (42/250) for SSTIgroup and 3% (20/749)for SURVgroup (p<0.001);MSSA rates were 19% and 17%, respectively. Of 158 cultured in SSTIgroup, 66% grew MRSA and 20% MSSA (p<0.0001). MRSA Carriers with MRSA SSTI had identical antibiograms. Genotyping revealed 98%(41/42) were USA 300; all were PVL positive. Antibiograms showed: 94% Clindamycin, 100% TMP/SMX, and 81% Ciprofloxacin susceptible. In SSTIgroup,antibiotic use and family SSTI history were identified to be associated with MRSA carriage (p<0.001). Of 215 followed after enrollment, 96% improved. In the SURVgroup(n = 20): Genotyping revealed 60% (12/20) were USA 300, followed by USA 700(3), USA 100(1), USA 200 (1), and USA 800 (1). Antibi‐ograms showed: 95% Clindamycin, 100% TMP/SMX, and 80% Ciprofloxacin susceptible. Recent antibiotic use was associated with MRSA carriage (p<0.001). SIGNIFICANCE OF STUDY: MRSA colonization is more common in children with SSTI than the general ED population. Colonizing and infecting strains appear to be similar based on antibiograms and genotyping. Two‐thirds of the SSTI presenting in the ED are due to MRSA. Carriage can lead to subsequent infection.

A‐019

OBSERVED COMMUNICATION IN ADOLESCENTS WITH TYPE 1 DIABETES AND THEIR MOTHERS

Jaser SS ¹, Grey M¹  ¹Yale University, New Haven, CT, United States

OBJECTIVES: The purpose of the current study was to examine observed communication behaviors in adolescents with type 1 diabetes and their mothers during a stressful interaction. METHODS AND POPULATION: This cross‐sectional pilot study of adolescents age 10‐16 with T1D (n = 30, mean age = 12.6, 55% female) included questionnaire (family conflict and adolescent behavior) and clinical data (HbA1c). Adolescents and their mothers participated in a 15‐minute discussion about a stressful diabetes situation. Interactions were coded for specific communication behaviors (e.g., prosocial behavior, listener responsiveness, effective communication) using the Iowa Family Interaction Rating Scales, a global coding system that uses verbal and nonverbal behaviors to rate individuals on each scale. RESULTS: Overall, mothers exhibited positive communication behaviors during the stressful interaction; 97% scored higher for positive communication than negative communication. Adolescents exhibited high levels of anxious and avoidant behaviors, but they also demonstrated effective communication skills (e.g., reasoning, explanations, and clarifications), and active listener responsiveness. Bivariate correlations indicated that higher levels of observed positive communication in mothers were related to lower levels of diabetes‐related family conflict (r = ‐.42, p = .026) and fewer symptoms of aggression in adolescents (r = ‐.48, p = .008). In addition, higher levels of observed maternal positive communication were related to better metabolic control in adolescents (r = ‐.50, p = .005). SIGNIFICANCE OF STUDY: These findings highlight the importance of specific maternal communication styles that may decrease family conflict and adolescent aggression, and improve metabolic control. Results begin to identify the specific parent/adolescent communication behaviors that warrant further investigation.

A‐020

MAPPING THE BURDEN OF MALARIA IN THE DEMOCRATIC REPUBLIC OF THE CONGO

Juliano J ¹, Taylor SM^2,3, Tshefu A⁴, Messina J⁵, Way AA⁶, Ayad M⁶, Emch M⁵, Meshnick SR²  ¹University of North Carolina, Chapel Hill, NC, United States, ²University of North Carolina, Chapel Hill, NC, United States, ³Duke University Medical Center, Durham, NC, United States, ⁴Kinshasa School of Public Health, Kinshasa, Congo, The Democratic Republic of the, ⁵University of North Carolina, Chapel Hill, NC, United States, ⁶Measure DHS, Calverton, MD, United States

OBJECTIVES: Most global malaria data are based on sentinel surveillance systems, not nationally representative population‐based surveys. The Democratic Republic of the Congo (DRC) has estimated 23 million cases of clinical malaria each year, but reliable estimates of malaria prevalence are lacking. Our goal is to use molecular surveillance to improve our understanding of the burden and distribution of malaria in the DRC. METHODS AND POPULATION: Using dried blood spots collected during the 2007 Demographic and Health Survey (DHS), a cross‐sectional nationally‐representative geolocalized household survey of over 12,000 people, we are testing for malaria infection and evidence of antimalarial drug resistance using a high throughput real‐time polymerase chain reaction (PCR) algorithm. RESULTS: We have evaluated 867 patients, of which 234 (27%) were positive by a real‐time PCR assay that detects all Plasmodia sp. Twenty two of 115 (19%) human immunodeficiency virus (HIV) infected individuals were parasitemic (19%), whereas 212 of 754 HIV‐negative patients were par‐asitemic (28%). Samples positive by initial screen were subsequently tested in a speciation real‐time PCR assay, showing P. falciparum as the dominant species. Drug resistance genotyp‐ing revealed a high penetration of sulfa antimalarial resistance markers. SIGNIFICANCE OF STUDY: Our study demonstrates that the prevalence of asymptomatic parasitemia among community‐dwelling citizens of the DRC is high, and that nationally‐representative epidemio‐logic surveys can offer critical information on the burden of infectious diseases.

A‐021

COMPARING COST‐EFFECTIVENESS RESULTS ACROSS VTE PROPHYLAXIS STUDIES WITH INDEPENDENT MODELING TO STANDARDIZE TO COMMON HORIZON AND TO QALYS

Kapoor A ¹, Chuang W⁵, Radhakrishnan N¹, Smith K³, Berlowitz D¹, Segal J⁴, Katz J², Losina E²  ¹Boston University, Boston, MA, United States, ²Brigham and Women's Hospital, Boston, MA, United States, ³University of Pittsburgh, Pittsburgh, MA, United States, ⁴Johns Hopkins, Baltimore, MD, United States, ⁵Massachusetts General Hospital, Boston, MA, United States

OBJECTIVES: Standardize horizon used (time over which analysis was conducted) and effectiveness into quality adjusted life years (QALYs) METHODS AND POPULATION: We systematically reviewed cost‐effectiveness studies of VTE prophylaxis for patients undergoing total hip or knee replacement. To interpret short term studies which reported results in costs/VTE prevented, we developed an independent Markov model, standardizing incremental cost‐effectiveness ratios (ICERs) to $/QALY over a one year horizon. In the model, hypothetical patients could occupy one of several mutually exclusive health states. To calculate ICERs over a one year time horizon in $/QALY, we abstracted from each study the incremental cost, horizon, and the probability of occupying health states. These final costs and effects became the initial strategy costs and Markov state probabilities entered in our model. Other probabilities, costs, and utilities came from the literature. RESULTS: We found 52 cost‐effectiveness results. 23 had sufficient information to standarize to a one‐year horizon. In 4, conclusions about cost‐effectiveness changed after standardization. In these 4 studies, the ICER went from costing money to prevent VTEs to saving money and gaining QALYs. In remaining studies, it cost money to prevent VTEs in the short term and cost money to gain QALYs in the standardized result. SIGNIFICANCE OF STUDY: When comparing short‐term, published cost‐effectiveness results, it is informative to construct an independent model to standardize results to a common horizon and to QALYs.

A‐022

SUBCLINICAL THYROID DYSFUNCTION AND INCIDENT HIP FRACTURE IN OLDER ADULTS

Lee JS ¹, Buzkova P⁴, Fink H³, Vu J¹, Carbone L², Bauer D⁵, Cappola A⁶, Robbins J¹  ¹University of California Davis, Sacramento, CA, United States, ²Univ. of Tennessee, Memphis, TN, United States, ³Univ. of Minnesota, Minneapolis, MN, United States, ⁴Univ. of Washington, Seattle, WA, United States, ⁵UC San Francisco, San Francisco, CA, United States, ⁶Univ. of Pennsylvania, Philadelphia, PA, United States

OBJECTIVES: Subclinical thyroid dysfunction is common and may be related to adverse outcomes in older women and men. However its prospective relationship to hip fractures has not been reported. METHODS AND POPULATION: This is a prospective analysis of 3567 U.S. community‐based adults ages 65+ years with baseline thyroid function testing. The incidence of validated hip fractures and hazard ratio (HR) with 95% confidence intervals (CIs) are reported in men and women with subclinical hypo‐ and hyperthyroidism, versus euthyroidism (median follow‐up=13 years). RESULTS: Men with endogenous subclinical hyperthyroidism had a multivariable (MV)‐adjusted HR of 4.91 (CI=1.1‐21.3) for hip fracture. When including those taking thyroid medication, the HR attenuated to 3.27 (CI=0.99‐11.3). Men with endogenous subclinical hypothyroidism had a MV‐adjusted HR of 2.45 (CI=1.27‐4.73) for subsequent hip fracture. When including those taking thyroid medication, the HR attenuated to 2.31 (CI=1.25‐4.27). Women with endogenous subclinical hyperthyroidism had a MV‐adjusted HR of 2.42 (CI=0.84‐6.31), but the CI included unity. No association in women with endogenous subclinical hypothyroidism was observed. SIGNIFICANCE OF STUDY: Subclinical hyperand hypothyroidism are associated with a 2‐ to 4‐fold increase in hip fracture risk in older men, and subclinical hyperthyroidism appears to increase risk in women. This study provides new evidence that hip fracture risk assessment should include subclinical thyroid dysfunction in both older women and men.

A‐023

PARENTING PRACTICES & CHILD OBESITY

Lowry KW ^1,2, Lavigne JV^1,2  ¹Children's Memorial Hospital, Chicago, IL, United States, ²Northwestern University, Chicago, IL, United States

OBJECTIVES: Up to 25% of children 2‐5 years of age are overweight and up to 13% are obese, supporting the need for early prevention and intervention. Parents play a critical role in the development of child behavior patterns, but the mechanisms are unclear. The aim of this project is to better understand the associations between parenting, child behavior, and child weight. METHODS AND POPULATION: Participants in this sample were originally recruited to examine behavioral and emotional problems in pediatric primary care settings. For this project, participants were 232 children aged 2‐5 years of age (M=3.69; SD=1.12 years; 61% male, 61% Caucasian; 22% overweight, 8% obese) and their parents. Variables of interest included child BMI z‐score, parent report of child behavioral concerns, and parent report of child temperament characteristics. Pearson coefficient correlations were used. RESULTS: Heavier children were more likely to be described by their parents as having more externalizing behavioral concerns (p=.01), being more timid in social situations (p=.01), and having more whiny behavior (p=.03). SIGNIFICANCE OF STUDY: The recommended intervention for child obesity, particularly in young children, is behavioral treatment delivered to parents. However, parents of heavier children described their children as more difficult to parent, suggesting that parents of overweight children may benefit from general parenting skill development in addition to specific advice on eating and physical activity. The results of this and future studies will explore the various pathways by which parenting practices impact child obesity risk. Results have the potential to lead to the development of more effective, practice‐based messages to be provided to parents of young children to build and support a lifetime of healthy eating practices and habits.

A‐024

HOSPITAL (HOSP)‐LEVEL PREDICTORS OF COMMUNITY‐ASSOCIATED VERSUS HOSPITAL‐ASSOCIATED METHICILLIN‐RESISTANT STAPHYLOCOCCUS AUREUS (CA‐MRSA VS. HA‐MRSA) COLONIZATION AMONG INTENSIVE CARE UNIT (ICU) PATIENTS (PTS)

Lyles, MD, MS RD ¹, Weinstein, MD RA^1,2, Trick, MD W¹, Lin, MD, MPH M²  ¹John H. Stroger, Jr. Hosp of Cook Cty, Chicago, IL, United States, ²Rush Univ Med Ctr, Chicago, IL, United States

OBJECTIVES: Although pt‐level predictors of CA‐MRSA and HA‐MRSA colonization among ICU pts have been studied, hosp characteristics are unknown. To identify hosp characteristics associated with CA‐MRSA and HA‐MRSA colonization among ICU pts in a region. METHODS AND POPULATION: We recruited Chicago hosps with ≥10 ICU beds for 2 single‐day point prevalence MRSA colonization surveys. Cultures were obtained from all ICU pts and centrally processed for methicillin resistance and pulsed‐field gel electrophoresis genotype (CA‐MRSA defined as USA300/400/1000/1100; HA‐MRSA, all others).We used a 2007 public database to obtain hosp‐level variables: hosp bed size; ICU bed size, yearly admissions, occupancy rate, and average daily census; hosp bed to infection preventionist ratio; Medicare and Medicaid payer proportion. RESULTS: All 26 eligible hosps participated; 1716 pts were cultured. Hosp‐level ICU variables denoting larger and busier wards (greater than median ICU size, yearly admissions, occupancy rate, and average daily census) were associated with decreased risk of CA‐MRSA and HA‐MRSA. High Medicare payer mix was associated with a 2fold increased prevalence of CA‐MRSA (PR 2.21, 95% confidence interval [CI] 1.32 – 3.72, P <0.01) and HA‐MRSA (PR 2.12, CI 1.42 ‐ 3.19, P <0.01), while high Medicaid payer mix was associated only with CA‐MRSA (PR 1.98, CI 1.19 – 3.30, P <0.01). SIGNIFICANCE OF STUDY: For public reporting of hosp MRSA rates, stratification along some hosp‐level covari‐ates may lead to more meaningful inter‐hosp comparisons.

A‐025

THE ROLE OF BLOOD CULTURES IN HOSPITALIZED PATIENTS WITH E. COLI BACTERIURIA

Marschall J ¹, Doherty J², Foxman B³, Henderson J¹, Warren D¹  ¹Washington University School of Medicine, St Louis, MO, United States, ²BJC Healthcare, St Louis, MO, United States, ³School of Public Health, Ann Arbor, MI, United States

OBJECTIVES: To compare patients (pts) with E. coli bacteriuria based upon whether blood cultures (bcx) were obtained, and subsequent patient outcomes. METHODS AND POPULATION: We conducted a 7‐week prospective cohort study of adult, hospitalized pts with E. coli bacteriuria at a tertiary‐care hospital. Bcx were at the discretion of the treating physician & had to occur within ±1 day of the bacteriuria. RESULTS: 113 pts had E. coli bacteriuria. In 54(48%) pts a bcx was obtained and 9/54 (17%) were bacteremic. Bacteriuric pts who had bcx drawn were more likely to be male [22/54 (41%) with bcx vs. 8/59 (14%) without bcx; p=0.001], have underlying malignancy [12 (22%) vs. 5 (9%); p=0.04], pyelonephritis [29 (54%) vs. 12 (29%); p<0.001], fever [28 (52%) vs. 12 (20%); p<0.001], sepsis [36 (67%) vs. 19 (32%); p<0.001], and sepsis‐induced hypotension [10 (19%) vs. 2 (3%); p<0.01]. Of the 29 pts with pyelonephritis in whom bcx were taken, 7 (24%) were positive. Bcx were obtained in 10 (19%) pts with asymptomatic bacteriuria; none were positive. 18 (16%) of 113 pts received no effective antibiotic therapy during the hospital admission & this did not differ whether bcx were obtained or not (p=0.8). Length of hospital stay after bacteriuria was longer in pts who had bcx taken [median 4.5 (range 0‐36) vs. 3.1 days (0.2‐13.9); p=0.04]. In‐hospital mortality was similar whether bcx were taken or not [6 (13%) vs. 2 (4%); p=0.1]. SIGNIFICANCE OF STUDY: Blood cultures were more frequently drawn in pts with pyelonephritis and in febrile or septic pts, but no difference in mortality could be detected in this small sample. Bcx were more frequently drawn in male pts. Bcx in pts with asymptomatic bacteriuria had a very low yield and should not be obtained.

A‐026

PRACTICE PATTERNS, EPIDEMIOLOGIC FACTORS, AND OUTCOMES FOR PURULENT SKIN AND SOFT TISSUE INFECTIONS IN THE EMERGENCY DEPARTMENT

May L ¹, Yadav K¹, Keim A¹  ¹The George Washington University, Washington, DC, United States

OBJECTIVES: There is a lack of quality prospective data to guide management of skin soft tissue infections (SSTIs). The study objective was to collect prospective data on SSTI epidemiology and management in our emergency department (ED) with the hypothesis that antibiotics may often be unnecessary. METHODS AND POPULATION: Prospective observational study of adults with purulent SSTI in a busy urban academic ED. A survey of patients and their healthcare provider, wound culture, and structured follow‐up were conducted. Data collection included patient and provider characteristics and management strategy. Clinical improvement was defined as decreasing erythema, pain, swelling and absence of fever, return visit or phone follow‐up. RESULTS: 82 patients (47 female) were enrolled in four months, of which 81 completed follow‐up. 28% of patients had comorbidities, mainly diabetes. Extremity abscesses were most frequent (39%), and 22% of patients had multiple abscesses. Although providers suspected MRSA 78% of the time, only 46% of cultures grew MRSA. Identified predictors of MRSA were a prior history of abscesses and extremity location. 94% of isolates were susceptible to clindamycin and 98% to TMP‐SMX. 2.5% of all staph aureus isolates had d‐test positivity. Incision and drainage (I&D) was done in 90%, with antibiotic use in 91% including 85% of those with less than 5 cm of erythema. 7% were admitted, and 15% had a failed outcome requiring re‐treatment. SIGNIFICANCE OF STUDY: There were few predictors for MRSA in our population. Most patients were treated with antibiotics, despite a lack of clear indication. Microbial resistance patterns varied substantially from national rates, suggesting antibiotic selection should be based on local data. This study supports further study to determine best practices on a local level.

A‐027

SURVEILLANCE OF METHICILLIN‐RESISTANT STAPHYLOCOCCUS AUREUS (MRSA): A COMPARISON OF TWO PATIENT POPULATIONS

McGregor J ^1,2, Bearden DT¹, Kraemer DF^1,2, Townes JM², Smith DH³  ¹Oregon State University, Portland, OR, United States, ²Oregon Health & Science University, Portland, OR, United States, ³Kaiser Permanente Northwest Center for Health Research, Portland, OR, United States

OBJECTIVES: MRSA infections are associated with increased morbidity and mortality compared to methicillin‐susceptible infections. Surveillance studies of MRSA have largely been centered at academic tertiary care hospitals (AHs), which serve patients generally considered at greater risk for drug‐resistant infections. Our objective was to retrospectively compare the prevalence of MRSA among S. aureus isolates from an AH and community hospital (CH). METHODS AND POPULATION: Antibiogram methodology was used to analyze 2005‐2007 microbiology data for inpatients from an AH and CH. Prevalence of MRSA among S. aureus was compared between AH and CH across time using logistic regression; the proportion of MRSA susceptible to clindamycin was analyzed as a marker of community‐associated MRSA. RESULTS: 701 and 2,235 unique S. aureus isolates were identified from CH and AH, respectively. The prevalence of MRSA varied from 42.9% in 2005, to 44.8% in 2006, and 39.3% in 2007 at CH, and 35.5%, 40.5%, and 38.85%, respectively, at AH; differences between hospitals were significant (p=0.049). Statistically non‐significant increases in clindamycin susceptibility among MRSA were observed over time (CH: 39.5% in 2005, 46.3% in 2006, 49.4% in 2007; AH: 43.5%, 47.2%, and 48.1%, respectively); differences were not significant between institutions (p=0.70). SIGNIFICANCE OF STUDY: The prevalence of MRSA was consistently higher among CH S. aureus isolates. This may be due to an increasing prevalence of community‐associated MRSA or to differences in clinical practice or patient characteristics. Future work will examine potential contributors to the differences in MRSA prevalence among inpatients and outpatients in CH and AH settings.

A‐028

PARTDSA FOR CENSORED SURVIVAL OUTCOMES

Molinaro A ¹, Lostritto K¹  ¹Yale University, New Haven, CT, United States

OBJECTIVES: Previously, we proposed a new partitioning algorithm for generating predictors based on an intensive and comprehensive search over the entire covariate space. This new algorithm, partDSA, builds ’and’ and ’or’ statements allowing combinations and substitutions of regions for the purpose of discovering intricate correlations patterns and interactions in addition to main effects. Thus far, we have only addressed an always observed outcome. However, in clinical settings, we are frequently confronted with missing data in the outcome variable. For example, if the outcome of interest is death from disease, then we may observe either the time of the actual event or the last time the patient was seen without having incurred the event of interest. Here we extend partDSA to handle an ’inverse probability of censoring weighted’ (IPCW) loss function as well as the Brier score to accommodate the censored outcome. METHODS AND POPULATION: We performed a comparison between partDSA with the IPCW loss function and previously suggested approaches such as CART. Simulated, with 100 repetitions, 250 or 500 training set observations and 10,000 test set observations, each with zero and twenty percent censoring. RESULTS: partDSA with IPCW performs well in comparison to CART when predicting a survival outcome. Next we will investigate partDSA with the Brier score. SIGNIFICANCE OF STUDY: We propose extensions to partDSA for generating candidate estimators in the presence of a censored outcome. Thus far in simulations, we see that this approach will supersede previously suggested methods by being not only more aggressive but also more flexible.

A‐029

THYROID CANCER IN A MULTI‐ETHNIC POPULATION: DISPARITY EXISTS

Morita SY ^1,2   ¹Queen's Medical Center, Honolulu, HI, United States, ²University of Hawaii, Honolulu, HI, United States

OBJECTIVES: The incidence of thyroid cancer is rapidly increasing and has doubled over the last decade.Our primary aim was to assess outcome in ethnicities with the principal hypothesis that the Filipino cohort will have the worse overall survival. METHODS AND POPULATION: This was a retrospective review of 622 patients with thyroid carcinoma treated at the largest private hospital in Hawaii from January 1990‐December 2008. A log‐rank test was employed to determine survival between the Filipino and non‐Filipino cohorts. In order to model the survival of Filipinos vs. non‐Filipinos adjusted for by age, gender, extra‐capsular extension, and stage,the Cox model was utilized. RESULTS: The Filipinos were most commonly affected (21.9%). Overall five‐year survival for all of the ethnicities was 91.9%. Caucasians had the best survival (96.3%), followed by Chinese (91.6%), Japanese (90.5%), Hawaiians (89.3%), Pacific Islanders (88.2%), and Filipinos (86.3%). The Filipinos (86.3%) had a worse mortality than the non‐Filipinos (93.5%)(P= 0.05).Furthermore, when adjusted for age, gender, stage, and extra‐capsular extension,Filipino ethnicity was independently found to harbor a worse prognosis (HR 1.77)(P< 0.04). SIGNIFICANCE OF STUDY: We determined that the Filipinos comprised the largest percentage of patients with thyroid cancer(21.9%)and had the worst survival (86.3%). This seminal finding of a worse survival in the Filipino group relative to the non‐Filipino group is compelling. Furthermore, after adjusting for potential confounders, we determined that Filipinos independently have a higher likelihood of dying that is nearly two‐fold. Age, gender, tumor type, advanced stage, and T4 status did not appear to be different amongst all groups. Our findings necessitate further investigation to elucidate if environmental or genetic factors may be implicated to account for these disparities.

A‐030

GENDER DIFFERENCES IN DECEASED SOLID‐ORGAN DONORS AND TRANSPLANTATION RATES IN THE UNITED STATES

Murugan R ¹, Sileanu F¹, Wahed AS², Al‐Khafaji A¹, Kellum J¹  ¹University of Pittsburgh, Pittsburgh, PA, United States, ²University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA, United States

OBJECTIVES: Gender disparity has been reported in the living donors and in the recipients of solid‐organs. Since deceased donors are the most frequent source of organs, we explored gender differences in donors and the rates of organ transplantation, accounting for demographic, clinical, and processes of care. METHODS AND POPULATION: Twelve‐year U.S. cohort of 62,643 deceased donors using the United Network for Organ Sharing data from 1994 through 2005. We estimated age‐, gender‐specific and direct age‐standardized organ transplantation rates, and adjusted transplantation rate ratios. RESULTS: Despite increase in organ donors over time, there was a higher proportion of male donors (58.8%). Overall, the male donors were younger (mean age of male vs. female: 40.3 vs. 46.6 years, P < 0.001). Age‐specific organ transplantation rates from males was higher only for donors younger than 35 years of age (3.88 vs. 3.56, organs, P < 0.001). Following age‐standardization, lower rate of organs were transplanted from male donor (2.78 vs. 2.85 organs, adjusted rate ratio, 0.97). This gender disparity persisted when adjusted for differences in donor demographics, biometric profile, mechanism of death, comorbidity, and processes of care such that 3% lower rate of organs were transplanted from male donors (adjusted rate ratio, 0.97 [0.96‐0.98]). SIGNIFICANCE OF STUDY: Lower transplantation rates from deceased male donors may reflect residual confounding, or it could signal post‐mortal biologic differences in organ function. Focused interventions to improve organ recovery rates from male donors could narrow gender disparity and increase organ availability.

A‐031

ACTIVE DRUG USE AND SMOKING CESSATION COUNSELING AMONG METHADONE MAINTAINED SMOKERS

Nahvi S ¹, Bernstein SL², Li X¹, Arnsten J¹  ¹Albert Einstein College of Medicine, Bronx, NY, United States, ²Yale University, New Haven, CT, United States

OBJECTIVES: There is a marked prevalence of tobacco use among methadone maintenance patients, but smoking cessation services in methadone programs are sparse. We sought to evaluate factors associated with smoking cessation counseling by substance abuse counselors. METHODS AND POPULATION: We conducted a cross‐sectional study of smokers receiving methadone treatment in seven clinics with on‐site primary care in the Bronx, NY. Social and demographic characteristics; tobacco use behavior; receipt of smoking cessation advice or assistance from a methadone counselor; substance abuse treatment history; and self‐reported illicit sedative, opiate and cocaine use were assessed. RESULTS: Our sample of current smokers (n = 223) was 57% female, 64% Latino, 24% black with a mean age of 46 years. A minority (n = 105, 44%) reported receipt of smoking cessation advice or assistance from a methadone clinic counselor. There was no significant difference in age, race/ethnicity, sex, methadone dose, cigarettes per day, nicotine dependence or stage of change among patients who did or did not receive smoking cessation advice. Smokers reporting past 6 month illicit opiate (36 v 47%, p=0.18), sedative (33 v 46%, p=0.23) or cocaine use (35 v 47%, p=0.11) were less likely to report receipt of smoking cessation counseling, but these differences were not statistically significant. Significantly fewer patients with any past 6 month drug use (36 v 51%, p = 0.04) reported receiving smoking cessation counseling from a methadone clinic counselor. SIGNIFICANCE OF STUDY: Results suggest that a minority of methadone maintained smokers receive smoking cessation counseling, and that active drug use is associated with fewer smoking cessation services. Research is needed to expand smoking cessation services to this high‐risk population.

A‐032

ROC CURVE ANALYSIS FOR REPEATED OBSERVATIONS: BOOTSTRAP VERSUS MIXED EFFECTS MODEL APPROACHES WITH AN APPLICATION TO DIAGNOSIS OF DISTAL ESOPHAGEAL SPASM

Nietert PJ ¹, Ciolino J¹, Pohl D¹  ¹Medical University of South Carolina, Charleston, SC, United States

OBJECTIVES: A receiver operating characteristic (ROC) curve is useful for assessing diagnostic accuracy of continuous predictor variables. ROC curve analysis typically assumes independence among observations and can be calculated using standard statistical software. Prior research has been done using a generalized linear mixed model (GLMM) approach to handle correlated observations (e.g. repeated observations on the same individuals). We developed an alternative strategy using a bootstrapping method and compared it to the GLMM approach. We then applied our technique to diagnosis of distal esophageal spasm (DES) using propagation velocity and amplitude as predictors of incomplete bolus transit. METHODS AND POPULATION: The bootstrap algorithm involved sampling 1 of the repeated observations for each individual patient, pooling samples across multiple patients, calculating an ROC curve and the area under the curve (AUC), and repeating the process 1,000 times. Simulated training and validation datasets were constructed to reflect different disease prevalences and predictors that varied in accuracy. In each case, the bootstrap and GLMM algorithms were compared. Additionally, we compared the approaches using DES data collected on 1,003 observations from n = 107 subjects. RESULTS: In the training datasets, the bootstrap approach typically resulted in higher AUCs than with the GLMM approach. However, both approaches performed similarly in the validation datasets. In the DES dataset, the 2 variables were strong predictors of swallow completeness, with AUCs of 0.84 and 0.85 using the bootstrap and GLMM approach, respectively. SIGNIFICANCE OF STUDY: Our bootstrap algorithm is a useful alternative for assessing diagnostic accuracy in the context of repeated measurements.

A‐033

FEAR OF FALLING IN COMMUNITY DWELLING OLDER ADULTS

Oh‐Park M ¹, Holtzer R², Verghese J¹  ¹Albert Einstein College of Medicine, Bronx, NY, United States, ²Yeshiva University, Bronx, NY, United States

OBJECTIVES: Fear of falling (FOF) poses a great risk of loss of independence among older adults. The objective of this study is to investigate the predictors for development and resolution of FOF among community dwelling older adults. METHODS AND POPULATION: We conducted longitudinal analysis of a community based cohort study. The inclusion criteria were age 70 and older, residing in the Bronx. Exclusion criteria included dementia, disability, or institutionalization. Main outcome was FOF status assessed using a single‐item question, “Do you have fear of falling?”. Subjects who reported no FOF at baseline were followed up every 2 months for 24 months. The individuals with incident FOF were subdivided into either persistent group (FOF > 2 months) or transient group (FOF < 2 months). Cox proportional hazard (PH) analysis was performed to identify the predictors for incident and subsequent resolution of FOF. RESULTS: Of 449 subjects (210 men, 239 women), 203 developed FOF over 24 months. Fear of falling resolved in 130 (68.1%) 2 months after the date of incident FOF, and 61 (31.9%) continued to report FOF. Predictors for incident FOF were female gender (hazard ratio; HR 1.41, 95% CI 1.02‐1.97), depression score (HR 1.16; CI 1.07‐1.26) and clinical gait abnormalities (HR 2.33; CI 1.62‐3.37). Predictors for resolution of FOF were male gender and absence of clinical gait abnormalities. SIGNIFICANCE OF STUDY: Fear of falling in older individuals is dynamic in nature with high incidence rates and subsequent resolution in short term. Status of gait abnormality and gender predicts development and resolution of FOF.

A‐034

COHORT OF PATIENTS WITH SYSTEMIC SCLEROSIS (SSC) AND PULMONARY HYPERTENSION

Phillips K ¹, Byrne‐Dugan C¹, Impens A¹, Schiopu E¹, Mahmood F¹, Seibold J¹  ¹University of Michigan, Ann Arbor, MI, United States

OBJECTIVES: To examine whether baseline clinical test results in patients with systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH) predict clinical course. METHODS AND POPULATION: : Consecutive patients in a tertiary care referral center with PAH and a confirmed diagnosis of scleroderma over the past 5 years were assessed. Clinical examination, medications, ECG, echocardiogram, BNP, six minute hallwalk, pulmonary function tests and imaging, and right heart catheterization results were recorded. RESULTS: Of the 64 patients included in this study, more than 75% were women. In these patients with a diagnosis of SSc and pulmonary hypertension, mortality was high, with most of the deaths occurring within 1‐2 years of PAH diagnosis. Patients with improved survival were more likely to have normal ECGs. More than half of the patients in the study had abnormalities of the right ventricle, either structural or physiologic. At the time of evaluation, greater than 50% had evidence of right axis deviation (QRS >90 degrees) and a majority of these patients exhibited right ventricular strain in the precordial leads. Evidence of right ventricular strain by ECG (ST deviation and T wave inversion in V1‐V3) was associated with decreased survival (p<0.05). Right ventricular hypertrophy was seen with increased frequency, as was an increased p wave amplitude (>0.25 mV in lead II). SIGNIFICANCE OF STUDY: ECG results reflecting abnormalities in the right ventricle are associated with a poor prognosis and may be useful for therapeutic decisions in patients with SSc.

A‐035

GENOME‐WIDE ASSOCIATION STUDY IDENTIFIES VARIANTS AT 19P13.2 ASSOCIATED WITH PLATELET RESPONSE TO ASPIRIN THERAPY

Qayyum R ¹, Becker LC¹, Faraday N¹, Mathias R¹, Yanek LR¹, Becker DM¹  ¹Johns Hopkins School of Medicine, Baltimore, MD, United States

OBJECTIVES: Inter‐individual variability in platelet response to aspirin (ASA) therapy is partly due to genetic variations. While a few candidate gene polymorphisms have been associated with post‐ASA platelet response, a genome‐wide association study (GWAS) has not been reported. METHODS AND POPULATION: Fasting blood samples were obtained from 1257 white participants of the GeneSTAR cohort. Impedance aggregometry in whole blood after collagen‐induced platelet aggregation was used to measure lag‐time, slope, and maximal platelet aggregation before and after 14‐day of ASA therapy. Genotyping was conducted with Illumina 1M BeadChip array. Mixed effects models in SAS (9.1.3 for Linux OS) were used to test for association between each SNP and the 6 phenotypes for all SNPs that met standard quality control criteria. RESULTS: The most significant finding was an association between a cluster of 11 SNPs spanning 300 kb on chromosome 19p13.2 and ASA response at genome‐wide significance level with p‐values<10⁻⁸. These SNPs were in linkage disequilibrium with each other and the region contains two genes RGL3 (Ral guanine nucleotide dissociation stimulator‐like 3) and LPPR2 (lipid phosphate phosphatase‐related protein type 2). At the most significant locus, rs222603, an A‐>G substitution was associated with greater lag‐time (AA=4.9±0.5s; GA=5.1±0.4s; GG=5.4±0.2s; p=1.9x10⁻¹⁰) and decreased aggregation (AA=1.1±0.7Ω; GA=0.8±0.7Ω; GG=0.3±0.3Ω; p=1.2x10⁻⁵) after ASA. SIGNIFICANCE OF STUDY: In this first GWAS of platelet response to ASA therapy we show a relationship between post‐ASA platelet response and the 19p13.2 region. This finding may have important clinical implications for arterial thrombosis and anti‐platelet therapy.

A‐036

METABOLIC DYSFUNCTION AND LIPODYSTROPHY IN HISPANICS WITH HIV IN PUERTO RICO

Ramirez‐Marrero FA ¹, Frontera WR¹, Joyner MJ²  ¹University of Puerto Rico, San Juan, United States, ²Mayo Clinic, Rochester, MN, United States

OBJECTIVES: The specific aims of this study were to: 1) determine the prevalence of metabolic risk factors in Hispanics with HIV and lipodystrophy (HIV‐lipo), HIV without lipodys‐trophy (HIV‐no lipo), and non‐HIV controls (non‐HIV), and 2) study the association between health behaviors and metabolic risk. We hypothesize that the prevalence of metabolic risk factors is higher in HIV‐lipo, and health behaviors are inversely associated with metabolic risk factors. METHODS AND POPULATION: Sixty Hispanic adults (29 HIV‐lipo, 16 HIV‐no lipo, and 15 non‐HIV) were evaluated for health behaviors (activity monitor and nutrition questionnaire), fitness (VO₂max), and metabolic risk factors [HDL, triglycerides, glucose tolerance (OGTT), insulin resistance (HOMA‐IR), BMI, waist circumference, waist‐to‐hip ratio (WHR), resting blood pressure (BP)]. ANOVA and linear regressions were conducted to test for differences between groups and associations among variables. RESULTS: Differences between HIV‐lipo, HIV‐no lipo, and non‐HIV were observed for WHR, OGTT, HOMA‐IR and triglycerides (0.97, 0.83, and 0.88; 115.2, 92.2 and 86.8 mg/dl; 7.3, 4.2 and 2.4; 214.1, 176.6 and 128.9 mg/dl; respectively). A higher proportion of HIV‐lipo and HIV‐no lipo met the criteria for metabolic syndrome than non‐HIV (79, 81, 47%, respectively). Significant associations were observed between saturated fat intake, BMI and waist circumference (r = 0.33, 0.40, respectively); physical activity and saturated fat intake and VO₂max (r = 0.31. 0.36, respectively); and VO₂max and B P, BMI, waist circumference, and OGTT (r = ‐0.24, ‐0.31, ‐0.32, ‐0.32). SIGNIFICANCE OF STUDY: Lipodystrophy is not the only cause of metabolic dysfunction in Hispanics with HIV in PR. Nutritional and exercise programs must be integrated in the clinical care of this population.

A‐037

DESCRIPTION OF TRAUMATIC BRAIN AND SPINAL CORD INJURIES IN FOUR YEAR OLD AND YOUNGER CHILDREN REQUIRING NEUROSURGICAL EVALUATION IN AN EMERGENCY ROOM

Rodriguez‐Rivera IV ¹, Garcia E², Brau R¹  ¹School of Medicine, University of Puerto Rico, San Juan, Puerto Rico, ²University of Puerto Rico, San Juan, Puerto Rico

OBJECTIVES: This study aims to determine the demographics, mechanisms of injury, events associated with the injury, severity of injury and type of traumatic brain and spinal cord injuries for patients four year old and younger who were evaluated by a neurosurgeon in an emergency room. METHODS AND POPULATION: A descriptive analysis of data from a database containing information from 1,534 patients, all ages, with neurological traumatic injuries consulted and evaluated by the Neurosurgery Service at the Emergency Room of the Ad‐ministración de Servicios de Emergencias Médicas in San Juan, Puerto Rico from January 1, 2007 to July 31, 2008 will be performed. A registration form was used as a data collection instrument. RESULTS: It is anticipated that the most prevalent mechanisms of injury, as well as gender distribution reported in the literature for other pediatric age groups, will be similar to the findings for the age group of interest. SIGNIFICANCE OF STUDY: The findings of this study will provide recent information from Puerto Rico, otherwise unavailable, on traumatic brain and spinal cord injury for patients age 4 and younger requiring neurosurgical evaluation.

A‐038

OBESITY AND SLEEP DISORDERED BREATHING ARE ASSOCIATED WITH SEVERE PEDIATRIC ASTHMA

Ross KR ¹, Hart M¹, Kibler A¹, Rosen C¹, Kercsmar C², Redline S¹  ¹Rainbow Babies and Childrens Hospital/CWRU, Cleveland, OH, United States, ²Cincinnati Children's Hospital, Cincinnati, OH, United States

OBJECTIVES: Obesity is a risk factor for the development of asthma, but the influence of obesity on asthma morbidity is less clear. We sought to determine if obesity and related co‐morbidities were associated with asthma severity during follow up. METHODS AND POPULATION: A cohort of children underwent physiological, anthropometric, and sleep assessments; participants were followed prospectively for one year. Asthma severity was classified as mild, moderate or severe after one year of treatment by pediatric pulmonologists. Sleep Disordered Breathing (SDB) was defined by parental report of habitual snoring and ≥5 desaturations/hr by overnight oximetry. Group differences were assessed using Pearson's chi‐square test, analysis of variance, and logistic regression. RESULTS: Baseline and follow‐up data were available for 99 children (mean age of 9.3 + 3.4 years; 49% Caucasian, 45% obese, 7% metabolic syndrome). Asthma was mild in 42%, moderate in 40%, and severe in 17%. More children with severe asthma at follow‐up had a BMI above the 99th percentile (29%) compared to those in the mild or moderate categories(14% and 5% respectively, p=0.04). SDB at baseline was associated with severe asthma at follow‐up; 47% of children with severe asthma at follow‐up had SDB compared to those with mild (19%) or moderate (15%) severity. After adjusting for BMI, children with SDB at baseline had significantly higher odds of having severe asthma at follow‐up (OR 3.8, 95% CI 1.2‐12.2). SIGNIFICANCE OF STUDY: Severe asthma was associated with marked obesity and SDB. The data suggest that there may be an asthma phenotype associated with severe obesity and SDB. SDB may influence asthma control by augmenting systemic or airway inflammation or altered autonomic control.

A‐039

CETP GENETIC VARIABILITY IS INDEPENDENTLY ASSOCIATED WITH SLOWER AGE‐ASSOCIATED MEMORY DECLINE

Sanders A ¹, Wang C¹, Katz MJ¹, Derby CA¹, Barzilai N¹, Ozelius L², Lipton RB¹  ¹Albert Einstein College of Medicine, Bronx, NY, United States, ²Mt. Sinai School of Medicine, Bronx, NY, United States

OBJECTIVES: To test the hypothesis that genetic variability at CETP codon 405 (isoleucine to valine; V405; NCBI dbSNP rs5882) is associated with slower age‐associated cognitive decline. METHODS AND POPULATION: Prospective cohort study of 523 community‐dwelling non‐demented older adults (≥70 years) from the Einstein Aging Study (Bronx, NY) systematically sampled from population lists of Medicare recipients (1994‐2004) or registered voters (2004‐2009) and genotyped for CETP/APOE. Standardized neuropsychological tests were administered annually from 1994‐2009. Linear mixed‐effects models adjusted for sex, race/ethnicity, education, medical comorbidities, and apolipoprotein (APOE) ɛ4 examined associations between V405 genotype and longitudinal performance on cognitive tests of attention (Digit Span), episodic memory (Free and Cued Selective Reminding Test [FCSRT]), and psychomotor speed (Digit Symbol Substitution). V405 heterzygotes and homozygotes were separately compared to an isoleucine homozygote reference group. RESULTS: Valine allele frequency was 43.5%. Mean follow‐up time was 4.3 (SD 3.1) years. Valine homozygotes had significantly slower memory decline on the FCSRT (0.43 points/year of age for isoleucine; 95% Confidence Interval [CI] ‐0.58 to ‐0.29 versus 0.21 points/year of age for valine; 95% CI ‐0.39 to ‐0.04; difference in linear age slope, 0.22; 95% CI 0.02 to 0.41; P = 0.03) and no significant differences on the Digit Span or Digit Symbol Substitution tests. SIGNIFICANCE OF STUDY: CETP V405 valine homozygosity was independently associated with slower episodic memory decline in models including adjustment for APOE.

A‐040

FORMATIVE WORK TOWARDS UTILIZATION OF NETWORKS TO BUILD UPON EXISTING HIV PREVENTION PROGRAMS FOR HIGH RISK MEN IN INDIA

Schneider JA ¹, Kumar P², Laumann E¹, Yeldandi V⁴, Dandona L², Mayer K³  ¹University of Chicago, Chicago, IL, United States, ²Public Health Foundation of India, Hyderabad, India, ³Brown University, Providence, RI, United States, ⁴SHARE‐India, Hyderabad, India

OBJECTIVES: There is a lack of evidence of the effectiveness of peer‐educator models and community popular opinion leader interventions ‐ the only two HIV social network interventions to be utilized in India. Leveraging existing networks of friends including linked or unlinked dyads may give additional dimensions to enacting behavior change. Investigation into this sub‐level of “organic” friend networks could lead to effective multilevel interventions. METHODS AND POPULATION: Through 25 qualitative interviews and 5 focus groups of truck drivers at high risk for HIV infection in Hyderabad India, we examine levels of friend closeness and influence and how these attributes might be used to improve an outcome of interest – such as HIV testing. RESULTS: We have found that truck drivers have categories of friends whom they interact with regularly which are broken down into “close” friends, or those from their native place and originate from childhood; “other” friends; or “parking lot” friends, those with whom they have the weakest ties. Bond strength and closeness appear to be potential assets for influence, however, ego rarely discloses infidelity when close friends are in a radial structure that includes ego's family. “Other” friends were more likely to discuss sexual behavior, however, if found to be infected, ego would likely revert back to disclosing status to “close” friends. SIGNIFICANCE OF STUDY: A candidate network intervention of “other” friends providing HIV prevention information, could complement and build upon currently available peer‐educator HIV prevention models.

A‐041

LONG TERM USE AND THIAZOLIDINEDIONES AND THE RISK OF PNEUMONIA IN PATIENTS WITH TYPE 2 DIABETES: A META‐ANALYSIS

Singh S ¹, Loke YK²  ¹Johns Hopkins University, Baltimore, MD, United States, ²University of East Anglia, Norwich, United Kingdom

OBJECTIVES: To systematically review the long‐term effects of thiazolidinediones on the outcome of pneumonia in patients with type 2 diabetes. METHODS AND POPULATION: We searched MEDLINE, the pharmaceutical company clinical trials register, the US Food and Drug Administration Web site, clinical trials.gov and product information sheets for randomized controlled trials, systematic reviews, and meta‐analyses published in English through November 2009. Studies were selected for inclusion if they were randomized controlled trials of thiazolidinediones (rosiglitazone or pioglitazone) for prevention or treatment of type 2 diabetes, had at least 12 months of follow‐up, and provided numerical data on pneumonia or lower respiratory tract adverse events. Ten trials were included after detailed screening of eligible trials for pneumonia. Relative risks (RRs) of pneumonia was estimated using a fixed‐effects meta‐analysis of 10 randomized controlled trials (n = 17627 including 8169 receiving thiazo‐lidinediones and 9458 receiving control therapy, with a duration of follow‐up of 1‐4 years). RESULTS: Thiazolidinediones significantly increased the risk of pneumonia (n = 130/8169 vs 100/9458; 1.59 % vs 1.06 %; RR, 1.40; 95% confidence interval [CI], 1.08‐1.82; P = .01) with no heterogeneity (I2 = 0%). The estimates were robust to the choice of statistical models and restriction of outcomes to serious pneumonia adverse events. The Number Needed to Harm for pneumonia associated with thiazolidinediones was estimated to be at 239 (95% CI, 95% CI, 117 to 1191) per year based on the control event rate in the trial. SIGNIFICANCE OF STUDY: Among patients with type 2 diabetes, the long term use of thiazolidinediones for more than one year is associated with a significant increase in the risk of pneumonia.

A‐042

MAINTENANCE OF WAKEFULNESS TEST (MWT), BUT NOT IMPAIRED OLFACTION, DIFFERENTIATES PARKINSON'S DISEASE FROM IDIOPATHIC REM BEHAVIOR DISORDER

Trotti L ¹, Juncos J¹, Factor S¹, Freeman A¹, Wilson A¹, Hollars S¹, Greer S¹, Wood‐Siverio C¹, Rye D¹, Bliwise D¹  ¹Emory University School of Medicine, Atlanta, GA, United States

OBJECTIVES: REM sleep behavior disorder (RBD) frequently manifests as a prodrome of Parkinson's disease (PD). Impaired olfaction occurs in both diseases as an early marker of neu‐rodegeneration. We evaluated whether excessive daytime sleepiness (EDS), also a common and early symptom of PD, is similarly present in RBD. METHODS AND POPULATION: Patients with PD (n = 26, mean [SD] age = 64.3 [9.5]) and RBD (n = 5, age = 67.2 [10.2]) underwent 2 consecutive nights of polysomnography, each followed by a 4‐nap MWT. Sleep latency (SL) and sleep efficiency (SE) were obtained for each nap and means calculated. UPSIT (olfaction) and Epworth (subjective EDS) were completed. RESULTS: Olfaction was substantially impaired and not different between groups (PD = 21.9; RBD = 22.8). Epworths were similar (11.5 vs 11.6). Mean MWT SL (12.9 mins vs. 28.6 mins, t = 2.42, p = .02) and MWT SE (37.8% vs 15.7%, t = 1.83, p = .08) confirmed less alertness in the PD group. Pergolide dose equivalents were unrelated to MWT measures (all p values > .50). Levodopa use was common (18/26) but dosing showed positive relationship to MWT SL (rho = .56, p = .003) and a negative relationship to MWT SE (rho = ‐.37, p = .06), indicating that higher dosages were related to greater alertness, i.e., MWT differences in SL between PD and RBD were further accentuated by the elimination of those cases. No other medications contributed to differences in MWT. SIGNIFICANCE OF STUDY: Following current models of early brainstem neurodegeneration in PD, a range of functional neuroanatomic features would be expected to deteriorate synchronously. These data suggest that the loss of olfactory function and daytime alertness are disassociated early in the course of PD.

A‐043

INFLAMMATORY MARKERS IN ENDOMETRIAL CANCER AMONG POSTMENOPAUSAL WOMEN

Wang T ¹, Xue X¹, Gunter M¹, Strickler H¹, Rohan T¹, Rajpathak S¹, Smoller S¹, Kaplan R¹, Ho G¹  ¹Albert Einstein College of Medicine, Bronx, NY, United States

OBJECTIVES: Obesity is the most significant risk factor of endometrial cancer. Because obesity is considered a systematic inflammatory condition, inflammation may be one major mechanism to link obesity and endometrial cancer risk. However, few studies evaluated the association of different inflammatory biomarkers in the plasma with risk of endometrial cancer. METHODS AND POPULATION: We examined the associations of three inflammatory markers (CRP, TNF‐α and IL6) with risk of endometrial cancer by a case‐cohort study in the Women's Health Initiative Observational Study. A total of 287 incident cases and a random subcohort of 481 subjects were included in our analysis. Cox models were used to estimate association between risk factors and risk of endometrial cancer. RESULTS: Our data show that the levels of CRP were positively associated with risk of endometrial cancer in an age‐adjusted model among women not using hormone therapy (HR_q4‐q1, 2.36; 95%CI, 1.28‐4.35; p_trend=0.0008). Among women who use hormone therapy, the levels of CRP were reversely associated with risk of endometrial cancer in an age‐adjusted model (HR_q4‐q1, 0.46; 95%CI, 0.21‐0.99; p_trend=0.0129. There was a marked negative interaction between hormone therapy use and the levels of CRP (HR, 0.24; 95%CI, 0.11‐0.49; p=0.0001) on risk of endometrial cancer. Our data did not provide any evidence of the associations of TNF‐α and IL6 with endometrial cancer. SIGNIFICANCE OF STUDY: Elevated CRP levels had significantly increased risk of endometrial cancer among postmenopausal nonusers of hormone therapy, but increased less risk among users of hormone therapy. The detailed biological mechanism by which CRP and hormone therapy act interactively in endometrial cancer is unclear.

A‐044

DETECTION OF HUMAN INFLUENZA VIRUS IN NON‐RESPIRATORY SITES

Wootton SH ¹, Jewell AM², Patel KD², Sreenivasula S³, Aguilera E¹, Wanger A¹, Murphy JR¹, Piedra PA²  ¹University of Texas Health Science Center at Houston, Houston, TX, United States, ²Baylor College of Medicine, Houston, TX, United States, ³University of Texas School of Public Health, Houston, TX, United States

OBJECTIVES: Children with influenza infection may develop gastrointestinal (GI) symptoms. Novel 2009 influenza/A (nH1N1) is commonly associated with respiratory and GI symptoms. Whether disease manifestations at non‐respiratory sites is associated with the presence of influenza virus has not been established. This study explores non‐respiratory sites (stool and blood) for the detection of seasonal and novel influenza viruses using RT‐PCR and cell culture. METHODS AND POPULATION: Children age <18 yrs admitted during January 2009 – January 2010 with laboratory‐confirmed influenza infection were eligible for enrollment. Up to 3 nasal wash (NW), 1 blood and 3 stool specimens were collected from enrolled patients. Specimens were tested by cell culture (NW, stool) and RT‐PCR (NW, blood, stool) for seasonal and novel influenza viruses. RESULTS: 11 (6.7%) of 164 eligible children were enrolled. 41 specimens (18 NW, 9 blood, 14 stool) were collected. Of 32 specimens sent for viral culture, influenza was isolated from 4 (12.5%) NW and 0 stool specimens. Influenza was detected by RT‐PCR in 4 (28.5%) stool specimens (all nH1N1), 1 (11.1%) blood (RBC, nH1N1) and 16 (88.8%) NW specimens (12 nH1N1 and 4 seasonal). SIGNIFICANCE OF STUDY: Despite small sample size, nH1N1 was identified in the stool of 2 children and blood of 1 child by RT‐PCR. The assumption that detection of human influenza virus is generally confined to respiratory specimens should be revisited. Non‐respiratory sites should be further evaluated.

A‐045

RISK ASSESSMENT OF GLOBAL AFLATOXIN‐INDUCED LIVER CANCER

Wu F ¹, LiuY¹  ¹University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: We estimated the global burden of hepatocellular carcinoma (HCC), or liver cancer, attributable to aflatoxin exposure. HCC is the third leading cause of cancer deaths worldwide. Aflatoxin, a mycotoxin produced by the fungi Aspergillus flavus and A. parasiticus in maize and nuts, is a known human liver carcinogen. METHODS AND POPULATION: We conducted a quantitative cancer risk assessment. Exposure to aflatoxin was estimated by collecting global data on foodborne aflatoxin levels, consumption of maize and nuts in different parts of the world, and hepatitis B (HBV) prevalence. Cancer potency factors of aflatoxin for HBV+ and HBV‐ individuals, and uncertainty in all variables, were considered in estimating the global burden of aflatoxin‐induced HCC. We further estimated how aflatoxin‐induced HCC cases would change if HBV vaccination were introduced globally. RESULTS: Of the roughly 560,000 new HCC cases worldwide per year, about 25,200‐155,000 may be attributable to aflatoxin exposure. Most cases occur in sub‐Saharan Africa, Southeast Asia, and China, whose populations are highly exposed to both HBV and largely uncontrolled aflatoxin in the food. If HBV vaccination were introduced globally such that HBsAg seroprevalence were ≤2% worldwide, the number of aflatoxin‐related HCC cases could drop to 13,400‐65,400 annually. SIGNIFICANCE OF STUDY: Aflatoxin may play a causative role in 4.6‐28.2% of all global HCC cases. A number of public health interventions have been developed to control aflatoxin; efforts should be made to introduce and increase adoption of these interventions in world regions where aflatoxin is still a significant public health risk. Specifically, HBV vaccination can significantly reduce aflatoxin‐related HCC cases in future generations.

A‐046

FACILITATING PHARMACOGENETIC STUDIES OF WARFARIN OUTCOMES USING INFORMATICS METHODS

Xu H ¹, Cunningham AJ¹, Roden DM¹, Stein CM¹  ¹Vanderbilt University, Nashville, TN, United States

OBJECTIVES: Electronic medical record (EMR) databases are emerging as valuable resources for clinical research, including pharmacogenetic studies, which identify associations between genetic variations and drug efficacy and toxicity. One obstacle to the use of EMR data is that much of the detailed clinical information is embedded in narrative text which is difficult and costly to mine manually. Information technologies, such as natural language processing (NLP), which can extract structured data from clinical narratives, provide automated ways to extract data from EMR for clinical research. Our goal is to develop advanced informatics methods to accelerate the efficient use of EMR data for pharmacogenetic studies. METHODS AND POPULATION: As a first step to achieving this goal, we focus on a pharmacogenetic study of warfarin and bleeding complications. While there have been many studies of warfarin pharmacogenetics, these have focused on predictors of dose, and not of the serious outcome of bleeding. The aims of this ongoing research are 1) To develop and evaluate NLP‐based informatics approaches that can accurately extract various types of clinical phenotypes from EMR; and 2) To use a candidate gene approach to discover associations between genetic polymorphisms and warfarin associated bleeding events by linking phenotypic data to genotypic data in our DNA databank. RESULTS: We anticipate that the informatics‐based approaches will allow us to conduct the warfarin pharmacogenetic study in a time and cost efficient way. SIGNIFICANCE OF STUDY: The work will not only establish new information for predicting outcome with this drug, but also will lay the groundwork for approaches to exploit EMR systems as a tool for pharmacogenetics.

A‐047

UTILITY OF EMERGENCY DEPARTMENT VISITS FOR ASTHMA EXACERBATIONS FOR SYNDROMIC SURVEILLANCE

Yadav K ¹, MayL ¹, Carim M¹  ¹The George Washington University, Washington, DC, United States

OBJECTIVES: Syndromic surveillance uses emergency department data to monitor influenza‐like illness (ILI). Prior studies have shown conflicting evidence of an association of asthma exacerbations and upper respiratory infections. Our hypothesis is that asthma is not an effective indicator for use in syndromic surveillance for detection of ILI or respiratory infection. METHODS AND POPULATION: Retrospective electronic chart review during the 2005‐2006 influenza season (10/1/2005‐5/19/2006) of adult emergency department patients at an urban teaching hospital with chief complaint and ICD9 diagnostic coding related to asthma, upper respiratory illness (URI), and pneumonia. Weekly influenza‐like illness (ILI) visit rates were obtained from CDC South Atlantic Region reports. Time series analysis was performed using backwards stepwise model building with appropriate regression diagnostics. RESULTS: There were 38,820 patient visits during study period with 188 visits with a chief complaint of asthma, 544 diagnoses of asthma, 1046 chief complaints of URI, 432 diagnoses of URI, and 448 diagnoses of pneumonia. Pneumonia diagnosis modeling (R2 = 0.292) was positively correlated with ILI visits (correlation coefficient = 0.341 [0.146 to 0.535]). ILI visit modeling (adjusted for autocorrelation) was positively correlated with URI visits (correlation coefficient = 0.667 [0.289 to 1.045]) and negatively correlated with asthma visits (correlation coefficient = ‐0.664 [‐1.147 to ‐0.181]). SIGNIFICANCE OF STUDY: Asthma alone may not be a good surrogate for respiratory infection in ED data sources in adults for the purposes of syndromic surveillance. Nevertheless, exploring the inclusion of asthma severity in syndromic criteria should be considered to augment traditional public health surveillance for asthma.

A‐048

ADULT ASTHMA EXACERBATIONS AND ENVIRONMENTAL TRIGGERS

Carim M¹, M a y L ¹, Yadav K ¹  ¹The George Washington University, Washington, DC, United States

OBJECTIVES: Aware of an association of environmental triggers with pediatric asthma, our hypothesis is that adult asthma exacerbation (AAE) is associated with environmental triggers both for ED visits and hospital admissions. METHODS AND POPULATION: Retrospective electronic chart review (6/1/05 to 5/30/06) of adult emergency department (ED) patients from a single urban teaching hospital with chief complaint and diagnostic coding related to asthma, upper respiratory infection (URI), and pneumonia. Monthly aeroallergen data (ragweed and tree pollen) and air quality data (fine particulate matter and ozone) were obtained from local sources. Time series analysis was performed with outcome variables of ED visits and admissions. Backwards stepwise model building was performed with regression diagnostics. RESULTS: There were 56,747 visits with 554 asthma visits, 1514 URI visits, and 544 pneumonia diagnoses. Asthma visits (R2 = 0.527) were positively correlated with tree pollen counts (correlation coefficient = 0.390 [0.075 to 0.706]) and negatively correlated with URI visits (correlation coefficient = ‐1.312 [‐2.621 to ‐0.003]). Asthma admissions (R2 = 0.5377) were positively correlated with URI visits (correlation coefficient = 0.820 [0.064 to 1.576]) and negatively correlated with ozone counts (correlation coefficient = ‐0.547 [‐1.040 to ‐0.054]) when adjusting for confounding by fine particulate matter. SIGNIFICANCE OF STUDY: ED AAE visits are positively correlated with tree pollen. While paradoxically negatively correlated with ED visits, URI is positively correlated with AAE admissions, suggesting an association with increased asthma severity. These results reinforce the need for early interventions during periods of increased risk, such as treatment of seasonal allergies, influenza vaccination, and early use of steroids in AAE.

CLINICAL TRIAL

A‐049

TREATING COGNITIVE DEFICITS WITH LOVASTATIN: PHASE 1 TRIAL IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1

Acosta MT ¹, Walsh KS¹, Kardel P¹, Gioia GA¹, Packer RJ¹  ¹Children's National Medical Center, Washington, DC, United States

OBJECTIVES: Lovastatin has been widely used to treat hyperlipidemia in humans. In a mice model of NF1, lovastatin has improved cognitive deficits and executive functioning. We examined the safety and biological impact of lovastatin as a treatment for the neurocognitive deficits in children 10‐17 y/o with diagnosis of NF1. METHODS AND POPULATION: Lovastatin was administered to 24 patients in a daily doses of 20, 30, 40 mg for 12 weeks. Neuropsycho‐logical testing was performed pre and post treatment. Pharmacokinetics studies were done in a subset of patients. RESULTS: Lovastatin absorption was extremely variable as Tpeak concentration ranged from 0.38ng/mL to 4.01ng/mL. Medication was safe in all patients with minimal side effects. Changes in cholesterol from pre to post ranged from +8.3% to −28.8%. Relation of cholesterol subtypes stayed in the normal limits. Other metabolic measurements stayed in normal limits through the study. Interestingly, change in cholesterol was nearly significantly correlated with a cognitive variable, specifically the Sky Search Attention within the TEA‐Ch, r=0.420, p=0.052. Additionally, subtests within the WRAML that assess memory, recall, & recognition showed significant improvement (p<.05) as compared to baseline SIGNIFICANCE OF STUDY: Lovastatin was well tolerated and no safety concerns arose during the three month period of our study. Despite small number of patients and variability in test performance, metabolism of cholesterol correlated with neuropsychological assessment. While the data is encouraging, further studies of drug efficacy on neuropsychological functioning are necessary. A phase 2 study is currently ongoing to further assess these observations.

A‐050

CORRELATION OF STRUCTURE AND FUNCTION IN PATIENTS WITH NON‐LESSIONAL PARTIAL EPILEPSY

Andrade E ¹, Parekh M¹, Triplett W¹, Liu Z¹, Marecci T¹, Carney P¹  ¹University of Florida, Gainesville, FL, United States

OBJECTIVES: This study aims to understand the relationship between the ictal EEG onset and findings on a 3 Tesla brain MRI. METHODS AND POPULATION: The study has 2 phases: prospective and retrospective. The retrospective part involves reviewing medical records, EEGs, 1.5 Tesla brain MRI and phase I epilepsy surgery evaluation which includes neuropsychology evaluation, PET, SPECT and MEG study. The prospective phase enrolls patients for a 3.0 Tesla MRI and phase II epilepsy surgery evaluation which includes somato‐sensory evoked potential response, functional mapping and electrocorticogram. We have enrolled 14 subjects out of 75 planned cases all with non‐lesional partial epilepsy ranging between 6 months and 75 years of age. RESULTS: The Brain MRI and EEG studies of 14 patients with non‐lesional partial epilepsy intractable to medical treatment were revised. Of the two cases that have undergone 3T MRI thus far, one reveals increased number of fibers in the mesial portions of the temporal lobes. There were no significant abnormalities in the 3T MRI of the second case enrolled. Most patients on this study have an ictal onset over the mesial portion of the temporal lobe and underwent an anterior temporal lobectomy. The pathological finding most commonly identified is subpial (Chasling) gliosis. Most patients that underwent a temporal resection have remained seizure‐free at 1 year. SIGNIFICANCE OF STUDY: Prior to epilepsy surgery, the cases were scrutinized to confirm the candidacy for a surgical resection. It is not clear if patients with a 1.5T MRI will have an abnormal 3.0T MRI. Accurate definition of the ictal zone will lead to limited surgical resection and higher likelihood of long‐term seizure freedom.

A‐051

TRIALX: A WEB‐BASED PATIENT RECRUITMENT REGISTRY AND PLATFORM

Atreja A ¹, Patel CO², Trunick C¹, Garg V², Serpil E¹  ¹Cleveland Clinic, Cleveland, OH, United States, ²Applied Informatics Inc, New York, NY, United States

OBJECTIVES: As an industry‐academia initiative within the CTSA, we have focused on developing, TrialX, a customizable and comprehensive web‐based registry and patient recruitment platform aimed to reduce inefficiencies in the clinical trial recruitment process. METHODS AND POPULATION: TrialX enables patients and investigators to find and connect with each other directly, eliminating any intervening steps. It is designed to be a full functioning and searchable patient registry and also serves as a ‘Do‐it‐yourself’ recruitment solution. The system provides patients the ability to enter their health information in the registry or import the same from personal health record platforms of Microsoft HealthVault and Google Health. Patients can find matching trials using consumer‐friendly terms and communicate with the relevant investigators through a secure messaging platform. Investigators can add their trials and customize the look and feel of the trial page through a web page creation toolkit. They can also target the trial to relevant participants through search keywords using TrialX's integration with the online advertising platform of Google. TrialX also provides investigators an analytics dashboard to track their recruitment goals. The system provides the ability to query the patient registry using a terminology based semantic matching technology. RESULTS: Trial X is currently being implemented at the Clinical Research Unit of the Cleveland Clinic. The system provides several ways to customize the installation to meet the regulatory and administrative needs of the local institution (such as defining user roles, authorization schemas). SIGNIFICANCE OF STUDY: TrialX is an industry‐academia web‐based patient recruitment solution that offers a modern patient registry with a trial listing, matching, marketing and tracking solution.

A‐052

THE STUDY OF HISTOPATHOLOGY OF SKIN IN VASCULARIZED COMPOSITE ALLOGRAFTS

Cendales L ¹, Kleiner D², Kirk A¹  ¹Emory University, Atlanta, GA, United States, ²National Cancer Institute, NIH, Bethesda, MD, United States

OBJECTIVES: Given the success of solid organ transplantation, therapies have been proposed for transplantation of tissue loss. Vascularized composite allograft(VCA) refers to the transfer of peripheral tissues including skin, muscle, nerve, and bone as a functional unit (e.g.hand) to replace non‐reconstructible tissue‐defects.To date over 50 patients have received a VCA and all have experienced rejection. METHODS AND POPULATION: Recognizing that the limiting factor in studying VCA pathology is the scarce number of clinical cases, we initiated the collection of samples from international centers in which hand and abdominal wall VCA have been performed. RESULTS: In our studies on 29 specimens,we observed that rejection appeared as a perivascular infiltrate progressing to involve the dermis. We noted arteritis only in the medium‐to‐large size arteries of the subcutis. Perineural involvement without frank neuritis was present in advanced rejection. The infiltrate was predominantly CD4+ in milder cases and CD8+ in advanced cases. HLA‐DR was minimally expressed in keratinocytes. Based on this survey we proposed the first classification system for acute rejection of a VCA. Classification systems in transplantation have developed at the Banff Conferences. Thus, we organized the first public international consensus discussions for VCA rejection at the 9th Banff Conference resulting in the Banff CTA 2007 working classification of skin allograft pathology. We agreed that defining features to diagnose acute skin rejection includes inflammatory cell infiltration with epidermal and/or adnexal structure involvement,epithelial apoptosis, dyskeratosis,and necrosis,and that severity of rejection will be graded under five categories. SIGNIFICANCE OF STUDY: This classification system serves as the schema for acute skin rejection in VCA.

A‐053

NOVEL RISK FACTORS FOR NEW ONSET DIABETES MELLITUS AFTER KIDNEY TRANSPLANTATION

Chakkera H ¹, Devarapalli Y¹, Heilman R¹, Hamawi K¹, Mazur M¹, Cook C¹  ¹Mayo Clinic Arizona, Phoenix, AZ, United States

OBJECTIVES: New onset diabetes mellitus after kidney transplantation (NODAT) adversely effects health care costs, quality of life and allograft and patient survival. Several well known traditional risk factors for T2DM are associated with NODAT. However, characterization of the inpatient hyperglycemia immediately post transplant (Tx) in patients with no Hx of DM before Tx and its association NODAT is not clearly established. We studied the magnitude of inpatient hyperglycemia and assessed the risk it confers on development of NODAT. METHODS AND POPULATION: We studied all adult non‐diabetic kidney Tx recipients between 6/1999 and 1/2008. Post‐Tx inpatient hyperglycemia was defined as any bedside capillary blood glucose ≥ 200 mg/dL or insulin Rx during hospitalization. NODAT = HbA1C ≥ 6.5%, fasting serum glucose ≥ 126 mg/dL, or on diet or medical Rx for DM within 1 year post‐Tx. RESULTS: Study cohort = 377 patients. Incidence of NODAT: 27%. 327 (87%) had inpatient hyperglycemia prescribed insulin. NODAT developed in 2 (7%) of the 27 patients without inpatient hyperglycemia, 3 (13%) of 23 patients with inpatient hyperglycemia but not Rx with insulin, and in 98 (30%) of the 327 of the patients who were diagnosed with inpatient hyperglycemia and Rx with insulin. Presence of inpatient hyperglycemia adjusted for immunosuppression, age, BMI conferred a 4 fold risk (RR 4.01, p = 0.006) for NODAT. Insulin requirements during hospitalization were positively associated with risk of NODAT. The risk was 2.9 higher (RR 2.9, p < 0.001) if patients required 10 or more units of insulin vs. none post‐Tx. SIGNIFICANCE OF STUDY: High incidence of inpatient hyperglycemia observed immediately after kidney Tx among previously non‐diabetic patients and its presence significantly increases the risk of NODAT by 4 fold.

A‐054

EVALUATION OF CLINICAL OUTCOMES OF AN ONLINE TELEDERMATOLOGY MODEL FOR THE MANAGEMENT OF PSORIASIS: A RANDOMIZED CONTROLLED TRIAL

Chambers CJ ¹, Armstrong AW¹  ¹University of California Davis, Sacramento, CA, United States

OBJECTIVES: (1) To determine if an asynchronous online model of teledermatology can provide similar or better clinical outcomes compared to conventional in‐office care for the management of psoriasis (2) To determine the effects of such a model on quality of life and patient satisfaction. METHODS AND POPULATION: We conducted a randomized, controlled trial comparing the clinical course of psoriasis patients followed in telemedicine clinic with those receiving traditional in‐office care. Following an initial baseline visit, sixty‐two subjects were randomized in a 1:1 non‐stratified fashion to continue follow up either inperson or on‐line. Clinically validated, disease‐specific measures including the Psoriasis Area Severity Index (PASI), Investigator Global Assessment, and Dermatology Life Quality Index were assessed in‐person at the baseline and outcome visits for all patients. The study had a 90% power to detect a minimal clinically relevant mean difference of 2.5 points in the PASI, the primary outcome measure, with a standard deviation of 3 and an alpha of 0.05. RESULTS: We anticipate that compared to traditional in‐office care the online care model will result in similar improvements in psoriasis disease severity, quality of life and patient satisfaction. SIGNIFICANCE OF STUDY: Studies suggest that teledermatology may improve patient satisfaction, reduce costs and improve access to dermatologic specialty care. The diagnostic accuracy and reliability of teledermatolgoy is similar to conventional care; however, comparability of clinical outcomes has not been well studied. Rigorous clinical outcomes research utilizing validated disease‐specific measures is required if this innovative health care delivery model is to be incorporated into standard clinical practice.

A‐055

COMPUTER‐ASSISTED SELF‐INFUSION OF ETHANOL (CASE) IN HUMANS

Cooke M ¹, Vatsalya V¹, Issa J¹, Hommer D¹, Zimmermann US¹, O’Connor S¹, Heilig M¹, Ramchandani VA¹  ¹NIAAA, Bethesda, MD, United States

OBJECTIVES: The CASE system is a method of intravenous (IV) alcohol administration that provides individuals with choices for self‐administering alcohol in a laboratory setting, while controlling the breath alcohol concentration (BrAC) exposure using a physiologically‐based pharmacokinetic model‐based algorithm. The objective of this study was to determine the test‐retest reliability and to evaluate the influence of recent drinking history on alcohol self‐administration. METHODS AND POPULATION: Healthy social drinkers (11 female, 17 male) participated in this 2‐session study. Each session included an initial 25‐min priming phase during which subjects were prompted to push a button to receive individually standardized alcohol infusions. This was followed by a 2‐hr open‐bar phase, during which subjects had ab‐lib access to the alcohol infusions. Serial BrAC measurements were obtained during the study session. Primary measures included total number of button presses (NBP), peak BrAC (PEAK) and average BrAC (AVG). RESULTS: There was high degree of reliability among the primary measures between sessions (correlation coefficients for NBP: r=0.83, PEAK: r=0.73, AVG: r=0.65; all p‐values <0.01). Correlations among measures within‐session were also high (NBP vs. PEAK: R2 = 0.82; NBP vs. AVG: R2 = 0.80). There was a significant association between recent drinking history measures and self‐administration measures. Multiple regression revealed drinks per drinking day as the strongest predictor of NBP (p<0.001), while number of drinking days was the strongest predictor of both PEAK and AVG. There were no sex differences in self‐administration measures. SIGNIFICANCE OF STUDY: The CASE paradigm is a reliable, reproducible method. It is being extended to evaluate the effect of medications on alcohol self‐administration in heavy drinkers.

A‐056

ASSESSING THE CULTURAL COMPETENCY AND DISEASE AWARENESS OF INPATIENT AND OUTPATIENT ONCOLOGY NURSES PROVIDING CARE FOR PATIENTS DIAGNOSED WITH ADULT T‐CELL LEUKEMIA/LYMPHOMA (ATLL)

Cortese M ^{1, 1, 1}, Godbold J¹

¹Mount Sinai School of Medicine, New York, NY, United States

OBJECTIVES: 1. To assess the cultural competency and disease awareness of inpatient and outpatient oncology nurses at Mount Sinai Medical Center who provide care for patients diagnosed with ATLL. 2. To assess if nurses who have graduated from a nursing baccalaureate program in the past 10 years have more cultural competence than those nurses who have graduated more than 10 years ago. METHODS AND POPULATION: The study will be conducted at Mount Sinai Medical Center. Subjects will be recruited based on the following eligibility criteria: at least 18 years of age, hold at least a Bachelor's degree in nursing, have a New York State License as a Registered Nurse, must be fluent in English, must have at least 1 year of nursing experience working on an inpatient or outpatient oncology unit. Two surveys will be utilized: one survey assessing knowledge regarding Japanese and Caribbean culture; and another survey assessing disease awareness regarding HTLV‐1 and ATLL. The target sample is 123 nurses. This sample size was based on a 2 sided t‐test with a significance level of 5%, 95% confidence interval, 20% Pearson's correlation coefficient and a power of 80%. RESULTS: In the context of this study, it is expected that 50% or more of oncology nurses working at Mount Sinai Medical Center that were surveyed will obtain less than 50% of the questions correct. In addition, nurses who have graduated from a nursing baccalaureate program within the past 10 years will have more cultural awareness regarding the Japanese and Caribbean culture. SIGNIFICANCE OF STUDY: Cultural competence in the part of nursing has shown better patient care outcomes. We hypothesize that nurses who are culturally competent will deliver better care to ATLL patients.

A‐057

PROOF OF CONCEPT CLINICAL TRIAL OF CHOLECALCIFEROL IN DIABETIC KIDNEY DISEASE

de Boer IH ¹, Flynn AV¹, Rue TC¹, Kestenbaum B¹, Probstfield JL¹, Weiss NS¹, Brunzell JD¹  ¹University of Washington, Seattle, WA, United States

OBJECTIVES: Vitamin D supplementation may be a novel intervention for the prevention and treatment of diabetic kidney disease. We designed and initiated a proof of concept clinical trial to evaluate whether cholecalciferol (vitamin D3) may lower urine albumin excretion and improve cardiovascular risk in the setting of type 2 diabetes. METHODS AND POPULATION: This is a randomized, placebo‐controlled, parallel group clinical trial. Eligibility criteria include type 2 diabetes, elevated urine albumin‐creatinine ratio (ACR, 30‐1000 mg/g), preserved glomerular filtration rate (≥60 mL/min/1.73m2), established treatment with an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker, and low serum 25‐hydroxyvitamin D concentration (<30 ng/mL). Participants are randomly assigned to cholecalciferol 2000 IU by mouth daily or matching placebo for 1 year. The specified primary study outcome is change in urine ACR. Secondary outcomes include changes in serum 25‐hydroxyvitamin D, 24‐hour ambulatory blood pressure, plasma lipids and lipoproteins, circulating inflammatory proteins, and circulating markers of mineral metabolism and insulin sensitivity. RESULTS: Twenty‐two participants were randomly assigned to a treatment group. At baseline, for the first 20 participants, mean age was 59 years, 40% were women, 35% were non‐Caucasian, mean 25‐hydroxyvitamin D was 18 ng/mL, median urine ACR was 85 mg/g, and mean estimated glomerular filtration rate was 85 mL/min/1.73m2. Each participant completed a 3‐month study visit, and all study visits will be complete in July, 2010. SIGNIFICANCE OF STUDY: Results of this trial will help determine whether larger, longer trials of vitamin D are indicated for the prevention and treatment of diabetic kidney disease and, if so, will provide preliminary data to inform the design of such studies.

A‐058

VANCOMYCIN PHARMACOKINETICS AND PHARMACODYNAMICS DURING SHORT‐DAILY HEMODIALYSIS

Decker BS ¹, Sowinski K^1,2, Kays M^1,2, Kraus M¹, Moe S¹  ¹Indiana University School of Medicine, Indianapolis, IN, United States, ²Purdue University, West Lafayette, IN, United States

OBJECTIVES: The purpose of this study was to investigate the effect of short‐daily hemodialysis (SDHD) on the pharmacokinetics (PK) of vancomycin and the intradialytic removal of vancomycin. METHODS AND POPULATION: Six adults treated with SDHD were studied and received 4 dialysis sessions over 4 days. Following the completion of a subject's first SDHD, vancomycin IV 15 mg/Kg was given. Blood samples were obtained over the ensuing 3 days during each subsequent inter‐ and intradialytic period. Vancomycin concentrations were determined by EMIT. Pharmacokinetic models were fit to the concentration‐time data using ADAPT5 modeling software and PK parameters were determined. AUC(0‐48 hours) was calculated by the trapezoidal rule. Monte Carlo simulations were performed to calculate the probability of target attainment (PTA) at an AUC(0‐48 hour)/MIC ratio greater than or equal to 800 for 15 and 20 mg/Kg doses after every other HD session. RESULTS: Five men and 1 woman were studied. A two compartment open model best fit the pharmacokinetic data. The median AUC(0‐48hhours)measured 882 (620‐1050) ug/hr/ml. Systemic clearance was 7.4 (5.3‐10.0)ml/min and dialytic clearance measured 84 (59‐101)ml/min. The volume of the central compartment was 84 (59‐101)L. The volume of distribution at steady state measured 56.5 (34.8‐77.2)L. Finally, the PTA was greater than 90% for 15 and 20 mg/Kg doses at MICs 0.5 g/ml and 1 g/ml. SIGNIFICANCE OF STUDY: Vancomycin PK parameters in SDHD are consistent with data from thrice weekly HD. Vancomycin dialytic clearance values were higher than previous data with conventional HD. Vancomycin doses of 15 or 20 mg/Kg every other HD session provide adequate exposure for treating infections in which organisms have MICs of 1 ug/ml or less.

A‐059

ANTIVIRAL AND IMMUNOLOGICAL EFFECTS OF INTENSIFICATION OF SUPPRESSIVE ART WITH MARAVIROC, A CCR5 ANTAGONIST

Evering T ¹, Mehandru S¹, Poles M ², Tenner‐Racz P³, Parker T⁴, Markowitz M¹  ¹Rockefeller University, New York, NY, United States, ²New York University School of Medicine, New York, NY, United States, ³Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany, ⁴The Rogosin Institute, New York, NY, United States

OBJECTIVES: GI tract CCR5+CD4+ T cells are selectively infected and depleted during acute HIV‐1 infection. Despite ART, GALT T cell depletion and activation persists. We hypothesized that ART intensification (INT) with the CCR5 antagonist maraviroc (MVC) could effect immune reconstitution and decrease immune activation if this was due to ongoing viral replication. METHODS AND POPULATION: We enrolled adults infected with CCR5‐tropic HIV‐1 and treated with ART during acute/early infection for ∼4 yrs prior to entry. Subjects were randomized 2:1 to Arm A: INT with MVC for 24 weeks (n = 4); or Arm B: NRTI INT for 12 weeks followed by cross‐over to MVC for 12 weeks (n = 2). RESULTS: Plasma HIV‐1 RNA was <50 copies/ml and GI biopsy RNA was <50 copies of HIV‐1 NL43 gag (∼1.5×106 copies GAPDH/sample) for all subjects at entry through week 24. Immunohistochemistry revealed 5.36 + 0.86 CD4+ T cells/unit area in the lamina propria (LP) at entry in Arm A. This did not increase significantly after 24 weeks. In Arm A, flow cytometry revealed significant differences (p<0.02) between the PBMC and GALT at entry in the CD4+/CD8+ T cell ratio (1.47 + 0.14 vs 0.91 + 0.06) and % activated (CD38+) CD8+ T cells (2.61 ± 0.41 vs 17.61 ± 5.02). In Arms A and B, no statistically significant change (p>0.32) was noted in %CD38+ or % proliferating (Ki67+) CD4+ or CD8+ T cells in the GALT between entry, weeks 12 and 24. In both arms, serum endotoxin activity did not significantly change after 24 weeks. SIGNIFICANCE OF STUDY: Thus far, we observe no statistically significant effect of intensification of ART with MVC on a variety of immunologic and virologic parameters in the GALT.

A‐060

A CLINICAL TRIALS TRAINING CURRICULUM DESIGN

Farrar JT ¹   ¹University of Pennsylvania, Philadelphia, PA, United States

OBJECTIVES: Development of an innovative clinical trials curriculum (CTC) to enhance research training, education, and career development of clinical research trainees. METHODS AND POPULATION: Clinical trials training is not new. Primarily this occurs through the active participation in clinical trials. To try to shorten the timeframe for developing the necessary skills and provide exposure to appropriate research experiences, syllabi were collected from almost all of the academic centers awarded Clinical and Translational Science Awards (CTSAs), and a number of Schools of Public Health. The focus and specifics were compared to create a comprehensive list of skills appropriate for a CTC. A suggested four course curriculum was created that could be added to standard training in epidemiology and biostatistics to educate clinicians towards clinical trials at a Master Degree Level and a potential curriculum for PhD level training is being developed. RESULTS: Four courses were created: 1)Introduction to clinical trials 2)Advanced clinical trials 3)Practical aspects of clinical trials – a practicum 4)Statistical methods in clinical trials Additional electives are possible from the comprehensive list of topics that served as the basis for this exercise. The next step is to widely circulate the specifics of these courses for comments by the many experts at other institutions for their comments and the input. Finally this information will be made available for all who may wish to create or extend their own training programs along these lines. SIGNIFICANCE OF STUDY: The development of sufficient manpower to design, conduct, analyze, and publish this type of research will require a concerted effort by clinical research training programs. The length of clinical trials slows down training. The focused exposure of young researchers to the various aspects of clinical trials should facilitate their development.

A‐061

THE EFFECT OF NON‐SURGICAL PERIODONTAL THERAPY ON GLYCEMIC CONTROL AND BACTERIAL LEVELS IN A MEXICAN‐AMERICAN POPULATION WITH TYPE 2 DIABETES

Gay IC ¹, Tribble G¹, Katancik J¹  ¹UTHSCH‐DB, Houston, TX, United States

OBJECTIVES: 1) Determine the association between diabetes mellitus control and periodontal disease severity assessed by HbA1c values and periodontal examination; 2) measure the burden of oral bacteria before and after therapy; 3) Verify oral and systemic changes after therapy. METHODS AND POPULATION: The sample size of 142 subjects was calculated based on change in HbA1c with 80% power. Blood will be processed for HbA1c values, and peri‐odontal status will be evaluated. Dental plaque will be taken from periodontitis sites and healthy sites to compare microbial burden and profile by 16s PCR identification and qRT‐PCR. At 4 months post‐treatment, a second plaque and blood sampling will be performed to observe microbiological changes and final HbA1c values RESULTS: Type 2 diabetes is a pandemic in the United States; in Mexican‐Americans prevalence rates are up to 50%. Periodontitis is also common in this population. Periodontitis and diabetes share common pathways in pathogenesis, and studies indicate that periodontal therapy may improve glycemic control. This study will determine if treatment of periodontitis is therapeutic for glycemic control in Mexican‐Americans. SIGNIFICANCE OF STUDY: Periodontal disease and diabetes mellitus are closely associated, highly prevalent chronic diseases with many similarities in pathobiology. This study will shed light on the importance of periodontal disease treatment for the overall improvement in the health of a diabetic population.

A‐062

ADULTS WITH ORNITHINE TRANSCARBAMYLASE DEFICIENCY (OTCD) DEMONSTRATE PERSISTENT ABNORMALITY IN CEREBRAL GLUTAMATE METABOLISM

Gropman AL ^1,2, Sailasuta N³, Harris K³, Abulseoud O^4,2, Ross BD²  ¹Children's National Medical Center, Washington, DC, United States, ²Georgetown University, Washington, DC, United States, ³Huntington Medical Research Institute, Pasadena, CA, United States, ⁴Keck Medical School, Los Angeles, CA, United States

OBJECTIVES: To determine cerebral glutamate turnover rate in adults with partial ornithine transcarbamylase deficiency (OTCD) as compared to normal control adults. METHODS AND POPULATION: All subjects signed informed consent to participate in the study. We performed MRI, 1H MRS and 13C MRS studies in 6 patients with OTCD and 4 normal controls, imaged in stable condition. Each received i.v. 13C glucose (0.2g/kg) C1 or C2, as a 15 min bolus. Cerebral metabolites were determined with proton decoupling in posterior cingulate gyrus (PCG, N=9) and without proton decoupling in anterior (N=1) cingulate gyrus (ACG) over 60 – 120 minutes. RESULTS: 1. Uptake and removal of cerebral glucose (13C‐C1 or C2) were comparable in normal controls and subjects with OTCD (P = 0.1). 2. Glucose C1 was metabolized to glutamate C4 and glucose C2 to glutamate C5 at comparable rates, both of which were significantly reduced in OTCD (combined P = 0.04). 3. No significant differences in glut‐amine formation were found in OTCD (P = 0.1). 4. 13C ‐ 2 glucose and its metabolic products were observed in ACG without proton decoupling in a single subject with OTCD. SIGNIFICANCE OF STUDY: Reduced glutamate neurotransmission (GNT) secondary to impaired cerebral glucose metabolism was documented in OTCD using 13C MRS of occipital lobe. Feasibility of 13C MRS in frontal brain structures was demonstrated. Treatment(s) which improve cerebral glucose metabolism and GNT may improve neurological outcome in OTCD as prevention and treatment of hyperammonemic episodes appears insufficient.

A‐063

HIGH PUFA VS HIGH CHO DIET IN CONTROL, NAFLD AND HEPATITIS C PARTICIPANTS

Han‐Markey TL ¹, Rothberg AE², Burant C²  ¹University of Michigan, Ann Arbor, MI, United States, ²University of Michigan, Ann Arbor, MI, United States

OBJECTIVES: Diet's effect on lipid metabolism and viral titers in healthy controls, NAFLD and hepatitis C was studied. METHODS AND POPULATION: Participants randomized to either a 3 week, wt maintenance high PUFA diet or high CHO diet; they immediately crossed over to the other diet for 3 additional weeks. Baseline, post‐diet blood work was collected including viral loads, LFT's, plasma insulin, lipid and RNA expression profiles. OGTT was administered. Participants were weighed weekly and total calories were adjusted to maintain weight within 2.5% of baseline. RESULTS: 12 healthy, 5 NAFLD and 3 hepatitis C participants completed the study. Control and NAFLD participants had lipid profile decreases from baseline and after 21 days of high PUFA diet. After 21 days of high CHO diet, serum lipid levels increased. Pending data includes hepatitis C free fatty acid and RNA expression results for all groups. OGTT results were not significantly different. LFT's remained unchanged in the control group. Baseline AST and ALT in the NAFLD group were higher than control; however, after diet interventions, no significant change was seen. SIGNIFICANCE OF STUDY: Bionu‐trition staff is critical to performing any diet study to manipulate human metabolic parameters. Their significant role is evidenced by near 100% diet completion rate and maintenance of baseline weight within +/− 1.5%. These diets were safe as evidenced by no change in LFT's for the control group. Though there was no change in the NAFLD group, the length of study and/or sample size contributes to these results.

A‐064

EFFECTS OF EXERCISE TRAINING MODES ON SYNTHESIS OF INDIVIDUAL MUSCLE PROTEINS

Irving BA ¹, Nair S¹, Lanza I¹, Henderson G¹  ¹Mayo Clinic, Rochester, MN, United States

OBJECTIVES: Sarcopenia contributes to many of the metabolic disorders and frailty of our aging population. Endurance and resistance exercise training have been shown to reverse the age‐related decline in metabolic and contractile muscle functions. SPECIFIC AIMS: 1.) to measure fractional synthesis rates (FSR) of multiple muscle proteins and identify those that are enhanced by an endurance exercise program 2.) to determine whether changes in protein FSR in response to endurance exercise programs are dependent on age 3.) to measure FSR of multiple muscle proteins and to identify those that are enhanced by a resistance exercise program 4.) to determine whether changes in protein FSR in response to resistance programs are dependent on age. METHODS AND POPULATION: We will measure FSR of individual muscle proteins in 36 young (18‐30y) and 36 elderly (>65y) people to determine their response to 8 weeks of endurance, resistance, or combined training relative to no exercise training. Measurements of gene transcript and other regulatory proteins will enable us to identify specific metabolic and molecular pathways and specific functional molecules (proteins) that respond to endurance and resistance exercise programs. The study will also address whether young and older people respond differently and if so what specific molecular pathway/proteins are affected by age. RESULTS: We expect to identify specific proteins that are responsive to endurance (e.g. mitochondrial proteins) and resistance (e.g. contractile proteins) exercise. SIGNIFICANCE OF STUDY: We anticipate that the discoveries of the proposed study will offer exciting opportunities to develop therapeutics that target the specific protein synthesis steps that are altered in response to specific exercise programs that could benefit the large number of elderly people who are unable to exercise.

A‐065

PLANNING FOR DMD FUTURE TRIALS: EXON SKIPPING INFORMED CONSENT STUDY PRELIMINARY DATA

Bradbury MK¹, Mills EM¹, Joseph JG ¹  ¹Children's National Medical Center, Washington, DC, United States

OBJECTIVES: Phase I clinical trials of a gene therapy (exon‐skipping/ES) are currently being considered for Duchenne muscular dystrophy (DMD), intended to modify the natural history of this uniformly fatal heritable neuromuscular disorder. Future clinical trials will require a suitable informed consent process for parents considering enrollment of their affected sons. This consent process will require knowledge of 1) Phase I randomized trials and 2) unique ES therapies. METHODS AND POPULATION: This study describes knowledge and attitudes regarding these issues in 60 parents of boys with DMD. Participants are interviewed to document potential influences on their choice to participate in and knowledge of potential risks/benefits of future ES clinical trials, as well as knowledge of randomized clinical trials methods. Parents were approached during their son's clinic visit as a follow‐up to a mailed introductory letter. RESULTS: Preliminary findings include willingness to participate; of the 43 parents approached in clinic, all but 3 were interested in enrolling. To date (2.5‐months of operation), we have recruited 25 parents through the CNMC Neuromuscular Clinic of whom 18 have been interviewed. Of these, only 8 participants understood that ES was a type of gene therapy (44%), and there is evidence of confusion about the potential therapeutic benefits of ES. Six parents believed it was a cure for DMD (33%) while 9 did not (50%); the remainder held no opinion. However, 16 parents correctly agreed that Phase I ES trials would be conducted to determine the safety of the treatment (88%). SIGNIFICANCE OF STUDY: Future clinical trials of novel ES therapies for DMD may need to pay careful attention to the process of consent, incorporating appropriate education.

A‐066

DULOXETINE AND CARE MANAGEMENT TREATMENT OF OLDER ADULTS WITH DEPRESSION AND CHRONIC LOW BACK PAIN

Karp JF ¹, Weiner DK¹, Dew M ¹, Begley A¹, Miller MD¹, Reynolds CF¹  ¹University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

OBJECTIVES: In older adults, major depressive disorder (MDD) and chronic low back pain (CLBP) are common and mutually exacerbating. We predicted that duloxetine pharmacotherapy and Depression and Pain Care Management (DPCM) would result in (1) significant improvement in MDD and CLBP and (2) significant improvements in health‐related quality of life, anxiety, disability, self‐efficacy, and sleep quality. METHODS AND POPULATION: Design and Intervention: Twelve week open‐label study using duloxetine up to 120 mg/day + DPCM. Setting: Outpatient late‐life depression research clinic. Patients: Thirty community‐dwelling adults >60 years old. Outcome Measures: Montgomery Asberg Depression Rating Scale (MADRS) and McGill Pain Questionnaire‐Short Form (MPQ‐SF). RESULTS: 46.7% (n = 14) of the sample had a depression remission. All subjects who met criteria for the depression remission also had a pain response. 93.3% (n = 28) had a significant pain response. Of the subjects who met criteria for a low back pain response, 50% (n = 14) also met criteria for the depression remission. The mean time to depression remission was 7.6 (SE=0.6) weeks. The mean time to pain response was 2.8 (SE=0.5) weeks. There were significant improvements in mental health‐related quality of life, anxiety, sleep quality, somatic complaints, and both self‐efficacy for pain management and for coping with symptoms. Physical health‐related quality of life, back pain‐related disability, and self‐efficacy for physical functioning did not improve. SIGNIFICANCE OF STUDY: Serotonin and norepinephrine reuptake inhibitors like duloxetine delivered with DPCM may be a good choice to treat these linked conditions in older adults. Treatments that target low self‐efficacy for physical function and improving disability may further increase response rates.

A‐067

THE PEDIATRIC HYPERTENSION OUTCOMES MEASURES STUDY

Kaskel FJ ¹, Hsu D¹, Reider J¹, Shamoon H¹, Isasi C¹, Kahn U¹  ¹albert einstein college of medicine, Bronx, NY, United States

OBJECTIVES: A multidisciplinary and multicenter CTSA consortium will examine the antecedents of adult cardiovascular disease in children and adolescents and its effective prevention. The specific aims are: 1. to develop a multicenter consortium of investigators in: pediatric adolescent and primary care, nephrology, cardiology, endocrinology, genetics, nutrition, epidemiology and biostatistics; 2. to conduct a cross‐sectional study of cardiorenal/metabolic risk factors and biomarker profiles in pediatric essential hypertension; and, 3. to conduct a pilot randomized clinical trial of a home‐based, life‐style modification intervention. METHODS AND POPULATION: A web‐based database that includes data collection, reporting, and querying tools available to all participating institutions with role‐based level of access granted to co‐investigators. Children between 10 and 18 years of age with essential hypertension will undergo bseline and 6‐month examinations of cardiorenal/metabolic parameters including: 24 hr ambulatory blood pressure monitoring (ABPM), echocardiogram, exercise testing, biomarkers, and quality of life and nutritional assessment. Hypertensive children without left ventricular hypertrophy (LVH) will be randomized to a home‐based intensive life‐style modification or to a standard of care intervention. RESULTS: A collaborative consortium of 7 Pediatric Child Health Oversight Committees have submitted IRB applicatons and are prepared to enroll patients. A web‐based home study program with 24 nutrition and exercise modules has been developed for implementation. SIGNIFICANCE OF STUDY: This study will evaluate the feasibility of enrolling and retaining patients during follow‐up, providing preliminary data on the efficacy of the intervention to justify the design and conduct a larger, long‐term clinical trial in this at risk population.

A‐068

PIOGLITAZONE FOR MAJOR DEPRESSIVE DISORDER AND CO‐OCCURRING ABDOMINAL OBESITY: PRELIMINARY EVIDENCE FOR INSULIN SENSITIZATION AS A NOVEL MECHANISM OF ANTIDEPRESSANT ACTION

Kemp DE ¹, Calabrese JR¹, Ismail‐Beigi F¹  ¹Case Western Reserve University, Cleveland, OH, United States

OBJECTIVES: Metabolic syndrome with abdominal (visceral) adiposity is associated with increased depression severity and has been identified as a predisposing factor for the development of depression. It is hypothesized that in patients experiencing an acute major depressive episode and co‐occurring abdominal obesity or metabolic syndrome, treatment with the insulin‐sensitizer pioglitazone would result in decreased depression severity. METHODS AND POPULATION: A total of 17 patients with abdominal obesity (i.e. waist circumference > 40 inches in males and > 35 inches in females) and major depressive disorder (MDD) received open pioglitazone (15‐45mg/day) for 12 weeks. The primary outcome measure was the change from baseline to endpoint on the Inventory of Depressive Symptoms (IDS‐C) total score. RESULTS: At baseline, participants (n = 17) were moderately to severely depressed as indicated by a mean Clinical Global Impressions‐Severity Scale (CGI‐S) score of 5.4 (SD=0.5). 13 (76%) patients also met criteria for metabolic syndrome. Patients experienced a decrease in depression severity according to the IDS‐C (‐19.8 ± 12.7; p<0.001) and Quick Inventory of Depressive Symptoms (QIDS‐SR) (‐6.9 ± 6.6; p=0.001). 67% (n = 10) met response criteria (≥ 50% reduction in IDS‐C score) and 27% (n = 4) met criteria for remission (IDS‐C ≤ 12). Significant reductions in fasting glucose, triglycerides, insulin sensitivity, and waist circumference also occurred. SIGNIFICANCE OF STUDY: Pioglitazone treatment in patients with MDD and co‐occurring abdominal obesity resulted in clinically significant reductions in both clinician‐and patient‐rated assessments of depression severity.

A‐069

CHANGES IN OBSTRUCTIVE SLEEP APNEA SEVERITY, BIOMARKERS, AND QUALITY OF LIFE AFTER MULTILEVEL SURGERY

Kezirian EJ ¹, MalhotraA², Goldberg AN¹, White DP¹

¹University of California San Francisco, San Francisco, CA, United States, ²Harvard Medical School, Boston, MA, United States

OBJECTIVES: To evaluate the impact of a multilevel obstructive sleep apnea surgical treatment on sleep disordered breathing severity, health‐related measures, and sleep‐related quality of life and to examine the association between changes in sleep disordered breathing severity and other outcomes. METHODS AND POPULATION: Prospective cohort study of subjects with obstructive sleep apnea unable to tolerate positive airway pressure therapy and with evidence of multilevel obstruction underwent uvulopalatopharyngoplasty genioglossus advancement, and possible hyoid suspension. All subjects had preoperative and postoperative assessments, including blood draw for C‐reactive protein, interleukin‐6, homocysteine, homeostasis model of insulin resistance, and leptin and evaluation with the Functional Outcomes of Sleep Questionnaire. RESULTS: Thirty subjects underwent multilevel surgical treatment. The mean apnea‐hypopnea index decreased from 44.9±28.1 to 27.8±26.4 events/hour (p=0.008). Thirteen (43%) subjects achieved a response to surgery (defined as an apnea‐hypopnea index reduction of ≥50% to an absolute level <15 events/hour), and body mass index ≤32 kg/m2 was associated with a higher likelihood (55%, 12/22) of response (p=0.04). There was no change in C‐reactive protein levels in the entire cohort, but responders demonstrated a decrease (‐1.02±0.98 mg/L, p=0.003) independent of changes in body weight. There were no significant changes in other health‐related measures. Responders and nonresponders both demonstrated improvements in sleep‐related quality of life. SIGNIFICANCE OF STUDY: Multilevel surgery was associated with a low likelihood of response with body mass index >32 kg/m2. Responders had decreased C‐reactive protein levels that were independent of changes in body weight.

A‐070

REVASCULARIZATION WITH OPEN BYPASS VS. ANGIOPLASTY AND STENTING OF THE LOWER EXTREMITY TRIAL (ROBUST)

Malas MB ¹, Qazi U¹, Perler B¹, Freischlag J¹  ¹Johns Hopkins University, Baltimore, MD, United States

OBJECTIVES: Peripheral Arterial Occlusive Disease (PAD) is the most common vascular condition affecting 3‐10% of the general population, and as high as 15‐20% of those over 70 years of age. PAD is also a major marker for cardiovascular disease and stroke. The Transatlantic Inter‐Society Consensus (TASC II) classified superficial femoral artery (SFA) lesions into 4 categories based on length and extent of disease. For TASC II A (short) lesions angioplasty with stenting (PTA/S) has shown to be effective. For TASC II D (long occlusion) open bypass (OB) is superior to PTA/S in patency and long term outcome. However for TASC II B and C (moderate) lesions there are conflicting reports on the best treatment modality. There is no level‐1 evidence on the cost effectiveness of each treatment modality. ROBUST is the first randomized clinical trial comparing OB and PTA/S in TASC II B and C lesions. Primary objective: Comparing the cost effectiveness of the two treatment modalities. Secondary objectives: Patency (<50% restenosis on duplex), re‐intervention rate, walking distance, quality of life improvement, morbidity and mortality rate. METHODS AND POPULATION: Patients with intermittent claudication who fail medical management or patients with rest pain or tissue loss, with TASC II B or C lesions are eligible. Patients are maximized medically by hypertension control, antiplatelet, and lipid lowering medications. A total of 266 patients will be prospec‐tively randomized into either OB or PTA/S group and followed at 1, 6 and 12 month post‐operatively with physical exam, ABI, duplex and QOL questionnaire. RESULTS: We expect to reach our enrollment goal by June 2011. SIGNIFICANCE OF STUDY: Providing level‐1 evidence, ROBUST will establish treatment guidelines in such lesions and eliminate un‐necessary procedures and reduce health care costs.

A‐071

COMPARISON OF TWO MACROLIDES FOR ACCELERATION OF GASTRIC EMPTYING IN PATIENTS WITH GASTROPARESIS

Moshiree B ¹, Larson J¹, Toskes PP¹, DraneW¹  ¹University of Florida, Gainesville, FL, United States

OBJECTIVES: The most common prokinetic used currently to treat gastroparesis (GP), Erythromycin (EES), is linked to possible causes of sudden cardiac death due to its interactions with inhibitors of P450 isoenzymes. In contrast, another macrolide, Azithromycin (AZI), lacks inhibition of P450 isoenzymes. Our aim was to compare the effect on gastric emptying half‐time(t½) between AZI and EES in patients with GP diagnosed by symptom criteria and gastric emptying scintigraphy(GES). METHODS AND POPULATION: GES data on 60 consecutive patients at the University of Florida undergoing clinical evaluation for GP were reviewed. Thirty patients were administered EES 250mg IV as part of provocative testing after finding of delayed gastric emptying during the GES and the next 30 patients were given AZI 250mg I V. Patients underwent GES as per our radiology protocol at UF. A simple linear fit was applied to the rate of gastric emptying with calculation of the gastric emptying t½ (normal= 45‐90 min). At 75‐80 minutes into the study, if an abnormal percentage of retained food was visualized by GES, the patients were given either EES(n = 30) or AZI(n = 30) infused over 20 minutes with calculation of the new post‐treatment gastric emptying t½. RESULTS: Comparison of the gastric emptying t½ in patients receiving either EES or AZI showed a similar positive effect on gastric emptying t½ (mean gastric emptying t½ for AZI=11.7min±7.2min, and mean gastric emptying t½ for EES=10.63min±5.1 min, p‐value<0.74). SIGNIFICANCE OF STUDY: We demonstrate that AZI is equivalent to EES in accelerating the gastric emptying time of adult patients with GP and given the better side effect profile and lack of P450 interaction, AZI should be the more desirable macrolide alternative for the treatment of G P.

A‐072

A DOUBLE BLINDED RANDOMIZED TRIAL ON EVALUATING THE ROLE OF INTRAVENOUS ASCORBIC ACID (AA) OR PLACEBO IN PREVENTING OR AMELIORATING LIVER ISCHEMIC REPERFUSION INJURY (IRI), AND EVALUATING THE USE OF PROTEOMICS AND INTRACELLULAR BIOMARKERS TO MEASURE LIVER IRI

Nair S ¹, Scher C¹  ¹Mount Sinai School of Medicine, New York, NY, United States

OBJECTIVES: To determine the safety of using intravenous AA in hepatic resections or allotransplantations to prevent ischemic reperfusion injury. To determine whether intravenous AA attenuates liver IRI. Identifying protein biomarkers to detect liver IRI. Evaluating the role of reactive oxygen species(ROS) in causing liver IRI. METHODS AND POPULATION: All liver transplant and liver resection patients are candidates for this study. DCD organs are excluded from the study. Pre and post surgical AA will be determined. Patients will receive an infusion of AA at 500mg/hr, or a placebo of sodium chloride for 12 hours after the initiation of anesthesia. Preoperatively, the surgeons excises 10mm of liver tissue for evaluation of the histochemistry and proteomics. IRI injury will be assessed by 10mm‐sized liver biopsy at surgical closing. Pre and post surgical biopsies will measure oxidative stress markers such as glutathione/oxidized glutathione ratio (GSH/GSSG), thiobarbituric assays and trans‐4‐hydroxy‐2‐nonenal (4‐HNE) proteins. Integrating proteomics will determine protein expression patterns in IRI compared to control protein expression in pre‐ischemic hepatocytes. This should increase our understanding of IRI. RESULTS: At the time of submission of this abstract, liver samples are being collected and will be analyzed en bloc and the results will be ready at the time of this meeting. SIGNIFICANCE OF STUDY: In this investigation, the use of AA represents an inexpensive, relatively safe and potentially powerful drug to prevent IRI. In addition, the use of proteomics and intracellular biomarkers may yield a new paradigm to give an accurate assessment of IRI and thus lead to other drugs to improve IRI.

A‐073

PARTNERS FOR BETTER HEALTH IN ADOLESCENTS WITH TYPE 2 DIABETES: THE BUDDY STUDY

Nandagopal R ¹, Rother KI¹  ¹NIH, Bethesda, MD, United States

OBJECTIVES: We present a novel clinical trial design to test a non‐pharmacologic intervention (assignment of a volunteer patient partner, or “buddy”) in youth with type 2 diabetes (T2D). Primary outcome will be assessment of changes in blood glucose control, based on changes in hemoglobin A1c (HbA1c). Secondary outcomes include changes in body weight, number of home glucose monitor checks, compliance with medications, adherence to visit schedule, and psychological well‐being. METHODS AND POPULATION: Youth (12‐20y) with T2D and suboptimal glucose control (HbA1c > 7%) will be randomized to conventional treatment versus interventional group (buddy arm) and followed for 6 months. Buddies will be carefully‐screened, motivated volunteers of similar age (18‐25y). Patients will undergo 3 visits, including HbA1c level 3 months apart. Those in the buddy arm will have weekly phone/ online contact and monthly home visits from the buddy; systematic questionnaires and a secure database for data collection and management will be used. RESULTS: We anticipate that participation of a buddy in the care of youth with T2D will lead to improved blood glucose control, and to positive changes in treatment adherence and quality of life. SIGNIFICANCE OF STUDY: This study design was conceptualized as a result of our and other investigators’ experiences: adolescents with T2D are often non‐compliant with clinic appointments and medications. If shown to be of benefit, involvement of lay volunteers may provide a widely applicable, alternative strategy for improving health in this challenging population. ClinicalTrials.gov identifier: NCT01007266

A‐074

PARTICIPATION COMPETENCE STRATEGIES OF LIVE‐ALONE WOMAN ELDERS

Orellano EM ¹, Mountain G⁴, Labault N³, Varas N²  ¹Medical Sciences Campus University of Puerto Rico, San Juan, Puerto Rico, ²University of Puerto Rico, San Juan, Puerto Rico, ³Medical Sciences Campus University of Puerto Rico, San Juan, Puerto Rico, ⁴University of Sheffield, Sheffield, United Kingdom

OBJECTIVES: The aims of this study will be to identify occupational participation challenges of Puerto Rican live‐alone woman elders and determine the occupational competence strategies used to overcome these challenges from the individuals’ perspective. METHODS AND POPULATION: Thirty Puerto Rican live‐alone women 70 years and older will be included in this study. A sequential mixed method design will be used. The quantitative phase will consist of the administration of a tool to measure areas of participation restrictions. The qualitative phase will consist of interviews with a subsample of the previous phase to facilitate interpretation of the quantitative results. Data analysis will include descriptive statistics and conventional thematic content analysis. RESULTS: This study will lead to the development of a new intervention for Puerto Rican live‐alone women elders with an occupational approach to healthy aging. The findings will be used to understand the variables that influence occupational participation of live‐alone women elders. SIGNIFICANCE OF STUDY: Live‐alone elders, particularly women, are at greater risk for participation restrictions compared to elders living with others. These restrictions have been associated with decreased health and wellbeing in older age. The results of this study will be used to develop a new intervention to diminish the excessive health burden of participation restrictions in daily life activities in Puerto Rican live‐alone women elders. In doing so, this study will support the achievement of the goal of Healthy People 2020 on the development of healthy behaviors.

A‐075

HOST DENDRITIC CELL VACCINATION AFTER ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION

Osman K ¹, Merad M¹, Paluka K^2,1, Grosskreautz C¹, Scigliano E¹, Malone A¹, Isola L¹  ¹Mount Sinai School of Medicine, New York, NY, United States, ²Baylor Institute for Immunology Research, Dallas, TX, United States

OBJECTIVES: Allogeneic hematopoietic cell transplantation (AHCT) is a potentially curative treatment for patients with hematological malignancies. The success is largely based on im‐munologic graft‐versus‐tumor effects mediated by donor T lymphocytes. Yet, a fraction of patients relapse after transplant. There is evidence in animal models that host dendritic cells (DCs) play a critical role in priming donor T cells to induce anti‐tumor response at the time of transplant and following donor lymphocyte infusion. These observations form the basis for our hypothesis: Vaccination of patients undergoing AHCT with ex vivo generated host DCs will enhance graft versus tumor responses. METHODS AND POPULATION: We are conducting a clinical trial to determine the feasibility of immunizing patients with hematological malignancies using ex vivo‐generated host‐derived DCs. The trial includes two cohorts of patients: i) Patients that have minimal residual disease will receive host DC injections; and ii) Patients that relapse after AHCT will receive host DC injections with donor lymphocyte infusions. Patients will receive four intravenous vaccinations with DCs on monthly basis; These two cohorts of patients will be analyzed separately. RESULTS: We will measure immune responses specific to host minor histocompatibility antigens in vaccinated patients by assessing T cell response directed against antigens related to the hematopoietic system including the malignant cells. We hypothesize that injection of host monocyte‐derived DCs will trigger and/or boost a donor T cell allo‐response against antigens expressed by the host hematopoietic cells and hematopoietic malignant cell clone. SIGNIFICANCE OF STUDY: The preliminary results of this clinical trail will be presented.

A‐076

VITAMIN D3 RAISES SMALL LDL LEVELS

Ponda M ¹, Grossman A¹, Bernal‐Messinger D¹, Holt PR¹, Breslow J¹  ¹Rockefeller University, New York, NY, United States

OBJECTIVES: Serum 25‐OH Vitamin D levels are associated with cardiovascular health. However, the effect of vitamin D repletion on biomarkers of cardiovascular disease has not been well studied. METHODS AND POPULATION: Vitamin D deficient subjects (25‐OH vitamin D < 20ng/ml) with either chronic kidney disease or insulin resistance (n = 22) were given Vitamin D3 30,000 units weekly for 8 weeks. Cardiovascular biomarkers including nuclear magnetic resonance (NMR)‐based lipid profiles, IL‐6 and high sensitivity C‐reactive protein (hsCRP) levels were measured. RESULTS: After therapy, mean 25‐OH vitamin D levels were significantly higher than baseline (38.2±2.0 ng/ml vs. 14.8 ± 1.2 ng/ml; P <0.0001). With vitamin D repletion, small low density lipoprotein (sLDL) particle number increased 13% (P = 0.04). We also found that levels of the pro‐inflammatory cytokine IL‐6 increased from 2.39±0.31 to 2.97±0.43 pg/ml (P = 0.02). hsCRP levels increased from 0.50±0.09 to 0.71±0.19 mg/dl (p = 0.26). SIGNIFICANCE OF STUDY: Vitamin D deficiency is common, with an estimated prevalence of >20% in adults. While low 25‐OH vitamin D levels are associated with cardiovascular disease, it is unclear whether this relationship is causal, or if vitamin D is a mere marker of health. Therefore, the association between Vitamin D levels and health outcomes cannot be conflated with a presumed benefit of vitamin D repletion. Our pilot study demonstrates that vitamin D repletion may have unintended pro‐atherogenic and pro‐inflammatory consequences. To further investigate our pilot data, we have begun an adequately powered, placebo‐controlled clinical trial of vitamin D repletion to test its effect on lipid metabolism (clincaltrials.gov identifier NCT01008384).

A‐077

TESTING TRAITS OF PERSONALITY DISORDERS AS MODERATORS OF TREATMENT EFFICACY AMONG CRIMINAL OFFENDERS

Swogger MT ¹, Conner KR¹, Wa ls h Z ², Caine ED¹  ¹University of Rochester Medical Center, Rochester, NY, United States, ²University of British Columbia ‐ Okanagan, Kelowna, BC, Canada

OBJECTIVES: Forensic populations represent a clinical challenge; despite evidence of considerable levels of psychopathology, these populations have been proposed to have an attenuated capacity to benefit from therapeutic interventions. We propose that the increased exploration of heterogeneity among personality features may increase the impact of interventions for offenders. METHODS AND POPULATION: An example of this approach is a pilot RCT we have initiated that examines the efficacy of a brief, psychotherapeutic intervention to decrease cocaine use among offenders in a jail diversion program. Drawing upon personality disorders research, we hypothesize that offenders with low levels of core psychopathic personality traits, such as deceitfulness and lack of empathy, will derive greater benefit (i.e., decreased cocaine use, lower rates of recidivism) than individuals with higher levels of these traits. RESULTS: pending SIGNIFICANCE OF STUDY: Given the high rate of psychopathic traits among offenders, the determination of the extent to which these traits are associated differentially with positive treatment response is an important research goal. Moreover, if psychopathic traits moderate treatment response, the potency of substance use interventions for criminal offenders with minimal psychopathic traits may have thus far been underestimated. Similarly, assessing traits of other personality disorders among offenders may enable the identification of individuals most likely to show a positive treatment response, thus providing clinicians with information for matching offenders to treatments. Such translational work has the potential to increase treatment options for offenders and to inform the allocation of limited resources for this high‐risk population.

A‐078

A MULTI‐COMPONENT PILOT TO ENHANCE AGING‐IN‐PLACE CAPACITY FOR LOW‐INCOME OLDER ADULTS

Szanton SL ¹, Tanner EK¹, Thorpe RJ¹, Agree E¹, Seplaki C¹, Boyd C¹, Weiss CO¹, Gitlin L²  ¹Johns Hopkins University, Baltimore, MD, United States, ²Thomas Jefferson University, Philadelphia, PA, United States

OBJECTIVES: With the number of older adults expected to double by 2030, reducing the societal burden of age‐related chronic disease is crucial. Currently, the United States spends $250 billion annually on medical care for older adults, of which the majority is spent on chronic conditions. Even though many chronic conditions lead to disability, little information exists on interventions that can delay the onset of chronic‐disease related disability. Given the multi‐factorial nature of many of the age‐related conditions and their associated risk factors, the best interventions are likely multi‐component with the components synergistically targeting multiple risks for disability. However, this is not yet known. METHODS AND POPULATION: The Community Aging in Place –Advancing Better Living for Elders (CAPABLE) pilot is a client‐centered home‐based intervention to increase mobility, functionality, and capacity to “age in place” for low‐income older adults. CAPABLE is comprised of an occupational therapist intervention, a nurse intervention and safety and access handyman services. RESULTS: Each service synergistically builds on the others by increasing the participants’ bio‐psycho‐functional capacity to function at home. This is theorized to avert costly health utilization by increasing medication management, problem‐solving ability, strength, balance, nutrition, and home safety, while decreasing isolation, depression, and fall risk. The goal of the pilot is to assess feasibility, titrate intervention dose, and understand tri‐service coordination. SIGNIFICANCE OF STUDY: To date, we have randomized 16 of 45 clients to intervention or control. All three interventions have started. Results available Autumn 2010.

A‐079

OMEGA‐3 FATTY ACID AUGMENTATION IN ADOLESCENTS WITH FAMILIAL BIPOLAR DISORDER

Unal SS ¹, Karguljac N¹, Pavuluri M²  ¹Mayo Clinic, Rochester, MN, United States, ²University of Illinois at Chicago, Chicago, IL, United States

OBJECTIVES: This 16‐week placebo controlled randomized trial conducted to examine safety, tolerability and efficacy of omega‐3 fatty acid treatment in adolescents with bipolar disorder. METHODS AND POPULATION: Patients were included in the study if they were 12‐18 years of age, met DSM‐IV criteria for a diagnosis of bipolar disorder. The patients were randomized to treatment arm or placebo treatment arm (olive oil ethyl esters) in a 1:1 ratio. The patients received total daily dose of (Omega‐3 fatty acid Tri Epa brand) 600 mg of eicosapen‐taenoic acid, 340 g of docosahexanoic acid, 96 mg gamma‐linoleic acid, (Omega‐3 fatty acid:Tri Epa brand) or placebo. The safety, tolerability and efficacy measures obtained weekly. RESULTS: The CDRS‐R scores were lower in the treatment group at the study end point (p<0.003; df=48). The OFA compound used was generally well tolerated, with mild to moderate side effects. SIGNIFICANCE OF STUDY: OFA treatment may be a safe and effective augmentation strategy for the depressive symptoms of pediatric bipolar patients.

A‐080

AGE AND SEX EFFECTS ON ELIMINATION RATES, GH‐IGF1 REGULATION AND SUBJECTIVE EFFECTS OF INTRAVENOUS ALCOHOL

Vatsalya V ¹, Issa J¹, Momenan R¹, Hommer D¹, Ramchandani VA¹  ¹NIAAA, Bethesda, MD, United States

OBJECTIVES: To study age and sex effects on alcohol elimination rates (AER), GH‐IGF1 regulation and subjective effects during intravenous (IV) alcohol infusion in social drinkers. METHODS AND POPULATION: 48 subjects, 12 males and 12 females each in 21‐25 and 55–65 yr groups, received individualized IV infusions of 6% v/v alcohol to 50mg% breath alcohol level or placebo for 3 hrs in separate sessions. Subjective effects were assessed with drug effects questionnaire and visual analog scale. Blood samples were collected pre‐ and post‐infusion for hormonal values. RESULTS: AER (g/hr) showed significant effect of sex (p<0.01) but no effect of age (Mean±SD; younger male: 8.6±2.5, older male: 8.4±1.4, younger female: 5.7±0.9, older female: 6.7±1.3). AER per unit LBM showed no age or sex differences. Peak feelings of high, intoxication and “drug effects” showed major treatment differences (all p‐values<0.01), with no sex‐based effect. Older subjects reported lower intensity of “liking effects” (p=0.02) and “wanting more” (p=0.03) than younger subjects. Younger females showed alcohol‐related IGF1 rate increase (‐3.7±6.1 to ‐2.8±7.2) with GH decrease (185.0±341.8 to 44.9±184.5); older females showed estradiol (‐8.7±8.5 to 19.0±30.0) and GH (16.7±76.7 to 395.3±907.6) increase. Younger males had overall drop in free testosterone (6.0±32.2 to ‐6.4±27.2), estradiol (21.7±51.6 to 5.5±25.9), IGF1 (‐2.3±4.6 to ‐6.3±5.4) and GH (1858.3±2463.2 to 1533.8 ± 3303.9). Older males showed GH decrease (781.3±779.2 to 210.5±475.9) with IGF1 increase (‐4.1±10.4 to ‐2.9±11.5). SIGNIFICANCE OF STUDY: Sex differences in AER may be partly due to LBM differences. Younger females and older males showed hepatic pathways of IGF1‐mediated GH inhibition. Older females demonstrated steroid‐mediated hypothalamic pathway of GH synthesis; young males had total inhibition of both pathways.

A‐081

EFFECTS OF LABELING PATIENTS AS PREHYPERTENSIVE

Viera A ¹, Lingley K¹, Esserman D¹  ¹UNC Chapel Hill, Chapel Hill, NC, United States

OBJECTIVES: Hypertension has some negative labeling effects on patients. The effects of being labeled as having prehypertension are unknown. We sought to examine whether the label of prehypertension exerts a negative effect on patients’ perceived health and whether it motivates people to adopt lifestyle recommendations to prevent hypertension. METHODS AND POPULATION: Design: Randomized trial comparing effects of a labeling message to a generic (no‐label) message. Setting: Primary care clinic affiliated with a public university. Patients: 100 adults aged 24 to 55 years with confirmed prehypertension. Measurements: Self‐reports of (1) change in perceived health at three months, (2) general health status, and (3) adopting lifestyle recommendations to try to prevent hypertension. RESULTS: Except for a few more participants with asthma in the label group, the two groups were similar at baseline. Overall self‐reported health was not significantly different between the groups. Among the 69 participants who provided three‐month follow‐up data, 19 people (56%) in the no‐label group and 21 people (60%) in the label group reported their health as the same; 1 person (in no‐label group) reported health as worse, and 14 people in each group (41% and 40%) reported health as better. At three months, there were no differences in reports of changing eating habits (RR 1.03; 95% CI 0.83‐1.27), cutting down on salt (RR 1.04; 95% CI 0.86‐1.25), reducing alcohol intake (RR 1.23; 95% CI 0.81‐1.86), or exercising (RR 1.17; 95% CI 0.90‐1.53) to try to prevent hypertension. SIGNIFICANCE OF STUDY: Being labeled as prehypertensive seems to exert neither harmful nor helpful effects. Public health strategies rather than clinical ones may be more effective in preventing hypertension.

A‐082

IMPROVING SAMPLE SIZE AND POWER CALCULATIONS FOR RESEARCH PROPOSALS

Wang L ¹, Byrne D¹, Yu C¹  ¹Vanderbilt University School of Medicine, Nashville, TN, United States

OBJECTIVES: To evaluate and improve sample size and power calculations for research proposals. METHODS AND POPULATION: At Vanderbilt's CTSA, biostatisticians interact with investigators at all stages of VICTR submissions (Vanderbilt Institute for Clinical and Transla‐tional Research). Each protocol was fully reviewed by VICTR statisticians regarding study design, sample size justification, and statistical analysis plan (SAP). We require that all studies have a sample size justification using hypothesis testing, estimation of precision, or more advanced statistical methods. During the process of protocol reviews, we aim to educate investigators basic concepts of statistics and technicalities of sample size estimation. RESULTS: In 2009, 163 protocols were submitted for CTSA support and reviewed by VICTR statisticians. Only 42% of the protocols passed pre‐reviews. For the remaining protocols, 71% had sample size issues (e.g., did not have sample size justification, was not reproducible, or used incorrect method), 43% had non‐appropriate SAP or did not have SAP, 7% categorized continuous outcome, 6% used effect size, and 7% had problems with the study design and hypothesis. VICTR offered various solutions to the problems including collaboration plan, Studios, Biostatistic Clinics and one‐on‐one sessions to work with investigators to improve this important aspect. SIGNIFICANCE OF STUDY: Sample size and power estimation are crucial in medical research and grant applications. It is also evidence that the study was well planned, the primary outcome and anticipated effect were pre‐determined. Sample size justification and SAP still remained a major issue in biomedical research. VICTR biostatisticians helped raise the level of sophistication of the sample size justification and SAP and improved the quality of science and the chance of publishing paper.

ETHICS

A‐083

CODE STATUS DISCUSSIONS BETWEEN ATTENDING HOSPITALIST PHYSICIANS AND MEDICAL PATIENTS AT HOSPITAL ADMISSION

Anderson W ¹, Chase R², Pantilat S¹, Auerbach A¹  ¹University of California, San Francisco, San Francisco, CA, United States, ²Boston University, Boston, MA, United States

OBJECTIVES: To determine whether attending discussions of code status at hospital admission follow professional society and ethical consensus recommendations. METHODS AND POPULATION: We audio‐recorded initial encounters between attending hospitalist physicians and patients admitted under their care on the general medical services at two hospitals within a University system between August 2008 and March 2009. Code status discussions were identified by physician survey and review of audio‐recording transcripts. A codebook was developed and implemented to determine whether the discussions followed recommended guidelines. RESULTS: Audio‐recordings were obtained from 80 patients of 27 physicians. Code status discussions were identified in 19 (24%) of the encounters. Most (n = 15, 79%) discussions occurred with patients whom the physician felt had a low (0‐25%) likelihood of requiring cardio‐pulmonary resuscitation (CPR). The median length of the code status discussions was 1 minute (range 0.2–8.2). Prognosis was discussed in 1 (5%) of encounters in which code status was discussed. Discussions of patients’ preferences focused on the use of life‐sustaining interventions as opposed to larger life goals. Descriptions of CPR as an intervention used medical jargon, and the indication for CPR was framed in general as opposed to patient‐specific scenarios. In no discussions did the physician give a quantitative estimate of the outcome of CPR and no physicians gave a recommendation to the patient about the use of CPR. SIGNIFICANCE OF STUDY: Code status discussions were brief and did not include elements recommended by professional societies and ethical consensus. Research and clinical practice should focus on how to accomplish these recommendations.

A‐084

CURRENT STATUS OF DEBATE OVER THE ETHICS OF SURGICAL PLACEBOS IN CLINICAL RESEARCH

Entezari V ¹, Fern S¹, Nazarian A¹, Snyder BD^1,2, Gebhardt MC¹  ¹BIDMC, Boston, MA, United States, ²Children's Hospital, Boston, MA, United States

OBJECTIVES: History of surgery is filled with examples of procedures which have failed to demonstrate superiority to placebos. Placebo controlled surgical trials (PCST) are proposed to fill this gap by generating unbiased evidence for surgical interventions. The goal of this paper is to review the ongoing debate over ethics of surgical placebos. METHODS AND POPULATION: This is a non‐systematic review based on PubMed database using MeSH terms of “surgical procedures, operative” and “placebo” under subsets of “human” and “bioethics” papers. Three PCSTs which have been subjects of extensive debates are added to the pool of papers. Total of 82 papers are reviewed for discussion. RESULTS: PCSTs can be considered while designing a study, when a strong placebo effect is documented, a subjective outcome is under study, or blinding subjects to the nature of treatment is necessary. In general, PCSTs are ethically accepted for conditions with no standard surgical therapies or those with considerable cost or risk. Whenever an established medical/surgical standard of care exists, an “add‐on” design is recommended. PCSTs are still controversial in other situations. Some make a distinction between the ethics of research and clinical practice by viewing PCSTs as “scientific tools” to improve medical care that do not necessarily lead to an individual patient's benefit. Another view opposes this arbitrary distinction and demands balancing the risk of surgical placebos with potential benefit to the subject under the study as opposed to gain in science. SIGNIFICANCE OF STUDY: Ethical judgments over the use of PCSTs should be case‐specific, be based on a methodological rationale, and provide objective risk/benefit analysis, where participating subjects are informed of the lack of therapeutic benefit and the associated risks.

A‐085

DECISION REGRET IN RECIPIENTS OF IMPLANTABLE CARDIOVERTER DEFIBRILLATORS

Hickman R ¹   ¹Case Western Reserve University, Cleveland, OH, United States

OBJECTIVES: Insertion of an implantable cardioverter defibrillator (ICD) is a complex decision for patients. Recipients of an ICD are likely to manifest decision regret, when health care providers do not provide adequate informational and psychological support. Therefore, the purpose of this study was to determine the associations between clinical and psychological factors and decision regret in ICD recipients. METHODS AND POPULATION: Cross‐sectional, descriptive study with a convenience sample 109 recipients of an ICD implanted during 2006‐2008 at an academic medical center in Northeast, Ohio. Surveys were administered during telephone interviews: abbreviated Miller Behavioral Style Scale to measure informational coping style, Control Preferences Scale to assess decision making preference, Medical Outcomes Study Short Form (SF)‐12 to assess quality of life, Profile of Mood States Short Form to capture post‐decision emotional status, and Decision Regret Scale was used to capture regret associated with an ICD decision. Clinical data such as indication for ICD, shock status, and demographic characteristics were abstracted from medical records. RESULTS: The amount of decision regret (no regret vs. regret) was not associated with demographic or clinical variables, such as the ICD indication (primary vs. secondary prevention) or ICD shock status (no shock vs. shock); while adjusting for the recipient's age, gender and number of post‐decision complications. However, the informational coping styles, monitoring and blunting, were significant predictors of decision regret; while adjusting for clinical and psychological variables. SIGNIFICANCE OF STUDY: Tailored communication interventions based on an assessment of the patient's informational coping style may reduce decision regret and support the patient's engagement in subsequent health seeking behaviors.

A‐086

RACE AND ETHNICITY IN RESEARCH ON BRCA MUTATIONS

Kline K ¹   ¹University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

OBJECTIVES: This study evaluates how researchers studying BRCA mutations explain the relevance of racial, ethnic and religious categories to their studies. The project also examines whether using racial or ethnic categories has yielded clinical results. METHODS AND POPULATION: Medline was used to identify articles published 1999‐2008 that met inclusion criteria: keyword of BRCA, BRCA1 or BRCA2; use of 1 or more racial, ethnic, religious, or national category in the abstract; original research. Content analysis of 597 articles was conducted. RESULTS: The authors of most articles using racial categories justify using race by stating that they explored known disparities between groups (19/55,) or do not explain why they used race (18/55). 44/55 have group‐specific results but only 9/55 discussed clinical relevance. Studies using national categories seek to develop group‐specific testing or treatment practices (162/383), or do not explain why nation was used (156/383). 160/162 of the articles aiming to develop testing or treatment have group‐specific results and 116/162 discuss clinical significance. Authors using Ashkenazi (Ashk) do so to develop treatment or testing practices (30/130) or out of convenience (29/130) or do not explain (51/130). Articles rarely yield group‐specific results (80/180), often because they only include Ashk subjects and do not discuss if findings apply to other groups. SIGNIFICANCE OF STUDY: The ethically‐dubious means of racially, ethnically, or religiously classifying subjects yield clinically‐useful ends in a minority of studies. Studies that most often produce group‐specific, clinically‐relevant findings are those which 1) use region or nation and 2) aim to develop testing or treatment procedures for the groups in question. While work in the ‘90s identified common Ashk mutations and enabled testing, recent studies rarely yield results specifically applicable to Ashkenazim.

A‐087

TRAPPED IN THE CHASM: COMMUNICATION BREAKDOWNS IN INFORMED DECISION‐MAKING

Lyndon A ¹, Africa D¹, Lee KA¹, Kennedy HP²  ¹UCSF, San Francisco, CA, United States, ²Yale University, New Haven, CT, United States

OBJECTIVES: Little is known about nurses’ perspectives on patient safety. Studies in emergency, critical, and maternity care suggest nurses possess vital knowledge about safety threats. A previous study found that maternity nurses viewed safety as protecting women's physical, emotional, and psychological integrity and identified inadequate information for decision‐making about treatments as a threat to safety. This analysis aims to describe maternity nurses’ perspectives specifically about their role in the process of women's informed decision‐making to assure patient safety. METHODS AND POPULATION: A purposive sample of 12 maternity nurses participated in open‐ended interviews and participant observation. Grounded theory guided data collection and analysis. Constant comparison, reflexivity, investigator and data triangulation, peer analysis, and member checking assured study rigor. RESULTS: Nurses identified informed decision‐making as a property of safe care and believed the quality of information received by women was highly variable. They perceived that full disclosures of risks associated with common obstetric medications and procedures were often lacking. They described moral distress from their ambiguous role in verifying that women's decisions were truly informed. Their lack of authority sometimes led to behaviors that trapped women in a chasm between nursing and medicine when nurses used “cross‐counseling” of women and other indirect strategies to manage conflict rather than addressing communication breakdowns with the attending physician. SIGNIFICANCE OF STUDY: Informed decision‐making is a fruitful area for interdisciplinary research and quality improvement. Differing perspectives about providing information can reveal new opportunities for addressing communication breakdowns among health professionals.

A‐088

MODELING THE FUTURE OF A PROACTIVE ETHICS KEY RESOURCE

McKinney E” ¹, Carter M¹  ¹University of Texas Medical Branch, Galveston, TX, United States

OBJECTIVES: The purpose of this presentation is to discuss lessons learned in the development of an integrated and collaborative venture in which practitioners of science and ethics work together to facilitate the goals and priorities of the CTSA consortium. We illustrate novel, integrated, and proactive strategies that enhance the partnerships essential to translational research. METHODS AND POPULATION: These strategies resulted from the use of the LOGIC model, a planning and assessment tool. The model clarified a process for prioritizing activities and allocating resources in order to best support the goals of the translational enterprise. Through the creation of a visual representation of our plans, embedding humanities scholars in research teams, and sharing these models with others, the Ethics Key Resource demonstrates how a medical humanities perspective enhances institutional integrity and leads to public trust. RESULTS: The Ethics Key Resource planning model illustrates an alternative to the purely reactive approach to research ethics consultation and how a research ethics consultation service can play an important interactive role in translational research. SIGNIFICANCE OF STUDY: By engaging in this process and sharing information we have already begun to observe the cultural changes that the UTMB CTSA and the national CTSA consortium have envisioned. Ethics personnel are accepted as research team partners.

A‐089

CREATING A CBPR PROPOSAL THROUGH CAMPUS‐COMMUNITY CONSENSUS

Reifsnider E ^1,2, Cooks J², Hargraves M^2,1, Luxon B¹, May M³, McKinney E”¹, Peranteau J³, Sullivan J¹, Williams K^1,2, Wu H¹  ¹University of Texas Medical Branch, Galveston, TX, United States, ²Galveston Island Community Research Advisory Committee, Galveston, TX, United States, ³St. Luke's Episcopal Health Charities, Houston, TX, United States

OBJECTIVES: The purpose of this abstract is to describe the process that a university‐based Community Engagement and Research Key Resource(CER KR) component of a CTSA undertook to partner with community agencies to create and submit a research proposal designed to support community‐based, research‐related infrastructure. METHODS AND POPULATION: The release of ARRA 09‐010 “Building Sustainable Community‐Linked Infrastructure to Enable Health Science Research (RC4)” catalyzed the potential partners to investigate creating a responsive proposal. The lead community agency (#2 above) had previously collaborated with several of the co‐authors to write and submit research proposals. The community agency was currently conducting research in the community identifying concerns that could be addressed by research. Their preliminary findings included a number of issues that could be addressed through research infrastructure funding and formed the basis of the RC4 proposal. RESULTS: The research collaboration occurred between a health science center with a longstanding community relationship and several relatively new community organizations. Results: The CER KR convened multiple meetings with other CTSA Key Resources on campus as well as with several community agencies to determine interest, issues, problems, and contributions. The meetings identified prior issues, overlapping areas of interest, conflicting interests, and areas of convergence. SIGNIFICANCE OF STUDY: Four KRs from the University CTSA along with 2 community agencies collaboratively wrote and submitted a proposal that can be used for other RFAs.

A‐090

BRONX COMMUNITY RESEARCH REVIEW BOARD

Strelnick H ¹, Casado J²  ¹Albert Einstein College of Medicine, Bronx, NY, United States, ²The Bronx Health Link, Bronx, NY, United States

OBJECTIVES: The Bronx Community Research Review Board (BxCRRB) is an academic‐community partnership between the Bronx Health Link (TBHL) and the Einstein‐Montefiore Institute for Clinical and Translational Research (ICTR). Our aim is to develop an independent research review board of community residents that pilot tests a model of community consultation and informed consent by reviewing community‐based research proposals. METHODS AND POPULATION: TBHL is conducting focus group with community members to develop an empirical foundation for the BxCRRB. Based on these findings, TBHL will recruit 10 community residents and train them in research design and the protection of human subjects and their communities. This board will pilot test the format and process for reviewing research proposals from candidates for the Masters degree in the Clinical Research Training Program at Einstein by reviewing written and oral presentations, thus, opening a face‐to‐face dialogue between the investigators and board members about community perspectives on the proposed research. The goal of the BxCRRB is to formulate guidelines for research that are consistent with an understanding of community ethics. Follow‐up of revisions and research outcomes will be developed. RESULTS: Our vision for the future is a for a free‐standing, independent, self‐sustaining community research review board that may (or may not) take on full IRB status. SIGNIFICANCE OF STUDY: Bioethicists have recognized that narrow focus on protecting autonomous individuals in research neglects the impact that research may have on the community. “Community consent” has been modeled by Native American tribal councils, but given the complex nature of vulnerable urban communities, an alternative, perhaps more realistic approach may be such “community consultation”

HEALTH SERVICES RESEARCH

A‐091

EFFECTIVENESS OF INTERVENTIONS TO IMPROVE PARENT‐ADOLESCENT COMMUNICATION ABOUT SEX: A SYSTEMATIC REVIEW

Akers A ¹, Holland C¹, Bost JE¹  ¹University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: To systematically review published literature to assess the effectiveness of interventions to improve parent‐adolescent communication about sex in the U.S. METHODS AND POPULATION: We searched 5 electronic databases for studies that were published in peer‐reviewed journals; used experimental or quasi‐experimental study designs that included a control group and a pre/post‐test design; were published between January 1980 and July 2008; and targeted parents of adolescents aged 11‐18. We examined eight communication outcomes: frequency, quality, comfort, self‐efficacy, intentions, outcome expectations, attitudes and content. We assessed study quality using a validated methodological quality score (MQS) scale (max score=20). RESULTS: Twelve studies met inclusion criteria. Most (n = 11) had predominantly mother participants; included 100‐300 participants (n = 9); and recruited a convenience sample (n = 8). Only 2 calculated the sample size needed to assess their study outcomes with adequate power. Most examined communication frequency. Almost all studies demonstrated significant improvement in the communication domains examined with medium effect sizes. MQS scored ranged from 6 to 16 with a mean of 12 corresponding to medium quality. Effective studies were theoretically grounded, had larger sample sizes and targeted multiple communication outcomes. SIGNIFICANCE OF STUDY: Parent‐adolescent communication interventions demonstrate moderate effectiveness at improving multiple domains of communication. However, they have primarily focused on mothers. Disseminating effective programs may improve adolescent sexual health outcomes.

A‐092

ENABLING MULTIDISCIPLINARY TEAMS USING COMPLEXITY SCIENCE THEORY

Arar N ^2,1   ¹UTHSCSA, San Antonio, TX, United States, ²VHA, San Antonio, TX, United States

OBJECTIVES: The work of multi‐disciplinary research teams (MDT) is vital for translation research. Our objectives are to develop and test strategies to enable the formation of and collaboration among teams’ members. We used complex adaptive system (CAS) theory to understand the structure, function and cycles of MDTs. MDTs are CAS, comprised of diverse agents who can learn, interconnect, self‐organize, and interact with their environment in a way that demonstrates non‐linear dynamic behavior. METHODS AND POPULATION: Semi‐structured interviews were conducted with 23 (64% females) researchers working in different departments at UTHSCSA and UTSA. About 34% were Mexican Americans or None Hispanic White and 30% identified themselves as Asian Americans. The average age was 39.5 (range: 35‐50 year‐old). Semi‐structured interviews focused on understanding interpersonal, organizational and environmental factors that affect team formation, collaboration and growth across various research domains. Interview materials were tape‐recorded, transcribed and content analyzed using qualitative methods. RESULTS: MDTs operate through forming multiple team cycles. Each team cycle consists of four basic elements: (1) Team formation, (2) Team collaboration, (3) Sustainable collaborative activities, and (4) Team maturity. We have developed several strategies to enhance the formation of and collaboration among teams’ members based on our understanding of MDT structure, function and cycles. We will present two newly developed approaches [Translation Researchers Activation Method, Translation Research Active Facilitation for Improving Collaboration] and discuss their conceptual and practical aspects using CAS. SIGNIFICANCE OF STUDY: Viewing MDTs as CASs have broad implications for translation research. Our work contributes to the current efforts aimed at fostering the translation of knowledge to improve human health.

A‐093

IMPROVING OUTCOMES IN MEDICAL EDUCATION VIA TELEMEDICINE: A NEEDS‐BASED, TRANSCULTURAL APPROACH TO LEARNING IN DERMATOLOGY

Armstrong AW ¹, Wu G ¹, Zhao Y², Chambers C¹  ¹University of California Davis, Sacramento, CA, United States, ²Peking University, Beijing, China

OBJECTIVES: To determine if transcultural tele‐education can enhance education, cultural sensitivity, and clinical practice both locally (UC Davis) and abroad (Peking University). METHODS AND POPULATION: We performed a comprehensive needs assessment of all UCD and PU dermatologic faculty, residents and rotating medical students to identify barriers, determine gaps in learning, and relate participant experience to program design. RESULTS: The needs assessment revealed a high level of interest in international health exposure and education both locally and abroad (4.25, SE: 0.12 95% CI: 4.01‐4.49) and strong support for the concept of videoconferenced Global Grand Rounds (4.34, SE: 0.11, 95% CI: 4.10‐4.56). Ninety‐seven percent of all participants reported they would attend and 83% would present or moderate (4.60, SE: 0.13, 95% CI: 4.32‐ 4.88) a Global Grand Rounds videoconference. Residents were significantly more likely than faculty in both institutions to agree or strongly agree that regular participation in grand rounds directly influenced their ability to provide improved patient care (p<.03). SIGNIFICANCE OF STUDY: This assessment indicates a demonstrable need and strong support for this tele‐educational program. Utilization of pre‐defined, outcome‐based evaluation measures will provide an objective assessment of the program's impact on our students, residents and the dermatologic community. Global Grand Rounds may be an effective, relatively low‐cost adjunct to established learning methods to enhance medical education, while building constructive relationships between academic institutions from different nations.

A‐094

BARRIERS TO FOLLOWUP CARE IN WOMEN WITH RECENT GESTATIONAL DIABETES MELLITUS: A QUALITATIVE STUDY

Bennett WL ¹, Ennen C¹, Carrese J¹, Hill‐Briggs F¹, Levine D¹, Nicholson W¹, Clark JM¹  ¹The Johns Hopkins University School of Medicine, Baltimore, MD, United States

OBJECTIVES: Women with a history of gestational diabetes mellitus (GDM) have increased risk of type 2 diabetes. We explored barriers to followup care in women with GDM. METHODS AND POPULATION: We recruited 23 patients with GDM from an obstetric practice using consecutive sampling. Inclusion criteria were insurance coverage during and beyond the pregnancy and being English speaking. Participants completed a baseline questionnaire; we abstracted information from the medical record. We conducted semi‐structured interviews, which were audiotaped and transcribed. Two investigators independently coded transcripts. Codes and themes were explored using the Atlas.ti program. Quantitative analyses were conducted in STATA. RESULTS: We completed 22 interviews, 13 in person and 9 by telephone; one participant declined the interview. Mean age was 31.8 (SD 4.6), 61% were non‐white, 48% were primiparous, and mean body mass index was 26.7 kg/m2 (SD 7.0). Nineteen women attended a postpartum visit. We identified four major themes addressed by every participant. Sub‐categories (after each theme) illustrate barriers to followup medical care: 1) Experience being a patient with GDM: Frustration with self‐ and clinical monitoring. 2) Recent delivery and baby's health: Delivery concerns/questions. 3) Personal and family adjustment to the new baby: Anxiety/feeling overwhelmed. 4) Concerns about postpartum and future health: Fear of bad news of diabetes diagnosis. SIGNIFICANCE OF STUDY: Women with recent GDM report multiple barriers to followup medical care. These results will inform interventions aimed at enhancing communication and coordination of care to improve care for these women.

A‐095

THE EFFECT OF MOTORCYCLE HELMETS ON CRANIOFACIAL TRAUMA AND ASSOCIATED INJURIES

Bhatt RA ², Gart M², Thurmond P², Oh AK¹  ¹Children's National Medical Center, Washington, DC, United States, ²Brown Medical School, Providence, RI, United States

OBJECTIVES: The objectives of this study were to determine the relationships between helmet use, injury patterns, and outcomes after motorcycle accidents (MCA). Data obtained on mortality, blood alcohol concentration (BAC), extracranial injuries, injury severity score (ISS), operative intervention(s), ICU length of stay (LOS), ventilator duration, hospital LOS, payor distribution, and total cost of care were analyzed. METHODS AND POPULATION: The authors conducted a retrospective cohort study of patients presenting to a single level one trauma center with craniofacial injuries secondary to MCA from 1999 to 2008. Study variables among helmeted and unhelmeted motorcyclists were compared and investigated. RESULTS: A total of 486 patients were identified: 329 operators were unhelmeted (68%), and 157 were helmeted (32%). Seventyone percent of men were unhelmeted, compared to 34% of women (p<0.001). Unhelmeted motorcyclists were more likely to die in the field (67% vs. 33%, 95% CI 57‐77%). They also had higher risk of death during hospitalization (RR=1.89, p<0.05), particularly with concomitant traumatic brain injury or cranial vault fracture (RR=2.1, p<0.05). Unhelmeted patients also were found to have a higher mean BAC (0.08 vs. 0.038; p<0.0001) and were more likely to operate a motorcycle over the legal limit of 0.08 BAC (42.0% vs. 19.1%; p<0.0001). Soft tissue injuries of the head and neck region were more common (80.2% vs. 67.8%, p<0.01) among unhelmeted operators, who also required more craniofacial operative interventions (211 vs. 68 procedures, p<0.00). SIGNIFICANCE OF STUDY: Our study documented that unhelmeted motorcyclists had worse outcomes. Helmeted motorcyclists were more likely to survive motorcycle accidents and suffer less severe craniofacial trauma.

A‐096

BUILDING T3 & T4 RESEARCH CAPACITY AMONG DIVERSE STAKEHOLDERS

Boden‐Albala, DrPH B ¹, Aguirre, MPH AN¹, Moon‐Howard, DrPH J¹, Bigger, MD J¹, Bakken, DNSc, RN, FAAS SR¹, Quarles, MPH L¹, Lantigua, MD RA¹  ¹Columbia University, New York, NY, United States

OBJECTIVES: Develop a novel educational training curriculum, the Community Based Research Traineeship, to build research capacity among junior academic investigators, community clinicians, and community based organizations (CBO). METHODS AND POPULATION: The Community Engagement Resource (CER) of the Columbia University Medical Center (CUMC) developed a 9 month curriculum on research methods, community‐based participatory research, and responsible conduct of research. Participants were matched with a mentor for the entire training period. Participants developed a pilot proposal for funding consideration by the CER. Traineeship participants included 3 senior administrators from CBOs, 2 CUMC junior faculty, and 4 community clinicians. Participation in the Traineeship was free and a $2,000 stipend was provided per participant. RESULTS: On average, participants attended 75% of sessions. Of the eligible participants, 63% submitted a proposal for pilot funding. Reasons most often cited by participants who did not submit a proposal were time constraints and competing priorities. Four grants were awarded totaling $26,000. Minority researchers represented 75% of award recipients. SIGNIFICANCE OF STUDY: The confluence of diverse health professionals promoted bi‐directional learning and affirmed the value of academic‐community partnerships in research. The Community Based Research Traineeship with its educational curriculum, design structure, and unique mix of diverse participants does build research capacity. This traineeship is the first of its kind and has served as a model for other CTSAs interested in building capacity in translational research among beginning researchers from diverse settings.

A‐097

RACIAL VARIATION IN TUBAL STERILIZATION RATES: THE ROLE OF PATIENT‐LEVEL FACTORS

Borrero S ¹, Abebe K¹, Dehlendorf C², Schwarz EB¹, Creinin MD¹, Nikolajski C¹, Ibrahim S¹  ¹University of Pittsburgh, Pittsburgh, PA, United States, ²UCSF, San Francisco, CA, United States

OBJECTIVES: African American (AA) women are significantly more likely to use female sterilization as a contraceptive method than white women. The objective of this study was to assess racial differences in attitudes and knowledge about sterilization. METHODS AND POPULATION: A survey was mailed to 300 African‐American (AA) and white women aged 18‐45 who had undergone sterilization. We compared responses by race using t‐tests, chi‐squared tests, and multivariable models that adjusted for age, education, insurance, and marital status. RESULTS: We received 193 completed surveys (32% of respondents were AA and 68% were white). AA woman were more likely to have a family member who had undergone tubal sterilization, to report that their mothers influenced sterilization decisions, and to report that prior unintended pregnancy was an important factor in their decision to undergo sterilization. AA women more often thought that sterilization reversal could easily restore fertility (62.3% vs 36.2%; p<0.001); that sterilization would reverse itself after 5 years (59.9% vs 23.1%; p<0.001); and that men cannot ejaculate after vasectomy (37.7% vs 13.1%; p<0.001). Fewer AA women had heard of IUDs (10.×% vs 1.×%; p=0.013). Racial differences in knowledge persisted after adjusting for socioeconomic confounders. SIGNIFICANCE OF STUDY: Misinformation about sterilization and limited awareness of contraceptive alternatives among AA women may contribute to racial disparities in sterilization rates. Providers should assess women's understanding of tubal sterilization so that all women, regardless of race/ethnicity, can make informed and satisfactory reproductive decisions.

A‐098

RISK REDUCTION DURING NATUROPATHIC TREATMENT FOR HYPERTENSION IN PATIENTS WITH AND WITHOUT TYPE 2 DIABETES

Bradley R ¹   ¹U. of Washington, Seattle, WA, United States

OBJECTIVES: This study had three specific aims: 1. describe ND care for hypertension (HTN) including patient population, 2. determine mean blood pressure changes during care, and 3. determine if the proportion of patients in “control” to <140/90 mmHg increased during care. METHODS AND POPULATION: We conducted a retrospective, observational cohort study of ND care for HTN, in patients with and without type 2 diabetes, in an academic clinic in Seattle, WA. All patients had a 6‐month minimum duration of ND care for HTN. Two‐sided, paired t‐tests were used for continuous blood pressure comparisons at baseline vs. last available record. Chi2 tests were used for comparisons of the proportion “in control”. RESULTS: 123 charts were abstracted, including 38 patients with type 2 diabetes. Patients tended to be older adults (mean age: 61.1 years) with mean baseline blood pressure 152 (±22) /88 (±12) mmHg. 54% of patients were on anti‐hypertensive medications at baseline and 42% had stage 2 HTN ≥160/100 mmHg. Mean changes in systolic/diastolic blood pressure (in mmHg) overall, and for patients with and without diabetes, were: ‐13.3 (p<0.0001)/ ‐6.7 (p<0.0001); ‐7 (p=0.03)/ ‐5 (p=0.004); and ‐16 (p<0.0001)/ ‐7.4 (p<0.0001) respectively. At last observation, a significantly higher proportion of patients was in control for systolic, diastolic and combined blood pressures (62% vs. 28% for systolic, 80% vs. 48% for diastolic and 59% vs. 24% for both, all p<0.0001). There was no difference in the odds of new blood pressure control during ND care for patients with diabetes vs. those without diabetes. SIGNIFICANCE OF STUDY: This retrospective, observational cohort study suggests clinically significant blood pressure reductions occur during ND care for HTN in patients with and without type 2 diabetes. though causation cannot be determined from the chosen methods.

A‐099

CORRELATES OF MAMMOGRAPHY SCREENING PRACTICE AMONG IMMIGRANT WOMEN IN SOUTHERN CALIFORNIA

Caro B ¹, Shaheen MA¹, Galal O²  ¹Charles Drew University, Los Angeles, CA, United States, ²University of California, Los Angeles, Los Angeles, CA, United States

OBJECTIVES: We examined factors associated with mammography screening among immigrant women in Southern California. METHODS AND POPULATION: A cross‐sectional study of 517 women aged = >40 years. The survey was conducted using a self administered questionnaire in the women's preferred language. The outcome variables were the % of women who ever received a mammogram and the % of women who received a mammogram in the past year. Independent variables were demographics, frequency of visits to health care provider, and scores of the BC knowledge, symptoms and risk factors, perceived benefits, motivation and barriers to obtaining a mammogram. RESULTS: of the 517 women, 50% were Iranian and 21% were Asian, 28% had family history of BC, 63% had friend with BC, and 47% had yearly visit to the health care provider. Ever had a mammogram was reported by 88% and 73% reported they had mammogram last year. women had low knowledge of BC symptoms (mean = 7, SD=3.5, range=1‐13) and low knowledge of BC risk factors (mean = 8, SD=3.6, range=1‐21). Women showed high health motivation (mean = 4.4, SD=0.6, range=1‐5) and low barriers (mean = 2.4, SD=0.6, range=1‐5). Predictors of ever had a mammogram were age, having a friend with BC, and having a high score of health motivation. Factors associated with having a mammogram within the past year were having frequent visits to the health care provider, a high score in knowledge of BC symptoms, and a lower score of perceived barriers to obtaining a mammogram. SIGNIFICANCE OF STUDY: The findings indicated that health care provider may influence the BC screening among immigrant women. There is a need for a culturally sensitive educational intervention to enhance the knowledge and awareness of BC. Intervention can be provided through the health care provider, social support, and family groups.

A‐100

DETECTION OF DISABLEMENT IN CANCER PATIENTS WITH AN ITEM RESPONSE THEORY‐BASED COMPUTER ADAPTIVE TEST

Cheville AL ¹, Yang P²  ¹Mayo Clinic Medical School, Rochester, MN, United States, ²Mayo Clinic, Rochester, MN, United States

OBJECTIVES: Functional decline due to cancer is a significant source of disability. Early detection and treatment of preventable disability is rare. Item response theory (IRT)‐based computer adaptive tests (CAT) assess function with minimal respondent burden. We studied the feasibility of using an IRT‐CAT to characterize the trajectory of functional decline in patients with advanced lung cancer. METHODS AND POPULATION: A prospective cohort of patients with advanced lung cancer (LC) was administered the Ambulatory Post Acute Care Computer Adaptive Test (AM‐PAC‐CAT) Basic Mobility (BM) and Daily Activity (DA) domains at three week intervals along with 11‐point numerical rating scales (NRS) for pain (average and worst), fatigue, and dyspnea. Study endpoints included participant death and drop out. RESULTS: AM‐PAC‐CAT BM scores proved sufficient to detect disablement independently of the DA scores. BM and DA scores were highly correlated (r = 0.77), but BM scores displayed less variability (SD 9.5 versus 15.2). The BM and DA AM‐PAC‐CATs imposed minimal respondent burden as the mean total session duration was 203 seconds. Participants experienced a significant rise in distress over their loss of functionality when their AM‐PAC‐CAT BM scores fell below 66, a level corresponding to increasing limitations in household mobility and ADL performance. Changes over time in functional status, e.g. AM‐PAC‐CAT BM and DA scores, were significantly associated with changes in NRS “worst pain” (BM p=0.002, DA p=0.016) and changes in NRS fatigue scores (BM p=0.021, DA p=0.043) scores. SIGNIFICANCE OF STUDY: An IRT‐based CAT (AM‐PAC‐CAT) detects early functional change in patients with advanced lung cancer. Functional decline is associated with increased pain and fatigue.

A‐101

PREDICTORS OF IN‐HOSPITAL MEDICAL CRISES REQUIRING RAPID RESPONSE TEAM ACTIVATION

Clark S ¹, Sevick M¹, Simmons RL², Kapoor W¹  ¹University of Pittsburgh, Pittsburgh, PA, United States, ²University of Pittsburgh Medical Center, Pittsburgh, PA, United States

OBJECTIVES: Rapid Response Teams have been organized at many hospitals to provide safety nets for patients showing signs of physiological deterioration or other medical crises. The objective of this study is to derive and validate a clinical prediction rule to identify patients at high risk for these events. METHODS AND POPULATION: We will conduct a case‐control study to identify predictors of medical crisis events using patient, hospital, and staffing characteristics available during the first 24 hours of the hospitalization. Cases and controls will be matched based on type of unit to which they are hospitalized. Approximately 2,300 medical crisis patients between 11/08‐10/09 will be included. Data will be used from the Medical Emergency Database, a newly developed database with automated feeds that extracts clinical information from the electronic medical record. Multivariable logistic regression will be used to determine the independent association of suspected risk factors with medical crisis events. Recursive partitioning will be used for building a prediction rule and also for identifying important interactions or risk‐thresholds to include in the model. RESULTS: Data acquisition is still underway. We anticipate that risk factors for medical crisis events are likely to be multi‐factorial, including patient, hospital and staffing characteristics. SIGNIFICANCE OF STUDY: With more than 39 million annual hospital admissions in the US (HCUP 2006) and estimates suggesting that adverse events are experienced by 2% to 16% of hospitalized patients (Studdert 2000; Brennan 1991; Kohn 2006) patient safety is an important concern. If predictors of adverse events, such as medical crises, can be identified, interventions could be designed to decrease the incidence of these events.

A‐102

BARRIERS FOR EARLY DETECTION OF DIABETIC RETINOPATHY

Cumba RJ ¹, Al‐Attar L²  ¹University of Puerto Rico, San Juan, United States, ²Retina Center of Puerto Rico, Manati, United States

OBJECTIVES: Diabetic retinopathy is one of the most common and potentially blinding complication of diabetes in the population age 18 and older. However, only half of adults diagnosed with diabetes are evaluated to detect early manifestations of diabetic retinopathy. Furthermore, the incidence of diabetes is increasing worldwide. In the US, the Hispanics, Native Americans, and African Americans show a high incidence of diabetes. In 2008, 12.4% or 347,000 Puerto Rican Hispanics had diabetes. Our preliminary data with 138 diabetic patients shows that it takes a mean of 9 years for them to have the first eye exam and that visual acuity worsened as time to first eye exam increased. Based on this data we propose to study the barriers to compliance among Puerto Rican Hispanics with the American Diabetes Association (ADA) guidelines for vision care. METHODS AND POPULATION: The study design will be cross sectional using a questionnaire to collect data among Puerto Rican Hispanic diabetes patients and their Primary Care Physicians. The questionnaire will assess the patient's knowledge and attitudes about diabetes and eye exams and perceived barriers to have an annual eye exam. Questionnaires to the Primary Care Physicians will evaluate attitudes toward the ADA guidelines and perceived barriers to provide effective eye care. Descriptive statistics will be used to analyze the data. RESULTS: We anticipate that we will gather important data showing the barriers limiting early detection of diabetic retinopathy among Puerto Ricans. SIGNIFICANCE OF STUDY: Identifying the barriers limiting compliance to retinopathy screening in Puerto Rican Hispanics will help develop interventions to increase the compliance to screening rates of diabetic retinopathy targeting both, patients and their Primary Care Physicians.

A‐103

MEASURING A STATE CHILDREN'S HEALTH INSURANCE INTERVENTION: A MIXED‐METHODS APPROACH

DeVoe J ¹, Wallace L²  ¹OHSU, Portland, OR, United States, ²Univ of TN, Knoxville, TN, United States

OBJECTIVES: The Children's Health Insurance Program (CHIP) was a policy intervention designed to expand public health insurance for children. CHIP featured prominently in health insurance reform debates, but public options received criticisms. States rely on health services researchers to help measure CHIP interventions and to conduct translational studies to inform future steps. We examined — both quantitatively and qualitatively ‐ whether families with children eligible for CHIP reported differences between how public versus private coverage affected their children's access to care. METHODS AND POPULATION: We conducted 24 interviews and used a standard iterative process for analysis. Findings from in‐depth qualitative analyses guided secondary quantitative analyses of survey data from 2,681 Oregon households to assess multivariate associations between children's insurance type and unmet needs. RESULTS: Interviewees perceived a difference between private and public coverage; however, in quantitative analyses, there were only a few significant differences in parental reports of unmet needs among children with public versus private coverage. Cross‐sectionally, compared with privately‐covered children, those with public coverage had higher odds of having big problems obtaining specialty care (OR 3.54; 95% CI 1.52‐8.24). When comparing full‐year coverage patterns, those with public coverage had lower odds of having unmet prescription needs (OR 0.60, 95% CI 0.36‐0.99) and having big problems obtaining mental health counseling (OR 0.24, 95% CI 0.10‐0.63), as compared with the privately‐covered children. SIGNIFICANCE OF STUDY: Families with children eligible for CHIP reported few differences between unmet needs among children covered by public versus private insurance suggesting that a public option could provide similar coverage to a private option.

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MEDICARE PART D'S IMPACT ON HIGH RISK MEDICATION USE AMONG OLDER ADULTS

Donohue JM ¹, Marcum Z³, Zhang Y¹, Men A¹, Gellad W², Lave J¹, Hanlon JT³  ¹University of Pittsburgh, Pittsburgh, PA, United States, ², Pittsburgh, PA, United States, ³University of Pittsburgh School of Medicine, Pittsburgh, PA, United States

OBJECTIVES: The National Committee on Quality Assurance recently added a “high risk medications in the elderly” measure to the Healthcare Effectiveness Data and Information Set (HEDIS) to improve medication appropriateness among older adults. Expansions in drug coverage under Medicare Part D may have lowered the out‐of‐pocket costs and increased the use of these drugs. METHODS AND POPULATION: We obtained data for 34,679 elderly beneficiaries continuously enrolled in a Medicare managed care plan 2 years before and after Part D's implementation (2004‐2007). We used a pre‐post‐with‐a‐comparison‐group study design to examine changes in use of the HEDIS drugs. Three groups (one with no coverage and two with quarterly caps of $150 or $350) were automatically enrolled in the plan's Part D plans in 2006. We estimated likelihood of high risk medication use before and after Part D adjusting for trends in a comparison group in the same managed care plan with stable drug coverage throughout. RESULTS: The comparison group reduced use of high risk drugs from 20.4% in 2004 to 18.1% in 2007. In contrast, who moved from no coverage to Part D increased their use of high risk medications from 15.2% to 17.0% between 2004 and 2007. After adjusting for trends in the comparison group, those who enrolled in Part D increased slightly their use of high risk drugs [Adjusted Ratios of the Odds Ratios post‐ vs. pre‐Part D were 1.33 (95% CI 1.21‐1.47) for the No coverage group; 1.10 (95% CI 1.00‐1.22) for the $150 cap group; and 1.08 (95% CI 1.02‐1.14) for the $350 cap group]. SIGNIFICANCE OF STUDY: One unintended consequence of expanded drug coverage to Medicare beneficiaries may be a slight increase in use of high risk medications among the elderly.

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A DECREASE IN PHYSICIAN REIMBURSEMENT REDUCES NON‐INDICATED HORMONE THERAPY USE IN PROSTATE CANCER

Elliott SP ¹, Jarosek S¹, Wilt TJ¹, Virnig B¹  ¹University of Minnesota, Minneapolis, MN, United States

OBJECTIVES: Androgen suppression therapy (AST) utilization in prostate cancer increased more than three‐fold from 1991‐1999. We describe the influence of a large reduction in Medicare physician reimbursement in 2004‐5 on indicated vs. non‐indicated AST utilization as a model of the influence of financial incentives on overtreatment. METHODS AND POPULATION: Men diagnosed with prostate cancer in 1992‐2005 were identified from SEER. Using Medicare claims data, indicated AST was defined as ≥3 months of AST in the first year in men with metastatic disease. Non‐indicated AST was defined as AST given without other therapies such as radical prostatectomy or radiation in men with low risk disease. Unadjusted annual rates of AST utilization were plotted against the median Medicare AST reimbursement. A multivariate model calculated the odds of AST in low risk and metastatic men with the etiology of interest being the calendar year of the payment change. RESULTS: AST use in the low risk group peaked at 9.9% in 2003 then declined to 6.9% in 2004 and 5.7% in 2005. AST use was stable at 60% in the metastatic group during the payment change. The adjusted odds of AST use in low risk men was 0.59 (95%CI 0.51‐0.68) in 2005 compared to 2003. In the metastatic group the odds of AST use was unchanged in 2004‐5. SIGNIFICANCE OF STUDY: A large reduction in physician reimbursement for AST was associated with a 41% reduction in non‐indicated AST. In contrast, indicated use of AST remained stable. These findings may inform our understanding of the effect of payment changes on healthcare utilization.

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IMPORTANCE OF APPLYING COMMUNITY‐BASED PRINCIPLES IN PACIFIC NORTHWEST TRIBAL NATIONS: SUCCESSES OF THE COMMUNITIES ADVANCING THE STUDIES OF TRIBAL NATIONS ACROSS THE LIFESPAN (COASTAL) COHORT

Grattan L², Roberts S², Fialkowski MK ¹, Tracy K², Boushey C³  ¹Purdue University, West Lafayette, IN, United States, ²University of Maryland, Baltimore, MD, United States, ³Purdue University, West Lafayette, IN, United States

OBJECTIVES: Native Americans display a disproportionate burden for many diseases and are at a greater risk of being exposed to harmful environmental contaminants in comparison to the general population. Our objective is to demonstrate the importance of applying community‐based methodologies in the CoASTAL cohort. METHODS AND POPULATION: The CoASTAL cohort's objective was to examine the risk associated with low level exposure to the neurotoxin domoic acid (DA) that is consumed in locally found razor clams. Preliminary investigations indicated that community members had insufficient knowledge regarding risk factors for DA related illness and a sense of helplessness regarding exposure prevention. RESULTS: To combat these sentiments a community‐based health education program was developed to empower these communities through improving knowledge and self‐efficacy in a reservation‐specific manner. To emphasize collaboration, advisory committees were created to counsel CoASTAL investigators. Through this effort multiple mechanisms for community education were set in place including publication of a Pacific Northwest Community Cookbook, a Razor Clam Cook‐Off, Native Artists event, Parade and regional tasting events. SIGNIFICANCE OF STUDY: Based upon evaluation of all community activities, findings highlighted the importance of community leadership and involvement, the utility of active dissemination as opposed to passive dissemination, and the importance of celebrations of cultural pride in the CoASTAL cohort to effectively empower these communities to reduce their risk for exposure to DA.

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TRANSITION OF LIVER TRANSPLANT RECIPIENTS FROM PEDIATRIC TO ADULT CARE: ASSESSING PATIENT READINESS

Fredericks EM ¹, Freed G¹, Well A¹, Dore‐Stites D¹, Shieck V¹, Magee JC¹, Lopez M¹  ¹University of Michigan, Ann Arbor, MI, United States

OBJECTIVES: To assess adolescent liver transplant (LT) recipients’ preparation for transition from pediatric to adult‐centered care. METHODS AND POPULATION: Adolescent LT recipients completed a transition attitudes survey during a routine Pediatric Liver Transplant clinic visit. Level of prior thought and interest in transition were graded on a scale of 0 to 3. Knowledge of the process, perceived importance, and concerns about the transfer were scaled 0 to 4. Allocation of responsibility for healthcare tasks was scaled 1‐5 (parents alone=1, adolescents alone=5). Responses were analyzed according to age, sex and time since transplantation. RESULTS: 38 adolescents aged 12‐21 years (mean = 16.6) were assessed. Mean readiness scores were low, with deficiencies in prior thought (0.95 + 0.9), knowledge (1.1 + 1.0) and interest (1.6 + 1.0). Adolescents reported moderate levels of concern about the transfer (2.0 + 1.2), with leaving pediatric providers behind being the greatest worry (2.3 + 1.4). Perceived importance of transition received the highest score (mean 3.5 + 0.7), with knowledge about medications (3.8 + 0.5) being the most important step. The allocation of responsibility scale (2.74 + 1.6) suggests shared responsibility for healthcare tasks. Older age (>16 years) was associated with greater prior thought (p=0.001), knowledge about the process (p=0.007), interest (p=0.002), and allocation of responsibility (p=0.001). SIGNIFICANCE OF STUDY: Adolescent LT recipients perceive the importance of transition, but demonstrate poor knowledge of the process. Readiness improves with age, but remains insufficient, particularly with respect to independence with healthcare tasks. These results highlight the need for improvements in transition planning during adolescence.

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BELIEFS ABOUT THE PAP SMEAR AMONG MEXICAN IMMIGRANTS

Gregg JL ¹   ¹OHSU, Portland, OR, United States

OBJECTIVES: 1.Characterize beliefs and attitudes about the Pap smear among Mexican immigrants using qualitative methods. 2. Determine knowledge, beliefs, attitudes, and behaviors about the Pap smear for a population of Mexican immigrants. 3.Develop and pilot test an intervention based on results of our survey, qualitative data, and community input. METHODS AND POPULATION: This is a mixed‐methods study, employing Community‐Based Participatory Research (CBPR) and qualitative (in‐depth interviews using snow‐ball sampling) and quantitative measures (a survey of 500 Latino immigrants) to investigate Latino men and women's understanding, attitudes, and beliefs about the Pap smear. RESULTS: 1. In‐depth interviews with 28 Mexican immigrant women and 23 Mexican immigrant men demonstrated that individuals learned about the Pap smear from a wide variety of sources and generally understood the exam to be a screening test for sexually transmitted infections in general. They also related the need for Pap smears and the development of cervical cancer to high risk sexual behaviors. Participants considered men to have a significant role as vectors for disease and as barriers to screening, refusing to let their partners seek screening. 2. We have completed 400 of 500 surveys based on in‐depth interviews in order to deteermine generalizability of qualitative results. SIGNIFICANCE OF STUDY: Our results suggest that interventions to improve cancer prevention among Mexican immigrants may be most effective if they include both men and women, and that health education regarding cervical cancer within this population must also recognize and address valid concerns about STI spread and prevention. Furthermore, interventions must recognize that even when women know how to prevent disease, they may feel disempowered with regard to making behavioral changes that will decrease their risk for STIs or cancer.

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EFFECT OF REVISED IOM WEIGHT GAIN GUIDELINES ON FETAL GROWTH

Halloran DR ¹, Wall TC², Caughey AB³  ¹Saint Louis University, St Louis, MO, United States, ²University of Alabama at Birmingham, Birmingham, AL, United States, ³University of California, San Francisco, San Francisco, CA, United States

OBJECTIVES: To determine the risk of low birth weight (LBW), very low birth weight (VLBW), and macrosomic infants born to mothers with a prepregnancy BMI of 25 kg/m2 who gained within the original and revised IOM weight gain guidelines. METHODS AND POPULATION: This retrospective cohort study utilized birth records for all singleton infants born in Missouri (2000‐2006) to a mother with a BMI greater than or equal to 25.0 kg/m2 and less than 26.0 kg/m2. We excluded infants born with congenital anomalies or born to mothers with a history of diabetes, hypertension, or previous cesarean section. We completed multiple logistic regression models adjusting for maternal race, age, education, smoking status, level of prenatal care, insurance status, and infant gender. The primary predictor was women who gained 15‐25 lbs (2009 guidelines) versus 25‐35 lbs (1990 guidelines). RESULTS: 26,046 had a BMI of 25 kg/m2. 9955 women (38%) gained within the 2009 guidelines (15‐25 lbs). Within this group, 7.3% delivered LBW infants; 1.5% delivered VLBW infants; and 6.2% delivered macrosomic infants. 16,091 women (62%) gained 25‐35 lbs. Within this group, 4.3% delivered LBW infants; 0.8% delivered VLBW infants; and 9.1% delivered macrosomic infants. If a mother gained 15‐25 lbs rather than 25‐35 lbs, the adjusted odds ratios of delivering a LBW infant was 1.7 (95% CI 1.5, 1.9), VLBW infant was 1.8 (95% CI 1.4, 2.3), and macrosomic infant was 0.6 (95% CI 0.6, 0.8). SIGNIFICANCE OF STUDY: Limiting weight gain in women with a BMI of 25 kg/m2, per the 2009 guidelines, increases the risk of low fetal growth but decreased the risk of excessive fetal growth. Further studies should explore the optimal weight gain to reduce the associated poor outcomes.

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PATIENT PERCEPTIONS OF DISCHARGE CARE

Horwitz L ^1,2, Goodrich K¹, Gray J¹, Ziaeian B¹, Brewster U¹, Hryniewicz‐Czeneszew K¹, Jenq G¹, Kanade S², Moriarty J¹, Wagner K¹, Cleary P¹, Krumholz H¹  ¹Yale School of Medicine, New Haven, CT, United States, ²Yale New Haven Hospital, New Haven, CT, United States

OBJECTIVES: To assess the quality of provider‐patient communication at the time of discharge in a large cohort of older patients at high risk of readmission. METHODS AND POPULATION: Prospective cohort study. English‐ or Spanish‐speaking community‐dwelling patients 65 and older admitted with acute coronary syndrome, pneumonia or heart failure were interviewed by telephone within 1 week of hospital discharge and their charts reviewed. For patients who failed a mini‐cognition test, caregivers were interviewed instead. RESULTS: To date, 296 of 524 eligible (56%) patients or caregivers have been interviewed. Recruitment of 400 patients is planned. Study subjects are a mean of 76.9 years; 52% are male, 82% are white, 25% did not complete high school, and 46% report annual household income <$30,000. On preliminary chart review, 66% of patients received no primary care appointment prior to discharge; 13% of admission medications were omitted from discharge instructions; and 38% of discharge summaries were not sent to any physician. 31% of patients reported receiving less than one day's notice prior to discharge. Nonetheless, patients were satisfied: 87% knew who to call for worsening symptoms at home, 86% reported understanding written discharge instructions, 96% reported understanding their diagnosis, 90% reported understanding the purpose of their medications. Assessment of the accuracy of patient knowledge is in progress. SIGNIFICANCE OF STUDY: Objective criteria suggest transitional care is inadequate, yet patients report a high level of satisfaction with discharge. Patients may not know what they do not know. Relying on patient reports to assess the quality of transitional care may be insufficient for identifying discharge‐related gaps in care.

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SICK AND OLD: DO ELDERLY TRAUMA PATIENTS HAVE LESS LIKELIHOOD OF RECEIVING TRAUMA CARE FOR THEIR INJURIES?

Hsia RY ¹, Wang E², Auerbach A³  ¹UCSF, SF, CA, United States, ²Stanford, Stanford, CA, United States, ³UCSF, SF, CA, United States

OBJECTIVES: We seek to determine whether trauma patients 65 or older have less likelihood of receiving care at a trauma center (TC) compared to those less than 65 and associated factors predicting admission to a TC. METHODS AND POPULATION: We performed an observational study of California adults admitted for acute trauma to acute care hospitals in California between January 1, 1999 and December 31, 2007. We analyzed patient‐level data collected from a statewide administrative database in California. The key outcome for our study was whether or not a patient was admitted to a TC. RESULTS: Of 389,863 admissions from 1999 to 2007, our multivariate regression models show that after controlling for injury severity, insurance, income, proximity to trauma hospital, and availability of a TC within the county of the patient, patients aged 65 or older have dramatically decreased likelihood (OR 0.16, p<0.0001) of being admitted to a TC compared to patients less than 65. This trend was consistent as patients aged; the older the trauma patient, the less likely they were to be treated in a TC (ORs of admission to TC for 46‐65 years old= 0.54; for 66‐85, 0.325; for 85+, 0.29, all p<0.05). SIGNIFICANCE OF STUDY: We demonstrate that elderly trauma patients are less likely to be admitted to a trauma hospital for care, even when controlling for factors such as injury severity, insurance, income, proximity to a TC, and TC availability within the patient's county. It could be that elderly trauma patients are either less likely to be brought initially a TC or less likely to be transferred from the emergency department to a TC. These findings suggest that closer analysis of triage criteria as well as in‐hospital transfer criteria for the elderly may be warranted to improve patient care of elderly trauma patients.

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PREDICTORS OF COLORECTAL CANCER SCREENING AMONG MEMBERS OF INTERNET HEALTH COMMUNITIES

Hwang KO ¹   ¹The University of Texas Medical School at Houston, Houston, TX, United States

OBJECTIVES: In preparation for intervention development, the purpose of this study is to evaluate behaviors, attitudes, and barriers which predict colorectal cancer (CRC) screening status among members of an Internet weight loss community and an Internet smoking cessation community. METHODS AND POPULATION: I will administer an online survey to randomly selected members of the SparkPeople (weight loss) and BecomeAnEx (smoking cessation) online communities who are aged 50 to 75 years. The survey will assess variables shown to predict CRC screening in other populations, such as social coherence, self efficacy, perceived susceptibility, barriers, intentions, and social influence. CRC screening status will be assessed with validated questions. Logistic regression will identify significant predictors of CRC screening status while controlling for demographic variables. RESULTS: The study will determine the prevalence of being up to date with CRC screening and predictors of CRC screening status among members of the online communities. SIGNIFICANCE OF STUDY: Understanding predictors of CRC screening will guide the development of the online intervention to promote CRC screening. For example, a certain predictor might function as a target for the intervention. Notable features of the overall project include the potential to save lives by enhancing the adoption of CRC screening, efficiency and scalability of the intervention, and exploration of Internet health communities as a new frontier for community‐based clinical research.

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PHYSICIANS’ ATTITUDES REGARDING COLLABORATIVE CARE FOR CHRONIC KIDNEY DISEASE (CKD): A NATIONAL STUDY

Jonas CM ¹, Troll MU¹, Powe NR², Charles RF¹, Boulware L¹  ¹Johns Hopkins, Baltimore, MD, United States, ²University of California at San Francisco, San Francisco, CA, United States

OBJECTIVES: Primary care physicians’ (PCPs) and nephrologists’ collaborative care of patients with CKD is widely advocated. However, physician preferences regarding the content of collaboration are unclear. METHODS AND POPULATION: We studied PCPs’ and nephrolo‐gists’ attitudes about collaborative care for CKD. Physicians were provided a hypothetical scenario of a patient with stage 4 CKD cared for by a PCP, and reported via questionnaire their: recommendation for nephrology referral, preference for collaborative care, desired intensity of nephrologist involvement, and types of nephrology guidance needed. We identified physician (awareness practice guidelines, participation in CME) and practice (region, setting, ancillary support) characteristics independently associated with attitudes. RESULTS: Among 124 PCPs and 120 nephrologists, a smaller majority of PCPs than nephrologists (85% vs 94%, p=0.02) desired collaborative care. Nephrologists were more likely than PCPs to recommend nephrologist guidance regarding dialysis preparation (73% vs 52%) and electrolyte management (81% vs 46%), both p<0.05. PCPs were more likely to desire collaborative care if the hypothetical patient in their scenario had both diabetes and hypertension, or if they believed the medical care they provided was helpful, and were less likely to desire collaborative care if they felt insurance played a role in their ability to refer to nephrology (all p<0.05). SIGNIFICANCE OF STUDY: Although the majority of PCPs and nephrologists desire collaborative care, preferences regarding its intensity and content differ. Greater consensus between PCPs and nephrologists regarding collaborative care's potential value, optimal intensity, and preferred content are needed.

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FURTHER INVESTIGATION OF RESOLUTION OF ACUTE CONFUSION (DELIRIUM) FOLLOWING BRAIN INJURY AND THE NEED FOR OBJECTIVE MARKERS OF RECOVERY

Kean J ^1,2, Abell M¹, Malec JF²  ¹Indiana University, Bloomington, IN, United States, ²Rehabilitation Hospital of Indiana, Indianapolis, IN, United States

OBJECTIVES: To partially replicate a study by Stuss et al. (1999) investigating memory and attention impairments, and extending the investigation by adding measures of executive function, sleep‐wake cycle and semantic comprehension. METHODS AND POPULATION: The study population included 90 patients with moderate to severe, non‐penetrating traumatic brain admitted to inpatient brain injury rehabilitation at 60 days or less since date of injury. Bedside cognitive and neurobehavioral assessments were conducted using the Orientation‐Log, the Cognitive Log, and the Delirium Diagnostic Tool‐Provisional. RESULTS: As in the Stuss et al., study, the Sign Test with p<0.05 was used to compare time from injury to normal range performance between pairs of measures. At the group level, cognitive measures demonstrated a similar pattern of recovery to that reported previously. However, exploration of a subgroup of 48 individual cases demonstrated 48 different patterns of recovery – no two patients were alike. SIGNIFICANCE OF STUDY: This study provides further support that the acute period following traumatic brain injury is better described as a period of delirium or acute confusion. Perhaps more importantly, the study highlights the need for objective markers of neuropathophysiology and recovery from brain injury.

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MENTAL HEALTH REFERRALS FROM PEDIATRIC CARE: WHY DO SOME FAMILIES NOT FOLLOW THROUGH?

Larson JJ ¹, DosReis S¹, Stewart M¹, Kushner R¹, Frosch E¹, Solomon B¹  ¹Johns Hopkins, Baltimore, MD, United States

OBJECTIVES: This study investigated barriers to mental health care in an urban, low‐income population. We examined the importance of tangible barriers (e.g. appointment time) and intangible barriers (e.g. stigma) on the likelihood of a mental health follow up visit. METHODS AND POPULATION: A 26‐item survey (9 tangible items; 17 intangible items) was given to the parents of 55 children referred for mental health services from a pediatric primary care clinic. Scored on a 6‐point Likert‐scale, items on each subscale were summed to create two composite scores. Each score was divided at the mean to create a high and low group. Mental health appointment follow‐up was obtained from the mental health clinic. The association between barriers and follow‐up were analyzed using logistic regression. RESULTS: The subscales had good internal consistency (tangible‐0.75; intangible‐0.77). Many (64%) followed up with mental health. Stress resulting from the child's behaviors predicted follow up (OR=11.94, p‐value=.02). Uncertainty about what will happen at the visit negatively predicted follow up (OR=.04, p‐value=.02). Composite scores were not associated with follow up. Among parents endorsing low intangible barriers, the association between tangible barriers and follow‐up approached significance (OR=.125, p‐value=.08); but not for those with high intangible barriers (OR=1.13, p‐value=.90). SIGNIFICANCE OF STUDY: When parents are stressed by their child's behaviors, they may be more likely to follow up with mental health. Uncertainty about what will happen at the visit is a deterrent. Tangible barriers may be stronger predictors of follow up when there are fewer intangible barriers. Further research is needed to understand how these barriers affect children's access to mental health care.

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HOSPITAL COMPARISON OF INFECTIONS IN VERY LOW BIRTH WEIGHT INFANTS

Lee HC ^1,2, Chien AT³, Bardach N¹, Gould JB^2,4, Dudley R⁵  ¹University of California, San Francisco, CA, United States, ²California Perinatal Quality Care Collaborative, CPQCC, CA, United States, ³Children's Hospital/Harvard University, Boston, MA, United States, ⁴Stanford University, Stanford, CA, United States, ⁵University of California, San Francisco, CA, United States

OBJECTIVES: Hospital comparisons inform quality improvement, public reporting, and pay‐4‐performance. Measurement conventions may impact quality assessment inclusion and ratings. This is of particular interest in pediatrics with lower patient volumes. Our aim was to examine how 3 measurement conventions affect proportion of NICUs and Very Low Birth Weight (VLBW) infants included in quality assessment and rating distributions. METHODS AND POPULATION: This was a cross‐sectional study of nosocomial infection rates among VLBW infants born at or transferred to NICUs 2007‐2008 in CPQCC, which collects data on >90% of California NICUs. We calculated risk adjusted rates of positive bacterial/fungal culture. We compared 3 methods: 1. Excluding “low‐volume” (<30 VLBW infants/year); 2. Bayesian vs. frequentist; 3. Aggregation across 2 vs. 1 year. Outcomes were percent of NICUs and patients excluded in comparisons, percent of “average” NICUs, and percent of NICUs changing rating by method. RESULTS: 39% of NICUs were omitted from comparisons with low‐volume exclusion conventions, whereas 1% of NICUs were for 2‐years and Bayesian. 16% of VLBW infants were omitted with low‐volume exclusion, while <1% of patients were excluded for 2 years and Bayesian. However, 91% of NICUs were average by Bayesian and 1 year, while 68‐79% were considered average by other methods. Up to 41% of NICUs changed ratings based on method. SIGNIFICANCE OF STUDY: When low‐volume providers are common, the proportion of providers excluded from quality assessment shift dramatically by measurement method. Bayesian method and data aggregation allow maximal inclusion.

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APPROACHES TO CALCULATING PREFERENCE‐TREATMENT CONCORDANCE IN BREAST CANCER PATIENTS

Lee CN ¹, Sepucha K²  ¹University of North Carolina, Chapel Hill, NC, United States, ²Massachusetts General Hospital, Boston, MA, United States

OBJECTIVES: To compare two approaches to calculating concordance between patient preferences and treatments. METHODS AND POPULATION: Cross sectional survey of breast cancer survivors. Patients completed measures of knowledge, involvement, preferred treatment, and goals/concerns. In approach 1, we calculated the percent who received their preferred treatment and the percent for each option. Approach 2 was a multivariable logistic regression for each option (mastectomy or not; chemotherapy or not; hormone therapy or not; reconstruction or not). Demographic and clinical variables, whether the doctor mentioned the options, and goals/concerns significant at p<0.1 were considered for regression. Final models included variables significant at 0.05. Treatments predicted by models with probability >0.50 were considered “matched”. RESULTS: Patients eligible for surgery (n = 396), chemotherapy (n = 322), hormone therapy (n = 300), and reconstruction (n = 81) were included. Three goals (keep breast, remove breast, avoid radiation) and the doctor mentioning mastectomy were associated with surgery type. Age, stage, mastectomy, no hormonal treatment, and two patient goals (live as long as possible, avoid serious side effects of chemotherapy) were associated with chemotherapy choice. Only insurance status was associated with hormone therapy. No goals/concerns were associated hormone therapy. Four goals/concerns were associated with reconstruction. SIGNIFICANCE OF STUDY: Some patients (8‐33%) do not receive care concordant with preferences. Approach 1 was simple to perform and suggested better match than the prediction models. Multivariable analysis provided more insight into influences of demographic and clinical factors, provider behaviors, and patient goals/concerns on treatment choice.

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PATIENTS AND HEALTH CARE PROVIDERS TRUST IN SOCIOTECHNICAL HEALTH SYSTEMS

Montague E ¹   ¹University of Wisconsin‐Madison, Madison, WI, United States

OBJECTIVES: Trust is a fundamental aspect of doctor‐patient relationships; the introduction of technologies into that relationship can enhance or diminish the interpersonal relationship. Understanding trust in medical technologies will provide insight into which technologies will be accepted or rejected, which system designs will lead to positive patient outcomes and which have the inverse effect. The objective of this study was to assess how patients and care providers make decisions about the trustworthiness of mutually used medical technology. In this study, patients are passive users of technologies whose trusting relationships have the potential to affect the way technology is used or not used in their care. METHODS AND POPULATION: Using a grounded theory methodology, we conducted semi‐structured interviews with 25 obstetric patients and 12 health care providers to examine the decision‐making process for developing trust in technologies in an obstetric work system. RESULTS: We expected the two groups to have similar criteria for developing trust in medical technology, though we found patients and physicians differed in processes for developing trust in medical technology. Trust in care providers, the technologies characteristics and how care providers used technology were all related to trust in medical technology for the patient participant group. Trustworthiness of the system and trust in self were related to trust in medical technology for the physician participant group. SIGNIFICANCE OF STUDY: Users with different perspectives of the system have different criteria for developing trust in medical technologies. Therefore, designers and implementers of technologies should consider patients’ and care providers’ differing perceptions of technologies when be decisions about technologies that will be used by both groups.

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A CLINICAL DECISION RULE TO PREDICT ADULT PATIENTS WITH TRAUMATIC BRAIN INJURY WHO DO NOT NEED INTENSIVE CARE UNIT ADMISSION

Nishijima DK ¹, Holmes JF¹  ¹UC Davis School of Medicine, Sacramento, CA, United States

OBJECTIVES: To develop a clinical decision rule to identify adult emergency department (ED) patients with traumatic brain injury (TBI) who are at low risk for requiring critical care resources during hospitalization. METHODS AND POPULATION: This is a retrospective cohort study of patients (>18years) with TBI and traumatic intracranial hemorrhage (tICH) presenting to the ED. The need for intensive care unit (ICU) admission was defined as the presence of a critical care intervention including: intubation, neurosurgical intervention, blood product transfusion, vasopressor or inotrope administration, invasive monitoring for hemodynamic instability, and cardiac arrest. We used binary recursive partitioning to develop our rule. RESULTS: A total of 320 patient medical records (mean age 48 years, ±21 years) were abstracted and 137 patients (43%; 95% CI 38‐48%) met the primary outcome of a critical care intervention. We performed binary recursive partitioning with Classification and Regression Trees (CART) software to develop our clinical decision rule. The decision rule consisted of a normal mental status (Glasgow Coma Score=15), isolated head injury, and age<60 to identify patients at low risk for a critical care intervention. The derived rule had a sensitivity of 99% (95% CI 96‐100%) and a specificity of 46% (95% CI 39‐54%). The lone patient not identified by this rule was a 42 year old male who received one unit of fresh frozen plasma but no further critical care interventions. SIGNIFICANCE OF STUDY: Improved ICU triage in patients with TBI would improve resource utilization and health care costs. This clinical decision rules identifies low risk patients with TBI who do not need ICU admission. Futures prospective studies are required to validate if this rule can serve as a safe, cost‐effective triage tool for ICU admission.

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VARIATION IN EMT TEAM CONFIGURATION AND TEAMMATE FAMILIARITY

Patterson D ¹, Yealy DM¹, Krackhardt D², Abebe K³, Weaver MD¹

¹University of Pittsburgh, Pittsburgh, PA, United States, ²Carnegie Mellon University, Pittsburgh, PA, United States, ³University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: To characterize Emergency Medical Technician (EMT) team configuration and teammate familiarity in 3 Emergency Medical Services (EMS) agencies using Social Network Analysis (SNA). METHODS AND POPULATION: We used a case study design of 3 EMS agencies. We used administrative data to measure EMT team configuration, defined as the patterns of partnerships in an EMS agency over time; and teammate familiarity; defined as the mean number of different EMT teammates over 12 months. We calculated the rate of different EMT teammates for every 10 shifts worked. We produce sociograms ‐visual illustrations of the structural patterns of EMT team configuration. We calculated density and network centralization, two complimentary SNA summary measures, to quantify cohesion of EMT team configuration in agencies. Density and network centralization range from 0 to 100, with higher values indicating greater cohesion in the agency and concentration of EMT dyads with specific EMT employees, respectively. RESULTS: Across all agencies, the mean number of EMT shifts worked annually was 76.9(59.5). EMTs worked with 19.2(12.4) different EMT teammates over 12 months. The mean rate of different EMT teammates for every 10 shifts worked was 4.0(2.7). Sociograms depict variation in EMT team configuration across agencies. Density (cohesion) ranged from a low of 28.0 to 33.7%. Density was slightly higher in the EMS agency with fewer total EMTs. Network centralization ranged from a low of 34.7% to 36.8%. SIGNIFICANCE OF STUDY: There was wide variation in select measures of EMT teammate familiarity. SNA sociograms provide a standardized approach for visualizing EMT configuration across EMS agencies.

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PROFESSIONAL BURNOUT AMONG EARLY CAREER PHYSICIAN INVESTIGATORS

Primack BA ¹, Switzer GE¹, Rubio DM¹, Bryce CL¹, Seltzer DL¹, DilmoreTC¹, Li J¹, Landsittel DP¹, Kapoor W¹  ¹University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: Burnout—which is characterized by emotional exhaustion, cynicism, and a sense of low personal accomplishment—is a pervasive problem among clinicians. It is associated with factors such as poor empathy for patients, increased likelihood of making errors, and low patient satisfaction. However, very little is known about burnout among early career clinical investigators. The purpose of this study was to determine the prevalence of and demographic associations with burnout in a cohort of early career clinical investigators. METHODS AND POPULATION: A validated burnout scale was administered to a cohort of 185 physician trainees at the Institute for Clinical Research Education at the University of Pittsburgh in 2007‐2008. Other questionnaire items assessed demographic factors such as age, gender, race/ethnicity, and type of training program. RESULTS: Of the 185 participants, 32 (17.3%) reported feeling burned out. Burnout was more common among those over 35 years of age compared with those <35 (30.8% vs. 12.4%, P=.004). Burnout was more prevalent among females vs. males (23.1% vs. 12.0%, P=.048). Compared with Asians, who had the lowest rates of burnout, underrepresented minority members (African‐Americans, Hispanics, or Native Americans) had higher odds of being burned out (OR=7.0, 95% CI=1.3, 37.9). Although the point estimate of the association between White race (vs. Asian) and burnout was also elevated, it did not reach statistical significance (OR=3.5, 95% CI=0.8, 15.8). SIGNIFICANCE OF STUDY: Rates of burnout were substantial in this cohort, especially considering the early career status of these research trainees. Certain demographic subgroups—including older trainees, females, and underrepresented minorities—may benefit from extra attention and support in clinical research training programs.

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LEVERAGING COMMUNITY ASSETS TO COMBAT HEALTH DISPARITIES IN SUBURBAN COUNTIES IN CHICAGO

Simon M ¹, Taylor S², Reyes B², Endress R², Murphy K²  ¹Northwestern University, Evanston, IL, United States, ²Access Dupage, Carol Stream, IL, United States

OBJECTIVES: To detail the construction of a successful community development tool: preventing and eliminating growing health disparities in a suburban community setting. Through the Dupage County Patient Navigation Project, we aim to increase the proportion of women with diagnostic evaluations for breast and cervical cancer as compared to both previous performance and care controls. We aim to build community based research capacity through focused education and training in research design, methods, and dissemination of research results. METHODS AND POPULATION: The Navigation Project focuses on navigating 600 uninsured suburban women who have had an abnormal screening result for breast and/or cervical cancer through a diagnostic resolution. Through qualitative methodology, we transcribed and thematically coded interviews with participants and their navigators. Through quantitative methodology mean time between abnormal screening and definitive follow‐up for the intervention will be tracked. RESULTS: Women who receive the navigation intervention will have reduced time to definitive diagnosis and a smaller portion lost to care compared to subjects that did not receive the intervention. It will be more cost effective to provide cancer diagnosis and treatment to patients with a patient navigator in comparison to control group. SIGNIFICANCE OF STUDY: Tailored integration into DuPage County will pave the way for a self‐sustaining community resource that can be a model for caring for the growing population of under‐insured, and medically underserved. Through our strong community‐campus partnership, we successfully built a navigation program that is participant‐centered, culturally relevant, and most important, relevant to the community which it serves.

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PATTERNS OF CARE FOR AMERICAN INDIAN AND ALASKA NATIVE MEN WITH AN ELEVATED PSA — A COMMUNITY BASED FEASIBILITY STUDY

Tilburt JC ¹, Petersen W¹, Nicometo A¹, James K¹, Patten C¹  ¹Mayo Clinic, Rochester, MN, United States

OBJECTIVES: Objective: To characterize the timeliness of care and patient's experiences of care for AI/AN men with a newly elevated PSA test. Aim 1: describe the demographic, clinical, and service use characteristics from IHS administrative data (and medical records) of targeted samples of Northern Plains American Indian and Alaska Native men age 50‐85 with elevated PSA; Aim 2: assess patient‐report experiences and outcomes of care among Northern Plains American Indian and Alaska Native men age 50‐80 who have had an incident PSA elevation in the last 3 years. To determine the feasibility of future research in this area, this study will systematically sample 100 American Indian and Alaska Native men with a newly elevated PSA and will examine what happened thereafter in the course of their diagnosis, treatment, and self‐reported experience. METHODS AND POPULATION: Approach: Community‐based participatory research Methods: Retrospective chart review, and mixed methods face‐to‐face interviewing RESULTS: Median time to follow‐up of newly elevated PSA will be longer than in US male population. Patients will identify a broad range of concerns about the cultural appropriateness of the care they received for elevated PSA. SIGNIFICANCE OF STUDY: The quality and timing of care for American Indian and Alaska Native men with elevated prostate specific antigen test (PSA), may explain why they experience more advanced disease and die at higher rates from prostate cancer than other groups. To determine the feasibility of future research in this area, this study will systematically sample 100 American Indian and Alaska Native men with a newly elevated PSA and will examine what happened thereafter in the course of their diagnosis, treatment, and self‐reported experience.

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OUTCOMES OF A TELEPHONE INTERVENTION IN HEART FAILURE

Wongpiriyayothar A ¹, Piamjariyakul U², Williams PD²  ¹Mahasarakham University, Kantarawichai District, Thailand, ²University of Kansas Medical Center, Kansas City, KS, United States

OBJECTIVES: Dyspnea, resulting in poor physical functional status is a pervasive problem among persons with heart failure (HF). The purpose of this study was to examine the effects of a telephone coaching intervention on dyspnea and physical functioning in HF. METHODS AND POPULATION: A pilot study was conducted using a pretest‐posttest, experimental design. Twenty‐two patients (mean age = 62 years; 59% female) with HF were randomly assigned to experimental and active usual care groups. The experimental group first received the coaching intervention by a cardiac research nurse, in‐person at the cardiology clinic. The intervention focused on coaching patients on early identification of HF symptoms and on developing symptom management skills. Follow‐up telephone coaching was conducted twice each week for 3 weeks, with each telephone coaching session lasting, on average 30‐60 minutes. Standard hospital and out‐patient education only was provided to patients in the usual care group. RESULTS: The experimental and usual care group participants were comparable. There were no significant differences between groups in severity of dyspnea scores at baseline. Four weeks after the intervention, mean severity of dyspnea and physical functioning change scores were significantly improved in the experimental group compared with the control group (t = 4.03 and 3.83, respectively, p < .001). SIGNIFICANCE OF STUDY: The findings indicate coaching on HF self‐management is an effective method to help patients decrease the severity of dyspnea and improve physical functioning. Patients are coached on the importance of self‐monitoring and early recognition and management of symptoms of HF. This evidence‐based intervention can be used in hospital and home care based patient education programs for HF.

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DEFINING BEST SUPPORTIVE CARE (BSC) IN CANCER CLINICAL TRIALS

Zafar SY ¹, Currow D³, Cherney N², Strasser F⁴, Abernethy AP¹  ¹Duke University Medical Center, Durham, NC, United States, ²Shaare Zedek Medical Center, Jerusalem, Israel, ³Flinders University, Adelaide, SA, Australia, ⁴Cantonal Hospital, St Gallen, Switzerland

OBJECTIVES: Oncology clinical trials for advanced cancer frequently randomize patients to treatment vs. BSC, but BSC is not uniformly delivered in line with currently‐available best evidence, with variation by practitioner and center, potentially impacting internal & external validity of trial results. We aim to develop a standardized framework for delivering BSC in cancer trials. METHODS AND POPULATION: We are conducting structured Delphi surveys with an international panel of oncology, palliative care, nursing, and trial experts to develop a standard framework for BSC delivery in trials. The first round survey asked respondents to identify key BSC components that should be standardized within trials. The second round asked respondents to prioritize these components. RESULTS: 39 experts in 9 countries are participating. In round one, the most common key component of BSC was appropriate supportive care documentation, followed by symptom assessment at identical intervals as the intervention arm, validated symptom assessment, access to palliative care specialists, and multidisciplinary care in order of decreasing frequency. In round two, experts prioritize components. The highest ranked component was access to palliative care specialists, followed by supportive care documentation, validated symptom assessment, and identical symptom assessment as the intervention arm. SIGNIFICANCE OF STUDY: An international expert panel has identified key components of BSC within cancer clinical trials. Next steps in this Delphi study include assessing challenges to implementing BSC and methods to overcome those challenges.

OUTCOMES RESEARCH

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PLASMA GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP) AS A MARKER OF BRAIN INJURY AND PREDICTOR OF NEUROLOGIC OUTCOMES AFTER EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO)

Bembea M ¹, Savage W¹, Schwartz J¹, Graham E¹, Strouse JJ¹, Everett A¹  ¹Johns Hopkins University, Baltimore, MD, United States

OBJECTIVES: To determine if plasma GFAP is associated with brain injury during ECMO and with PICU mortality. METHODS AND POPULATION: Prospective patients age 1 day‐18 years who required ECMO from 5/2008 to 8/2009 were studied. GFAP was measured using an electrochemiluminescent immunoassay developed at Johns Hopkins. Control samples were collected from 60 healthy children (0.5‐16 years) and 85 NICU infants with normal head imaging and neurologic exams. Plasma GFAP was measured at 6, 12 and every 24 hours after ECMO cannulation. RESULTS: We enrolled 22 children who underwent ECMO. Median age was 7 days (2 days‐9 years), and primary ECMO indication was: cardiac failure, 5/22, respiratory failure, 13/22, ECPR, 3/22, and sepsis, 1/22. Six/22 (27%) patients developed acute neurologic injury (intracranial hemorrhage, brain death or severe cerebral edema diagnosed by imaging). Fifteen/22 (68%) survived to PICU discharge. The 95th percentile GFAP level in controls was 0.436ng/mL. Median peak GFAP levels were higher in children with brain injury than those without (10.2 vs 0.09ng/mL, p<0.01) and in non‐survivors compared to survivors to PICU discharge (5.9 vs 0.09ng/mL, p=0.01). The odds ratio (OR) for brain injury for each 1ng/mL increase in GFAP was 2.7 (95%CI, 1.2‐5.9) and the OR for death in the PICU was 6.7 (95%CI, 1.4‐32.8). SIGNIFICANCE OF STUDY: High GFAP during ECMO was significantly associated with acute brain injury and death. Brain injury biomarkers may play an important role in neurologic monitoring of ECMO patients to improve outcomes and benchmark new therapies.

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HOW SHORT IS TOO SHORT?: THE RISK OF PRETERM BIRTH WITH INADEQUATE BIRTH SPACING

Bryant A ¹, Madden E¹, Fuentes‐Afflick E¹  ¹University of California, San Francisco, San Francisco, CA, United States

OBJECTIVES: To determine the effect of short interpregnancy (birth‐to‐conception) intervals (IPI) on the risk of preterm birth among women in California. METHODS AND POPULATION: California birth certificate data from 1999‐2004 were linked with hospital discharge data. For women who had a first birth in 1999‐2000 and a second birth by 2005, multivariable modeling was used to determine risk factors for preterm birth (<37, <32 and <28 weeks), with a particular interest in the effect of short IPIs (<18, <12, <6 and <3 months). Tests of interaction were conducted to assess for modification of the effect of IPI on prematurity by race and by prior preterm birth. RESULTS: 190,099 women had a first birth in 1999‐2000 and a second birth by 2005. The risk of delivery at <37, <32 and <28 weeks in the second birth was 8.4%, 1.0% and 0.3%, respectively. The adjusted odds and 95% confidence intervals of extreme prematurity (<28 weeks) associated with a IPIs < 3m, 6m, 12m and 18m were 1.88 [1.1, 3.4], 2.2 [1.5, 3.3], 1.6 [1.3, 2.1] and 1.3 [1.1, 1.6], respectively. There were significant interactions between the effect of short IPI on extreme prematurity by race and by prior preterm birth, such that in the setting of an IPI < 6 months, Black women (AOR 6.9 [3.2, 14.9]) and women with a history of prematurity (AOR 7.5 [4.5, 12.6]) were much more likely to have a subsequent birth <28 weeks gestation than were women with longer IPIs. SIGNIFICANCE OF STUDY: The risk of prematurity varies by maternal race/ethnicity, prior preterm birth and short IPI, and the risks of race and prior prematurity and IPI are multiplicative. In particular, Black women and women who have already delivered a premature infant should be counseled to avoid very short interpregnancy intervals.

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WHAT IS THE QUALITY OF LIFE IMPACT OF LIVING DONOR NEPHRECTOMY?

Butt Z ¹, Jensen SE², Daud A¹, Sprague A¹, Friedewald JJ¹  ¹Northwestern University Feinberg School of Medicine, Chicago, IL, United States, ²NorthShore University HealthSystem, Evanston, IL, United States

OBJECTIVES: While there has been growing interest in the quality of life (QOL) of kidney transplant recipients, few studies have focused on living donors. We conducted a meta‐analysis to provide a clearer picture of QOL following kidney donation. METHODS AND POPULATION: We conducted a Medline search (through 2009) using relevant MeSH terms. After applying limits, 76 articles met initial inclusion criteria. We eliminated 63 articles that did not use a validated QOL instrument, were not longitudinal studies, or were otherwise not relevant. We further analyzed 11 of 13 remaining articles that used the generic SF‐36 instrument, which produces 8 subscales and physical and mental composite scores. We then transformed all scale scores to norm‐based scores (M=50; SD=10) using established procedures. These scores were used to produce sample‐size weighted estimates for QOL pre‐donation, 1‐mo, 3‐6 mos, and 12+ mos post‐donation. RESULTS: Data from 646 unique kidney donors were included in the analysis. Prior to donation, donors report slightly higher than average QOL on the SF‐36. Over time, there was impact on the Physical Composite score (F(3,12)=49.8; p<0.005), but not on the Mental Composite (p>0.05). Specifically, in the first month after donation, donors reported clinically significant decreases in Physical Function, Role‐Physical subscales. However, within 3‐6 mos and persisting for a year post‐donation, donors report QOL similar to their baseline scores (p>0.05). SIGNIFICANCE OF STUDY: Individual studies to date have generally reported on small samples, using QOL scores that are difficult to compare directly. The present analysis suggests that the long‐term QOL impact on donors is acceptable, and may provide useful information for donor education and consent.

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PEER AND DATING RELATIONSHIPS IN ADOLESCENTS WITH CANCER: ASSOCIATIONS WITH HEALTH BEHAVIORS

Carpentier MY ¹, Mullins LL², Elkin T³, Wolfe‐Christensen C²  ¹Indiana University School of Medicine, Indianapolis, IN, United States, ²Oklahoma State University, Stillwater, OK, United States, ³University of Mississippi Medical Center, Jackson, MS, United States

OBJECTIVES: This preliminary study assessed close peer and dating relationships in relation to health‐protective and health‐damaging behaviors among adolescents on active cancer treatment. METHODS AND POPULATION: Forty two adolescents with cancer, ages 12 to 19 years, participated in the study. Participants completed a series of paper‐and‐pencil measures, including a demographic questionnaire, an illness‐related questionnaire, the Network of Relationships Inventory‐Revised, and the Youth Risk Behavior Survey. Questionnaires were completed at regular outpatient clinic visits. RESULTS: Results indicated that increased negative interactions with romantic partners were significantly associated with increased adolescent cigarette use (r(30) = .40, p = .01) and decreased adolescent condom use prior to last sexual experience (r(30) = ‐.42, p = .008). In addition, increased fear of intimacy with romantic partners was significantly associated with decreased condom (r(37) = ‐.40, p = .006) and birth control (r(37) = ‐.39, p = .007) use prior to last sexual experience, as well as decreased levels of recommended physical activity (r(37) = ‐.27, p = .048). No significant relationships emerged among discrete aspects of close peer and dating relationships and nutrition and sun safety variables of interest. SIGNIFICANCE OF STUDY: Our results indicate that negative aspects of dating among adolescents with cancer are associated with health‐damaging behaviors. Although preliminary, results suggest that efforts to intervene with health‐damaging behaviors would be well‐justified in including adolescents’ romantic partners.

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BIOCHEMICAL SCREENING CRITERIA FOR ASSESMENT OF HYPOXIC ISCHEMIC ENCEPHALOPATHY (HIE) IN LATE PRETERM INFANTS

Chalak LF ¹, Sanchez P¹  ¹UTSW MC Dallas, Dallas, TX, United States

OBJECTIVES: Biochemical screening criteria based on fetal acidemia are utilized to identify infants 36 weeks of gestation for presence of HIE and subsequent hypothermia therapy (NICHD, NEJM 2005). Our objectives are to determine the frequency of abnormal biochemical criteria among late preterm infants(33‐35weeks)and their association with HIE. METHODS AND POPULATION: Retrospective review of neonatal databases that included all NICU admissions at Parkland Memorial Hospital, Dallas between 1/1/2005 and 12/31/2008 was performed. All records of inborn infants with gestational ages of 33‐35 weeks were reviewed for presence of the following biochemical screening criteria: #1) blood pH 7.0 or a base deficit 16 mmol/L in the first hour of age; or #2) blood pH 7.01‐7.15 or base deficit of 10‐15.9 mmol/L with presence of an acute perinatal event. Neonatal characteristics were reviewed, as well as short term neurological outcomes. RESULTS: Among 1305 newborns delivered at 33‐35 weeks’ gestation, 33 (2.5%) infants fulfilled the biochemical screening criteria (criteria #1, 20 [60%] infants; criteria #2, 13 [40%]). Mean birth weight was 2162 561 grams, 79% were Hispanic, 57% were male and 36% required intubation at birth. Maternal characteristics included PIH in 12 (35%) and diabetes in 6 (18%); 78% were c‐section deliveries. Clinical signs of HIE were noted in 6 newborns: 2, Sarnat stage I; 2, stage II; and 2, stage III. Three of these infants had clinical seizures and received anticonvulsant therapy. Using Sarnat stageII/III, seizures,or MRI, HIE occurred in 5 infants (3/1000 late preterm live births) and all were identified using criteria #1. SIGNIFICANCE OF STUDY: Biochemical screening abnormalities allowed identification of HIE in the late preterm infants. Optimal clinical assessment for HIE in these infants needs to be determined before implementation of hypothermia trials.

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EVALUATION OF RISKS FOR LATE DEATH AFTER TRAUMA

Claridge JA ¹, Golob JF¹, McCoy A¹, Malangoni MA^{1, 1}  ¹MetroHealth Medical Center, Cleveland, OH, United States

OBJECTIVES: The purpose of this study was to evaluate long‐term mortality after trauma, and to determine risk factors and possible disparities related to mortality after discharge (MAD). METHODS AND POPULATION: Level I Trauma Registry data from injured patients (2000‐2005) was linked to the electronic medical record, the National Death Index with cause of death codes (2000 through 2005), and census data utilizing geocoding methodology. Census data provided supplemental demographic and socioeconomic information. RESULTS: Hospital mortality of 15,285 patients was 3.3%, MAD was 4.8%, and overall mortality was 8.1% (average follow up = 2.8 years, one year mortality = 5.4%). MAD was related to trauma in 31%, potentially related in 24%, and unrelated to trauma in 45% of patients. Patients were discharged to home (84%), rehabilitation facility (8.4%), skilled nursing facility (6.5%), acute care facility (1.3%), and hospice (0.2%); with late mortalities of 3.4%, 7.7%, 18.7%, 20.7%, and 100%, respectively. Logistic regression analysis(LRA) demonstrated independent risk factors for hospital mortality were age, ISS, ventilator days, penetrating injury, and non‐vehicular injury (p<0.05 for all). However, significant risk factors for MAD were fall(OR=1.7; 95%CI = 1.3‐2.2), disposition other than home(OR=1.6; 95%CI= 1.2‐2.0), age(OR=1.06; 95%CI= 1.05‐1.07), sobriety on admission(OR=1.4; 95%CI= 1.1‐1.9), and hospital days(OR=1.03; 95%CI= 1.02‐1.04). The C statistic was 0.85. Bivariate analysis of census data demonstrated that lower socio‐economic status was associated with improved hospital survival, while non‐native status was associated with MAD. SIGNIFICANCE OF STUDY: There are important differences in risk factors for inpatient mortality after injury and MAD. Assessment of outcomes following trauma should not be based solely on hospital discharge information.

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LONGER PRE‐HOSPITAL TIME IS ASSOCIATED WITH MORTALITY FOR WOMEN WITH ACUTE CORONARY SYNDROME

Contreras JP ^1,2, Daudelin D¹, Goetz J¹, Schmid CH¹, Kent DM¹, Selker HP^1,2  ¹Tufts University, Boston, MA, United States, ²Tufts Medical Center, Boston, MA, United States

OBJECTIVES: The association between mortality rates and longer pre‐hospital time for women that present with ACS had been controversial. We sought to explore this issue and to identify the factors contributing to this association. METHODS AND POPULATION: Data was prospectively collected from adult patients that contacted emergency medical service (EMS) for symptoms suggestive of ACS. We used a multivariable logistic regression analysis to determine the factors associated mortality RESULTS: A total of 6,843 patients: 3,555 women and 3,435 men. Logistic regression demonstrated that patients whose pre‐hospital delays were above the 90th percentile had a 20% higher mortality compare to those below the 90th per‐centile. Prior history of diabetes, older age, and female gender were each independently associated with higher mortality rates. Among the patients with pre‐hospital time above the 90th percentile, women were overrepresented and were more likely to have a history of diabetes. SIGNIFICANCE OF STUDY: Our model showed that longer pre‐hospital time, females, elders and history of diabetes were independently associated with increased risk of all‐cause mortality, adding evidence regarding the triple jeopardy that women face with ACS, as their ACS presents later in life. Considering that the new available therapies that can reduce or prevent myocardial damage if deliver within a narrow time‐frame, it is important that strategies are developed that minimize the delay access to appropriate medical treatment in elderly women presenting with ACS.

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COCAINE USE PREDICTS LACK OF VIROLOGIC CONTROL BASED ON A RAPID SCREENING TOOL FOR ADHERENCE AND ACTIVE SUBSTANCE ABUSE IN AN OUTPATIENT HIV CLINIC

Desruisseau AJ ¹, Stinnette S², Kheshti A², Qian H²  ¹Meharry Medical College, Nashville, TN, United States, ²Comprehensive Care Center (Vanderbilt University), Nashville, TN, United States

OBJECTIVES: Illicit drug use plays an important yet ill‐defined role in human immunodeficiency (hiv) virologic control. we used a rapid clinical questionnaire to assess the effect of active drug use on plasma hiv‐1 rna. METHODS AND POPULATION: From may, 2008 through december, 2008, we administered a clinical questionnaire to assess active drug use and antiretroviral (art) adherence within the previous 7 days. RESULTS: We analyzed 1541 unique participant questionnaires. the median age was 44.5 years (iqr 38.2‐50.1), 34% were african american and 75% were male. at the time of the questionnaire, 79% were on art and approximately 10% reported missing any doses of art within the previous 7 days. marijuana (15.6%) and cocaine(2.9%) were the most common substances used. in the multivariable analysis, adjusting for age, gender, african american race, missed art, intravenous drug use, marijuana use, cocaine use, or “other” drug use, higher hiv‐1 rna was associated with having missed art in the previous 7 days(0.63 log/ml hiv‐1 rna, 95% ci 0.47‐0.79, p <0.01), any cocaine use in the previous 7 days(0.32 log/ml hiv‐1 rna, 95% ci 0.05‐0.60, p=0.02) and african american race(0.10 log/ml hiv‐1 rna, 95% ci 0.01‐0.20, p=0.04). SIGNIFICANCE OF STUDY: Active cocaine use and african american race, in a point prevalence study, are predictive of poorer hiv‐1 rna control. further studies are needed to explain these findings.

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THE IMPACT OF HEALTH BEHAVIORS ON HEMATOPOIETIC STEM CELL TRANSPLANT OUTCOMES

Ehlers SL ¹, Patten C¹, Gastineau D¹, Cerhan J¹, Ebbert J¹, Decker P¹, Porrata L¹, Ansell S¹, Hogan W¹, Dispenzieri A¹  ¹Mayo Clinic, Rochester, MN, United States

OBJECTIVES: Document the prevalence and impact of tobacco on HSCT immune reconsti‐tution and survival, from the time of the pre‐transplant evaluation to 1 year post‐transplant, with sociodemographic, clinical, and psychological covariates to build an intervention model. Secondarily, the impact of non‐tobacco health behaviors (obesity, physical activity, and alcohol use) on HSCT outcomes will be explored. METHODS AND POPULATION: Prospective cohort design with projected sample of 1,000 participants representing sub‐samples of hemato‐logic illness populations treated with HSCT. RESULTS: This research promises to provide 1) prospectively documented prevalence of tobacco use and other health behaviors in a large sample of HSCT patients, 2) valuable information regarding the impact of modifiable health behaviors on transplant outcomes, and 3) evidence‐ and theory‐ based understanding of health behaviors and possible factors of health behavior change in a large sample of HSCT patients. This research might identify controllable risk factors for delayed immune reconstitution and mortality in HSCT recipients and provide a foundation for intervention development tailored to the HSCT population. SIGNIFICANCE OF STUDY: Health behaviors are the leading preventable causes of death and disability within public health, and under studied in translational research among cancer‐survivors. Study results will enable HSCT clinicians to confidently advise patients and establish empirically based practice guidelines. Intervention development could enable patients to self‐manage aspects of their health and improve survivor outcomes in HSCT.

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SYSTEMATIC REVIEW AND META‐ANALYSIS OF THE EFFICACY AND SAFETY OF CONTINUOUS GLUCOSE MONITORING VERSUS SELF MONITORING OF BLOOD GLUCOSE IN TYPE 1 DIABETES MELLITUS

Floyd BD ¹, Hall SP¹, Chandra P², Alema‐Mensah E¹, Phillips CO¹, Strayhorn G¹, Ofili E¹, Umpierrez G²  ¹Morehouse School of Medicine, Atlanta, GA, United States, ²Emory University School of Medicine, Atlanta, GA, United States

OBJECTIVES: Our objective was to determine if continuous glucose monitoring (CGM) confers an advantage over self monitoring of blood glucose (SMBG) in glycemic control in type 1 diabetes mellitus (T1DM), aiming to determine differences in hemoglobin A1c (A1c), hypo‐glycemia, and hyperglycemia between T1DM patients using CGM and SMBG. METHODS AND POPULATION: MEDLINE (1966–September 2009), the COCHRANE REGISTRY (all years), EMBASE (1980–September 2009), and article bibliographies were searched for English language randomized controlled trials (RCTs) investigating CGM, T1DM, and outcomes including A1c, hypoglycemia, or hyperglycemia. Two reviewers extracted study data via a standardized instrument, rated study quality, and resolved disagreements by consensus. Seventeen RCTs met eligibility criteria and were analyzed (N=1082 patients; mean age 28.2±15.3 years; men 47.3%; Caucasian 90%; DM duration 14.7±10.2 years). RESULTS: CGM resulted in a 3.47% (p<0.0001) greater A1c reduction than SMBG from baseline to 4‐6 weeks, a 1.63% (p<0.0001) greater A1c reduction than SMBG from baseline to 12‐16 weeks, and a 3.49% (p<0.0001) greater A1c reduction than SMBG from baseline to 24‐26 weeks. CGM resulted in 51.47 (p<0.0001) more minutes/day with blood glucose (BG) at 71‐180 mg/dl than SMBG, 22.63 (p<0.0001) fewer minutes/day spent with BG ≥ 150 mg/dl than SMBG, and 49.46 (p<0.0001) fewer minutes/day spent with BG ≥ 240 mg/dl than SMBG. CGM resulted in 0.0312 (p<0.0001) fewer hypoglycemic (<70 mg/dl) episodes/day than SMBG. SIGNIFICANCE OF STUDY: Available evidence suggests that CGM has a positive effect on metabolic control in T1DM, with an overall reduction in A1c, hyperglycemia, and hypoglycemia.

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SLOW INDOMETHACIN INFUSION DOES NOT ALTER CEREBRAL OXYGENATION IN VERY LOW BIRTH WEIGHT (VLBW) NEONATES

Garner RS ¹, Miller C¹, Burchfield DJ¹  ¹University of Florida, Gainesville, FL, United States

OBJECTIVES: To determine if indomethacin (INDO) decreases cerebral O2 saturation and increases cerebral O2 extraction in VLBW neonates. METHODS AND POPULATION: The study was IRB approved and parental consent obtained. Inclusion criteria were <30 weeks GA, BW <1500 grams, and arterial access. Exclusion criteria were cyanotic heart lesion or limited viability. Arterial saturations (SpO2) were monitored as part of routine care. Additionally, a cerebral probe monitored regional saturations (rSO2) using NIRS (Somanetics, Troy, Michigan). At 30‐60 second intervals, SpO2 and rSO2 were recorded in a VitalSync (Somanetics) monitor. Neonates < 1000 grams received INDO for IVH prophylaxis at a dose of 0.1 mg/kg IV over 1‐2 hours, and the majority received first dose within 6 hours. Average fractional cerebral O2 extraction (FCOE = (SpO2‐cerebral rSO2)/SpO2) was determined in patients from the minute‐to‐minute recordings for the hour prior to INDO infusion, the first hour of infusion and 2 hours after infusion. Control patient data were collected at a similar age in patients who did not receive INDO. The pre‐, during and post‐ treatment FCOE, SpO2 and cerebral rSO2 were compared using ANOVA. RESULTS: We enrolled 33 VLBW neonates, 18 in the INDO group and 15 controls. SpO2, rSO2 or FCOE did not change before, during or after INDO infusion, and did not differ between the INDO and control groups. In the INDO treated group, FCOE was 22±13% pre‐INDO, 22±11% during infusion, and 24±11% after infusion (p>0.7). SIGNIFICANCE OF STUDY: Because rSO2 and FCOE did not change during or after INDO infusion compared to baseline, cerebral blood flow (CBF) most likely did not change due to INDO. In studies which found that INDO decreased CBF, INDO was given as a rapid infusion over 30 minutes. We propose that INDO does not decrease CBF when given over one to two hours.

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INCOMPATIBLE TRANSPLANTATION IN THE UNITED STATES: RESULTS OF A NATIONAL SURVEY

Garonzik Wang J ¹, Montgomery R¹, Berger J¹, Kucirka L¹, Segev D¹  ¹Johns Hopkins University, Baltimore, MD, United States

OBJECTIVES: Use of incompatible live donor kidney transplantation (IKT) is growing in response to the organ shortage and the increase in sensitization among patients seeking transplantation. However, recent regulatory mandates threaten innovative approaches such as IKT. The potential impact of these mandates cannot be estimated because, outside of journal reports, dissemination of IKT and desensitization remains unknown. Our goal was to better understand the use of IKT in the United States. METHODS AND POPULATION: Surgical directors from all 187 unique active adult kidney transplant programs in the United States were contacted to complete a survey of IKT practices. Respondents answered questions about transplantation across the following antibody barriers: positive Luminex but negative flow cross‐match (PLNF); positive flow but negative cytotoxic crossmatch (PFNC); positive flow and cytotoxic crossmatch (PFPC); and ABO incompatible transplants (ABOi). RESULTS: Responses were received from 125 centers (representing 67% of eligible centers and 84% of the live donor transplant volume in the US in 2008). Barriers of PLNF, PFNC, PFPC, and ABOi are being crossed in 70%, 52%, 18%, and 24% of transplant centers that responded, respectively. Desensitization was performed in 58% of PLNF, 78% of PFNC, 100% of PFPC, and 67% of ABOi. Desensitization modalities included plasmapheresis and low‐dose IVIg (PP/IVIg) in 70‐77% of the responses and high‐dose IVIg in 32‐47% of the responses. SIGNIFICANCE OF STUDY: A higher proportion of transplant centers perform IKT than might be inferred from the literature. Cutoffs for antibody strength and desensitization practices are highly varied. IKT needs to be recognized by regulatory agencies as an important and widely disseminated practice so that further innovation is not hindered.

A‐138

GLYCEMIC STATUS AND ADVERSE OUTCOMES IN PATIENTS WITH CANCER

Hammer MJ ¹, Melkus GD¹  ¹New York University, New York, NY, United States

OBJECTIVES: Infections are a major complication and contributor to the morbidity and mortality associated with malignancies. Evidence is emerging regarding the contribution of glycemic status to infections and related complications among patients with cancer, particularly among hematopoietic cell transplant recipients. The contribution of glycemic status to infections and adverse outcomes in other populations of patients with cancer has not been well established. Glycemic control may contribute to infection prevention in all patients with cancer. The aims of this pilot study are to 1) describe associations between glycemic status and infection rates among patients with various types of cancer and 2) evaluate key contributors to abnormal glycemic status. METHODS AND POPULATION: Preliminary data from a cross‐sectional study design using a convenience sample of individuals aged 18‐75 years old, newly diagnosed with any type of cancer, and receiving care through the New York University Cancer Institute will be presented. Descriptive statistics and logistic regression will be used to determine associations between potential contributors to abnormal glycemic levels and glycemic status, and glycemic status and the outcomes of infection and mortality. RESULTS: This study will describe the contribution of glycemic status to infections and mortality among patients with various malignancies. Findings will also identify key contributors to abnormal glycemic status. SIGNIFICANCE OF STUDY: Understanding the role of glycemic status in patients with cancer and the contributors to abnormal glycemic levels are paramount for future care that can address these issues and potentially lead to more favorable outcomes.

A‐139

LEARNING AND COORDINATION IN INFANTS BORN PRETERM

Heathcock J^1,2  ¹The Ohio State University, Columbus, OH, United States, ²Nationwide Children's Hospital, Columbus, OH, United States

OBJECTIVES: The overall goal of this research project is to compare and contrast the performance of full‐term and preterm infants in a tradition learning paradigm (mobile paradigm) and a novel paradigm (end‐point paradigm) in order to more accurately identify cognitive and/or coordination deficits. METHODS AND POPULATION: 30 infants born at < 32 weeks will participate in this project. Infants will be seen in two experimental conditions that follow operant conditioning procedures of baseline, acquisition, extinction. Mobile Paradigm:Two identical white plastic mobile stands will be attached to the right and left sides of the infants’ home cribs. A white ribbon and a small, soft cuff will be used to tether each infant's right leg to the right stand. During the acquisition period infant kicks result in reinforcement from the moving mobile. End point Paradigm: Infants will be seated in a custom‐made infant seat with a secure strap around their chest. Removable headrests will be used as needed. Small reflective markers will be placed on the infant's limbs. During the acquisition period end point touches result in reinforcement from the moving target. RESULTS: Learning and coordination abilities will be compared to non‐sedation MRIs of the infants’ brain. SIGNIFICANCE OF STUDY: The results of preterm birth are devastating as these infants are at high‐risk for cerebral palsy, coordination disorders, learning and behavioral disabilities. This project pairs early learning differences in the mobile paradigm with non‐sedation MRI's of the preterm infant brain to more fully understand brain‐learning relationships in young preterm infants. Similarly, this project pairs early coordination differences of the legs with non‐sedation MRI's of the preterm infant brain to more fully understand brain‐coordination relationships in young preterm infants.

A‐140

NUTRITION & PHYSICAL EDUCATION IN THE SUMMER MIGRANT CLASSROOM (MEP)

Kilanowski JF ¹   ¹Case Western Reserve University, Cleveland, OH, United States

OBJECTIVES: The aims of this pilot study were to test effectiveness of a supplemental curriculum intervention in nutrition and physical education in a summer Midwest MEP with the children of migrant farmworkers (MFWs), and to evaluate the study feasibility.Outcomes were: changes in body mass index (BMI), BMI percentile, weight, and knowledge.We hypothesize that students assigned to the intervention group will show greater improvement in outcomes in contrast to the comparison site. METHODS AND POPULATION: Two summer MEPs that support MFW children in remedial education were study sites: intervention group n = 138, comparison group n = 33.Students had 4 interventions a week (2 of each) and structured recess.Curriculum was ethnically‐tailored with subject oriented, Latino themed children's trade books, cooking classes and a field day. RESULTS: Bivariate analysis showed that more MEP days attended, the larger change in wt (r = .24, p = .03, n = 78), and larger change in BMI (r = .27, p = .01, n = 78); the means of change in BMI and change in BMI % were negative(n = 110).The intervention site had marginal significance with change in BMI (Kendall Tau's, r = ‐0.16, p = 0.07, n = 110).In the nonparametric Wilcoxon 2 sample test, the intervention site was significant for change in wt (p = .05) with the comparison group being heavier in wt. When looking at change in BMI, the intervention group had a greater than 4‐fold decrease in change in BMI (‐.14 vs. ‐.03) with marginal significant (Wilcoxon 2 sample test, p = .06, n = 110).In‐creases in age‐appropriate knowledge scores from baseline to intervention conclusion were seen in 2 assessments by 70% (n = 47) and 63% (n = 46) of the students. SIGNIFICANCE OF STUDY: Summer MEPs can provide opportunities to instruct MFW children on healthy eating and activity with positive results.

A‐141

RACIAL DIFFERENCES IN LIPOPROTEIN‐ASSOCIATED PHOSPHOLIPASE A2

Lee KK ¹, Fair JM¹, Varady A¹, Go AS², Hlatky MA¹, Quertermous T¹, Fortmann SP¹, Iribarren C²  ¹Stanford University School of Medicine, Stanford, CA, United States, ²Kaiser Permanente of Northern California, Oakland, CA, United States

OBJECTIVES: Lipoprotein‐associated phospholipase A2 (Lp‐PLA2), a predictor of cardiovascular events, has been shown to vary with race. We examined the etiology of this racial variation. METHODS AND POPULATION: We measured Lp‐PLA2 mass and activity in 714 healthy adults with no clinical coronary heart disease and not taking dyslipidemia medication. We evaluated racial variation in Lp‐PLA2 levels by adjusting for a number of covariates using multivariable linear regression. Biological covariates included: age, sex, diabetes, hypertension, body mass index, and lipid measurements, while the lifestyle covariates were smoking status, physical activity and dietary data. Genetic covariates were three single nucleotide polymorphisms shown to be associated with Lp‐PLA2 levels. RESULTS: The mean age was 66 years. Whites had the highest Lp‐PLA2 levels, followed by Hispanics and Asians, and then African‐Americans. In age and sex adjusted analyses, race was associated with Lp‐PLA2 mass and activity levels (p < 0.0001). African‐Americans were predicted to have a 55.0 ng/ml lower Lp‐PLA2 mass and 24.7 nmol/ml‐min lower activity compared to Whites (p < 0.0001). After adjusting for all the covariates, both the relationship between race and Lp‐PLA2 levels (p < 0.0001) and the differences between African‐Americans and Whites remained significant (44.8 ng/ml lower Lp‐PLA2 mass and 17.3 nmol/ml‐min lower activity, p < 0.0001). SIGNIFICANCE OF STUDY: Select biological, lifestyle, and genetic factors did not explain racial variations in Lp‐PLA2 levels in this study, suggesting that Lp‐PLA2 levels may need to be interpreted differently for various races.

A‐142

EFFECTS OF INTENSIFYING GLYCEMIC CONTROL IN FRAIL ELDERS

Lee SJ ^1,2, Cenzer IS², Boscardin J², Eng C³  ¹San Francisco VAMC, San Francisco, CA, United States, ²UCSF, San Francisco, CA, United States, ³On Lok Lifeways, San Francisco, CA, United States

OBJECTIVES: The 2003 Diabetes Guideline from the American Geriatrics Society (AGS) recommended an A1c<8 for frail elders. The effects of implementing this guideline are unknown. METHODS AND POPULATION: We examined A1c values, diabetic medications and rates of hypo‐ and hyperglycemia in diabetic enrollees of On Lok Lifeways, the original model for Programs of All‐Inclusive Care for the Elderly (PACE). In 2005, On Lok launched an intervention to encourage clinicians to intensify glucose control to A1c<8. We compared 262 diabetic subjects before the intervention (10/02–12/04) with 297 diabetic subjects after the intervention (7/06–12/08). We abstracted A1c values, medications and blood sugar (BS) values, categorizing BS<50 as hypoglycemia and BS>400 as hyperglycemia. Bootstrap methods and poisson regression were used to determine whether the before and after groups differed. RESULTS: Before and after cohorts were similar with similar mean age, ethnicity and function (all p>0.3). A1c levels were lower after the intervention with 72% achieving A1c<8 before the intervention compared to 84% afterward (p<0.001) and 48% achieving A1c<7 before the intervention compared to 60% afterward (p<0.001). Diabetic medication use increased with more patients using metformin (29% to 42%, p<0.001), thiazolidinediones (7% to 17%, p<0.001) and insulin (24% to 37%, p<0.001). Episodes of hyperglycemia (per quarter per 1000 patients) decreased dramatically (446 to 131, p<0.001), but episodes of hypoglycemia were unchanged (29 to 34, p=0.43). SIGNIFICANCE OF STUDY: Implementing the AGS Diabetes Guideline to nursing home eligible diabetic elders receiving PACE services led to lower A1c values, more diabetic medication use and fewer hyperglycemic episodes with no change in hypoglycemic episodes.

A‐143   SOCIO‐DEMOGRAPHIC VARIATION IN HOSPITAL LENGTH OF STAY AND CLINICAL OUTOME IN PATIENTS HOSPITALIZED WITH ACUTE CORONARY SYNDROME

Lee T ¹, Shaheen MA¹, Asuncion M¹, Ganesan K¹, Pan D¹  ¹Charles Drew University, Los Angeles, CA, United States

OBJECTIVES: To assess the variation in hospital admission, hospital length of stay & inhospital mortality due to Acute Coronary Syndrome (ACS) by demographics and overtime. METHODS AND POPULATION: We analyzed data from the California Hospital Discharge Data. Eligibility included adult patients who were hospitalized with principle diagnosis of acute coronary syndrome (ICD code 410 and 411) during 1991‐2000. Data were analyzed for admission, hospital length of stay, and in‐hospital mortality by demographics and health insurance status. RESULTS: The study included 923,386 admissions for ACS. The ACS percent hospitalization varied by year, gender, age group, race/ethnicity, and insurance status (p=0.0001). Although there was an overall reduction in the admission from 13% in 1991 to 8.3% in 2000, it was increased for older patients, Black, Hispanics, and Asian/other. The length of stay was = >7 days for 23% (median = 4 days) and it decreased overtime with 31% reduction in the percent who stayed = >7 days. Older patients, female, Hispanic, Asian/other, with Medicare/Medical insurance had higher adjusted odds to stay longer and to have higher mortality than other groups (p<0.05). There was an increase in the overall mortality over time. SIGNIFICANCE OF STUDY: There was a reduction in hospitalization and length of stay over time but an increase in mortality. ACS’ admission and mortality increased overtime and in older age and minority groups. Differential use of procedures may contribute to the poor outcome observed among older age group and minority population with ACS.

A‐144

REPRESENTATION OF OLDER ADULTS, WOMEN, AND ETHNIC MINORITIES IN PUBLISHED RANDOMIZED TRIALS OF DRUG THERAPY FOR TYPE 2 DIABETES

Lee K ¹, Bailey D¹, Diaz A¹, Bero L¹  ¹UCSF, San Francisco, CA, United States

OBJECTIVES: Historically, older adults, women and minorities have been underrepresented in clinical trials. This poses a challenge for evidence‐based practice as medicines may not have the same safety, efficacy or effectiveness in older adults, women, or certain ethnic groups. We determined the proportion of older adults, women and ethnic minorities in published clinical trials of drug therapy for the treatment of type 2 diabetes and how this enrollment compares with disease prevalence in the United States. METHODS AND POPULATION: Literature review of randomized trials (RCTs) in PubMed evaluating hypoglycemic agents for the treatment of type 2 diabetes (DM2) from 2003 to 2007. Unpublished and non‐English language reports were excluded. Data on year of publication, funding, trial location, sample size, intervention, inclusion and exclusion criteria, demographics and characteristics of the study sample, and primary outcome measured were extracted by two independent reviewers. Proportions of older adults, women, and ethnic groups enrolled in the trials were compared to the prevalence of DM2 in the United States. RESULTS: Participants in 527 RCTs of drug therapy for DM2 differ from patients with DM2 in the U.S. population. Older adults, Blacks, Hispanics, Asians and American Indian/Alaskan Natives are less likely to be enrolled in RCTs. Demographic characteristics of trial participants and outcomes stratified by age, gender or ethnicity were often poorly reported or not reported at all. SIGNIFICANCE OF STUDY: Older adults and ethnic minorities are frequently underrepresented in RCTs evaluating drug therapies for DM2. Adequate representation of these populations relative to their disease prevalence is necessary to provide a better evidence‐base for the treatment of DM2 and promote health equity among these high risk populations.

A‐145

TEMPORAL RELATIONSHIP BETWEEN STRESS AND SYMPTOMS IN PATIENTS WITH CROHN'S DISEASE (CD) UNDERGOING REMICADE TREATMENT

Litcher‐Kelly L ¹, Stone AA¹, Hanauer SB²  ¹Stony Brook University, Stony Brook, NY, United States, ²University of Chicago, Chicago, IL, United States

OBJECTIVES: Literature on the temporal relationship between stress and symptoms in CD has reported equivocal results, however interest in this topic remains because of animal studies and anecdotal reports from physicians and patients. The primary hypothesis is daily reports of stress and symptoms are correlated. The secondary and exploratory goal of this study is to examine the temporal relationships using 3 lagged models: 1)morning stress predicts afternoon symptoms, 2)previous day's stress predicts next day's symptoms, 3)previous week's stress predicts next week's symptoms. METHODS AND POPULATION: Adults with CD undergoing Remicade treatments were enrolled (n = 20) to examine the relationship between stress and symptoms within a day and over several days/weeks. Participants were trained to use an electronic diary to complete 6 assessments per day from their initial Remicade treatment until their next treatment approximately 8 weeks later. Stress was measured using the 4‐item perceived stress scale; symptoms using the 3 self‐report measures from the Crohn's Disease Activity Index: abdominal pain, well‐being, and loose/very liquid stools. RESULTS: Using multilevel modeling to analyze the nested data, we found a modest, but significant overall correlation between daily stress and symptoms (r=.38, p=.05). There was also a trend for a lagged relationship between morning stress and afternoon symptoms, controlling for morning symptoms (F(1,19)=3.88, p=.06). Surprisingly the other lagged models were not significant. SIGNIFICANCE OF STUDY: These findings add to our understanding of the complex relationship between stress and symptoms in CD. By understanding this relationship perhaps individuals can better plan for stressful times to avoid increases in symptoms.

A‐146

DO RADIATION USE DISPARITIES INFLUENCE SURVIVAL OF PATIENTS WITH ADVANCED BREAST CANCER?

Martinez SR ¹, Beal SH¹, Chen SL¹, Canter RJ¹, Khatri VP¹, Chen AM¹, Bold RJ¹  ¹University of California, Davis, Sacramento, CA, United States

OBJECTIVES: We previously identified racial/ethnic disparities in the use of radiation therapy (RT) in patients with advanced breast cancer (BCa). We hypothesized that racial/ethnic disparities in the use of RT is associated with overall survival (OS) differences favoring white patients compared to their black and Hispanic counterparts. METHODS AND POPULATION: The Surveillance Epidemiology and End Results (SEER) database was used to identify all white, black, Hispanic, and Asian patients with BCa associated with ≥ 10 metastatic lymph nodes diagnosed from 1988 to 2005. Multivariate analysis assessed age, sex, race, tumor size, histology, estrogen receptor (ER) status, progesterone receptor (PR) status, RT, and type of surgery. We further stratified for use of RT (yes vs. no) and type of surgery (mastectomy vs. lumpectomy). Risk of mortality was reported as hazard ratios (HR) with 95% confidence intervals (CI). Significance was set at p ≤ 0.05. RESULTS: Of 15,895 advanced BCa patients identified in the registry, 12,653 met entry criteria. On multivariate analysis, RT was associated with a decreased risk (HR 0.78, CI 0.74‐0.83, p<0.001) and black race an increased risk (HR 1.54, CI 1.42‐1.68, p<0.001) of mortality. After stratifying by type of surgery and use of RT, blacks demonstrated poorer survival than their white counterparts, regardless of surgery type or receipt of RT. SIGNIFICANCE OF STUDY: Although both black and Hispanic patients receive less RT than their white counterparts, only black patients have poorer OS relative to whites. When stratified by type of surgery and use of RT, blacks continued to demonstrate worse survival relative to whites. This OS disparity is thus unlikely to be due to lack of RT.

A‐147

CIRCLE OF SECURITY©, INDIVIDUAL PROTOCOL: AN INTERVENTION FOR THE INTERGENERATIONAL TRANSMISSION OF PSYCHOPATHOLOGY

Morcuende MA ¹, Troutman B¹  ¹University of Iowa Carver College of Medicine, Iowa City, IA, United States

OBJECTIVES: Millions of women experiencing emotional, physical, or sexual violence have a history of multiple traumas that lead to complex psychological difficulties affecting parenting. Importantly, maternal cumulative trauma is correlated with child attachment disorganization, which, in turn, is associated with child psychopathology. Current parent‐child interventions do not show benefit for a significant number of children, and little is known about their effect on maternal mental health. The Circle of Security^© (COS) is an intervention for high‐risk caregivers and their children showing remarkable response rates in preliminary studies used as group therapy. We hypothesize that highly ambivalent or resistant caregivers benefit from an individual approach. The aims of the study are to develop a standardized manual for the individual use of COS and an evaluation protocol. METHODS AND POPULATION: Adult mothers (n = 8) with cumulative trauma and a child age 18‐60 months will be recruited from the community. Maternal trauma history and psychiatric symptoms will be evaluated using standardized tests. Severe maternal psychiatric symptoms will be exclusion criteria. Participants will undergo weekly COS sessions, and a protocol manual will be created in collaboration with the developers of COS. RESULTS: Outcomes pre‐ and post‐ intervention will include maternal Post Traumatic Stress Disorder, depressive symptoms, and emotional regulation capacities. The Strange Situation Procedure will evaluate the parent‐child attachment. SIGNIFICANCE OF STUDY: The individual COS manual and evaluation protocol will be used for the first randomized clinical trial comparing COS‐individual protocol with a standard‐of‐care intervention and measuring effects on the child and on complex maternal psychopathology related to cumulative trauma.

A‐148

QUALITY OF ANTICOAGULATION MANAGEMENT IN PHARMACIST VS NURSE MANAGED MODELS OF CARE

Nutescu E ¹, Bautista A¹, Gao W¹, Stamos T¹, Galanter W¹, Bauman J¹  ¹Univ of Illinois Chicago, Chicago, IL, United States

OBJECTIVES: To evaluate the quality of oral anticoagulation management in 2 models of care: a pharmacist managed antithrombosis clinic (PMATC) and a nurse managed anticoagulation clinic (NMAC). METHODS AND POPULATION: Retrospective, randomized observational cohort study conducted at 2 university based clinics. RESULTS: Two hundred patients, 100 in each group, contributed 179.3 and 206.8 patient‐years of therapy for the PMATC and NMAC respectively (p<0.0001). The PMATC group reached goal INR faster then the NMAC group. (median of 9 days vs 22 days respectively; p=0.0003). The mean % of patients with INR within the therapeutic range (TTR) was 65.8% in the PMATC group and 71.2% in the NMAC group (p=0.009). The percent of patients who developed thromboembolic events and major bleeding were similar in the PMATC and NMAC groups (1.2% vs 0.5% per patient‐year of therapy, respectively; RR 2.40; 95% CI 0.096 to 4.26; and 4.7% vs. 4.9% per patient‐year of therapy, respectively; RR 0.96; 95% CI, 0.28 to 3.30). Hospital admissions and emergency department visits due to non‐therapeutic INRs were higher in the NMAC group compared to the PMATC group (9.2% vs 0.6% per patient‐year of therapy, respectively; RR 0.06; 95% CI 0.004 to 0.79; and 1.5% vs 0 per patient‐year of therapy, respectively.) SIGNIFICANCE OF STUDY: The PMATC model had better outcomes in attaining a faster therapeutic INR after initiating warfarin therapy and also demonstrated more judicious resource utilization by lower hospitalization rates and emergency room visits due to non‐therapeutic INRs. Although the TTR was lower in the PMATC group, the 2 groups faired similarly with regards to clinical outcomes such as recurrent thromboembolism and major bleeding.

A‐149

AFRICAN‐AMERICAN RACE IS PROTECTIVE FROM POSTOPERATIVE ATRIAL FIBRILLATION AFTER CARDIAC SURGERY

Rader F ¹, Blackstone E²  ¹MetroHealth Medical Center, Cleveland, OH, United States, ²Cleveland Clinic, Cleveland, OH, United States

OBJECTIVES: To investigate the association of African‐American race with postoperative atrial fibrillation (AF) after cardiac surgery. METHODS AND POPULATION: Out of 13,262 patients who underwent coronary artery bypass and/or valve surgery between 1997‐2003, 679 (5.1%) patients were African‐American. To adjust for confounding patient characteristics, we propensity score matched African‐American patients with non‐African‐American patients. RESULTS: 4,554 (36%) of 12,583 non‐African‐American patients and 154 (23%) of 679 African‐American patients developed postoperative AF (p <0.0001). African‐American patients were younger, had higher prevalence of hypertension, congestive heart failure, higher body mass index and preoperative creatinine levels, smaller left atrial volume and lower left ventricular ejection fraction. Procedural differences were less aortic valve replacements and mitral valve repairs and more mitral valve replacements in African‐American patients. In 620 propensity‐matched patient pairs standardized differences of these confounding variables were well balanced. Propensity‐adjusted analyses showed that African‐American patients had markedly lower occurrence of postoperative AF (OR 0.58, 95% CI 0.45‐0.75). A sensitivity analysis showed that a hidden confounder had to change the odds of African‐American patients developing postoperative AF by 0.45 to explain our results alternatively. SIGNIFICANCE OF STUDY: In this propensity‐matched study, African‐Americans had a markedly lower occurrence of postoperative atrial fibrillation, despite a high prevalence of risk factors for atrial arrhythmias. Although clinical confounders cannot be entirely excluded, our results suggest that genetic factors play a role in the development of atrial fibrillation after cardiac surgery.

A‐150

ASSOCIATION BETWEEN LOPINAVIR/RITONAVIR EXPOSURE AND FASTING LIPIDS IN HIV‐INFECTED CHIDLREN

Rakhmanina N ¹, Van Den Anker J¹, Scott M², Neely M³  ¹Children's National Medical Center, The George Washington University, Washington, DC, United States, ²Loyola University Chicago, Chicago, IL, United States, ³University of Southern California, Los Angeles, CA, United States

OBJECTIVES: The study was aimed to evaluate the relationship between the exposure to Lopinavir/Ritonavir (LPV/RTV) and the fasting lipid profiles in children. METHODS AND POPULATION: Prospective 52 weeks data were collected from HIV‐infected children (4‐17yrs) receiving LPV/RTV. The area under the concentration‐time curves (AUCs) were estimated for LPV/RTV using non‐parametric population models. Total cholesterol (TC), including LDL and HDL fractions, and triglycerides (TG) were measured after overnight fasting. Lipids were classified according to the National Cholesterol Education Program (NCEP). Mul‐tivariate linear regression models were used to estimate associations between plasma lipids or NCEP category and LPV/RTV AUCs, with inclusion of LPV/RTV therapy duration, body mass index (BMI), age, sex, or HIV RNA <400 copies/mL as covariates if they changed the primary association by >20%. RESULTS: 52 children were enrolled (median age 11.6 yrs). The majority of patients had a healthy weight (75%) with 9.6% overweight and 7.7% obese children. Abnormal NCEP category was seen in 19% (10) for TC, 27% (14) for HDL, 16% (8) for LDL and 45% (23) for TG. No association was found between NCEP category and LPV or RTV AUC, nor was any association found between lipids and LPV AUC. In contrast for every increase in RTV AUC of 10 mg*h/L, when adjusted for age and duration of LPV/RTV therapy, there was a mean TC rise of 21 mg/dL (P=0.04) and HDL rise of 8 mg/dL (P=0.006). SIGNIFICANCE OF STUDY: RTV, but not LPV, AUC was significantly associated with elevated TC in HIV‐infected children, largely driven by RTV‐associated increases in HDL. Further studies on RTV associated lipid abnormalities in children are warranted.

A‐151

INFLUENCING FACTORS FOR APPENDICEAL PERFORATION IN PUERTO RICAN CHILDREN

Ramos Irizarry C ¹   ¹University of Puerto Rico Medical Sciences Campus, San Juan, United States

OBJECTIVES: The Department of Health in Puerto Rico does not have any information on appendicitis and ruptured rates since 1996. Preliminary data from a single institution in Puerto Rico for the year 2008 showed an alarming perforation rate of 57% in children ages 2‐20 yrs. This pilot study inquires on factors influencing perforation of the appendix in this population. METHODS AND POPULATION: IRB‐approved retrospective review of the medical records of patients ages 2‐20 yrs from 2002‐2008 with appendicitis cared at a single institution. Patient demographics, body mass index for age and gender percentiles, laboratory values, imaging studies, time of onset of symptoms, time to diagnosis, time to surgery, appendiceal histology, and outcomes were recorded. RESULTS: Forty two medical records were reviewed. Mean age was 10 years (11F/31M). Perforation rate was 57%, with 73% of these patients being females. Bi‐variate analysis (Mann‐Whitney U test) showed no differences between groups in age, gender, body mass index for age and gender %, type and number of imaging studies, number of physicians examiners prior to diagnosis, time to diagnosis after arrival to hospital and time to surgery. The patients who presented with appendiceal perforation had a median onset of symptoms prior to arrival to hospital of 2.5 days versus patients with no perforation, who had a median onset of symptoms of 1 day (p=0.014). One hundred percent of the patients with government insurance (Reforma) presented with perforation of the appendix (p=0.071). SIGNIFICANCE OF STUDY: Perforation of the appendix in Puerto Rican children ages 2‐20 years could be influenced by a protracted period of symptoms and delays in seeking medical care. Further studies are being done with a larger sample size among two institutions caring for children in the Island.

A‐152

TIMELINESS OF SYMPTOM REPORTING IN HEART FAILURE

Reeder KM ¹, Smith CE¹  ¹University of Kansas, Kansas City, KS, United States

OBJECTIVES: People living with HF face many challenges. Armed with the instructions provided upon hospital discharge, patients must self‐manage their symptoms until their scheduled follow‐up appointment weeks later. Because patients are often discharged from the hospital with unresolved symptoms, the risk for re‐admission is high. While early recognition and reporting of HF symptoms can potentially prevent hospitalizations, the effect of these self‐management strategies remains largely unexplored. The purpose of this sub‐study of a randomized clinical trial testing the use of group appointments on HF self‐management outcomes was to examine how patients identify, evaluate, and report HF symptoms. METHODS AND POPULATION: Telephone interviews were conducted with 24 participants following a hospitalization. Semi‐structured questionnaires focused on patient perceptions of HF symptoms experienced prior to hospitalization and treatment‐seeking behavior. RESULTS: Dyspnea, edema, and fatigue were the most frequently reported symptoms experienced by patients prior to seeking treatment. While half of the patients did not report symptoms to their doctor before hospitalization, 6(25%) patients reported symptoms from 1 day to more than 2 weeks before hospi‐talization and another 6(25%) reported symptoms the same day they were hospitalized. Only 12(50%) patients recalled triggers for their HF symptoms; 5(21%) identified changes in their daily routine or self‐management regime as contributing factors. Eighteen (75%) patients engaged in activities to relieve symptoms. SIGNIFICANCE OF STUDY: Despite the use of self‐management interventions, early symptom recognition and symptom reporting patterns remain problematic. These pilot findings indicate the need to better understand how patient perceptions influence HF self‐management.

A‐153

CARDIAC AUTONOMIC FUNCTION ASSOCIATED WITH TREATMENT ADHERENCE AFTER A BRIEF INTERVENTION IN CHRONIC PAIN

Schmidt JE ¹, Joyner MJ¹, Farmer ME¹, Tonyan H¹, Reid K¹, Hooten WM¹  ¹Mayo Clinic, Rochester, MN, United States

OBJECTIVES: Multidisciplinary approaches to pain management often include training in diaphragmatic breathing. However, there is a paucity of evidence regarding physiological changes associated with use of diaphragmatic breathing. The objective of this study was to determine if training in a brief breathing technique was associated with changes in pain symptoms and cardiac autonomic function. METHODS AND POPULATION: Study participants were fibromyalgia(n = 14) or masticatory myofascial pain(n = 8) patients. Participants completed a laboratory assessment and breathing training session. Participants were instructed to practice daily, returning after two‐weeks. Palm Pilots were used to assess symptoms and breathing practice during the two‐weeks between lab visits. Patients were divided into two groups based on change in resting RMSSD and sequential baroreflex sensitivity (BRS) between lab assessments. RESULTS: Change in RMSSD and BRS were significantly different between the two groups (ps<.05). Palm data showed that improvers reported significant reductions in pain severity and fatigue and increase in sleep quality during the second week of monitoring (p<.05). The improvers also practiced the breathing significantly more (p<.01). SIGNIFICANCE OF STUDY: These data show that consistent and longer practice resulted in significant improvements in self‐reported pain symptoms and cardiac autonomic characteristics, suggesting a dose‐response relationship. The behavioral and physiological changes here suggest an increase in self‐regulatory capacity for these patients. Further, the use of electronic diaries for intervention monitoring appears to provide clinically useful adherence information.

A‐154

A MEASURE OF ACCULTURATION IN LATINA OBSTETRICAL PATIENTS IN A NEW GROWTH COMMUNITY

Torrente S ¹, Whitty JE¹  ¹Meharry Medical College, Nashville, TN, United States

OBJECTIVES: To measure the acculturation level in Latina patients in a new growth southern urban city and determine any association of acculturation on dietary intake and obstetrical outcomes, in particular gestational diabetes. METHODS AND POPULATION: We used an observational, prospective design, with 111 self‐identified pregnant Latinas. The acculturation rating scale for Mexican Americans II (5 point Likert scale) measured their acculturation level. A self administered food frequency questionnaire analyzed their food consumption and nutrient data. Obstetrical information was obtained after delivery from the medical records. Statistical analysis was by Mantel Haenzal test, linear regression, student t test, and Pearson correlation. RESULTS: Mean age was 25, and the mean time in the United States was 49 months, with an average acculturation score of ‐1.83. 10 gestational diabetics were identified. Gestational diabetes A1, A2, birth weight, and preeclampsia were not associated with acculturation. The means of Calcium, Niacin, Zinc, Thiamin, Iron, Riboflavin, and vitamin B12 in our population when compared to the dietary reference intake recommendation means were significantly higher (p<0.05) SIGNIFICANCE OF STUDY: In a new growth southern community, we found the Latina population has an extremely low level of acculturation (low acculturation< ‐.07). Our patient population was found to have a higher essential nutrient intake when compared to the recommended dietary reference intake values. There were no significant adverse obstetrical outcomes associated with this group. Larger studies are needed in new growth areas with a broader range of acculturation scores to explore nutritional and obstetrical associations.

A‐155

IMPACT OF CASE‐VOLUME AND QUALITY MEASURES ON MORTALITY FOLLOWING COLECTOMY FOR ULCERATIVE COLITIS

Velayos FS ¹, Maselli J¹, Auerbach A¹, Lindenauer P²  ¹University of California, San Francisco, San Francisco, CA, United States, ²Baystate Medical Center, Springfield, MA, United States

OBJECTIVES: Higher mortality has been recently reported in centers that perform few surgeries for ulcerative colitis. We set out to confirm these findings and to determine if other factors, such as surgeon volume or quality of care influences post‐operative mortality. METHODS AND POPULATION: Retrospective analysis of data from 836 adults with UC undergoing colectomy between 2003 and 2005 at 167 small to mid‐size hospitals across the United States. Hospital and surgeon case volumes and adherence to defined quality measures (beta blockers, prophylactic antibiotics, inappropriate antibiotics, venous thromboembolism protection) were measured. Multivariable hierarchical logistic models estimated associations between volume measures and quality, adjusted for age, urgent admission, comorbidity, and clustering by physician and hospital. RESULTS: Mortality was 7.5% in high (17‐252 annual surgeries), 3.3% in medium (8‐16), and 3.9% in low‐volume hospitals (<8). Mortality was 9.9% with high (12‐24 annual surgeries), <1% medium (5‐11), and 3.7% with low‐volume surgeons (<5). Number of missed quality measures was not associated with increased mortality. Multi‐variable hierarchical logistic models found no association between case‐volume or missed measures and mortality. SIGNIFICANCE OF STUDY: This study does not support an association between case‐volume nor missed quality measures and increased postoperative mortality for UC. Higher‐volume hospitals and surgeons may be taking care of more complex patients and these measures of complexity may be important when comparing mortality across centers; these measures of complexity are missing in our dataset

A‐156

THE IMPACT OF VOCAL FUNCTION EXERCISES ON THE AGING VOICE: PROFILE OF A HISPANIC POPULATION

Villanueva‐Reyes A¹, Stemple J²  ¹University of Puerto Rico, Medical Sciences Campus, School of Health Professions, San Juan, Puerto Rico, ²College of Health Sciences, University of Kentucky, Lexington, KY, United States

OBJECTIVES: Evidence of the deterioration of the voice with age is available in the literature. However there is limited documentation on the effects of therapy on vocal aging. Vocal Function Exercises (VFEs) are a holistic approach to voice therapy as they aim to balance the three major subsystems of voice production: respiration, phonation, and resonance. They have been shown to benefit teachers, singers, and normal adults. However, there are no studies on the effects of VFEs in the elderly Hispanic individual. This study will explore if VFEs enhance the physiologic ranges, improve glottal efficiency, and change self‐perception of the aging voice in an elderly Hispanic population. METHODS AND POPULATION: Thirty male and female volunteers with normal voice between the ages of 65 and 79 years will participate in this study. Vocal quality and personal perception of the voice will be pre‐ and post‐tested. Fifteen individuals will receive voice treatment, using the VFEs (experimental group), during eight weeks. RESULTS: Postest results for control and experimental groups will be compared, and a repeated measures design will be used to determine treatment effects. SIGNIFICANCE OF STUDY: This study will enhance the literature base on such appropriate therapy techniques by determining if VFEs enhance the physiological capabilities of the aging voice of Hispanic individuals.

A‐157

MR IMAGING AND MR SPECTROSCOPIC IMAGING FOR THE DETECTION OF LOCALLY RECURRENT PROSTATE CANCER AFTER RADIATION THERAPY

Westphalen A ¹, Coakley FV¹, McCulloch CE¹, Roach M¹, Kurhanewicz J¹  ¹University of California, San Francisco, San Francisco, CA, United States

OBJECTIVES: To determine if MR spectroscopic imaging improves detection of locally recurrent prostate cancer after definitive external beam radiation therapy (EBRT) when compared to T2‐weighted MR imaging alone. METHODS AND POPULATION: We identified 64 men who had MR imaging and MR spectroscopic imaging between 1999 and 2008 for suspected prostate cancer after EBRT. Two readers reviewed T2‐weighted MR images and MR spectro‐scopic images and rated recurrent tumor as present or absent in the left and right sides of the gland. TRUS‐guided biopsy was used as the standard of reference. We used the generalized estimating equations to estimate the predictive probabilities of MR imaging and combined MR imaging plus MR spectroscopic imaging. The performance of each method was calculated using receiver operating characteristic curve (ROC) analysis. We used cluster resampled boot‐straping to compare the differences between the areas under the ROC curves (AZ) and construct 95% confidence intervals. For all statistical analyses, a probability value of less than 0.05 was considered to indicate a significant outcome. RESULTS: The AZ for the integrated approach (0.79, 95%CI=0.72‐0.87) was higher than that of T2‐weighted MR imaging (0.67; 95%CI=0.60‐0.74%) (p<0.05). Fourteen hemi‐prostates were incorrectly classified as negative by both methods and the diagnosis of recurrent disease was missed in 8 patients. SIGNIFICANCE OF STUDY: The resulting information may help selecting men for whom targeted hemi‐prostate biopsy is appropriate to confirm disease since the most commonly recommended salvage treatments treat the entire gland.

A‐158

IDENTIFYING OPTIMAL DOSAGES OF ANTICOAGULANTS REQUIRING WEIGHT‐BASED CALCULATIONS IN OVER AND UNDERWEIGHT POPULATIONS

Wytiaz NP ¹, Kane‐Gill S¹, Seybert A¹  ¹University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: The primary aim is to determine dosages used for anticoagulants requiring weight‐based dosing in over and underweight populations. The secondary aim is to describe the outcomes associated with dosages of weight‐based dosed anticoagulants used in clinical practice. Outcomes (ADRs and therapeutic inefficacy) will be evaluated so that safe dosing ranges can be developed. METHODS AND POPULATION: New and discontinued anticoagulant orders requiring weight‐based dosing were evaluated daily over a 6‐week period for patients in the CCU. An outcome evaluation was completed for discontinued medication orders to determine the reason for the discontinuation. New drug orders were evaluated to determine if there was an increase in dose due to therapeutic inefficacy. The study results were based on 194 orders for which pertinent drug and patient data were collected. RESULTS: The results showed that dosing did not necessarily increase in proportion to weight classification. Interestingly, underweight patients received higher dosages than normal weight patients. Morbidly obese patients (n = 19 orders) did, however, receive higher dosages of anticoagulants (725 U/hr – 3510 U/kg) than other weight groups (p<0.001). Yet, morbidly obese individuals did not present with any ADRs, though these were seen in normal, overweight, and obese patients. SIGNIFICANCE OF STUDY: This limited sample suggests that the morbidly obese may benefit therapeutically from higher dosing while avoiding the associated risks such as bleeding and elevated aPTT. The next step in this research will be to continue to determine dosing in a real‐world setting with the hopes of providing a foundation for standardized guidelines in this special patient population.

A‐159

EXPLORING THE DYNAMICS OF URBAN NEIGHBORHOOD FACTORS ON CHILDHOOD ASTHMA CARE AND CONTROL

Yonas M ¹, Marsland AL¹, Wenzel SE^{1 1}University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: Almost 6.3 million children have asthma which is the third leading cause for childhood hospitalizations for those under age 15. Racial disparities in childhood asthma persist with African‐American children more likely to be hospitalized for asthma and are four times as likely to die, than whites. Recent research strongly implicates contextual conditions associated with poverty as contributors to mental health and the epidemic of asthma. This study examines the relationship of social and environmental context upon childhood asthma care and control outcomes. METHODS AND POPULATION: Quantitative and qualitative methodologies will be utilized. First, multilevel and trajectory analyses will be used to examine the role of depression and psychological distress upon asthma outcomes using a 12 year longitudinal cohort of urban infants and families with history of allergies or asthma. Second, guided by principles of community‐based participatory research (CBPR), we use concept mapping to identify, characterize and prioritize factors perceived to influence asthma care and control outcomes with young people with asthma (ages 8‐12) and parents/caregivers within a local urban neighborhood. RESULTS: Preliminary data analyses and key lessons learned regarding the formative phase of this community engaged research approach will be discussed. SIGNIFICANCE OF STUDY: Results from each phase of this investigation will be used to inform our understanding of the dynamic relationship between neighborhood context and asthma care and control outcomes. Findings and community‐based relationships cultivated through this research will be utilized to assess, tailor and translate evidence‐based childhood asthma care and control interventions which are community‐based and culturally relevant.

A‐160

DEVELOPING AN AEROBIC EXERCISE PROGRAM FOR COMMUNITY‐DWELLING OLDER ADULTS WITH ALZHEIMER'S DISEASE

Yu F ¹, Donna B¹, Leon A¹, Savik K¹, Dysken M¹, Painter P¹, Wyman J¹  ¹University of Minnesota, Minneapolis, MN, United States

OBJECTIVES: Background: Aerobic exercise has been shown to improve cognition and function in older adults without dementia and reduce psychological and behavioral symptoms in older adults with Alzheimer's disease (AD), the most common form of dementia. However, there are limited data about how to feasibly design and implement an aerobic exercise training program to community‐dwelling older adults with AD. The purposes of this study were to develop a feasible aerobic exercise prescription and training program and to identify potential executive function measures to inform future clinical studies in community‐dwelling older adults with AD. METHODS AND POPULATION: A one‐group repeated‐measures design was used. Submaximal cycle ergometer exercise testing was used to assist exercise eligibility determination and provided the heart rate limits during exercise training. RESULTS: Four men (mean age = 70 years, range 61‐82; 75% Caucasian, 25% Asian; baseline Mini‐Mental State Examination – MMSE scores 7.8, range 2‐12) underwent a two month aerobic exercise program using recumbent stationary cycles. Subjects were able to progress in intensity and duration of cycling from 30 minutes to 48 minutes at moderate intensity (peak HR increased from 94 bpm to 115 bpm) without any adverse events. Subjects were too advanced in AD stages to even understand the instructions for executive function measures. Informant‐reported measures in instrumental and basic activities of daily living could serve as outcome measures. SIGNIFICANCE OF STUDY: It is feasible to engage persons with AD who still live in the community to participate in a non‐home‐based aerobic exercise training program.

TRANSLATIONAL BASIC‐TO‐CLINICAL

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PROGENITOR CELL FUNCITONS DIFFER IN THE NORMAL AND CF AIRWAY

Ahmad S ¹, Ahmad A¹, Nichols DP¹, White CW¹, Reynolds SD¹  ¹National Jewish Health, Denver, CO, United States

OBJECTIVES: We hypothesize that human basal cells of non‐CF and CF airways differ in their mitotic and differentiation potential and that SERCA2 activity regulates these properties. Using purified basal cells and specific subsets of this progenitor cell pool, our specific aims are to use quantitative outcome measures to compare their: 1) mitotic potential, 2) the differentiation potential and 3) SERCA2 enzyme activity. The mechanism of SERCA2 function in progenitor cell activity will be addressed in Aim 4 through knockdown and overexpression of SERCA2. METHODS AND POPULATION: Airway epithelial basal cells were isolated from human tracheobronchial tissues of donor airways using established protocols. Tracheo‐bronchial basal cells, defined by expression of the hemidesmosomal protein (CD151) and tissue factor (TF1), were fractionated using FACS. RESULTS: All basal cells from non‐CF tra‐cheobronchial airways are TF1+. The TF1+ basal cells can be fractionated according to expression of CD151. Proliferation and differentiation of CD151‐ and CD151+ basal cells is in progress. Our next step will be to isolate and evaluate the CD151+/TF+ basal cells of CF airways to determine whether these cells are depleted in this chronic lung disease. SERCA2 expression and calcium signaling will then be evaluated and its impact on the functional properties of airway basal cells of non‐CF and CF subjects determined. SIGNIFICANCE OF STUDY: Demonstration that the functional properties of the CD151+/TF1+ basal cell subset varies in CF will support the conclusion that changes in progenitor cell function contributes to progression of CF disease. These results will serve as the basis for analysis of SERCA2 function in these critical cell types.

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SULFORAPHANE DESTABILIZES THE ANDROGEN RECEPTOR IN PROSTATE CANCER CELLS BY INACTIVATING HDAC6

Gibbs A¹, Schwartzman J¹, DengV¹, Alumkal JJ ¹  ¹Oregon Health & Science University, Portland, OR, United States

OBJECTIVES: High consumption of cruciferous vegetables is associated with reduced prostate cancer risk. Sulforaphane, a constituent of these foods, prevents and induces regression of prostate and other malignancies in pre‐clinical models, but its mechanisms of action are not fully defined. It is clear that the androgen receptor (AR) is the central signaling pathway in prostate cancer, and its inhibition is used to both prevent and treat this disease. However, the effect of sulforaphane on AR function was unknown. METHODS AND POPULATION: Prostate cancer cells were treated with sulforaphane followed by 1) co‐immunoprecipitation studies to assess changes in acetylation of the HSP90 chaperone and its interaction with AR, 2) western blots to assess the effect on AR protein expression, 3) QRTPCR to determine the effect on AR target gene expression, and 4) ChIP to assess the effect on enrichment of AR at its target genes. The effects of overexpression of HDAC6, a HSP90 deacetylase protein, in the setting of sulforaphane treatment, and siRNA to HDAC6 on AR protein levels were also assessed. RESULTS: Sulforaphane treatment increases the acetylation of HSP90, dissociating it from AR, and consequently leads to AR protein degradation, diminished AR target gene expression, and reduced AR enrichment at its target genes. Sulforaphane also depletes cells of HDAC6, and over‐expression of HDAC6 attenuates sulforaphane‐mediated AR protein depletion while small interfering RNA to HDAC6 recapitulates the sulforaphane treatment effects. SIGNIFICANCE OF STUDY: The inactivation by sulforaphane of HDAC6‐mediated HSP90 deacetyla‐tion and consequent attenuation of AR signaling represents a newly‐defined mechanism that may help explain this agent's activity in prostate cancer.

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IDENTIFICATION OF CLINICALLY SIGNIFICANT ANTIGENS IN STEM CELL TRANSPLANT USING GENOMICS

Armistead PM ¹, Liang S², Liu S², Van Bergen C³, Falkenburg F³, Molldrem J²  ¹UNC Chapel Hill, Chapel Hill, NC, United States, ²M.D. Anderson Cancer Center, Houston, TX, United States, ³Leiden Univeristy, Leiden, Netherlands

OBJECTIVES: Much of the graft versus leukemia (GvL) effect following allogeneic stem cell transplant (HSCT) is a result of minor histocompatibility mismatches between donor and patient. Our objective was to develop a genomics based method to efficiently screen >1,000,000 potential minor histocompatibility antigens (mHAgs) in a large patient sample cohort and to prioritize the immunologic evaluation of these antigens based upon patient clinical outcomes. METHODS AND POPULATION: DNA samples from 50 HLA‐A2+ leukemia patients and their matched related donors were genotyped at 13,917 non‐synonymous SNPs using DNA microarrays. The frequency of SNP disparities predicted to yield minor histocompatibility mismatches was correlated with the presence of a clinical immune response (cIR) using Fisher's exact test. RESULTS: Of the 13,917 SNPs, 14 were found to have disparities highly correlated with cIR. Using a cell based assay, 5 peptides associated with these SNPs bound HLA‐A2. Pep‐tide/HLA‐A2 tetramers for all 5 binding peptides were synthesized and tested in post‐transplant patient samples. A distinct population of T cells that bound to HLA‐A2 tetramer loaded with the, TRIM42 derived, peptide T4A (GLYTYWSAGA) was identified in post‐transplant samples from 3 of 4 patients predicted to have a minor histocompatibility mismatch while no tetramer positive lymphocytes were observed in post‐transplant samples in 3 of 3 HLA‐A2+ negative controls. SIGNIFICANCE OF STUDY: This study demonstrates that clinical outcomes can guide genomic studies in the HSCT setting. Future applications of this method should allow the discovery of mHAgs predicted to be the dominant T cell targets for either GvL or GvHD thereby separating these clinical entities.

A‐164

THE INTERFERON SCORE PREDICTS THE COURSE OF INTERSTITIAL LUNG DISEASE IN SYSTEMIC SCLEROSIS

Assassi S ¹, Tan FK¹, McNearney TA², Estrada‐Y‐Martin RM¹, Draeger HT³, Anderson J¹, Arnett FC¹, Mayes MD¹  ¹University of Texas Health Science Center Houston, Houston, TX, United States, ²UTMB, Galveston, TX, United States, ³UTHSC‐SA, San Antonio, TX, United States

OBJECTIVES: We investigated whether the interferon inducible genes (IFNIG) score could predict the rate of decline in forced vital capacity (FVC) among systemic sclerosis (SSc) patients. METHODS AND POPULATION: The whole blood gene expression profile of early SSc patients (disease duration <5 years) was examined utilizing whole genome BeadChips (Il‐lumina). None of the study participants were treated with immunosuppressive agents at the time of blood draw. We calculated a previously described composite score for IFNIG's in all samples. The annual rate of decline in percent predicted FVC was calculated. We examined the correlation of baseline clinical parameters and IFNIG score with an annual rate of decline in FVC. RESULTS: A total of 36 patients had two pulmonary function tests. Only 2 patients were current smokers. There was a time difference of 1.55 ± 0.6 years between the two FVC meas‐urements.There was a trend for association of baseline FVC with the decline in FVC (p=0.054, r = 0.11) whereas the IFNIG score showed a significant negative correlation with the outcome (p=0.011, r= ‐0.42). In the bivariate model of baseline FVC and IFNIG score as independent factors, the IFNIG score retained its significantly negative correlation with the decline in FVC (p=0.027). We are currently examining the changes in IFNIG score over time and are trying to confirm the above mentioned findings in an independent, larger sample. SIGNIFICANCE OF STUDY: The interferon score may be a useful biomarker to predict the progression of interstitial lung disease in patients with SSc.

A‐165

THE UCLA CLINICAL & TRANSLATIONAL SCIENCES INSTITUTE (CTSI) LEADERSHIP IN RESEARCH ORGANIZATIONS DEVELOPMENT PROGRAM: DETERMINING THE COMPETENCIES

Azziz R^5,2, Davidson P¹, Morrison J¹, Salusky I², Wang C^4,2, Norris K^3,2, Braun J²  ¹UCLA School of Public Health, Los Angeles, CA, United States, ²UCLA School of Medicine, Los Angeles, CA, United States, ³Charles Drew University, Los Angeles, CA, United States, ⁴Harbor‐UCLA Medical Center/LA BioMed, Los Angeles, CA, United States, ⁵Cedars‐Sinai Medical Center, Los Angeles, CA, United States

OBJECTIVES: An important challenge for the successful implementation of broad research consortia, such as the NIH‐funded Clinical & Translational Sciences Award (CTSA) initiative, is leadership development. To this end, the UCLA CTSI undertook an innovative study to investigate the competencies required for leading and managing research‐oriented organizations (ROOs). METHODS AND POPULATION: 40 leaders of successful ROOs from a variety of entities were interviewed using an opened ended questionnaire. RESULTS: Preliminary findings indicate that the top Strategic Issues facing ROOs included Financial, Faculty, Regulation, and Infrastructure‐related challenges. The top Leadership Competencies required to successfully lead ROOs (using the National Center for Healthcare Leadership [NCHL] Health Leadership Competency Model [NCHL 2005]) included Financial Skills, Collaboration, Professionalism, and Team Leadership. However, other leadership competencies, not readily classifiable under the NCHL Model, were noted to be important. For senior executives these included Scientific Achievement and Standing (30% of respondents) and Selflessness (20%); for emerging leaders these included Positive Attitude (30%), Work Ethic (20%), and People Skills (20%). SIGNIFICANCE OF STUDY: These data indicate that new competencies may be needed to assess and train leaders of ROOs, beyond those identified by the NCHL Model. These data will help determine the content of leadership development and succession planning within the UCLA CTSI, the CTSA program, and the broader ROO community.

A‐166

METFORMIN AS A NOVEL CHEMOTHERAPEUTIC STRATEGY FOR ENDOMETRIAL CANCER

Bae‐Jump VL ¹, Kaufman D¹, Gehrig PA¹  ¹University of North Carolina, Chapel Hill, NC, United States

OBJECTIVES: (1) To assess the effect of metformin on proliferation, apoptosis and expression of key targets of metformin cell signaling in vitro. (2) To select appropriate combination therapies based on the biology of endometrial cancer in obese and non‐obese women. (3) To determine the effect of metformin on the endometrium of obese and diabetic women with endometrial cancer by comparing each patient's diagnostic endometrial biopsy before treatment with metformin to their post‐treatment hysterectomy specimen. METHODS AND POPULATION: The effects of metformin on cell proliferation, apoptosis and cell signaling will be assessed in human endometrial cancer cells. Gene expression profiling of endometrial cancer tumors derived from obese and non‐obese women will be used to identify potential targets of treatment. From this analysis, targeted therapies will be selected to pair with metformin, and these combinations will undergo preclinical assessment of synergy in vitro. In a pilot clinical study, obese and diabetic women who are to undergo surgical staging for endometrial cancer will undergo short‐term treatment with metformin. Findings from our in vitro studies will be validated in vivo. RESULTS: We find that metformin is a potent inhibitor of cell proliferation in endometrial cancer cell lines, and that this effect is partially mediated through inhibition of the mTOR pathway. In addition, treatment with metformin in combination with paclitaxel resulted in a synergistic anti‐proliferative effect in these cell lines. SIGNIFICANCE OF STUDY: Obesity, diabetes and insulin resistance are strong risk factors for the development and risk of death from endometrial cancer; and thus, metformin may be an innovative pharmaceutical agent for the treatment of this disease.

A‐167

DIFFERENTIAL REGULATION OF TH17 CELL PLASTICITY BY INTERLEUKIN‐23 AND PROSTAGLANDIN E2

Barrie A ¹, KhareA¹, Henkel M¹, Barmada M¹, Duerr R¹, Ray A¹  ¹University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: Interleukin (IL)‐23 and Prostaglandin E2 (PGE2) are believed to exacerbate inflammatory bowel disease (IBD) by enhancing the development and function of IL‐17A expressing T helper (Th17) cells. We sought to understand how IL‐23 and PGE2 modulate human CD161+ Th17 cell plasticity in memory Th cell cultures. METHODS AND POPULATION: Memory Th cells were purified from peripheral blood and then stimulated in the presence of IL‐23, IL‐1p, and/or PGE2. Upon harvest, cell surface marker expression, cytokine expression, and transcription factor expression were determined via flow cytometry Secreted cytokines levels were measured in the culture supernatants via ELISA. RESULTS: We observed that PGE2 decreased the frequency of IL‐17A and ifn‐γ expressing CD161‐ Th cells, thereby enriching the cultures with CD161+ Th cells. PGE2 also increased the frequency of Foxp3+ CD161‐ Th cells. In contrast, IL‐23 had no direct effect on CD161‐ Th cells, however, in synergy with IL‐1p, IL‐23 increased the frequency of CD161+ Th cells that expressed IL‐17A and ifn‐γ. PGE2 decreased ifn‐γ and TNF‐a secretion in culture supernatants, while increasing IL‐17A levels. Interestingly, PGE2 decreased the secretion of another Th17‐associated cytokine, IL‐22. Conversely, IL‐23, in synergy with IL‐1p, showed a trend towards increasing both the secretion of IL‐17A and IL‐22 without significantly altering ifn‐γ and TNF‐a secretion. SIGNIFICANCE OF STUDY: Our results implicate an anti‐inflammatory role for PGE2 in Th17 plasticity that is not shared by IL‐23. Our studies also suggest that Th17‐mediated inflammation in IBD depends on the net response to both PGE2 and IL‐23, which influences the relative proportion of pathogenic and regulatory CD161+ and CD161‐ memory Th cells.

A‐168

THE ROLE OF GENDER ON THE ASSOCIATION OF BNP TO ENDOTHELIAL DEPENDENT AND INDEPENDENT MICROVASCULAR FUNCTION

Best PJ ¹, Chen HH¹, Gulati R¹, Rihal CS¹, Lerman A¹  ¹Mayo Clinic, Rochester, MN, United States

OBJECTIVES: Brain‐type natriuretic peptide (BNP) is a vasodilatory hormone which also decreases smooth muscle and fibroblast proliferation, and sympathetic nervous system activity. Elevated levels may serve as a marker for myocardial ischemia. Coronary microvascular dysfunction may lead to myocardial ischemia and potentially to LV dysfunction mainly in women. The association of BNP with endothelial and microvascular function in patients without congestive heart failure has been debated. Thus, the objective of this study was to determine the association of BNP with endothelial dependent and independent microvascular function and to determine if there are differences in this effect related to gender. METHODS AND POPULATION: Plasma BNP levels were determined in 457 patients (311 women and 146 men) who were underwent endothelial dependent and endothelial independent microvascular function studies in the cardiac catheterization laboratory at St. Mary's Hospital, Rochester, MN. Coronary endothelial‐dependent function was determined using intracoronary acetylcholine (10‐6 to 10‐4 M) and endothelial independent microvascular function was determined using maximal response to intracoronary adenosine. RESULTS: Women had significantly higher levels of BNP compared to men (59.8 ± 5.9 vs 32.1 ± 8.6, p=0.008). BNP was associated with the response to acetylcholine in women (p=0.03), but not in men (p=0.81). BNP was associated with endothelial‐independent microvascular function in response to adenosine in both women (p=0.03) and men (p=0.003). SIGNIFICANCE OF STUDY: Gender affects the association of BNP with endothelial‐dependent microvascular dysfunction. This suggests that BNP‐mediated responses may be of greater importance as a marker for microvascular dysfunction in women.

A‐169

RESEARCH TO PRACTICE: EFFICACY VS EFFECTIVENESS OF A COLORECTAL CANCER SCREENING INTERVENTION

Blumenthal DS ¹, Smith SA¹, McCray G¹, Johnson LL¹  ¹Morehouse School of Medicine, Atlanta, GA, United States

OBJECTIVES: 1. To demonstrate the rapid deployment into practice of an evidence‐based educational intervention to increase colorectal cancer screening among African Americans 2. To evaluate the effectiveness of the intervention in a practice setting METHODS AND POPULATION: In a community intervention trial using community‐based participatory research methods, we demonstrated the efficacy of a small group educational intervention in promoting colorectal cancer screening among African Americans. We then put the intervention into practice through a partnership between the academic research center and the county health department. The intervention was implemented in the county's 15 senior citizen centers as well as in several other sites RESULTS: In the intervention trial, 35% of participants were screened at follow‐up as compared to 17% of controls. In the practice implementation, we were able to reach relatively large numbers of participants quickly. However, at 3‐month follow‐up, only 19% of participants had been screened. SIGNIFICANCE OF STUDY: Implementation in practice required some compromises that may have reduced the effectiveness of the intervention and also hindered follow‐up. The intervention may be less effective in a practice setting than under research conditions. However, these results are preliminary and improved follow‐up may yield more promising outcomes.

A‐170

IMMEDIATE REWARD BIAS IN HUMANS: EFFECTS OF ALCOHOL USE, DOPAMINE, HORMONES, AGE, AND GENDER

Boettiger CA ¹, Smith CT¹  ¹UNC Chapel Hill, Chapel Hill, NC, United States

OBJECTIVES: Addictive disorders are characterized by the tendency to choose Now over Later. Despite the clinical importance of understanding such impulsive behavior, we know little about its biological bases, although we have found that frontal dopamine (DA) regulates Now/Later bias in adults (Boettiger et al., 2007). METHODS AND POPULATION: Here we tested Now/Later bias in adult females in a within subjects design at high and low estrogen levels to manipulate DA. RESULTS: We found a significant effect of cycle day (t₄₅=2.52, p<0.05) in low frontal DA women: impulsiveness decreased during high estrogen. We also found that Now/Later bias is higher in late adolescent (18‐21; n = 27) versus adult females (22‐40; n = 26); t₅₁=2.29, p=0.029). This age effect was also seen in a mixed gender sample (n = 66 late adolescents, n = 45 adults). A factorial ANOVA found significant main effects of gender (F_(1,103)=4.35, p=0.040) and age (F_(1,103)=4.10, p=0.046), with males choosing more impulsively than females and late adolescents choosing more impulsively than adults. We also found a significant three‐way interaction between effects of alcohol use, gender, and age on Now/Later bias (F_(1,103)=6.39, p=0.013). Specifically. among light drinkers (n = 66), adults chose less impulsively than did late adolescents (t₆₄=2.26, p<0.05). In contrast, among heavy drinkers (n = 45), this age‐dependent decrease in Now/Later bias was only seen in females (t₂₁=2.79, p<0.05). Among heavy drinking males we saw a trend toward greater Now/Later bias with age (t₂₀=1.94, p=0.067). Effects were not explained by SES. SIGNIFICANCE OF STUDY: These results have implications for addictions medication development, as late adolescents are an important target of such therapies.

A‐171

MIDLIFE MEMORY DECLINE IS ASSOCIATED WITH CHANGES IN BRAIN WHITE MATTER MICROSTRUCTURE IN LATE‐LIFE

Borghesani P ¹, Aylward E², Schaie W¹, Willis SL¹  ¹University of Washington Medical Center, Seattle, WA, United States, ²Seattle Children's Research Institute, Seattle, WA, United States

OBJECTIVES: How midlife (age 43‐60) cognitive changes are related to late‐life (age > 65) cognition and brain health remains unclear. This study examines if changes in midlife episodic memory (MEM), executive function (EXF) and speed of processing (SPD) are associated with altered white matter (WM) microstructure in late‐life. METHODS AND POPULATION: From the Seattle Longitudinal Study we retrospectively categorized 163 healthy, cognitively normal individuals (age range 53‐87) as having improving, declining, or stable cognitive function over a 14 year period in midlife in three domains: EXF, MEM, and SPD. Cerebral WM microstructure was evaluated at a single time point using diffusion tensor imaging (DTI) and tract based spatial statistics (TBSS, http://www.fmrib.ox.ac.uk) with permutation based general linear models. RESULTS: Age was associated with global changes in WM microstructure as demonstrated by reduced fractional anisotropy (FA) throughout the brain. Current MEM scores, but not EXF or SPD scores, were negatively associated with FA in the frontal/temporal superior longitudinal fasciculus. Midlife MEM decline, but not midlife changes in EXF or SPD, was associated with reduced FA in the anterior corpus callosum in late‐life. SIGNIFICANCE OF STUDY: A decline in midlife MEM scores is predictive of callosal WM microstructure in late‐life while a distinct region, e.g., the superior longitudinal fasciculus, was associated with MEM scores at the time of imaging. This suggests that degeneration of regions whose microstructure is most associated with a cognitive ability may not be responsible for age‐associated changes in that function.

A‐172

TUMOR‐SELECTIVE TARGETING USING MULTIMODAL SILICA NANOPARTICLE PROBES FOR CLINICAL TRANSLATION

Bradbury MS ¹, Penate‐Medina O¹, Benezra M¹, Zanzonico P¹, Schaer D¹, Ow H², Larson S¹, Wiesner U³  ¹Memorial Sloan Kettering Cancer Center, New York, NY, United States, ²Hybrid Silica Technologies, Ithaca, NY, United States, ³Cornell University, Ithaca, NY, United States

OBJECTIVES: To investigate the clinical potential of targeted multimodal (optical‐PET)silica nanoparticles using a well‐established integrin‐expressing human melanoma model METHODS AND POPULATION: Particles were coated with poly(ethylene glycol)or PEGs for attaching radioiodine (I‐124)and peptides(cyclic RGD)to form 124I‐cRGD‐PEG‐dots for optical‐PET imaging. 124I‐PEG‐dots were controls. In vitro receptor binding and molecular specificity assays, in vivo pharmacokinetics, formal toxicity testing, multimodal tumor targeting and lymph node mapping studies were performed. RESULTS: The targeted probe was non‐toxic. High receptor binding affinity and avidity were measured. RGD‐PEG‐dot specificity was found using integrin‐specific antibodies. Statistically significant differences in activities were found for blood, tumor, and major organs at all time points post‐injection (p.i.). Nearly half the injected dose was renally excreted over 24 hrs. The targeted probe was nearly eliminated at 1 week. At the time of maximum tumor uptake, 3x activity increases were seen in tumors vs. controls. Image‐derived tumor‐to‐muscle uptake (%ID/g) ratios for the targeted dots revealed enhanced tumor contrast at later times, while that for the control dots declined. A statistically significant correlation was found between PET‐derived tumor %ID/g values for both 124I‐cRGDY‐PEG‐dots and 124I‐PEG‐dots, and the corresponding ex‐vivo gamma‐counted tumor %ID/g values. SIGNIFICANCE OF STUDY: Targeted silica nanoparticles are the first particle probe that can be said to be clinically translatable as a combined optical‐PET probe on the basis of its favorable properties.

A‐173

MOLECULAR PHENOTYPES IN ASTHMA: STRATEGIES FOR MOLECULAR PROFILING AND PERSONALIZED MEDICINE

Brasier A ¹, Victor S¹, Ju H¹, Busse WW², Bleecher E³, Castro M⁴, Calhoun W¹  ¹University of Texas Medical Branch, Galveston, TX, United States, ²University of Wisconsin, Madison, WI, United States, ³Wake Forest, Winston‐Salem, NC, United States, ⁴Washington University, Saint Louis, MO, United States

OBJECTIVES: An unresolved challenge in personalized medicine is how to detect phenotypes of disease using molecular profiling. In this study, we evaluated methods to identify distinct disease asthma subtypes based on cytokine concentrations measured in bronchoalveolar lavage (BAL). METHODS AND POPULATION: Four largely distinct phenotypes in 1048 subjects enrolled in the US Severe Asthma Program were identified as those having eosinophilic inflammation, neutrophilic inflammation, bronchodilatory response to albuterol or bronchocon‐strictive response to methacholine. We next systematically compared the ability of Classification and Regression Trees (CART), logistic regression and multivariate adaptive regression splines using cytokine measurements in BAL from a subset of 83 individuals to predict these four distinct phenotypes. Models were compared for performance using accuracy and c‐statistic (AUC). RESULTS: Logistic regression and MARS classifiers were more accurate (75‐90% accuracy) and had a greater AUC (0.70‐0.85) for phenotypic prediction than models produced by CART. Analysis of cytokine features that contributed most to prediction accuracy showed that different cytokines were associated with the four distinct phenotypes, including Eotaxin, MIG, IL‐1Ra, IL‐8, and IL‐15. SIGNIFICANCE OF STUDY: How patterns of protein expression can be used to relate to airway disease is not known. These studies inform improved approaches that relate quantitative protein profiles to human phenotypes facilitating clinical studies and specific interventions.

A‐174

DIET SODA AUGMENTS GLP‐1 SECRETION IN HEALTHY YOUTHS AND TYPE 1 DIABETES, BUT NOT TYPE 2 DIABETES

Brown R ¹, Rother KI¹  ¹National Institutes of Health, Bethesda, MD, United States

OBJECTIVES: Sweet‐taste receptors that respond to both caloric sugars and artificial sweeteners are present in GLP‐1 secreting L cells of the gut mucosa as well as in lingual taste buds, and serve as critical mediators of GLP‐1 secretion. In this study, we examined the effect of diet soda on glucose, C‐peptide, and GLP‐1 in youths with and without diabetes. METHODS AND POPULATION: Subjects aged 12‐25y with type 1 diabetes (T1D, n = 9), type 2 diabetes (T2D, n = 10), or healthy volunteers (HV, n = 26) underwent two 75g OGTTs preceded by 8 oz of either caffeine‐free diet soda or mineral water, in randomized order. Each subject served as his/her own control. Area under the curve (AUC) for glucose, C‐peptide and GLP‐1 was calculated using the trapezoidal method; glucose AUC was corrected for fasting glucose. RESULTS: Glucose and C‐peptide AUCs were not significantly different following diet soda vs. mineral water in any group. GLP‐1 AUC (pg/ml/180min) was higher after diet soda versus mineral water in HV (soda 1411 ± 912, water 984 ± 544, p = 0.012) and T1D (soda 3157 ± 1752, water 2205 ± 1036, p = 0.020), but not in T2D (soda 2240 ± 1881, water 2201 ± 1270, p = 0.85). GLP‐1 AUC was significantly higher in T1D and T2D vs. HV after mineral water, and higher in T1D vs. HV after diet soda. SIGNIFICANCE OF STUDY: Ingestion of diet soda prior to a glucose load augmented GLP‐1 secretion in both HV and T1D. Consistent with prior studies, patients with T2D had elevated fasting and glucose‐stimulated GLP‐1, but did not respond to the added stimulus of artificial sweetener. We postulate that the increase in GLP‐1 secretion seen in HV and T1D is mediated via stimulation of sweet‐taste receptors on L‐cells by artificial sweetener. The clinical significance of this increased GLP‐1 secretion, and its absence in young patients with T2D, needs to be determined.

A‐175

PRELIMINARY RESULTS FROM SKELETAL MUSCLE FIBER RESPIRATION IN HIV1+ OLDER MEN

Buford TW ¹, Wohlgemuth SE¹, Joseph AM¹, Marzetti E¹, Leeuwenburgh C¹, Manini TM¹  ¹University of Florida, Gainesville, FL, United States

OBJECTIVES: Antiretroviral therapy has greatly extended life expectancy for patients infected with human immunodeficiency virus (HIV)‐1. Despite these benefits, this therapy is known to have negative consequences including mitochondrial toxicity in skeletal muscle cells. This study is investigating skeletal muscle fiber respiratory function in HIV1+ older (>55 yr) men with well‐controlled, undetectable viral loads and normal CD4 counts. METHODS AND POPULATION: Exclusionary criteria include severe vascular disease, renal disease, congestive heart failure, and other active viral infections. To determine mitochondrial function, biopsy samples were collected from the vastus lateralis. Approximately 5‐10mg of tissue was saponin‐permeabilized and oxygen consumption of the fibers was measured using high‐resolution respirometry (Oroboros Oxygraph 2K). Oxygen consumption data for were analyzed using DatLab software (Oroboros) and data for patients (N=12,60.92+/−4.13yr) were statistically compared to controls (N=3,59.00+/−1.73yr) using the Mann‐Whitney test. RESULTS: Preliminary results indicate that respiration rates of muscle fibers from HIV1+ patients in state 2 (pyruvate+malate; 2.83+/−0.74 pmol/s‐1/mg‐1) and state 3 (pyruvate+malate+ADP; 9.39+/−2.06 pmol/s‐1/mg‐1) were significantly reduced by over 40% compared to controls (4.63+/‐0.50 and 16.40+/−5.15 pmol/s‐1/mg‐1, p<0.005). No significant difference was observed for either state 4 respiration (oligomycin) or the respiratory control ratio (state 3/state 4). SIGNIFICANCE OF STUDY: Although preliminary, these results suggest that respiratory capacity of skeletal muscle fibers is impaired in older HIV1+ patients. Future plans include determining muscle mtDNA copy number and citrate synthase activity to evaluate the effect of mitochondrial number on these results.

A‐176

CATALYZING T1 TRANSLATIONAL RESEARCH THROUGH FOCUSED POSTDOCTORAL FELLOWSHIPS

Burns VA ¹, Sullenger B¹  ¹Duke, Durham, NC, United States

OBJECTIVES: We postulate that the discrepancy between scientific promise and clinical realization for novel therapeutics lies in the translational hurdles inherent to the academic environment. It is our objective to develop a postdoctoral fellowship model that will focus on imparting a broad understanding of the integral components that comprise translational research through team mentorship and hands‐on experiences. METHODS AND POPULATION: It is of critical importance to educate researchers about the translational process and on how and when to access, utilize and interface with available resources to achieve their overall aims. We propose a postdoctoral fellowship model utilizing integrated basic, translational, and clinical training to offer program participants exposure and training on the entire translational process: discovery, development, optimization, manufacturing, preclinical studies, regulatory and ultimately Phase I clinical design. Each program participant would play a key role in the development of a potential therapeutic, gaining training through real world experience while advancing translational research. RESULTS: We anticipate that this postdoctoral training model would not only have an immediate and direct impact on current translational research by offering continuity to the diverse and dynamic team‐based science environment, but it would also cultivate the next generation of translational researchers. SIGNIFICANCE OF STUDY: Despite enormous number of pre‐clinical articles that have been published on the potential utility of novel therapeutic agents, only a fraction have received FDA approval and only a few are in clinical development. The postdoctoral model proposed here provides young investigators with mentored, hands‐on training that will enable the academic researchers of the future to more effectively navigate the translational hurdles.

A‐177

ORAL HYPOGLYCEMICS LOWER ENDOTHELIN‐1 ACTIVITY IN DIABETICS

Campia U ^1,2, Barac A², Matuskey L², Panza J²  ¹Northwestern University, Chicago, IL, United States, ²Washington Hospital Center, Washington, DC, United States

OBJECTIVES: Type 2 diabetic patients have increased vascular activity of the vasoconstrictor endothelin (ET‐1), likely secondary to hyperglycemia and hyperinsulinemia. Whether antidia‐betic treatments affect ET‐1 activity remains unknown. This pilot study tested the hypothesis that oral hypoglycemic drugs reduce vascular ET‐1 activity in type 2 diabetic patients. METHODS AND POPULATION: 34 type 2 diabetics were enrolled. Baseline vascular ET‐1 activity was determined by intra‐arterial infusion of BQ 123 – a blocker of ET‐1 subtype A receptors – and measurements of the local vasculature response with forearm plethysmography; blood was drawn for laboratory studies. Patients were then randomized to either pioglitazone, metformin, or glyburide for 18 weeks. Vascular studies and laboratory tests were repeated at the end of the treatment period. RESULTS: In the whole group, when compared to baseline, fasting glucose at the end of treatment was significantly decreased (‐13%, P=0.05) and insulin sensitivity improved (+4.5%, P=0.02). There was a trend toward a decrease in the vascular response to ET receptor blockade (P=0.129 by 2way ANOVA). Peak (60 min) vasodilation during BQ 123 infusion decreased at the end of treatment, albeit not to a statistically significant level, in the whole group (23+/‐5% vs 38+/‐7%, P=0.09), and in the glyburide (24+/‐6% vs 46+/‐6%, P=0.22), metformin (23+/‐5% vs 32+/‐8%, P=0.53), and pioglitazone (22+/‐3% vs 34+/‐7%, P=0.39) subgroups. SIGNIFICANCE OF STUDY: This pilot investigation suggests that, in type 2 diabetic patients, oral hypoglycemics may reduce vascular ET‐1 activity, thus improving endothe‐lial function. These findings may serve as the basis for larger trials aimed to confirm the beneficial effects of oral hypoglycemic treatments on vascular ET‐1 activity.

A‐178

A HIGH PROTEIN DIET FOR REDUCING INFLAMMATION AND IMPROVING MUSCLE STRENGTH IN TRANSGENIC SICKLE CELL MICE

Capers PL ¹, Hyacinth HI¹, Chappa P², Cue S¹, Archer DR², Hibbert JM¹  ¹Morehouse School of Medicine, Atlanta, GA, United States, ²Emory University School of Medicine, Atlanta, GA, United States

OBJECTIVES: Sickle cell anemia (HbSS) is a blood disorder characterized by production of sickled erythrocytes. Key features of HbSS include vascular injury, hemolysis, and compensatory erythropoiesis. These features trigger inflammation and divert amino acid (AA) sources away from normal functions including tissue deposition for weight gain and muscle strength. It is our hypothesis that sickle cell mice on a high (35%) protein diet will experience improved muscle function and tissue replacement and repair, due to increased dietary L‐arginine availability. METHODS AND POPULATION: We are testing this hypothesis in the Berkley transgenic mouse model of human sickle cell hemoglobin at weaning and prospectively for three months. Experiments using protein expression, AA analysis of plasma, enzyme activity, body composition, and muscle strength are being used to test this hypothesis. RESULTS: Preliminary baseline results show that sickle mice on standard 20% diet for one week after weaning have significantly increased spleen and heart weights (0.77+ 0.25 & 0.19 + 0.01g, mean + SD, respectively, p<0.05) decreased liver (1.06 + 0.10, p=0.029) and body weights (16.06 + 1.78 p=0.021) compared with C57BL6 control mice (0.05 + 0.03, 0.12 + 0.01, 1.30 + 0.14, 20.94 + 1.39 respectively, p<0.05). As expected, muscle strength was 28.8% higher for the C57BL6 compared with the sickle mice (81.58 + 10.75 versus 117.27 + 36.98), but this difference was not significant. SIGNIFICANCE OF STUDY: These results demonstrate that the sickle mice have enlarged organs associated with blood supply, but low total body weight and possibly muscle strength. This model is good for investigating intervention in HbSS due to similar findings of low body mass index and malnutrition seen in children and adults with HbSS.

A‐179

MODELING PULSE GENERATING MECHANISMS USING A BAYESIAN COX PROCESSES

Carlson NE ¹, Grunwald GK¹, Johnson TD²  ¹University of Colorado Denver, Aurora, CO, United States, ²University of Michigan, Ann Arbor, MI, United States

OBJECTIVES: Many hormones are intermittently secreted in boluses, called pulses, rather than continuously over time. Pulsatile release often regulates the entire endocrine system. Thus, researchers are interested in understanding how pulsatile secretion, in particular the pattern of pulse locations, differs between diseased and healthy subjects. Currently the pulse generating process is characterized by the number of pulses per unit time. Using this pulse rate has worked well for identifying differences in pulse generation for many conditions, but doesn't work well for more subtle differences that might exist in complex diseases. Our objective is to develop a new more sophisticated pulse generator model. METHODS AND POPULATION: A new model for pulse generation using a Bayesian Cox cluster process is developed. We integrate this pulse generator model into an existing Bayesian deconvolution model for characterizing pulsatile hormone data, offering a fully integrated approach to characterizing pulsatile secretion. The combined model includes a set of biologically relevant parameters that greatly expands the features of the pulse generator that can be quantified. Examples include exogenous controllers of the pulse generator, and clustering of pulse locations within and across subjects. We develop a Birth‐death Markov chain Monte Carlo estimation algorithm to estimate the number and locations of the pulses along with the parameters defining the pulse generator model. RESULTS: The strengths of this model are exhibited on both simulated data and Cortisol data collected to study the HPA‐axis in depressed and non‐depressed women. SIGNIFICANCE OF STUDY: A Cox cluster model of pulse generation allows for greater understanding of the pathophysiology of endocrine systems.

A‐180

SPECTRAL DOMAIN OPTICAL COHERENCE TOMOGRAPHY IN AN ANIMAL MODEL OF COMPLEX RETINAL DETACHMENT

Cebulla CM ¹, Ruggeri M², Murray TG², Hernandez E², Feuer WJ², Bhattacharya SK², Fischer A³  ¹Ohio State University, Columbus, OH, United States, ²Bascom Palmer Eye Institute, Miami, FL, United States, ³Ohio State University, Columbus, OH, United States

OBJECTIVES: Retinal detachment (RD) is a prevalent cause of visual loss. Severe vision loss occurs in eyes that develop proliferative vitreoretinopathy (PVR), a scarring condition and the leading cause of RD repair failure. Spectral domain optical coherence tomography (SD‐OCT) was used to image retinal detachments in vivo, in a murine model of retinal detachment. METHODS AND POPULATION: IACUC approval was obtained. Subretinal injections of hyaluronic acid (Healon) were delivered to the right eye of eighteen 10‐20 week‐old C57Bl6 mice. Evaluation of the fundus with an operating microscope and fundus photography were performed. In vivo, non‐contact, ultra high resolution SD‐OCT imaging was performed on day 0, day 1‐2, day 5‐6 and day 15‐16 and day 21. The retinal morphology at the edge and in the area of maximal RD was evaluated. Eyes were enucleated for histologic analysis. The extent of the retinal detachment was evaluated by measuring the height of the retinal detachment. The retinal layers, including the photoreceptor layer, were evaluated. RESULTS: Retinal layers appeared indistinct day 1 after RD creation, particularly over areas of maximal detachment. By day 5 and 15 the external limiting membrane was no longer visible and there was increased reflectivity of the photoreceptor layer and undulation of the outer retina in areas of RD on both SD‐OCT and histology. The thickness of the outer nuclear layer and photoreceptor outer segments significantly decreased on day 5 and 15. Pre‐retinal and subretinal scarring was detected at day 21. SIGNIFICANCE OF STUDY: SD‐OCT is a promising technology to follow retinal detachment, PVR, and outer retinal abnormalities in a murine model.

A‐181

THE MURDOCK INTEGRATED DATA REPOSITORY(MIDR):A PLATFORM FOR BIOMARKER RESEARCH

Chakraborty S ¹, Blach C¹, McCourt B¹, Gardner M¹, Tenenbaum JD¹, Nahm M¹, Califf R¹  ¹Duke University, Durham, NC, United States

OBJECTIVES: The MURDOCK Study (Measurement to Understand the Reclassification of Disease Of Cabarrus/Kannapolis) consists of multiple project “horizons.” The objective of Horizon1(H1) is to establish biosignatures to predict disease progression and treatment response. H1 contains 4 different studies of 4 distinct diseases. Along with clinical data, biological assays like genomic, proteomic, metabolomic, and imaging techniques have been performed across these cohorts. We developed the MURDOCK Integrated Data Repository (MIDR), a centralized data warehouse solution to integrate these disparate data types from multiple data sources. METHODS AND POPULATION: Standard software engineering best practices were used to elicit customer requirements and existing data standards. We designed a flexible and scalable architecture based on metadata modelling to facilitate import of arbitrary data configurations. Data elements from the 4 studies were mapped to a single canonical representation. This upfront investment in semi‐automated data integration enables efficient incorporation of additional datasets in the future. RESULTS: The MIDR1.1 comprises data from 3 studies (cardiology, osteoarthritis and obesity) with about 8000 patients. About 50 clinical data elements, categorized into 10 domains, were mapped from 2 or more of the original studies into variables in the MIDR. Preconfigured reports and user‐specified query options are available online. SIGNIFICANCE OF STUDY: Future releases of the MIDR will incorporate high‐throughput molecular and imaging datasets, as well as additional study “horizons,” and will leverage existing technology both within and outside Duke to enhance user‐configured graphical queries.

A‐182

CHARACTERIZATION OF CLONAL B CELLS IN HCV‐ASSOCIATED MIXED CRYOGLOBULINEMIA

Charles ED ^1,2, Marukian S¹, Marks K², Talal A², Jacobson I², Rice CM¹, Dustin LB¹  ¹Rockefeller University, New York, NY, United States, ²Weill Medical College of Cornell University, New York, NY, United States

OBJECTIVES: HCV is associated with the B cell lymphoproliferative disorders mixed cryoglobulinemia (MC) and NHL. HCV+MC+ patients have clonal expansions of rheumatoid factor (RF)‐bearing memory B cells. We propose that HCV drives the expansion of autoimmune B cells that are at risk for malignant transformation. We have found that these RF+ B cells are transcriptionally similar to an anergic, CD21low B cell subset expanded in patients with HIV, H. pylori, and Sjögren Syndrome. We perform immunophenotypic and functional analysis of HCV+MC+ patients’ clonal B cells to assess these cells’ role in vivo. METHODS AND POPULATION: We used the G6 mAb specific for the VH1‐69 gene product to detect volunteers’ RF+ B cells. Immunophenotyping was performed with flow cytometry. 405/485 nm Indo‐1 AM emission was measured after F(ab’)2 α‐IgM stimulation. Naïve and CD21low / CD21high memory G6+ B cells were bulk sorted, cultured with stimuli, and assessed for RF production with ELISPOT and ELISA. RESULTS: HCV+MC+ patients’ clonal B cells were predominantly CD20high, CD11c+, FCRL4+, CD95+, CD21low, IL4Rlow memory B cells. After incubation with α‐CD95, >80% of the VH1‐69+, and <30% of the VH1‐69‐, B cells bound Annexin V. The CD21low memory B cell subset had attenuated cell signaling upon α‐IgM stimulation, suggestive of anergy. Naïve and CD21high, but not CD21low, memory G6+ B cells efficiently differentiated to RF‐secreting cells. SIGNIFICANCE OF STUDY: HCV+MC+ patients’ clonal peripheral B cells have a distinct immunophenotypic profile. The expanded CD21low memory subset is anergic and does not efficiently differentiate into RF‐secreting plasmablasts. The downregulation of CD21, part of the B cell coreceptor, may be a homeostatic mechanism to attenuate the expansion of autoreactive B cells in HCV MC.

A‐183

MDM2 BLOCKADE INHIBITS EARLY RETINAL VASCULAR DEVELOPMENT

Chavala S ¹, Milde T², Claros N², Rafii S², Lee TC³  ¹University of North Carolina, Chapel Hill, NC, United States, ²Weill Medical College Cornell University, New York, NY, United States, ³Childrens Hospital Los Angeles, Los Angeles, CA, United States

OBJECTIVES: To develop a novel approach to the treatment of pathologic ocular neovascu‐larization. Approximately ten percent of patients poorly respond to anti‐VEGF treatments for neovascular age‐related macular degeneration. Ocular anti‐angiogenesis treatments, such as anti‐VEGF antibodies, target specific cytokines, and may leave other important angiogenic factors unaddressed. Here, we use Nutlin‐3, a small molecule antagonist of MDM2, to activate the p53 pathway and non‐specifically target dividing endothelial cells in the post‐mitotic retina. METHODS AND POPULATION: HUVEC cultures were used for endothelial cell proliferation studies and Matrigel capillary tube formation assays. Immunohistochemistry, Western blot, and flow cytometry were performed along with an in vivo neonatal developing retinal vascular model. RESULTS: Nutlin‐3 prevents in vitro endothelial cell proliferation as well as formation of Matrigel capillary tubes. Immunohistochemistry and Western blot confirms an increased expression of p53 in the presence of Nutlin‐3 compared to control. Flow cytometry for apoptosis by annexin V and PI reveals increased co‐staining for Nutlin‐3 treated cells. An in vivo retinal vascular development model demonstrated abrogation of the retinal vasculature in Nutlin‐3 treated mice. Nutlin‐3 treated adult mice did not demonstrate retinal toxicity. SIGNIFICANCE OF STUDY: Nutlin‐3 inhibits in vitro endothelial cell proliferation and in vivo retinal vascular proliferation. Utilizing the p53 pathway may have potential benefit in treating ocular neovascular disorders refractory to current treatments.

A‐184

A NEW STRATEGY TO MINIMIZE ISLET CELL MASS IN TYPE 1 DIABETIC RECIPIENTS: DIANNEXIN IMPROVES EARLY GRAFT FUNCTION IN THE MARGINAL ISLET MASS TRANSPLANTATION MODEL

Cheng EY ¹, Yang H¹, Lagman M¹, Sharma V¹, Leeser D¹, Suthanthiran M¹  ¹Weill Cornell Medical College, New York, NY, United States

OBJECTIVES: Reducing the islet cell mass needed to accomplish normoglycemia in type 1 diabetic recipients is a major unmet challenge. Diannexin, a recombinant homodimer of annexin V, is currently undergoing clinical trials for the prevention of ischemia‐reperfusion injury (IRI) in solid organ transplants. We investigated the hypothesis that Diannexin will prevent IRI and improve early islet graft function. METHODS AND POPULATION: A marginal islet cell mass transplantation model was developed and 300 BALB/c islets were placed under the renal capsule of STZ‐diabetic syngeneic recipients. Diannexin (400μg/kg) was administered to islet cell donors immediately prior to pancreas harvest, added to islet isolation reagents, and infused into recipients at the time of transplantation and repeated daily until day +4. RESULTS: Diannexin therapy decreased the median time needed to achieve normoglycemia from 22 days among untreated controls to 6 days for Diannexin‐treated recipients (P=0.03). mRNA expression levels of Bid, a protein essential for death‐receptor induced apoptosis of islets, was significantly lower in Diannexin‐treated islet grafts harvested 3 days after transplantation, when compared with untreated controls. Although the Diannexin‐treated grafts displayed higher levels of mRNA for interferon‐γ, a proinflammatory cytokine, mRNA levels for the islet‐protective cytokines IL‐10 and IL‐6 were also significantly elevated. SIGNIFICANCE OF STUDY: Our study demonstrates that Diannexin is associated with a prompt return to normoglycemia and improves the early function of marginal mass islet grafts. Our data suggest that Diannexin may represent a novel and clinically useful strategy to reduce the islet mass required for achieving insulin independence in type 1 diabetic recipients.

A‐185

DNA DOUBLE STRANDED BREAK REPAIR PROTEINS IN MELANOMA AND NEVI

Cheung WL ¹, Brown JA¹  ¹University of Arkansas for Medical Sciences, Little Rock, AR, United States

OBJECTIVES: UV (ultraviolet) radiation has been linked to increased risk of skin cancer including melanoma. However, the mechanism of UV radiation in carcinogenesis is still unclear. A viable hypothesis is the accumulation of damaged DNA by way of UV radiation, leading to DNA double stranded breaks (DSB). When the DSB load has reached an irreparable sum, the cells activate the pathway of cell death or apoptosis. We want to determine if the downstream effector of DNA DSB, namely the DNA repair proteins, are recruited/overexpressed in melanoma cells as well. METHODS AND POPULATION: For this study, 15 cases of each of the following lesions have been retrieved from our archives: invasive melanoma, melanoma insitu, dysplastic melanocytic nevi and congenital nevi. Routine immunohistochemical using commercially available antibodies specific for DNA DSB repair pathway H2AX phosphoryla‐tion, MDC1, RAD50, 53BP1, and NBS1 will be employed. RESULTS: Thus far, DNA damage repair proteins such as NBS1 and H2AX phosphorylation are overexpressed in many of the melanoma cells while others are decreased. We are still examining the staining results for the other DNA DSB proteins but anticipate that some of these will be defective. SIGNIFICANCE OF STUDY: This is the first known systematic study to determine whether the DNA damage repair pathway is activated in human melanoma cells. Previous studies showed that histone H2AX phosphorylation, which is associated with DNA DSB, is enhanced in melanoma cells. In the context of these results, determination of whether the initial steps in the DNA damage repair pathway are defective is underway. Our preliminary results suggest that at least one of the DNA damage repair proteins is not localizing to the nucleus; therefore, supporting the idea that the increase in DNA DSB in melanoma may be due to a defective DNA DSB repair protein.

A‐186

LEUKOCYTE COUNT AND MATRIX METALLOPROTEINASE‐2 IN CEREBRAL VASOSPASM FOLLOWING SUBARACHNOID HEMORRHAGE

Chou SH ^1,2, Ning M^2,1, Konigsberg RG¹, Loesch EC², Alpargu G⁴, De Jager P¹, Feske SK¹, Lo EH³  ¹Brigham and Women's Hospital, Boston, MA, United States, ²Massachusetts General Hospital, Boston, MA, United States, ³Massachusetts General Hospital, Boston, MA, United States, ⁴California State University Fullerton, Fullerton, CA, United States

OBJECTIVES: Cerebral vasospasm (VSP) is a leading cause of morbidity and mortality in sub‐arachnoid hemorrhage (SAH). Peripheral leukocytes (WBC) release metalloproteinase‐2 (MMP‐2) which cleave big endothelin‐1 into vasoactive fragments and cause vasoconstriction in vitro. Association between WBC elevation and VSP remains controversial. Presence and time‐trend of MMP‐2 in blood and cerebrospinal fluid (CSF) after SAH has not been studied. We aim to determine the association between VSP the quantity and time‐trend of WBC and MMP‐2 in CSF and blood. METHODS AND POPULATION: In a prospective cohort of 53 SAH subjects, we measured daily WBC, recorded VSP status, and banked CSF and blood samples. In a subset of age‐matched subjects with and without VSP (N=14), we compared serial MMP‐2 measurements in blood and CSF by ELISA. Absolute measurements were compared by t‐test and time‐profile by longitudinal regression. RESULTS: SAH subjects with VSP had higher mean WBC on post SAH days 0‐3, 11, and 12. WBC time‐trend independently correlated with VSP (p=0.005) after adjusting for Hunt‐and‐Hess grade. MMP‐2 was simultaneously present in both blood and CSF. There is a trend towards higher CSF MMP‐2 in subjects with VSP (p=0.20). SIGNIFICANCE OF STUDY: WBC elevation on post‐SAH days 0‐3 and WBC time‐trend correlate with VSP. MMP‐2 is simultaneously present in blood and CSF after SAH and may be elevated in CSF of subjects with VSP. We need a larger sample size and simultaneous measurements of big endothelin‐1 and its fragments to further elucidate the role of WBC and MMP‐2 in VSP.

A‐187

THALAMOCORTICAL AND FRONTOSTRIATAL CIRCUITS IN ATTENTION‐DEFICIT/HYPERACTIVITY DISORDER: A FUNCTIONAL MAGNETIC RESONANCE AND DIFFUSION TENSOR IMAGING STUDY

Clerkin SM ¹, Tang CY¹, Halperin JM¹  ¹Mount Sinai School of Medicine, New York, NY, United States

OBJECTIVES: Attention‐Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder that commonly persists, with varying severity, into early adulthood. An emerging neuroimaging method will be used to test two hypotheses: 1) subcortical brain dysfunction within the noradrenergic system that manifests early in ontogeny and remains relatively static over time contributes to the cause of ADHD; and 2) maturation of the prefrontal cortex (PFC) and its associated neurocircuity is related to the degree of persistence of ADHD symptoms over time. METHODS AND POPULATION: A longitudinal sample of adults who were first diagnosed with ADHD in childhood, and adults who were never diagnosed with ADHD, will be scanned with functional (fMRI) and diffusion tensor (DTI) magnetic resonance imaging. fMRI of cognitive task performance will guide DTI tractography. Fractional Anisotropy (FA) of fibers in two distinct brain systems will be measured: 1) subcortical noradrendergic (NA) fiber tracts, which will provide an indication of non‐cortical dysfunction that might contribute to the cause of ADHD; and 2) fronto‐striatal tracts, the development of which is thought to be associated with the diminution of ADHD symptoms. RESULTS: We expect to find lower FA in NA tracts among all probands compared to controls, but no association between FA in NA tracts and ADHD persistence. Lower FA within fronto‐striatal fiber tracts will be associated with the persistence of ADHD symptoms. SIGNIFICANCE OF STUDY: This study might identify neural markers that can guide the development of treatment regimens to promote healthy development and/or recovery of neural systems implicated in ADHD, and thus alter the highly adverse and impairing trajectory of the disorder.

A‐188

POSTTRAUMATIC GROWTH DURING RECOVERY FROM STEM CELL TRANSPLANTATION

Costanzo ES ¹, Juckett MB¹, Coe CL¹  ¹University of Wisconsin, Madison, WI, United States

OBJECTIVES: The recovery from hematopoietic stem cell transplantation (HSCT) is marked by physical and emotional challenges, but cancer patients who undergo this treatment may also experience psychological growth. We investigated trajectories of growth during the year following HSCT. The extent to which avoidance versus engagement with cancer‐related thoughts and emotions hindered or facilitated growth was also examined. METHODS AND POPULATION: Hematologic cancer patients (N=153) completed self‐report measures of coping and posttraumatic growth prior to transplant and 1, 3, 6, and 12 months post‐transplant. RESULTS: Patients reported increasing levels of growth during the year after HSCT, p<.001, with the most pronounced changes between 1 and 6 months post‐transplant. Engagement coping strategies, including emotional processing, acceptance, and positive reappraisal, were associated with higher levels of posttraumatic growth (all ps <.05). Cognitive avoidance was also associated with higher PTGI scores initially, z=2.32, p=.02, but individuals who were low in avoidance showed marked increases in growth scores while those high in avoidance experienced little change over the year, z=‐2.39, p=.02. In a set of exploratory analyses, we found that patients reporting higher initial levels of growth had a better lymphocyte recovery as indicated by higher lymphocyte counts during the first 6 months post‐transplant, z=2.19, p=.03. SIGNIFICANCE OF STUDY: Results indicate that HSCT recipients experience significant post‐traumatic growth early in the post‐transplant period. Those who engage actively with cancer‐related emotions and thoughts report more growth. Exploratory analyses further suggest that these psychological processes could have implications for the immunological recovery following HSCT.

A‐189

PREDICTING ACUTE CORONARY EVENTS USING GENETIC, PROTEOMIC, AND CLINICAL TESTS; AN INDUSTRY ‐ ACADEMIA COLLABORATION

Cross D ¹, Hoefner D², Hytopoulos E³, Li W³, Phelps B³, Beggs M³, Harrington D³, McCluskey E³, McCarty C¹  ¹Marshfield Clinic Research Foundation, Wausau, WI, United States, ²Marshfield Labs, Marshfield, WI, United States, ³Aviir Inc., Palo Alto, CA, United States

OBJECTIVES: Our aim is to improve Myocardial Infarction prediction tools, through the addition of genetics and serum markers, to identify individuals at high risk for an acute coronary event within 5 years. METHODS AND POPULATION: We employed a case‐cohort design using individuals between the ages of 40 to 80 in the Marshfield Clinic Personalized Medicine Research Project (PMRP) cohort, a CTSA resource. ‘Cases’ experienced an initial non‐fatal Acute Myocardial Infarction (AMI) (n = 164), or unstable angina (UA) (n = 217), up to 5 years after enrollment. ‘Controls’ (n = 1058) were selected from the population. Sera went to Aviir, Inc. for proteomic measurements; a portion went to Marshfield Labs for clinical testing. Geno‐typing was performed previously for 51 alleles. Serum biomarkers, laboratory tests, and geno‐typing were analyzed separately and in combination. RESULTS: Six alleles were associated with AMI/UA and carrying at least 2 high‐risk genotypes increased the chances of incurring an AMI/UA, with an odds ratio (OR) of 1.85 (2.09 for females). The Aviir biomarker panel predicted AMI/UA as well as the Framingham model and may better identify true risk in individuals within the Framingham “moderate risk” category. When combined, genetics and the biomarker panel were both still significant for prediction. We are currently analyzing and incorporating the laboratory test data into the models. SIGNIFICANCE OF STUDY: Accurate prediction of an acute coronary event would be a powerful tool for heart disease assessment and treatment. This translational research demonstrates the ability of genetics, serum biomarkers, and clinical tests to enable personalized medicine.

A‐190

DOUBLE‐DOSE CLOPIDOGREL EFFECT IN INDIVIDUALS WITH HIGH ON‐TREATMENT PLATELET REACTIVITY (HTPR) AND KNOWN, RELEVANT CYP2C19 GENE VARIANTS

Damani S ¹, Colin B², Ornowski L¹, Libiger O¹, Price MJ¹, Topol EJ¹  ¹Scripps Translational Science Institute, La Jolla, CA, United States, ²University of Texas MS, Houston, TX, United States

OBJECTIVES: To determine whether double‐dose (DD) clopidogrel in individuals with HTPR provides incremental platelet inhbition in patients carrying CYP2C19 gene variants. METHODS AND POPULATION: Pts with recent coronary stent placement and HTPR to clopidogrel 75mg [platelet reactivity units (PRU) > 240] were given DD clopidogrel (150mg) with follow‐up PRUs obtained in all pts 7 days after treatment. Genotyping for CYP2C19 slow metabolizer (SM) (*2 through *8), rapid metabolizer (RM) (*17), and normal wt (*1) alleles were performed. A separate registry of pts systematically genotyped for CYP2C19 variants with platelet function assay results for genotype/phenotype correlation will be reported. RESULTS: 21 pts harboring clopidogrel SM alleles and 15 wt carriers with HTPR received clopidogrel 150mg. On‐treatment platelet reactivity improved in both groups (287 to 227 PRU, p=0.001; 285 to 203 PRU, p=1x10‐4). There was no significant intergroup difference in treatment response (p=0.35). The 4 patients homozygous for CYP2C19 loss‐of‐function (LoF) alleles had no significant change in platelet reactivity with higher dosing (267 to 246 PRU, p=0.12). There was a strong trend toward reduced reactivity in the 6 clopidogrel RM (262 to 202 PRU; p=0.05). Results from the considerably larger Scripps Clinic registry will be presented at the meeting. SIGNIFICANCE OF STUDY: In this prospective pilot study, DD clopidogrel in pts with HTPR appears to improve residual reactivity in CYP2C19 LoF allele carriers, but not in LoF allele homozygotes. Further, the *17 RM genotype was less common (14%) in our cohort of those with HTPR when compared to the general population (∼35%), which is consistent with its biologic effect.

A‐191

ROLE OF ANDROGEN RECEPTOR COFACTOR TBLR1 IN PROSTATE CANCER

Daniels G ¹, Basch R¹, Lee P¹  ¹New York University, New York, NY, United States

OBJECTIVES: The effects of androgen, via the androgen receptor (AR), are known to be a critical factor in the development and progression of prostate cancer. Androgen ablation therapy is used to treat advanced prostate cancer. However, the cancer often recurs into a hormone refractory state with no effective means of treatment. Transcriptional cofactors of AR may play an important role in recurrence and abnormal expression of cofactors are potential biomarkers for cancer progression. Our objective is to determine the role of TBLR1, a nuclear receptor co‐factor, in prostate cancer progression and identify it as a potential biomarker for hormone refractory disease. METHODS AND POPULATION: Luciferase assays: Dual luciferase assay using reporter plasmid containing four androgen receptor response elements. Proliferation assays: WST‐1 assay RESULTS: In our recent studies, we have found TBLR1 to act as an AR coactivator in the androgen‐dependent LNCaP prostate cancer cell line, yet acts as an AR corepressor in the androgenindependent LNCaP‐AI prostate cancer cell line. Additionally, expression of TBLR1 is lower in LNCaP cells compared to LNCaP‐AI cells. Interestingly, overexpression of TBLR1 in LNCaP cells, but not LNCaP‐AI cells, leads to androgen‐dependent growth inhibition. In contrast, TBLR1 is necessary for growth in LNCaP‐AI cells, as knockdown by siRNA leads to growth inhibition, but knockdown of TBLR1 has no effect on LNCaP cells. SIGNIFICANCE OF STUDY: Together these data suggest that TBLR1 has differential effects in androgen‐dependent versus androgen‐independent prostate cancer and may serve as a potential biomarker for the clinically important transistion of prostate cancer to a hormone refractory state. Further characterizing the role of TBLR1 in prostate cancer and its expression in clinical cases could provide novel insights into prostate cancer therapy.

A‐192

ROLE OF MACROPHAGE MIGRATION INHIBITORY FACTOR (MIF) IN THE PATHOGENESIS OF TUBERCULOSIS

Das R ¹, Koo M², Kaplan G², Bucala R¹, Dobos K³  ¹Yale University, New Haven, CT, United States, ²Public Health Research Institute, Newark, NJ, United States, ³Colorado State University, Ft. Collins, CO, United States

OBJECTIVES: Incomplete understanding of the interaction between Mycobacterium tuberculosis and the host immune system is a challenge facing tuberculosis control. MIF is a pro‐inflammatory cytokine produced by T‐cells and macrophages, which has been shown to mediate the pathogenesis of a variety of infectious diseases. Whether MIF plays a role in the pathogenesis of tuberculosis will be investigated. METHODS AND POPULATION: This work examined MIF release in response to stimulation with various tuberculous stimuli in murine and human systems. RESULTS: THP‐1 cells produced MIF in a concentration and time dependent manner in response to tuberculous purified protein derivative (PPD), glycolipids, lipomannan (LM) and phosphatidylinositol mannoside‐6 (PIM‐6), and irradiated tuberculosis bacilli. In contrast, mannosylated lipoarabinomannan (ManLAM) induced neither MIF nor TNFα production. Stimulation of primary human peripheral blood monocytes differentiated into macrophages led to the production of MIF, as well as upregulation of MIF on a transcriptional level. PIM‐6 stimulation also activated cells to produce TNF‐α. In the murine system, PIM‐6 activation of mif ‐/‐ bone marrow‐derived macrophages produced significantly reduced amounts of TNF‐cc, IL‐6, and IL‐10 compared to wild type (p<0.02), all cytokines that play a key role in the pathogenesis of tuberculosis. Staining of lung specimens from tuberculosis infected mice demonstrated MIF within the granuloma structures. SIGNIFICANCE OF STUDY: This work provides evidence for an important role of MIF in the evolution of tuberculosis infection and disease in both human and murine systems. Whether mif ‐/‐ mice have altered survival in response to pulmonary tuberculosis remains to be investigated.

A‐193

MICRORNA155‐MEDIATED REGULATION OF csk1y2, an INHIBITOR OF TGFfS SIGNALLING, IN CHRONIC LYMPHOCYTIC LEUKEMIA

Davidson J ¹, Zhang T², Furman RR³, Papavasiliou N¹, Tam W²  ¹Rockefeller University, New York, NY United States, ²Weill Cornell Medical College, New York NY United States, ³Weill Cornell Medical College, New York, NY United States

OBJECTIVES: MicroRNA‐155 (miR‐155) has been implicated in key B‐cell immune functions and is oncogenic. In chronic lymphocytic leukemia (CLL), miR‐155 is over‐expressed and is part of a miRNA signature associated with poor prognosis and disease progression. We aim to dissect the role of miR155 in the pathogenesis of CLL. METHODS AND POPULATION: Peripheral blood samples and clinicopathologic data were collected from untreated CLL patients with informed consent. RESULTS: We identified casein kinase 1 gamma 2 (csk1γ2) as a target for miR‐155. csk1γ2 is a negative modulator of the TGFβ signaling pathway by targeting the phosphorylated form of SMAD3 (p‐SMAD3) for degradation. MiR‐155 down‐regulates csk1γ2 mRNA but surprisingly enhances its translation in CLL. Previous studies have noted that some CLL cases carry mutations in the signal sequence of TGFβ receptor I, which render them insensitive to TGFβ signaling. Our preliminary data indicates that the subgroup of CLL patients expressing high levels of miR‐155 have an intact receptor whereas patients with low miR‐155 carry mutations in the signal sequence. SIGNIFICANCE OF STUDY: While TGFβ signaling is impaired in some CLLs by mutation of its receptor, it appears intact in other CLLs. However, the consequent induction of miR‐155 in the latter may prevent over‐activity of the TGFβ signaling pathway via a negative feedback mechanism involving csk1γ2 and p‐SMAD3, which may then reduce TGFβ‐induced apoptosis. Furthermore, since CLL cells are predominantly non‐proliferating, our findings that miR‐155 can enhance translation of csk1γ2 provide support to the model of cell cycle dependence of microRNA functions.

A‐194

GENOTYPE‐PHENOTYPE CORRELATIONS IN JOUBERT SYNDROME

Doherty D ¹, Knutzen D¹, RueT¹, Parisi M², Glass I¹

¹University of Washington, Seattle, WA, United States, ²NIH, Bethesda, MD, United States

OBJECTIVES: Joubert Syndrome (JS) is an autosomal recessive disorder characterized by a distinctive hindbrain malformation, intellectual disability, ataxia, and variable complications: cystic kidney disease, retinal dystrophy, liver fibrosis, polydactyly and encephalocele. Study goals: 1) To determine the prevalence of complications in patients with JS; 2) To determine the risk of complications associated with different genotypes; 3) To formulate a diagnostic testing strategy based on clinical features. METHODS AND POPULATION: Subjects were ascertained based on clinical findings of JS + supportive brain imaging. Clinical data were gathered through structured intake forms and medical record review. RESULTS: Cohort: 344 affected in 281 families: 54% male, 43% non‐US, 17% consanguineous and 49% <10 years old. Prevalence of complications: kidney disease 26%, retinal dystrophy 22%, polydactyly 20%, liver fibrosis 19%, coloboma 18%, encephalocele 14%. Strongest correlations: liver fibrosis and coloboma (OR 11, 95% CI 4.2‐29), liver fibrosis and kidney disease (OR 2.6, 95% CI 1.1‐6.3). Families with mutations in known JS genes: MKS3 11%, CEP290 11%, CC2D2A 9%, AHI1 8%, RP‐GRIP1L 2%, NPHP1 2%, OFD1 1%, ARL13B 0%. 80% of subjects with liver fibrosis and 47% with coloboma had MKS3 mutations. SIGNIFICANCE OF STUDY: This study provides the best estimates of medical complications in patients with JS to date and highlights the association of liver fibrosis and coloboma with MKS3 mutations. Based on our data and the literature, we propose the following strategy for JS genetic testing: 1) Liver disease and/or coloboma: MKS3, CC2D2A, RPGRIP1L; 2) Mild MTS: NPHP1; 3) Retinal dystrophy: AHI1, CEP290; 4) Kidney disease: NPHP1, RPGRIP1L, CEP290; 5) Retinal+renal disease: CEP290, CC2D2A; 6) No other features: AHI1, CC2D2A, CEP290.

A‐195

OPTICAL COHERENCE ELASTOGRAPHY FOR CORNEAL BIOMECHANICAL DIAGNOSIS

Dupps WJ ^1,2, Ford MR², Sinha Roy A¹, Rollins AM²  ¹Cleveland Clinic, Cleveland, OH, United States, ²Case Western Reserve University, Cleveland, OH, United States

OBJECTIVES: To obtain the first in vivo measurements of spatially resolved biomechanical properties in normal corneas, post‐LASIK corneas, and keratoconic corneas with a range of disease severity. METHODS AND POPULATION: A prospective clinical trial will enroll forty patients: 20 with keratoconus and 20 pre‐LASIK patients who will be re‐measured 1 week after myopic LASIK. A swept‐source clinical OCT elastography prototype coupled to a transparent contact interface will be used to image dynamic behavior during a short series of perturbations akin to clinical intraocular pressure measurement. Perturbations for eliciting a range of elastic and viscoelastic properties will be used. 3D patterns of optical feature flow will be analyzed with custom cross‐correlation routines to derive displacement fields indicative of biomechanical strain. RESULTS: In preclinical human donor eye studies, material heterogeneity could be differentiated within and between eyes from the same donor. It is expected that OCT elastography will be capable of discriminating between normal material heterogeneity, non‐pathologic property changes in post‐LASIK corneas, and pathologic changes with different grades of clinical ectasia in the living eye. SIGNIFICANCE OF STUDY: Optical coherence elastography can detect differences in local material resistance to a physiologic stress and provide estimates of elatic and viscoelastic material properties in 3 dimensions. The capability to detect low‐contrast spatial differences in strain behavior in individual eyes may address a critical need for more sensitive detection of early keratoconus in refractive surgery screening exams and may also discern preoperative material heterogeneity that could impact the optical response to corneal surgery.

A‐196

INHALED CYTOKINES AS A NOVEL THERAPY FOR RESPIRATORY SYNCYTIAL VIRUS IN INFANTS

Empey KM ¹   ¹University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: Respiratory syncytial virus (RSV) is the leading cause of pediatric viral respiratory tract infections worldwide. Severe RSV bronchiolitis in infancy has been associated with immature pulmonary immunity. Neonatal lung macrophages (LMs) are known to be functionally deficient and may contribute to severe RSV disease. Recently, dysfunctional LMs were implicated in severe RSV bronchiolitis among New Zealand Black mice. We hypothesize that LM‐directed, therapeutic cytokines will minimize disease severity and prevent subsequent asthma associated with severe infant RSV. The objective of this proposal is to evaluate the role of inhaled IFNγ and GM‐CSF in enhancing LM function, RSV clearance, and Th1 response in infant mouse lungs and the effect of these cytokines on human infant macrophages. METHODS AND POPULATION: RSV‐infected infant mice will be treated with i.n. IFNγ or GM‐CSF daily for 10 days. Flow cytometry will be used to determine LM infiltration, activation, and phagocytosis in BALF and lung tissue; Th1/Th2 cytokines will be evaluated by Luminex. Human cord blood‐derived macrophages will be cultured with RSV and IFNγ or GM‐CSF and LM activation determined as described above. RESULTS: Using a Pneumocystis‐infected infant mouse model, I have previously demonstrated that treatment with GM‐CSF increases LM activation and organism clearance compared to untreated mice. It is expect that IFNγ and GM‐CSF will increase LM function and reduce the Th2/Th1 ratio in RSV infected infant mice and human macrophages. SIGNIFICANCE OF STUDY: This research will determine the extent to which inhaled cytokine therapy improves neonatal LM function and alter outcomes of severe RSV disease. This research will fill existing gaps regarding the role of LMs in infant RSV disease. It has the potential to identify new therapeutic targets and new therapeutic uses for existing drugs.

A‐197

DNA COPY NUMBER VARIANTS AND PHENOTYPES OF SCHIZOPHRENIA

Epping EA ¹, Mugge S¹, Andreasen NC¹, Wassink TH¹  ¹The University of Iowa, Iowa City, IA, United States

OBJECTIVES: Schizophrenia is a psychiatric disorder with symptoms that disrupt perception, cognition, and behavior. A heterogeneous set of common and rare genetic risk factors contribute to its etiology. One class of genetic factors termed DNA copy number variants (CNVs) likely play a significant role. The objectives of this study are to identify CNVs and their associations with symptoms and neurobiology of schizophrenia. METHODS AND POPULATION: In this ongoing project, CNVs are identified from a sample of schizophrenia subjects using DNA comparative genomic hybridization (CGH) with ultra high‐density microarrays, which have 2.1 million probes per array. Parental DNA is also available to determine if the CNV is inherited or novel to the individual. CNVs identified are prioritized for follow‐up based on whether they been identified previously (with novel ones given a higher priority), contain genes of interest in the etiology of schizophrenia, or have been previously identified as a potential genetic risk factor for schizophrenia. CNVs are validated using quantitative PCR. Phenotypic information on subjects, including symptoms, cognitive functioning, and brain morphology are used to identify potential associations with CNVs. RESULTS: In the samples analyzed to date, the number of potential CNV candidates per individual ranges from approximately 50‐70, and range in size from 2000 bases in length to over one million bases (or a megabase). Analyses are underway to determine if any CNVs identified are potential genetic risk factors, and which genes are altered by the presence of a CNV. SIGNIFICANCE OF STUDY: This work will provide essential information into the biological pathways that cause the development of schizophrenia and provide a first step that may lead to the development of more effective treatments.

A‐198

A COMPARATIVE GLYCOPROTEOMICS APPROACH TO THE GERIATRIC SYNDROME OF FRAILTY

Espinoza S ¹, Pierce A¹, Halade D¹, Richardson A¹  ¹University of Texas Health Science Center, San Antonio, TX, United States

OBJECTIVES: Frailty is associated with physiologic dysregulation in many physiologic systems; however, its etiology is poorly understood. Proteomics allows the study of hundreds of plasma proteins. To date, physiologic alterations associated with frailty have almost exclusively demonstrated modifications in glycoproteins (GPs). The purpose of this study is to determine if pre‐frailty is associated with changes in expressed GPs, which might provide direction for future research identifying creative interventions for healthy aging. METHODS AND POPULATION: Subjects were age and sex‐matched pre‐frail (n = 4) and non‐frail (n = 4) community‐dwelling older adults (mean age 81, 50% female). Pre‐frailty was defined as 2 of 5 criteria: weak grip, slow walk, weight loss, exhaustion, and low physical activity. Approximately 200 GPs were isolated using Concanavalin A, wheat germ agglutinin, and Jacalin lectin affinity columns, were separated with 2‐dimensional polyacrylamide gel electrophoresis, and stained with Sypro ruby for quantification. Relative spot intensities were estimated using PDQuest; those showing ≥2‐fold difference by group were identified using mass spectrometry. RESULTS: Four GPs or their isoelectric isoforms were upregulated in pre‐frail compared to non‐frail individuals (transferrin, N‐terminal haptoglobin, transferrin, and kininogen‐1 variant). Five were down‐regulated (hemopexin precursor, kininogen‐1 variant, fibrinogen isoform, apolipoprotein E, and luceine rich alpha‐2‐glycoprotein 1). SIGNIFICANCE OF STUDY: Differential expression of several GPs related to inflammation and the hematologic system was found at the pre‐frailty stage, before frailty becomes clinically apparent. These findings may suggest the feasibility of this methodology for discovery of potential biomarkers for frailty and earlier identification of at‐risk older adults.

A‐199

RISK AND PREGNANCY: DECISION MAKING FOR FIRST TRIMESTER PRENATAL ANEUPLOIDY SCREENING

Farrell RM ¹   ¹Cleveland Clinic, Cleveland, OH, United States

OBJECTIVES: TThis study was designed to assess women's decision making process for prenatal genetic screening tests with the aim of improving the informed consent process for the clinical translation of reproductive genetic technologies. METHODS AND POPULATION: We recruited participants from Cleveland Clinic OB/GYN clinics. A total of 46 participants were recruited for nine focus groups to discuss first trimester aneuploidy screening. Participants also completed a quantitative survey assessing demographics, knowledge and experiences with prenatal testing. Data analysis was conducted using NVivo8 and SPSS. RESULTS: Most participants were aged 26‐30 (34%) or 31‐35 (25%), Caucasian (72%) or African American (23%), and had either a college (53%) or graduate (30%) degree. Over half (63%) were currently pregnant, 68% with >1 prior pregnancy and 41% who had undergone 1st trimester screening. Emerging themes pertained to the challenges to acquiring and processing new information during a period of intense emotional and physical changes. Other themes included the uncertainty regarding the benefits of genetic testing and maternal anxiety during and after testing. SIGNIFICANCE OF STUDY: Pregnant women face a unique set of challenges during the decision‐making process for prenatal genetic testing. First trimester screening amplifies these challenges. Few mechanisms exist to assist patients in this complex decision making process. Our findings demonstrate need to develop decision aides in conjunction with the translation of new genetic technology to support these important decisions.

A‐200

DETERMINATION OF BURN PATIENT OUTCOME BY LARGE SCALE QUANTITATIVE DISCOVERY PROTEOMICS

Finnerty CC ¹, Herndon D¹, Jeschke MG¹, Qian W², Kaushal A³, Xiao W³, Camp D², Moldawer LL⁴, Schoenfeld D⁵, Gamelli R⁶, Gibran N⁷, Arnoldo B⁹, Remick D⁸, Smith R², Davis R³, Tompkins RG⁵  ¹UTMB/Shriners Hospital for Children, Galveston, TX, United States, ²Pacific Northwest National Laboratory, Richland, WA, United States, ³Stanford University, Palo Alto, CA, United States, ⁴University of Florida, Gainesville, FL, United States, ⁵Massachusetts General Hospital, Boston, MA, United States, ⁶Loyola University, Maywood, IL, United States, ⁷University of Washington, Seattle, WA, United States, ⁸Boston University School of Medicine, Boston, MA, United States, ⁹University of Texas Southwestern, Dallas, TX, United States

OBJECTIVES: We profiled the plasma proteome of 16 non‐survivors & 16 survivors of massive burn injury in order to determine the proteomic survival signature, and potential bio‐markers of survival, following a major burn injury. METHODS AND POPULATION: Severely burned patients >17 yrs of age were enrolled. 16 surviving and 16 non‐surviving patients were matched for burn size, burn mechanism, gender, age, and ethnicity. Plasma samples were then selected for similar post‐burn time points. LC‐FTICR‐MS, multiplex cytokine analysis, and ELISA were used to measure plasma proteins. RESULTS: Circulating levels of 43 proteins were significantly different in survivors, 32 of which were not previously known to play a role in the host response to burn. Five of the proteins measured in plasma correlate well with survival and may serve as clinical biomarkers. SIGNIFICANCE OF STUDY: This is the first clinical application of a high‐throughput, large‐scale LC‐MS‐based quantitative plasma proteomic approach for establishing proteomic survival signatures as well as for biomarker discovery applied to the prediction of patient outcome following burn, trauma or critical illness. The identified proteins may provide reliable predictors of clinical outcome and may provide potential targets of therapeutic intervention to alter outcome.

A‐201

PROPRANOLOL ATTENUATES POST‐BURN HYPERTROPHIC SCARRING

Finnerty CC ¹, He J¹, Mecott G¹, Hegde S¹, Herndon D¹, Jeschke MG¹  ¹UTMB/Shriners Hospital for Children, Galveston, TX, United States

OBJECTIVES: Hypertrophic scarring is a major clinical problem affecting up to 91% of severely burned patients. These hypertrophic scars (HTSs) are hyperinflammatory, pruritic, painful, and disfiguring, and can only be treated surgically. We have recently found that administration of propranolol, a non‐specific β1, β2 adrenergic receptor antagonist, decreases hypertrophic scarring. This is the first agent found to reduce the severity of post‐burn hypertrophic scarring. We used genomics data to identify signaling pathways likely to be affected by propranolol treatment, leading to the hypothesis that blockade of the β‐ARs in HTS cells with propranolol will reduce the inflammatory response, improve cell viability, restore cell migration, and stimulate beneficial AR signaling. METHODS AND POPULATION: GeneChips were run on HTS biopsies harvested 3 & 22 months post burn; the data was analyzed using BRB Array Tools (p<0.001). Primary skin & scar fibroblast cultures were established from un‐burned skin and burn scar from children 3‐9 months post burn. Media was assayed for the expression of 17 cytokines. Cell migration was studied using a scratch assay. Cell viability was measured by MTT. Protein expression was confirmed via Western blot. RESULTS: Comparison between HTS harvested 3 & 22 months post burn showed differences in genes associated with β‐AR, IL6, G‐protein, and cAMP mediated signaling. Outcomes related to these genes were then examined in vitro. In HTS cells, propranolol treatment decreased cytokine production, increased cell viability, altered migration, and modulated expression of the β‐ARs and related proteins. SIGNIFICANCE OF STUDY: These results provide a mechanistic basis for the decrease in hypertrophic scarring following propranolol treatment.

A‐202

MR‐OXYGEN METABLIC INDEX PREDICTS INFARCTION BETTER THAN ADC IN ACUTE ISCHEMIC STROKE

Ford AL ¹, An H², Vo KD¹, Derdeyn CP¹, PowersWJ², Lin W², Lee J¹  ¹Washington University, St. Louis, MO, United States, ²University of North Carolina, Chapel Hill, NC, United States

OBJECTIVES: Prior PET studies have shown that cerebral metabolic rate of oxygen utilization (CMRO₂) predicts viable tissue in ischemic stroke. We have developed a novel MRI approach to measure oxygen metabolic index (OMI), a parameter closely related to CMRO₂. In a cohort of ischemic stroke patients, we directly compared the ability of OMI and apparent diffusion coefficient (ADC, MR sequence used to indicate irreversibly injured tissue), measured at <3 hrs and 6 hrs after symptom onset, to predict brain tissue destined to die or remain alive at 1 month. METHODS AND POPULATION: Ten ischemic stroke patients were imaged at 2.9 hrs (tp1) and 6.3 hrs (tp2) after onset. Eight patients received IV tPA prior to tp1. Bolus contrast method measured cerebral blood flow (CBF). Asymmetric spin echo measured oxygen extraction fraction (OEF). OMI=CBFxOEF. Co‐registration and segmentation aligned time‐points and separated gray from white matter, respectively. Histograms demonstrated the relative frequency of OMI (or ADC) values for tissue destined to die or survive on 1 month FLAIR. ROC analysis quantified OMI's (or ADC's) ability to distinguish living and dead tissue. Areas under the ROC curves (AUC) of OMI vs ADC were compared using Wilcoxon Signed Ranks test. RESULTS: For tp1 gray matter, mean AUC for OMI was 0.83 and 0.74 for ADC (p=0.02). For tp1 white matter, mean AUC's were 0.79 and 0.76 for OMI and ADC, respectively (p=0.17). For both gray and white matter at tp2, there were no significant differences between OMI and ADC. SIGNIFICANCE OF STUDY: Hyper‐acute measures of OMI predicted gray matter death better than ADC, suggesting that OMI may better delineate the core of an evolving in‐farct.

A‐203

MOLECULAR (MAL)ADAPTATIONS IN DOPAMINE‐MODULATED SIGNALING FOLLOWING DEVELOPMENTAL INSULT

Frederick AL ¹, Colbran R¹, Stanwood G¹  ¹Vanderbilt University, Nashville, TN, United States

OBJECTIVES: Developmental dysregulation of forebrain circuitry contributes to the pathogenesis of mental disorders, even though clinical phenotypes usually become apparent later in life. We hypothesize that abnormalities in dopamine (DA) signaling initiated developmentally result in changes in the activation of DA‐modulated signaling cascades and underlie neurobehavioral changes observed in adults following disrupted DA neurotransmission. To this end, our laboratory has demonstrated that cocaine exposure during rabbit embryogenesis permanently disrupts DA D1 receptor signaling in dopaminoceptive regions resulting in neurobehavioral deficits. We are investigating changes in phosphorylation of several key molecular mediators of the effects of D1 receptor signaling on excitatory synaptic transmission. METHODS AND POPULATION: We are utilizing complementary animal models: rabbits exposed to cocaine in utero, a model with pharmacologically induced reduction in cell‐surfaced expressed D1 receptors but not complete loss of receptor signaling, and D1 receptor null and haploinsufficient mice. The null mice allow us to examine effects of constitutive loss of D1 receptors on cell signaling pathways, while the hypomorphic models provide examination of adaptations after blunted signaling, the scenario more likely observed in human disease. RESULTS: Thus far, our data shows robust deficits in basal CaMKIIα autophosphorylation in striatal and cortical extracts from adolescent rabbits exposed to cocaine in utero. SIGNIFICANCE OF STUDY: These studies will inform our understanding of the molecular alterations induced by developmental disruptions of DA neurotransmission and their contribution to long‐lasting dysfunctions in neuronal activity and behavior.

A‐204

LONGITUDINAL RODENT HIND‐LIMB MRI

Fricke ST ^1,2, Guerron AD², Chiodo C³, Holdsworth DW⁴, Nagaraju K², Wong K⁵, Albanese CA⁷, Cleary K⁶  ¹Children's National Medical Center, Washington, DC, United States, ²Children's National Medical Center, Washington, DC, United States, ³ASI Instruments, Inc, Warren, MI, United States, ⁴The University of Western Ontario, Canada, London, ON, Canada, ⁵Virginia Tech‐National Capital Region, Alexandria, VA, United States, ⁶Georgetown University, Washington, DC, United States, ⁷Georgetown University, Washington, DC, United States

OBJECTIVES: Longitudinal small animal hindlimb muscle and bone MRI research is difficult because positioning of the animal the same way twice is problematic. METHODS AND POPULATION: We have introduced a customized stereotaxic Animal Handling System (AHS) that allows for the repeated positioning of research mice in a MRI, while monitoring and supporting vital physiological parameters. The device is anatomically correct to allow for the positioning the same animal, other animals of the same species and similar species that share a similar anatomical footprint. RESULTS: We found that there is at most a 4 pixel shift of any specific strain and 5 pixel shift between two different strains when measuring the tibia‐spine length and angle. Thus the same muscle group and, in many cases the same cell group, is being studied. It is observed that overall tissue thigh diameter varies depending on the strain of the animal and also is apparently different from left side to right side or the animal yet muscle cell groups remain trackable. SIGNIFICANCE OF STUDY: Longitudinal MRI microscopy of tissue structure and function are possible using the described stereotaxic device and hardware. This should be of particular use for time‐course studies of tissue where precise reproducible visualization of anatomical structure and function is required. Similar methods could be used for long‐term human tissue evaluation.

A‐205

BEHAVIORAL APPROACHES TO RESTORE CORTICOSPINAL TRACT CONNECTIONS AND FUNCTION IN A CAT MODEL OF HEMIPLEGIC CEREBRAL PALSY

Friel KM ¹, Chakrabarty S², Joshi A³, Martin JH^2,3  ¹Columbia University Medical Center, New York, NY, United States, ²City College of New York, New York, NY, United States, ³Columbia University Medical Center, New York, NY, United States

OBJECTIVES: We developed a cat model of hemiplegic cerebral palsy (CP). Neural activity in motor cortex (M1) was unilaterally blocked during a critical period. This inactivation produces permanent deficits in visually‐guided movement and a loss of corticospinal tract (CST) terminations in the spinal cord. Within the motor map, distal forelimb representations are lost. Balancing activity on the two sides, by blocking activity contralateral to the first inactivation or electrically stimulating the inactivated CST, promotes recovery. Objective: To determine the efficacy of training the impaired arm and constraining use of the ipsilateral (unimpaired) arm in improving motor skill, CST termination organization, and the motor map. METHODS AND POPULATION: M1 was inactivated during postnatal weeks (PW) 5‐7, a critical period for motor development, by infusing a GABA‐A agonist. Cats were trained from PW 8‐14 or PW 20‐24 on a reaching task. Cats wore a restraining jacket, tethering their unimpaired arm to their chest. Cats were trained 5 days/week, 2 30‐min sessions/day. The CST was anterogradely labeled. Intracortical microstimulation was used to map the M1 forelimb representation. RESULTS: Constraint and training (PW 8‐14 or 20‐24) improved accuracy of reaching and stepping on a horizontal ladder. Training redirected CS terminations to their normal location in the spinal cord. The inactivated M1 forelimb representation was similar to normal controls. SIGNIFICANCE OF STUDY: Extending these results to human hemiplegic CP suggests the rehabilitative potential of training the affected arm and constraining the unaffected arm.

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PREIMPLANTATION MOUSE EMBRYO SELECTION GUIDED BY LIGHT‐INDUCED DIELECTROPHORESIS

Garcia MM ^1,2   ¹University of California San Francisco, San Francisco, CA, United States, ²University of California Berkeley, Berkeley, CA, United States

OBJECTIVES: In Vitro fertilization (IVF) in the U.S. are limited significantly by our inability to reliably select the healthiest embryo for transfer to the uterus. Currently, embryos are selected on the basis of morphologic (visible) maturity. A more sensitive, specific approach to selection would improve clinical outcomes. METHODS AND POPULATION: We demonstrate how light‐induced dielectrophoresis, termed Optoelectronic Tweezers (OET), exploits the scaling electrical properties of pre‐transfer mouse embryos, to quantitatively discern relative individual embryo maturity within cohorts of visually identical appearing mouse embryos cultured in optimized (KSOM) and suboptimal (M16) medium, and compare paired cohort responses to show that OET response alone can guide selection of the most mature embryo within any cohort. RESULTS: Across development from 1‐cell through blastocyst stages, response to OET steadily trends from attraction (positive) to repulsion (negative) to the OET field. At any stage of development, mean response of embryos cultured in optimized medium is significantly more negative than for embryos cultured in suboptimal medium (p<0.05). Following OET assay and return to culture conditions, embryos continue to develop at a normal rate, and hatch. SIGNIFICANCE OF STUDY: OET provides a simple, noninvasive, quantitative, and reproducible assay of embryo maturity for use in IVF, and, to guide embryo selection for embryonic stem cell harvest.

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QUANTITATIVE TRAIT HOT‐SPOTS IN SUBJECTS WITH CHROMOSOME 18Q‐ DISORDER

Gelfond JA ¹, Cody JD¹  ¹UT Health Science Center, San Antonio, TX, United States

OBJECTIVES: The objective of the study is to identify the genes or genomic segments that are critical to human development in the event of large‐scale chromosomal deletions. Statistical methods for quantifying and understanding the influence of chromosomal deletions are relatively underdeveloped compared to the analysis of single nucleotide polymorphisms. We propose a Bayesian spatial model that can be used to identify critical regions of the genome that, when deleted, are disproportionately associated with quantitative traits such as height, cognitive function (IQ), and position within the autistic spectrum. METHODS AND POPULATION: The study population consists of individuals with 18q‐ disorder that are missing substantial segments of chromosome 18. The subjects are especially interesting because they have a range of sizes and positions of genetic deletions that can be correlated to clinical phenotypes. This cohort has been longitudinally studied and carefully assessed for a range of phenotypes including height, growth hormone deficiencies, MRI traits, cognitive impairments, social impairments, and autistic features. RESULTS: We found that there is a height critical region with 80% posterior probability in the 60 megabase position of 18q after adjusting for mid‐parental height. We are in the process of analyzing more quantitative traits. SIGNIFICANCE OF STUDY: Chromosomal abnormality is one of the leading causes of cognitive impairment in children, and understanding this mechanism is extremely important. We focus on the height trait because early treatment with growth hormone has been shown to give favorable outcomes in terms of stature and cognitive performance. Our method for localizing the particular genes involved gives insight and direction to future therapies.

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IDENTIFICATION OF SALIVARY GLYCOPROTEINS INVOLVED IN IMMUNE PROCESS BY MUDPIT TECHNOLOGY

Gonzalez‐Begne M ¹, Sanz I¹, Lu B², Yates JR²  ¹University of Rochester, Rochester, NY, United States, ²The Scripps Research Institute, La Jolla, CA, United States

OBJECTIVES: Saliva is secreted by the major and minor salivary glands and is vital for the maintenance of oral homeostasis. Physiological changes associated with different diseases are reflected by changes in the glycoproteome composition. Thus mapping the salivary glycoproteome will provide a better understanding of health and disease processes. METHODS AND POPULATION: Lectin chromatography and MudPIT (multidimensional protein identification technology) mass spectrometry were used to isolate glycopeptides and glycoproteins from submandibular/sublingual (SM/SL) ductal saliva. RESULTS: 903 proteins were catalogued in human SM/SL saliva. The Gene ontology analysis revealed that salivary glycoproteins are involved in different biological processes, such as cellular process (17.9%), response to stimulus (13.2%), biological regulation (12.7%), metabolic process (11.8%), developmental process (8.0%) and immune system process (7.5%) among others. Of significance is the presence of proteins which over expression is associated with rheumatoid arthritis (S100A8, S100A9, rheumatoid factor C6 light chain, MMP9), Sjögren's syndrome (CRISP3, IGHG1, α‐enolase) and Systemic lupus erythematosus (IGLV3‐21, IGLV2‐14, V1‐19) suggesting the possible use of saliva as a diagnostic tool for immune diseases. SIGNIFICANCE OF STUDY: The results showed that MudPIT technology on saliva was crucial for identifying glycoproteins with high mass accuracy and analytical sensitivity, two important parameters for biomarker validation. This research project was supported by 5 KL2RR024136‐04.

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SELECTIVE DECLINE IN PROXIMAL SEGMENT NERVE CONDUCTION VELOCITY IN HEALTHY ELDERLY

Green AJ ¹, Songster C¹, Engstrom J¹  ¹UCSF, San Francisco, CA, United States

OBJECTIVES: Evaluate the relationships between age and nerve conduction velocity (NCV) in a healthy aged population to determine the independent effect of age on peripheral myelin function in the elderly. Increasing age has been associated with slower NCV after middle age, especially in distal nerve segments. Most of these series have included patients with clinical conditions known to impact NCV. METHODS AND POPULATION: 77 subjects (59% female) underwent upper‐extremity (ulnar and median) and lower‐extremity sensory NCS (sural). This is a healthy community‐dwelling population between the ages of 65‐90 (Total n = 110). Exclusion criteria for participation included any major medical illnesses. Specific nerve segments with known or clinically identifiable neuropathy (e.g. polyneuropathy, ulnar neuropathy, carpal tunnel syndrome) or signs suggestive of neuropathy on screening neurological examination were also excluded. RESULTS: Proximal, but not distal, segments of median and ulnar motor nerves showed a decline in NCV associated with age (p=0.008‐0.05). This finding was independently confirmed by segregating the sample by side (left/right). There was also an interaction between age and sex with most of the effect being observed in men. This correlated to a decline in NCV of 3‐3.5 meters/second (m/sec) per decade in the total population and 4‐5 m/sec per decade in the men. Controlling for height and BMI had no effect on these declines. SIGNIFICANCE OF STUDY: Among the healthy elderly, age is associated with a decline in NCV in proximal motor segments of the ulnar and median nerves. This effect is especially pronounced among men. This decline appears to reflect the selective development of dysfunction in the proximal nerve segments. It would be important to understand the biological basis of this decline to understand the impact of aging on peripheral myelin.

A‐210

ISOLATION OF HUMAN DENDRITIC CELL SUBTYPES

Gupta MR ¹, Kolli D¹, Garofalo RP¹  ¹UTMB, Galveston, TX, United States

OBJECTIVES: Dendritic cells (DCs) are potent antigen presenting cells in the peripheral blood and tissues. Depending on their derivation, DCs either initiate or regulate immune responses. The heterogeneity in function likely derives from the presence of functionally distinct subsets (mDC1, mDC2, pDC); however the specific roles have not been defined. Studies of human DC subtypes are limited by their relative rarity and difficulty in isolation. Thus, little is known about the individual function of DC subtypes in the propagation and regulation of immune responses. We have devised a method to isolate three distinct subpopulations from human peripheral blood utilizing specific blood dendritic cell antigens (BDCA) on the cell surface. METHODS AND POPULATION: Buffy coats from healthy adult blood donors were obtained from the UTMB blood bank. Peripheral blood mononuclear cells were separated using Ficoll‐hypaque density centrifugation and enriched for DCs by depletion of lineage positive cells (CD3,CD14,CD15,CD19,CD56) magnetically labeled with antibody‐conjugated microbeads. DC enriched fractions were then labeled with flourochrome‐conjugated antibodies for FACS sorting and analysis. Subpopulations were defined by DC specific cell surface markers. RESULTS: Using this method, three phenotypically distinct DC subpopulations were isolated. Cell numbers ranged between 1‐3 ×10⁵ with >88% purity for each subpopulation. Additionally, cytokine expression data after in vitro infection with RSV and hMPV demonstrates these subpopulations are functionally distinct. SIGNIFICANCE OF STUDY: This method of direct isolation of human DC subtypes from peripheral blood will allow for further study of the role specific DC subtypes play in the propagation and regulation of immune responses.

A‐211

ENDOTOXIN‐INDUCED DEPRESSIVE‐LIKE SYMPTOMS

Hannestad J¹  ¹Yale University, New Haven, CT, United States

OBJECTIVES: Depression is associated with increased serum levels of inflammatory cytokines. Immune system activation produces mild depressive symptoms in humans which suggests that inflammation could contribute to the pathogenesis of depression. We are using endotoxin to induce depressive symptoms in humans to determine whether this experimental paradigm can be used for PET studies of immune‐brain interactions. METHODS AND POPULATION: We enrolled 13 healthy subjects and administered endotoxin (0.8 ng/kg) or placebo intravenously in a cross‐over, double‐blind design. We measured depressive symptoms and serum levels of TNF and IL‐6 at 60, 120, and 180 minutes after endotoxin administration. RESULTS: Endotoxin produced increases in serum levels of IL‐6 and TNF. Repeated‐measures ANOVA showed a main effect of endotoxin on depression, as measured with the MontgomeryÅsberg Depression Rating Scale (F=9.1, p=0.01), fatigue, as measured by the MADRS Lassitude item (F=8.2, p=0.014), and anxiety, as measured by the Profile of Mood States (F=6.3, p=0.026), and a trend towards an effect on anhedonia (F=3.8, p=0.076) and cognition (F=3.9, p=0.071). SIGNIFICANCE OF STUDY: Our results show that endotoxin administration reliably induces depressive‐like symptoms in healthy subjects. One caveat is that endotoxin induces sad mood in only a subset of subjects, while other symptoms of depression, such as anxiety and fatigue are more reliably induced. Sad mood is one of two core symptoms of depression. The other is anhedonia. We are using a computer program to measure anhedonia to further validate our endotoxin model. Our second goal, which is ongoing, is to use PET imaging to measure brain metabolism and microglial activation. Current treatments for depression show poor efficacy and there is a need for drugs that target novel pathways. Studies of the potential pathogenic role of inflammation in depression may translate into new treatments.

A‐212

SMOKING AND ACTIVATION OF VITAMIN D IN THE LUNGS

Hansdottir S ¹, Monick MM¹, Powers L¹, Hunninghake GW¹  ¹University of Iowa, Iowa City, IA, United States

OBJECTIVES: Cigarette smoke impairs host defense in the lungs and smokers are at increased risk of respiratory infections. Smokers have higher levels of proinflammatory chemokines and inflammatory lung diseases, like asthma, cystic fibrosis and COPD, are exacerbated by smoking. Airway epithelium converts 25‐hydroxyvitamin D (25D =“storage form”) to 1,25‐dihy‐droxyvitamin D (1,25D =“active form”). Locally generated 1,25D has important immunomodulatory effects which include induction of antimicrobial peptides and dampening of chemokine production in virally infected cells. We hypothesize that cigarette smoke interferes with vitamin D metabolism in the lungs resulting in localized vitamin D deficiency. METHODS AND POPULATION: Primary lung epithelial cells were exposed to cigarette smoke extract (CSE), acrolein and/or dsRNA (polyIC) in the presence of inactive 25D. In some experiments aldehyde dehydrogenase was added at the same time as CSE or acrolein. Active vitamin D (1,25D) was measured in supernatants. 1α‐hydroxylase and 24‐hydroxylase mRNA was quantified with qRT‐PCR. RESULTS: Cigarette smoke significantly reduced the generation of active vitamin D by airway epithelium. Acrolein, a component of cigarette smoke, had similar effects. The effects of CSE and acrolein were reversed by aldehyde dehydrogenase. dsRNA, a surrogate for RNA viruses, increased production of active vitamin D but this increase disappeared in the presence of CSE. pIC increased and CSE decreased 1α‐hydroxylase mRNA. SIGNIFICANCE OF STUDY: Combined this data indicates that cigarette smoke decreases baseline and virally induced conversion of inactive to active vitamin D in the lungs, setting the stage for lower levels of active vitamin D, locally, in smokers. Lower levels of active vitamin D in the lungs may contribute to higher chemokine levels and exuberant inflammatory responses in smokers.

A‐213

ONCOFERTILITY AND AN ALGINATE IN VI TRO 3‐DIMENSIONAL(3‐D) FOLLICLE CULTURE SYSTEM

Harp D ¹, Chowdhury I¹, Matthews R¹, Thompson WE¹  ¹Morehouse School of Medicine, Atlanta, GA, United States

OBJECTIVES: Oncofertility is an emerging discipline which intersects cancer diagnoses and cancer treatment with the aim for fertility preservation by incorporating the related clinical science as well as basic science research in cell growth and gamete physiology. At the core of On‐cofertility, is a multidisciplinary approach which merges basic science research together with biomedical and social/ethical issues to assess and reduce the impact of cancer on reproductive physiology. At present there is imminent concern that the broad spectrum of chemotherapies used in clinical practice are capable of modulating hormonal responses, or, are directly toxic to human ovarian follicles, thereby interfering with normal physiological processes that are critical to maintaining fertility. In the present study, we aimed to standardize an alginate in vitro 3‐dimensional (3‐D) follicle culture bioassay. METHODS AND POPULATION: Immature mouse ovaries were collected from 12‐14 day‐old pups and follicles were isolated followed by encapsulated into a 0.5% alginate bead. Then encapsulated follicles were cultured in growth media for 7, 14 and 21 days at 37°C in the presence of 5% CO₂. Maturation was determined by measuring the diameter of follicles containing oocytes at different time intervals. RESULTS: Our results demonstrate that this bioassay permits normal growth and development of follicles and oocytes. Furthermore, we have used this culture system to address the chemotherapy impact on growth and maturation of follicles. SIGNIFICANCE OF STUDY: These studies suggest that an in vitro 3‐D follicle culture bioassay can be a useful bioassay in characterizing the impact of chemotherapy on folliculogenesis, follicular and oocyte growth, steroid secretion profile, and oocyte meiotic maturation capacity.

A‐214

A TRANSLATIONAL APPROACH TOWARD RNAI THERAPY FOR FSHD

Harper SQ ¹   ¹The Ohio State University, Columbus, OH, United States

OBJECTIVES: Facioscapulohumeral muscular dystrophy (FSHD) is a dominant genetic disorder caused by contraction of 4q35 D4Z4 repeats. FSHD is likely an epigenetic disorder in which D4Z4 contractions lead to aberrant up‐regulation of myotoxic genes. To date, no single gene has been definitively linked to FSHD pathogenesis. This insufficient understanding of the pathogenic mechanisms underlying FSHD has hindered development of effective therapies. RNA interference (RNAi) is emerging as an important strategy to treat dominant genetic disorders, but requires specific gene targets. We are performing parallel studies to (1) identify potential FSHD gene targets and (2) develop muscle‐targeted RNAi strategies to treat dominant muscular dystrophies. METHODS AND POPULATION: To date, FRG1 is the only FSHD candidate gene shown to cause dystrophy‐related phenotypes in vivo, but its involvement in human FSHD remains unclear. DUX4 has recently emerged as an FSHD candidate gene because it is located in each D4Z4 repeat, elevated in FSHD myoblasts, and causes apoptosis in vitro. In this study, we show the first in vivo evidence of DUX4 myotoxicity; in addition, we developed a therapeutic approach to knockdown FSHD candidate genes, including DUX4. RESULTS: We found that DUX4 caused abnormalities consistent with muscular dystrophy in animals, and that DUX4 myotoxicity was related to its ability to bind DNA as a transcription factor, since DUX4 DNA binding domain mutants mutants were not toxic. To establish proof‐of‐principle for RNAi therapy, we developed the first pre‐clinical RNAi strategy to knockdown a putative FSHD candidate gene (FRG1). SIGNIFICANCE OF STUDY: Together, our data suggest a role for DUX4 in FSHD pathogenesis, thereby justifying development of DUX4‐targeted treatments. Moreover, our results support the feasibility of RNAi therapy for dominant muscular dystrophies, including FSHD.

A‐215

NEURONAL NITRIC OXIDE LOCALIZATION IN NON‐DYSTROPHIC NEUROMUSCULAR DISEASES

Hedderick EF ¹, Simmers JL¹, Corse AM¹, Cohn RD¹  ¹Johns Hopkins University School of Medicine, Baltimore, MD, United States

OBJECTIVES: Neuronal nitric oxide synthase (nNOS), normally localized to the sarcolemmal membrane is known to be mislocalized to the sarcoplasm in several forms of muscular dystrophy but the signals controlling this mislocalization and the downstream consequences have not been clearly defined. Our objectives were to further define the range of neuromuscular conditions associated with abnormal nNOS localization and to correlate nNOS sarcolemmal staining with the functional status of the patient. METHODS AND POPULATION: Immunofluorescent staining for nNOS was performed on previously obtained muscle biopsy specimens from 158 patients with myopathic conditions, neurogenic conditions and hypotonia. Selected samples were also stained for dystrophin. Sarcolemmal nNOS staining was then correlated with the functional status of the patient in the following categories: 1 = normal; 2 = minimal/mild weakness; 3 = moderate weakness/wheelchair bound; 4 = severe weakness. RESULTS: Sarcolemmal nNOS staining was abnormal in 42% of patients with myopathic conditions, 93% with hypotonia and 67% with neurogenic conditions. Dystrophin staining was confirmed to be normal in selected patients with abnormal nNOS staining. Importantly, poorer functional status was correlated with reduced or absent sarcolemmal nNOS staining. For patients with a genetically defined muscular dystrophy, functional status was also correlated with nNOS mislocalization. SIGNIFICANCE OF STUDY: Neuronal nitric oxide synthase mislocalization occurs in a wide variety of non‐dystrophic myopathic and neurogenic conditions with an intact dystrophin‐associated glycoprotein complex. Importantly, this mislocalization is strongly correlated with functional status.

A‐216

DEFINING AND TESTING THE CIRCUIT MEDIATING MAJOR DEPRESSION

Henn FA ¹, Mirrone M¹, Schultz D¹, Li B³, Malinow R⁴, Sartorius A²  ¹Brookhaven National Laboratory, Upton, NY, United States, ²Central Institute of Mental Health, Mannheim, Germany, ³Cold Spring Harbor Lab., Cold Spring Harbor, NY, United States, ⁴U. of CA at San Diego, San Diego, CA, United States

OBJECTIVES: 1. We defined the circuit mediating helplessness in and animal model of depression. 2. We determined sites of pathophsiology in the circuit. 3. Tested the validity of this circuit using imaging and deep brain stimulation in patients. METHODS AND POPULATION: The circuit was defined using out bred strains of rats bred for susceptibility to helplessness called the congenitally helpless line cLH and the line bred for resistance is called the non helpless line nLH. The cLH rats have face and predictive validity with major depression. The patient was a treatment resistant patient treated at the Central Institute of Mental Health in Mannheim Germany. RESULTS: Using FDG PET the cLH and nLH lines were compared and differences were seen in cortical, limbic and midbrain areas. The area including the l.habenula showed significantly more activity in the cLH strain. This was confirmed via direct electrophysiological recording from l. habenular slices, suggesting habeular overactivity leads to a depressed state. Deep brain stimulation was performed on a treatment resistant patient with a HAM D of 42 a full remission was obtained, following removal of the stimulator due to an accident a psychotic depression returned and resolved after the stimulator was again activated. SIGNIFICANCE OF STUDY: These data suggest that cortical activity is sent to the l.habenula which controls affect through regulating the midbrain nuclei. Increased drive from the mPFC appears to lead to increased habenular activity and a depressive state. This led to a new target for DBS and new drug development.

A‐217

DICHLOROACETATE PROMOTES BRAIN FUEL METABOLISM DURING ACUTE HYPOGLYCEMIA IN RATS EXPOSED TO RECURRENT HYPOGLYCEMIA

Herzog R ¹, Jiang L², Sherwin R¹  ¹Yale School of Medicine, New Haven, CT, United States, ²YSM, New Haven, CT, United States

OBJECTIVES: Repeated episodes of hypoglycemia (RH), a common problem associated with intensive insulin therapy in type 1 diabetes, increases the risk of severe hypoglycemia, which leads to brain energy deficit and potentially significant brain injury. METHODS AND POPULATION: To characterize the changes that follow RH exposure, we used NMR spectroscopy to measure 2‐13C‐acetate metabolism in rat brain. RESULTS: We observed a reduction of neuronal PDH flux during acute hypoglycemia, a key step regulating the entry of substrates into the TCA cycle under hypoglycemic conditions. Since PDH flux reduction can be mediated via pyruvate dehydrogenase kinase (PDK) we tested the impact of a PDK inhibitor, dichloroacetate (DCA) on metabolic responses. First control rats were given 200mg/kg DCA i.v. to establish whether DCA could increase brain PDH flux during 2‐13C‐acetate infusion. We observed a dramatic reduction of brain glutamate and glutamine labeling from acetate by 50% in spite of their normal concentrations in brain, suggesting that DCA did stimulate PDH flux and in turn promoted brain metabolism of other substrates like glucose and lactate. We next tested the impact of DCA in rats exposed to RH during a 50mU/kg/min hyperinsulinemic‐hypoglycemic clamp. DCA produced a dramatic change in the plasma labeling of ketones, which rose from 3.3% to 38%. Brain acetate utilization again was suppressed leading to a 50% reduction in brain neurotransmitter labeling indicating significant stimulation of metabolism of unlabelled fuels such as glucose and derived substrates by the brain. SIGNIFICANCE OF STUDY: We conclude that DCA increases brain TCA cycle fuel utilization during acute hypoglycemia in rats exposed to RH. These data suggest that DCA might have a neuroprotective effect in insulin treated diabetes.

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GENERATION OF CHIMERIC BRAINS VIA IN UTERO TRANSPLANTATION ‐A POWERFUL ASSAY TO STUDY THE POTENTIAL OF HUMAN INDUCED PLURIPOTENT STEM CELLS (IPSC)

Huttner AJ ¹   ¹Yale University Medical School, New Haven, CT, United States

OBJECTIVES: Recent progress in our understanding of somatic cell reprogramming, particularly the isolation and characterization of human induced pluripotent stem cells (iPSCs) opened new avenues for modeling human disease. Several groups described the isolation of patient/disease specific human iPSCs. However, to this date it is not clear whether iPSCs are capable of faithfully recapitulating disease specific phenotypes, which would allow modeling of pathogenetic mechanisms. The targeted differentiation of iPSC's into tissue specific cell types of the brain as well as the transplantation of immature precursor cells into an embryonic rodent model provides an unparalleled opportunity to recapitulate human pathologic disease processes. METHODS AND POPULATION: iPSC lines were derived from skin biopsy specimens, grown in culture and charcterized in vitro. The in vivo potential of neural progenitors will be tested through the generation of chimeric brains, in which the donor cells will individually integrate into a xenogeneic host brain without elicitation of trauma or immune response. The human neural progenitor cells will be deposited into the cerebral ventricles of E12 embryonic mice, providing free access to large areas of the neuroepithelium. RESULTS: The engraft‐ment of individual cells will allow an assessment of their ability to follow local microenviron‐mental cues, migrate, differentiate and contribute to various regions of the brain. SIGNIFICANCE OF STUDY: This model will provide significant insight into the pathogene‐sis of human forms of lissencephaly.

A‐219

THE HYPERDYNAMIC CIRCULATORY SYNDROME IN PATIENTS WITH LIVER DISEASES

Iwakiri Y ¹, Groszmann R¹  ¹Yale University School of Medicine, New Haven, CT, United States

OBJECTIVES: The objective of this study was to examine serum vascular endothelial growth factor (VEGF) levels in the early and late stages of liver cirrhosis in patients and correlate these data with arterial and portal pressures in those patients. METHODS AND POPULATION: VEGF levels were determined in serums collected from patients (n = 79) who are categorized either into the early stages of compensated cirrhosis (portal pressure of less than 10 mmHg) or the late stages of compensated cirrhosis (portal pressure of more than 10 mmHg), and compare them with those obtained from healthy subjects without liver diseases. RESULTS: We hypo thesized that there is a positive correlation between serum VEGF and portal pressure in liver cir‐rhotic patients. In contrast to our hypothesis, we found a negative correlation between these values (r2 = 0.07, P=0.018). SIGNIFICANCE OF STUDY: In experimental models of portal hypertension with cirrhosis, it has been shown that there is a significant increase in VEGF levels and that VEGF blockers ameliorates portal hypertension. Since our data suggested that there is a negative correlation between serum VEGF level and portal pressure in cirrhotic patients, the use of VEGF blockers for the amelioration of portal hypertension needs to be carefully considered.

A‐220

THE ROLE OF THE ONCOGENIC SPLICE VARIANT KLF6‐SV1 IN PROSTATE CANCER DEVELOPMENT AND PROGRESSION

Izadmehr S ¹, Narla G¹  ¹Mount Sinai School of Medicine, New York, NY, United States

OBJECTIVES: Metastatic prostate cancer is the most lethal male hormonal‐cancer. Mortality persists despite multiple treatments because prostate cancer frequently recurs or metastasizes. Identifying the molecular mechanisms that underlie prostate cancer recurrence or metastasis will, accordingly, decrease the health burden of prostate cancer. The Krüppel‐like zinc finger transcription factor (KLF6) is a tumor suppressor gene whose splice variant, KLF6‐SV1, is a dominant negative regulator of the wild type KLF6. To validate KLF6‐SV1 as a biomarker of prostate cancer progression and explore the correlation between KLF6 and KLF6‐SV1 expression levels and clinicopathological features we will functionally characterize KLF6‐SV1 in several cell culture and in vivo models of prostate cancer progression. METHODS AND POPULATION: Using a transgenic murine model that overexpresses KLF6‐SV1 and the proto‐oncogene c‐myc we will histologically characterize the prostate every eight weeks after birth up to one year. If we find invasive prostate carcinoma, then we will study other tissues for evidence of metastasis. At each time point, we will sacrifice one mouse from each of the following groups for interim analysis: 1) wild type 2) c‐myc 3) SV1 and 4) c‐myc/SV1 double transgenic mice. At necropsy, we will examine the animals for any gross pathology. RESULTS: This novel double transgenic mouse model will further the molecular and biological characterization of the determinants of prostate cancer development and progression by using clinically relevant biomarkers of prostate cancer progression from PIN to metastatic disease. SIGNIFICANCE OF STUDY: This model may create a test of the efficacy and tolerability of anti‐cancer agents. It also will generate preclinical data for us in future translational studies.

A‐221

PROGESTERONE INHIBITS CILIA BEAT FREQUENCY OF HUMAN AIRWAY EPITHELIAL CELLS

Jain R ¹, Ray JM¹, Brody SL¹  ¹Washington University, Saint Louis, MO, United States

OBJECTIVES: Previous studies have demonstrated a female disadvantage in airway diseases such as asthma and bronchiectasis. Little is known about the molecular basis or reasons for this gender disparity. Our objective was to determine if the female sex hormone, progesterone, inhibits function of the normal airway mucociliary apparatus by inhibition of cilia beat frequency (CBF), contributing to more severe airway disease in women. METHODS AND POPULATION: Human lung tissue and airway epithelial cells were obtained from lung transplant donors. Primary cells were cultured at air‐liquid interface. Expression of Progesterone Receptor (PR) was assayed by western blot. Cell specific expression of PR utilized immunostaining with a fluorescent label for co‐localization with cell‐specific markers. An inverted microscope with high‐speed video recording and customized software was used to determine CBF. All experiments were repeated in at least 3 male and female independent specimens. RESULTS: Expression of PR‐B isoform was detected by western analysis in all cell preparations and was more abundant than PR‐A. Immunostaining of lung tissue from men and women revealed PR expression in the cilia of airway epithelium, confirmed by co‐localization of PR with cilia‐specific protein, acetylated α‐tubulin. Incubation of primary airway epithelial cells with Progesterone resulted in a decrease in CBF by 42.3%± 7.2. Progesterone receptor antagonist, RU‐486, blocked this inhibition as did addition of 17β‐estradiol. SIGNIFICANCE OF STUDY: Progesterone receptors are expressed in the cilia of airway epithelium. Exposure to progesterone results in an inhibition of CBF in airway epithelium that can be blocked with RU‐486 and 17β‐estradiol. These findings suggest a mechanism underlying the female disadvantage in airway disease.

A‐222

ELECTROPHYSIOLOGICAL AUTONOMIC MARKERS OF NEURODEGENERATION IN THE PUPILLARY AND CARDIOVASCULAR SYSTEMS IN PARKINSON DISEASE

Jain S ¹, Siegle G¹, Steinhauer SR^2,1, Jennings JR¹, Studenski SA¹, Greenamyre JT¹  ¹University of Pittsburgh, Pittsburgh, PA, United States, ²VA Pittsburgh Healthcare System, Pittsburgh, PA, United States

OBJECTIVES: PD neuropathology suggests neurodegenerative changes begin in peripheral autonomic structures and spread centrally along autonomic pathways. We therefore predict sequential changes in autonomic physiology in multiple organ systems which if quantified can serve as markers of PD progression. METHODS AND POPULATION: Pupillary and cardiovascular autonomic function was assessed in 28 participants (13 PD, 15 controls). Pupil constriction and redilation velocity was measured during the light reflex. ECG measures were respiratory sinus arrythmia, Valsalva Ratio and spectral power in low (0.04‐0.15Hz) and high (0.15‐0.40 Hz) frequency bands at rest. RESULTS: In PD, lower constriction velocities (PD vs. age and sex‐matched controls: 4.28 vs. 4.53mm/s, effect size (ES)=0.21) and higher redilation velocities (0.33 vs. 0.23,ES=0.64) were observed suggesting lower parasympathetic and higher sympathetic pupillary output respectively. Respiratory sinus arrythmia (7.67 vs. 13.81,ES=1.10), Valsalva ratio (1.53 vs. 1.62,ES=0.41) and spectral power in low (0.83 vs. 1.32,ES=0.63) and high frequency bands (0.31 vs. 0.73,ES=0.92) were all lower in PD suggesting lower parasympathetic and possibly lower sympathetic cardiovascular function in PD. SIGNIFICANCE OF STUDY: To our knowledge, this is the first report of simultaneous recordings of pupillary and cardiovascular autonomic function in PD. Findings cannot be explained by lesions is a single pathway and suggest physiological correlates to widespread PD neurodegenerative pathology in both central and peripheral nervous system structures.

A‐223

A KEY ROLE FOR OREXIN/HYPOCRETIN IN PANIC ANXIETY

Johnson PL ¹, Truitt W¹, Fitz SD¹, Minick P¹, Dietrich A¹, Sanghani S¹, Traskman‐Bendz L², Goddard A¹, Brundin L², Shekhar A¹  ¹Indiana University School of Medicine, Indianapolis, IN, United States, ²Lund University Hospital, Lund, Sweden

OBJECTIVES: Panic disorder is a severe anxiety disorder with recurrent panic attacks that can be reliably triggered with mild interoceptive stimuli such as intravenous sodium lactate (NaLac). In a preclinical panic model, chronic activation of the dorsomedial/perifornical hy‐pothalamus (DMH/PeF) of rats produces anxiety‐like states and a similar vulnerability to NaLac‐induced cardioexcitatory responses. The neuropeptide orexin/hypocretin (ORX) is almost exclusively synthesized in the DMH/PeF and adjacent lateral hypothalamus and plays a critical role in arousal, vigilance and central autonomic mobilization, which are key components of panic. Our hypothesis is that a hyperactive ORX system leads to anxiety and panic vulnerability. METHODS AND POPULATION: Using the preclinical panic model, ORX's role in panic anxiety responses was assessed in a series of 9 experiments coupled with immunohisto‐chemistry, gene silencing and pharmacology. For the human translational study, ORX concentrations in cerebrospinal fluid were radio‐immunoassayed from 53 medication free subjects that were assessed for panic anxiety using the comprehensive psychopathological rating scale. RESULTS: Here, we demonstrate that ORX neurons are hyperactive in panic‐prone rats, and either silencing the hypothalamic ORX gene product or systemic ORX1 antagonists blocks anxiety and the panic responses to NaLac. Moreover, we show that subjects with panic anxiety have elevated levels of ORX in the cerebrospinal fluid compared to subjects without panic anxiety. SIGNIFICANCE OF STUDY: Our results suggest that over activity of the ORX system may be a key component in the pathophysiology of panic anxiety, and that ORX antagonists constitute a potential novel treatment strategy for panic attacks and anxiety.

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MONOCYTE DYSREGULATION IS INDUCED BY NEF EXOSOME ENDOCYTOSIS

Johnson KL ¹, Bo‐Huang M¹, Ali SA¹, Roth B¹, Shelton M¹, Powell M¹, Bond VC¹  ¹Morehouse School of Medicine, Atlanta, GA, United States

OBJECTIVES: CD4+ T cell depletion and dysfunction are hallmarks of HIV infection but the mechanisms leading to such depletion/functional impairment are not fully understood. Our lab has shown that the protein Nef produced by both HIV and SIV has the capacity to direct its secretion via an exosomal pathway. Furthermore direct contact between Nef exosomes secreted by Nef transfected or HIV‐1 infected cells induces apoptosis in CD4+ T cells via activation of the CXCR4 receptor. Soluble Nef has also been found in plasma of HIV‐1 infected patients. Alternatively, our studies have shown that Nef vesicles are taken up in a Nef‐dependent and CXCR4‐independent manner. CXCR4 negative cells do not display apoptotic effects observed in CXCR4 positive cells. However, uptake of Nef could lead to unscheduled activation or dys‐regulation of gene expression. We hypothesize that Nef vesicles will have immune disruptive effects on uninfected monocytes. We will test this hypothesis through the following aims: AIM I: Examine the mechanisms underlying entry of Nef vesicles into cells. AIM II: Examine the effects of Nef vesicle uptake by cultured monocytes. AIM III: Correlate the quantity of Nef vesicles in HIV‐1 positive patient plasma with dysregulation markers identified in uninfected monocytes from infected patients. METHODS AND POPULATION: Peripheral Blood Mononuclear Cells and plasma will be collected from a cohort of HIV‐1 infected patients at Emory University Hospital and the Ponce de Leon Clinic in Atlanta, GA. RESULTS: We anticipate a correlation between the quantity of Nef vesicles in HIV‐1 positive patient plasma and dysregulation in uninfected monocytes. SIGNIFICANCE OF STUDY: This line of investigation should elucidate one aspect of the effects of Nef vesicles on bystander cells, and lead to diagnostic markers for processes involved in immune disruption and AIDS.

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GENOME‐WIDE ASSOCIATION STUDY OF TOXICITY RELATED TO BREAST CANCER TREATMENT

Jorgenson E ¹, Kroetz D²  ¹UCSF, Emeryville, CA, United States, ²UCSF, San Francisco, CA, United States

OBJECTIVES: An increasing number of reports of significant findings from genome‐wide association studies in cancer are being published. The success of these studies illustrates the power and validity of this approach for identifying genetic causes of disease. To date, there are only a few published reports of genome wide association analyses (GWAS) in pharmacogenet‐ics. We are conducting a GWAS analysis of participants in a cooperative group study with robust toxicity phenotype data to investigate the association of genetic variants with toxicity in women treated with adriamycin/cyclophosphamide or paclitaxel. Objectives: 1) To identify genetic markers associated with the risk of developing neutropenia in adri‐amycin/cyclophosphamide‐treated breast cancer patients. 2) To identify genetic markers associated with the risk of developing peripheral neuropathy in paclitaxel‐treated breast cancer patients. METHODS AND POPULATION: This study utilizes information from 2058 women receiving adjuvant therapy for breast cancer. The goals of the study were: 1) To determine the equivalence of paclitaxel with doxorubicin/cyclophoshamide (AC) for disease‐free survival (DFS) and 2) To determine if longer therapy, 12 weeks, is superior to shorter therapy, 8 weeks, of either AC or paclitaxel for DFS. RESULTS: We anticIpate the identification of SNPs that contribute to toxicity in women treated with adriamycin/cyclophosphamide or paclitaxel. SIGNIFICANCE OF STUDY: The identification of SNPs that contribute to response and tox‐icity of the three widely used drugs studied here will lead to additional studies to understand the mechanism for these associations and to investigate the application of genetic information for the optimization of breast cancer therapy.

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CAUDATE ATROPHY ON MRI IS A CHARACTERISTIC FEATURE OF FTLDFUS

Josephs KA ¹, Whitwell JL¹, Parisi JE¹, Jack CR¹, Petersen RC¹, Dickson DW²  ¹Mayo Clinic, Rochester, MN, United States, ²Mayo Clinic, Jacksonville, FL, United States

OBJECTIVES: Frontotemporal lobar degeneration with ubiquitin immunoreactive inclusions (FTLD‐U) can be subdivided into those in which the ubiquitinated protein is the TAR DNA binding protein 43 (FTLD‐TDP) and those in which the ubiquitinated protein is the fused in sarcoma protein (FTLD‐FUS). We have observed severe caudate atrophy at autopsy in FTLD‐FUS, and hence we aimed to determine whether caudate atrophy on MRI is a feature that can distinguish FTLD‐FUS from FTLD‐TDP. METHODS AND POPULATION: From a cohort of 78 cases of FTLD‐U we identified all cases of FTLD‐FUS that had a volumetric antemortem head MRI (n = 3). Caudate and frontal lobe volumes were measured in all three cases using atlas based parcellation and SPM5, and were compared to 10 randomly selected cases of FTLD‐TDP. Total grey matter volumes were also calculated for all cases. RESULTS: The FTLD‐FUS cases had significantly smaller caudate volumes (p=0.01), similar frontal lobe grey matter volumes (p=0.74), but slightly larger total grey matter volumes (p=0.13) than FTLD‐TDP cases. Caudate volumes when corrected for total grey matter volume (p=0.01) or frontal lobe grey matter volume (p=0.01) were significantly smaller in FTLD‐FUS than FTLD‐TDP, and showed no overlap between groups. SIGNIFICANCE OF STUDY: Caudate atrophy on MRI appears to be significantly greater in FTLD‐FUS compared with FTLD‐TDP further supporting the separation of FTLD‐U into FTLD‐FUS and FTLD‐TDP. Severe caudate atrophy may be a useful clinical feature to predict FTLD‐FUS pathology.

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IMPAIRED THERMOREGULATION AND PAIN PERCEPTION IN PPT1‐KO MICE

Khaibullina AA ¹, GuptillV¹, Kenyon N², Middleton L¹, Quezado Z^1,3  ¹NIH/Clinical Center, Bethesda, MD, United States, ²Stetson University, DeLand, FL, United States, ³Children's National Medical Center, Washington, DC, United States

OBJECTIVES: Infantile Neuronal Ceroid Lipofuscinosis (INCL) is a devastating neurodegenerative disease characterized by lysosomal accumulation of autofluorescent material in neurons and other cell types. The disease is caused by palmitoyl‐protein thioesterase‐1 (PPT1) deficiency. We have shown that INCL patients have lower basal temperature and are at risk for hypothermia during anesthesia. In this investigation, we evaluated thermoregulation and ther‐mosensation in an animal model of INCL. METHODS AND POPULATION: WT and PPT1‐KO mice of two age groups were tested for their ability to regulate body temperature in a heat or cold challenge. To assess current vocalization thresholds we used a nociceptive assay that evaluates sensory nerve fibers with help of Neurometer. Real‐time RT PCR was used to study the expression of sensory receptors in skin, DRGs and CNS; as well as PGC‐1 alpha and UCP in brown adipose tissue. RESULTS: We observed in this study that older PPT1‐KO mice had a blunted response to the environmental temperature challenges. Current vocalization thresholds in C and A‐delta fibers were higher in PPT1‐KO mice as they aged, in comparison with their WT counterparts (P<0.05). The expression of the termosensonsory receptors of PPT1‐KO mice was lower in skin and DRGs, but not in spinal cords or brains. Moreover, the expression of both, PGC1‐alpha and UCP, in PPT1‐KO mice after the cold challenge was substantially lower that that of the controls. SIGNIFICANCE OF STUDY: Taken together, these results suggest that PPT1 deficiency in mice is associated with impaired thermoregulation that likely results from abnormalities in thermosensation and nociception that are more severe with aging and disease progression.

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DIFFUSION TENSOR MRI IN COMBAT‐RELATED TRAUMATIC BRAIN INJURY

Kim J ¹, Jorge RE¹  ¹University of Iowa, Iowa City, IA, United States

OBJECTIVES: Traumatic brain injury (TBI) has been described as the “signature wound” of Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). The significant association of posttraumatic stress disorder and mood disorders with a history of loss of consciousness suggest that subtle forms of brain damage may contribute to the genesis of neuropsychiatric illness. However, the pathophysiology of the mood and anxiety disorders following a combat‐related TBI has not been fully elucidated. The purpose of the present study is to investigate the neurobiological underpinnings of the neurobehavioral changes observed after combat‐related TBI. We assessed structural brain alterations in a group of veterans who had a TBI during active duty in OIF/OEF using diffusion tensor imaging (DTI) technique. METHODS AND POPULATION: We studied 17 male veterans who have sustained a closed TBI during deployment to OIF/OEF and 37 control veterans without experience of TBI. Integrity of major white matter (WM) fiber tracts was inferred by means of mean diffusivity (MD), radial diffusivity (RD), fractional anisotropy (FA) and volume ratio (VR) metrics. Group DTI images were statistically analyzed using the tract‐based spatial statistics method. RESULTS: TBI patients had significantly lower FA and higher VR, MD and PD values than controls in the following WM fibers tracts: left inferior longitudinal fasciculus (ILF), left superior longitudinal fasciculus, left retrolenticular internal capsule, and left sagittal stratum. The left ILF showed the greatest FA reduction in TBI group. SIGNIFICANCE OF STUDY: This study found evidence for WM injury in subjects with combat‐related TBI. Our results are somewhat different from previous mild TBI studies in civilian populations, which may be due to the different pathophysiological mechanism associated with blast injuries.

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PHENOTYPIC HETEROGENEITY IN GENETIC ASSOCIATION STUDIES FOR CORONARY ARTERY DISEASE

Kitsios G ¹, Dahabreh IJ¹, Trikalinos TA¹, Schmid CH¹, Kent DM¹  ¹Tufts University Clinical and Translational Science Institute, Boston, MA, United States

OBJECTIVES: Meta‐analysis of genetic association studies (GAS) for coronary artery disease (CAD) may be hampered by variation in phenotypic definitions across the component studies. We aimed to systematically assess the extent and impact of phenotypic heterogeneity in GAS included in meta‐analyses for CAD. METHODS AND POPULATION: A systematic literature search for large (n≥15 studies) meta‐analyses for CAD was conducted and all GAS in these meta‐analyses were reviewed. Phenotypic definitions, demographics of included populations, study‐design aspects and reported results were extracted and summarized. RESULTS: A database of 957 individual GAS involving 32 distinct variants in 22 genes was created. Case‐control design was most commonly used (85%), early‐onset disease was studied by 19% of GAS, and the populations studied mainly involved Caucasians (67%) and male patients (70%). The phenotypes used were variable and were classified in 3 major categories: acute coronary syndromes (ACS) (44%), angiographically‐documented disease (34%) and “broadly‐defined CAD”, not otherwise specified and forming a “wastebasket” category (22%). Formal statistical significance for association (p<0.05) was reported in 21%, 22% and 25% of GAS for each definition, respectively. In the subset of 120 GAS examining ACS as a subgroup of a broader phenotypic definition (including either of the other two definitions), differential directionality of effects between the examined definitions (“flip‐flops”) and disagreement on statistical significance were observed in 16 (13%) and 12 (10%) comparisons, respectively. SIGNIFICANCE OF STUDY: Substantial phenotypic heterogeneity exists in the GAS literature for CAD, although the impact of phenotypic definition on magnitude or consistency of associations remains to be fully defined.

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GELATION TIME OF A NEW HYDROGEL DRUG DELIVERY VEHICLE IN DIRECT PULP CAPPING TREATMENT

Komabayashi T ¹, Wadajkar AS³, Opperman LA¹, Bellinger LL¹, Dechow PC¹, Ahn C², Antich PP², Nguyen KT³  ¹Baylor College of Dentistry, Dallas, TX, United States, ²University of Texas Southwestern Medical Center, Dallas, TX, United States, ³University of Texas at Arlington, Arlington, TX, United States

OBJECTIVES: Direct pulp capping treatment is an alternate way of preserving the vital pulp and avoiding 22 million definitive root canal treatments annually. However, a satisfactory material for caries‐exposed inflamed pulp in permanent teeth is not currently available. Thus, a biologically‐based material that promotes the continued formation of a new dentin‐pulp complex is needed. This study aimed to examine the gelation time of a new hydrogel drug delivery vehicle in teeth in vitro. METHODS AND POPULATION: The hydrogel solution was prepared by mixing poly(ethylene glycol)maleate‐citrate (45% w/v), acrylic acid crosslinker (5% w/v), 2,2’‐Azobis(2‐methylpropionamidine) dihydrochloride photoinitiator (0.1% w/v), and deionized water. A magnetic micro stir bar was placed in 96 well plates, placed on a magnetic stir plate, containing the solution, and a visible light‐curing system was used for polymerization, which took place at very low speeds. Observation lasted until the bar ceased stirring, which is defined as gelation time. For each volume of solution (50, 100, 150, and 200 μL), the experiment was repeated ten times. RESULTS: The mean(SD) of gelation times (seconds) were 85.7(10.7), 91.6(10.5), 116.0(11.5), and 147.3(26.7) for 50, 100, 150, and 200 μL, respectively. The fitted linear regression was Time=57.85 + 0.42*Volume with R‐square=0.66. SIGNIFICANCE OF STUDY: In future studies, the hydrogel will be mixed with NSAIDs; a dog model and clinical trials will commence following bioengineering studies. If successful, many definitive root canal treatments will be avoided by using the new direct pulp capping material for caries‐exposed inflamed pulp.

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THE RELEVANCE OF NEUREGULIN‐1β IN CHEMOTHERAPY CARDIOTOXICITY

Ky B ¹, Sawaya H², Geisberg C³, Smith H³, Putt ME¹, Demichele A¹, Domchek S¹, Carver JR¹, Wiegers SE¹, Sawyer DB³, Scherrer‐Crosbie M²  ¹University of Pennsylvania School of Medicine, Philadelphia, PA, United States, ²Massachusetts General Hospital, Boston, MA, United States, ³Vanderbilt University, Nashville, TN, United States

OBJECTIVES: Cardiotoxicity is a major potential side effect of chemotherapy used in breast cancer. However, the current methods for discriminating patients at risk for cardiac dysfunction are poorly defined. We sought to determine the potential utility of circulating Neuregulin‐1β (NRG‐1β) in predicting trastuzumab‐induced cardiotoxicity. NRG‐1β is a cardioprotective growth factor that is mechanistically relevant to chemotherapy‐induced cardiotoxicity and necessary for the maintenance of cardiac function during states of increased stress. METHODS AND POPULATION: Breast cancer patients receiving doxorubicin followed by trastuzumab were prospectively recruited. Echocardiograms and measures of plasma NRG‐1β were performed at 3 timepoints: prior to doxorubicin, prior to trastuzumab, and after 3 months of trastuzumab. Changes in NRG‐1β were compared with changes in ejection fraction (EF) as determined by modified Simpson's biplane method RESULTS: Of the 12 patients, 1 experienced cardiac dysfunction, as defined by a decline in EF by >10% to <55%. In this patient, a significant 6‐fold increase in NRG‐1β over time was observed. In those who maintained normal cardiac function, absolute NRG‐1β levels were lower, with minor changes in serial measures. SIGNIFICANCE OF STUDY: Although preliminary, these data suggest that circulating NRG‐1β may be altered in patients at risk for trastuzumab‐ induced cardiotoxicity and provides potential mechanistic insight into the cardiotoxic effects of trastuzumab. Further study of NRG‐1β will define its clinical utility as a novel prognostic biomarker in chemotherapy‐induced cardiotoxicity.

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FOLLICLE STIMULATING HORMONE RECEPTOR VARIANTS IN WOMEN WITH ABNORMAL RESPONSE TO FSH

Lalioti M ¹, Zattas D¹, Gerasimova T¹, Anastasakis D¹, Seli E¹, Sakkas D¹  ¹Yale, New Haven, CT, United States

OBJECTIVES: Follicle stimulating hormone (FSH) mediates cyclic follicle growth and is used for controlled ovarian stimulation in the treatment of infertility. The ovarian response to FSH is variable and it has been partly attributed to two common variants of the FSH receptor (FSHR). In addition, we have identified four abnormal FSHR splicing products (three exon deletions and one intron insertion) in 37% (13 of 35) of women undergoing IVF. All alterations affected the extracellular part of the receptor. We focused on the splice variant lacking exon 2 (del ex 2) because it was only detected in women with reduced response to FSH. Our aim was to characterize the function of the variants in vitro. METHODS AND POPULATION: All variants were cloned in expression vectors and transfected into HEK293 cells. Elevation of intracellular cAMP in response to FSH was measured. The subcellular localization was determined by immunofluorescence and surface protein biotinylation. RESULTS: All splicing variants showed markedly decreased cAMP activation compared to controls. The wild‐type (wt) protein was mainly localized on the cell surface, as expected. In contrast, the splicing variants were localized on the plasma membrane and other intracellular compartments, indicating impairment of the cellular processing machinery. When coexpressed with the wt, the del ex 2 was capable of forming functional heterodimers with the wt but decreased its ability to stimulate cAMP production upon stimulation. SIGNIFICANCE OF STUDY: Our analyses show that FSHR variants can modify downstream signaling cascades and contribute to abnormal response to stimulation in certain women undergoing IVF. Elucidation of the signaling cascades of the mutant receptors, in combination with newly developed fertility drugs, could in the future lead to individualized treatments that target other effectors of folliculogenesis.

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PEPSIN ASPIRATION MARKER

Lee A ¹   ¹Mayo Clinic, Jacksonville, FL, United States

OBJECTIVES: The clinical and research diagnosis of gastric to pulmonary aspiration is currently lacking. Detection of pepsin in bronchoalveolar lavage (BAL) fluid may serve as a quantitative and sensitive marker of gastric to pulmonary aspiration. We aimed to determine the frequency and levels of pepsin detection across different respiratory disorders and in patients with gastroesophageal reflux or dysphagia. METHODS AND POPULATION: Subjects were consecutive patients (>20 years old) undergoing bronchoscopy for clinical indications. Standardized surveys on dysphagia, respiratory symptoms, and reflux were administered. Clinical data was extracted by a standardized chart review blinded to the pepsin data. Pepsin was measured by an enzymatic activity assay. Additional markers tested included amylase, lipase, and bilirubin. RESULTS: Thus far, 26 subjects have been recruited (mean age 68 years, 50% men). Pepsin was detected in 42% of the BAL samples (mean 27 ± 32 ng/ml). No significant differences were observed in patients with cough, reflux, or dysphagia. 3 were clinically identified as having aspirated (mean 53 ng/mL). 1 patient had a documented tracheoesophageal fistula and the highest pepsin level (118 ng/mL). Bilirubin was not detected in any, and lipase was detected in 4. Amylase was identified at significant levels in all samples (mean 3213 U/L ±4465). SIGNIFICANCE OF STUDY: A quantitative assay for pepsin in BAL appears feasible. Pepsin detection in BAL was highest when aspiration was clinically obvious, but its detection was common even when aspiration was not suspected. This suggests a significant underappreciation of aspiration both clinically and in research. Recruitment is ongoing to further explore the clinical relevance of the pepsin BAL as a marker for gastric to pulmonary aspiration. Its success will have significant implications in mechanistic/therapeutic trials, as well as to the clinician managing a patient with a respiratory disorder.

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NAVIGATING GENOME‐WIDE RESISTANCE MECHANISMS OF THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR) TYROSINE KINASE INHIBITOR (TKI) ERLOTINIB IN NON‐SMALL CELL LUNG CANCER (NSCLC)

Li T ¹   ¹UC Davis School of Medicine, Sacramento, CA, United States

OBJECTIVES: To gain molecular insights into acquired resistance mechanisms, we compared genome‐wide alterations in erlotinib‐resistant R#2 NSCLC cells to parental erlotinib‐sensitive H3255 cells using Affymetrix Human SNP 6.0 array. METHODS AND POPULATION: Ge‐nomic DNA from parental H3255 and resistant R#2 cells was isolated using the Qiagen DNeasy tissue kit. Genome‐wide gene expression was analyzed on Affymetrix SNP/CNV 6.0 array, which contains approximately 1 million probes each for the detection of single nucleotide polymorphisms (SNPs) and copy number variants (CNVs). Selected drug targets were validated using in vitro assays. RESULTS: 9,983 statistically significant alterations in SNPs and CNVs between the two cell lines were identified. Potential effects of these alterations on cellular processes were subsequently analyzed using a customized paring tool to extract information from the KEGG pathway and GO molecular classification databases. Significant alterations are simultaneously present in several core functional groups, including HER family, PI3K/AKT/mTOR, apoptosis, DNA damage control and cell cycle. The genomic expression of several drug targets, such as ERCC1 and TS gene expression for the cellular sensitivity to cis‐platin and pemetrexed, respectively, are validated in these cell lines. SIGNIFICANCE OF STUDY: The genome‐wide array assay is feasible in assessing genomic changes related to drug treatment. Ongoing studies are evaluating the feasibility of this genome‐wide array‐based assay in assessing biomarkers and elucidating resistance mechanisms to erlotinib using paired, serum tumor‐shed DNA banked from NSCLC patients enrolled in an investigator‐initiated clinical study (ClinicalTrials.gov Identifier: NCT00950365).

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METHAMPHETAMINE IMPAIRS COGNITIVE AND CEREBRAL FUNCTION AND ALTERS THE EXPRESSION OF NEUROIMMUNE FACTORS IN MICE AND HUMANS

Loftis J ^1,2, Huckans M^1,2  ¹Portland VA Medical Center, Portland, OR, United States, ²Oregon Health & Science University, Portland, OR, United States

OBJECTIVES: Methamphetamine (MA) addiction causes serious cognitive impairments that persist following remission. We used a translational approach to compare and integrate the behavioral, neuroanatomical and neurochemical changes accompanying MA use in mice and humans. METHODS AND POPULATION: Thirty‐two mice were administered MA or saline (7 days). Twenty‐four hours or 3 weeks following the last dose, mice performed cognitive testing and were euthanized. Blood and brain samples were analyzed for changes in cytokine and intracellular adhesion molecule (ICAM‐1) expression. In addition, 18 adults in early recovery from MA abuse and 19 controls completed a diffusion tensor imaging protocol, neurocognitive testing, and a blood draw. RESULTS: Mouse and human data converged to show that MA adversely affected cognitive performance across multiple domains. These behavioral impairments were accompanied by alterations in fractional anisotropy and concentrations of neu‐roimmune factors, such as ICAM‐1, interleukin (IL)‐2 and IL‐1β. Since ICAM‐1 is induced by cytokines and recruits leukocytes to tissue injury, increases in ICAM‐1 expression could facilitate the adhesion of leukocytes that produce toxic mediators thereby contributing to white matter damage and cognitive impairment. Consistent with this hypothesis, we found that the degree of MA‐associated white matter changes in humans significantly correlated with the length and quantity of MA use as well as aspects of cognitive function. SIGNIFICANCE OF STUDY: This translational investigation: (1) provided evidence for white matter injury accompanying MA‐induced cognitive impairment and (2) identified neuroimmune factors that could be further studied as potential targets for therapeutic intervention.

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BLOCKADE OF MONOACYLGLYCEROL LIPASE IMPAIRS PROSTATE CANCER CELL PATHOGENICITY

Lombardi DP ¹, Nomura DK¹, Cravatt BF¹  ¹Scripps Translational Science Institute, La Jolla, CA, United States

OBJECTIVES: Cancer cells undergo metabolic alterations that correlate with malignancy, including changes in glycolysis and lipid metabolism. In 2010, we identified monoacylglycerol (MAG) lipase (MAGL) as a highly up‐regulated serine hydrolase in aggressive ovarian, melanoma and breast cancer cells, where it controls a fatty acid network enriched in signaling lipids that promote cancer pathogenicity. MAGL catalyzes the hydrolysis of MAG to free fatty acids and glycerol. The objective of this study was to ask whether MAGL is also up‐regulated in aggressive, androgen‐independent prostate cancer cells, PC‐3 and DU145, compared to a non‐aggressive, androgen‐sensitive line, LNCaP. METHODS AND POPULATION: We inhibited MAGL by pharmacologic and genetic blockade in PC‐3 cells and measured cell invasion/migration with Transwell chambers and xenograft tumor growth in SCID mice. We analyzed the metabolome of MAGL‐inhibited cells using untargeted liquid chromatography‐mass spectrometry. RESULTS: In PC‐3 cells, pharmacologic and genetic blockade of MAGL resulted in decreased invasion, migration and tumor xenograft growth. Metabolomic analysis of MAGL‐inhibited cells revealed reductions in fatty acid levels and in other downstream lipids such as lysophosphatidic acid and elevations in the endocannabinoid (EC), 2‐arachidonoyl‐glycerol. Consistent with these data, the defects in migration with MAGL blockade were partially rescued by either palmitic acid or the EC receptor antagonist, rimonabant, and fully rescued upon addition of both. SIGNIFICANCE OF STUDY: Our data provide evidence that MAGL controls a central node bridging the EC signaling pathway and a diverse lipid metabolic network. The up‐regulation of MAGL could explain, in part, the association between obesity and cancer. Therefore, targeting MAGL may be a novel approach in controlling prostate cancer cell progression.

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GENE NETWORK ANALYSIS AND IDENTIFICATION OF LYMPHOMA PROGNOSIS MARKERS

Ma S ^1,2   ¹Yale University, New Haven, CT, United States, ²VA Connecticut Health Care System, West Haven, CT, United States

OBJECTIVES: Extensive biomedical studies have shown that clinical and environmental factors do not have sufficient predictive power for lymphoma prognosis. Developments of high throughput profiling technologies have made it possible to survey the whole genome and search for genomic markers with predictive power. Most existing studies treat genes as interchangeable functional units and ignore the inherent coordination among them. METHODS AND POPULATION: We describe the interplay among genes using the weighted co‐expression network. Here, nodes represent genes, and nodes are connected if the corresponding gene expressions have similar patterns across samples. There are subsets of nodes, called modules, that are tightly connected to each other. RESULTS: We develop a network based marker selection method, which can identify not only influential gene modules but also influential genes within them. The proposed method is the first to conduct “two‐level” selection in network analysis. We analyze three lymphoma prognosis studies. New markers missed by using alternative methods are identified. We find that, by incorporating the gene network structure, the newly identified markers have superior prediction performances. SIGNIFICANCE OF STUDY: Gene network contains important information on the functionality of genes at the system level. Network measurements, for example connectivity, can be used to improve the identification of prognostic markers.

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MUC1‐ASSOCIATED PROLIFERATION SIGNATURE PREDICTS OUTCOMES IN LUNG ADENOCARCINOMA PATIENTS

MacDermed DM ¹, Khodarev NN², Pitroda SP², Edwards DC³, Pelizzari C², Kufe DW⁴, Weichselbaum RR²  ¹The Scripps Research Institute, La Jolla, CA, United States, ²The University of Chicago, Chicago, IL, United States, ³The University of Chicago, Chicago, IL, United States, ⁴Harvard Medical School, Boston, MA, United States

OBJECTIVES: MUC1 protein is highly expressed in lung cancer. The cytoplasmic domain of MUC1 (MUC1‐CD) induces tumorigenesis and resistance to DNA‐damaging agents. We used a DNA array approach to characterize MUC1‐dependent transcriptional programs and examined their significance in lung cancer patients. METHODS AND POPULATION: We identified 254 genes that were differentially expressed in cell lines transformed by MUC1‐CD compared to control cell lines. We then employed statistical analysis to select a MUC1‐Associated Proliferation Signature (MAPS) that was highly prognostic in 441 lung adenocarcinomas from a publicly available database. The MAPS was further validated for prognostic significance in 84 lung adenocarcinoma patients from an independent database of patients treated with primary surgical resection. RESULTS: MAPS genes were found to be associated with proliferation and cell cycle regulation and included CCNB1, CDC2, CDC20, CDKN3, MAD2L1, PRC1 and RRM2. MAPS expressors (MAPS+) had inferior survival compared to non‐expressors (MAPS‐). In the initial data set, 5‐year survival was 65% (MAPS‐) vs. 45% (MAPS+, p < 0.0001). In the validation data set, 5‐year survival was 57% (MAPS‐) vs. 28% (MAPS+, p = 0.005). SIGNIFICANCE OF STUDY: The MAPS signature, comprised of MUC1‐dependent genes involved in the control of cell cycle and proliferation, is associated with poor outcomes in patients with adenocarcinoma of the lung. These data provide potential new prognostic biomarkers and treatment targets for lung adenocarcinoma.

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GENITAL SECRETIONS FROM HIV INFECTED WOMEN EXHIBIT DECREASED ACTIVITY AGAINST HSV‐2

Madan RP ¹, Torres M¹, Kim M¹, Keller MJ¹, Herold BC¹  ¹Albert Einstein College of Medicine, Bronx, NY, United States

OBJECTIVES: Genital tract mucosal immunity may be modified in the setting of HIV and could impact HIV shedding and acquisition of STI. We quantified endogenous antiviral activity and immune mediators in cervicovaginal lavage specimens (CVL) collected from sexually active, HIV infected and uninfected women ages 15‐24. METHODS AND POPULATION: Anti‐HSV‐2 activity in CVL was quantified by plaque assay, antimicrobial proteins were quantified by ELISA, and cytokines by Bioluminex. RESULTS: HIV+ subjects (n = 10) were older than uninfected subjects (n = 8) (21 vs. 17.5 years, p=0.02) but were similar for race, HSV‐1,2 serostatus, history of abnormal Pap smear in the past 6 months, and vaginal pH (p>0.05). All HIV+ subjects were Category A (asymptomatic), 2 subjects were infected perinatally, 2 subjects received HAART, median years from HIV diagnosis was 3.5, and median CD4+ T cell count was 548 cells/ml. 8 subjects HIV VL (median 2169 copies/ml). CVL from HIV uninfected women had significantly more activity against HSV‐2 than CVL from HIV+ women (70.33% inhibition vs. 40.1, p=0.046). CVL from HIV+ women had significantly lower concentrations of IL‐6 (p=0.03) and a trend towards lower levels of HNP1‐3 (p=0.18), lactoferrin (p=0.13), lysozyme (p=0.07), IgA (p=0.2), IL‐8 (p=0.18), and IFNy (p=0.08). For all subjects, anti‐ HSV‐2 activity in CVL correlated with HNP 1‐3 (r=0.89, p=0.001), lysozyme (r=0.82, p<0.001), and IL‐8 (r=0.54, p=0.03). SIGNIFICANCE OF STUDY: Young women with asymptomatic HIV infection may have local immune dysregulation in the genital tract resulting in diminished antimicrobial activity, lower levels of key immune mediators, and possibly increased risk of STI acquisition.

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EFFECTS OF ACUTE PSYCHOSOCIAL STRESS ON SINGLE MOTOR UNIT DISCHARGE BEHAVIOR DURING VOLUNTARY CONTRACTIONS AND INSTRUCTED REST

Stephenson JL¹, Christou EA², Maluf KS ¹

¹University of Colorado Denver, Aurora, CO, United States, ²Texas A&M University, College Station, TX, United States

OBJECTIVES: Elevated muscle activity in the presence of psychosocial stress is thought to increase the risk of chronic neck pain. This aim of this study was to determine the effects of acute psychosocial stress on the discharge behavior of trapezius motor units during voluntary contractions and periods of instructed rest. METHODS AND POPULATION: Feedback‐controlled voluntary contractions followed by 60s of instructed muscle rest were performed by 21 healthy women under low and high stress conditions. RESULTS: Stress was manipulated using a verbal math task combined with social evaluative threat which significantly increased perceived anxiety, heart rate, and blood pressure (P<0.001). Single motor unit discharge behaviors during voluntary contractions did not change across stress conditions (P>0.121). Estimates of AF were positive and similar across stress conditions (P=0.405). Significant peaks in the power spectra were present at 0‐0.5 Hz and 16‐32 Hz for motor units active during periods of instructed rest. The magnitude of these peaks was also similar across stress conditions (P>0.089). SIGNIFICANCE OF STUDY: Results indicate that psychosocial stress does not alter trapezius motor unit discharge behaviors during feedback‐controlled voluntary contractions in healthy women. Spontaneous discharge is commonly observed during periods of instructed rest, and is modulated at frequencies consistent with common synaptic input from both respiratory and cortical sources that is not affected by exposure to acute stress. Future studies will determine if women with chronic neck pain are more susceptible to stress‐evoked changes in motor unit activity than women without a history of musculoskeletal pain.

A‐241

ETHNIC DIFFERENCE IN PHYSIOLOGICAL RESPONSES TO FEAR

Martinez KG ¹, Franco JA¹, Zeydan M², Milad M², Quirk G¹ University of Puerto Rico, San Juan, United States, Harvard University, Boston, MA, United States

OBJECTIVES: This is the first study to evaluate differential physiological responses between Hispanics and Caucasians during a fear learning and extinction protocol. METHODS AND POPULATION: We included 78 healthy subjects (39 Hispanics from UPR and 39 Caucasians from Harvard University) that were matched by sex, age and educational level. The experiment consisted of a fear learning task where subjects were taught that a specific colored light would be paired to an electrical shock (conditioning) and were then taught that this association was no longer true (extinction). Subjects were tested again the next day to assess the strength of the conditioning and extinction memory. Our fear measure was the skin conductance response (SCR). Averages of SCR measures were calculated for the Hispanic and Caucasian groups. Differences in SCR between the groups were evaluated using multiple comparison AN OVA. Individual phase differences between the groups was then evaluated using Scheffe's post‐hoc test. RESULTS: Hispanic males presented increased SCR throughout the whole experiment (F (1,36)=14.57; p=0.001) as compared to Caucasian males. Hispanic males showed increased SCR during habituation (p=0.003), less extinction of fear (p=0.006) and more renewal of fear (p=0.0001) than Caucasian males. In females, no statistically significant differences were found in physiological phases between the two ethnic groups. SIGNIFICANCE OF STUDY: Puerto Rico males showed increased physiological fear responses compared to a non‐Hispanic group in Boston. This increased arousal may be clinically relevant given the increased risk for PTSD seen in Hispanic male combat veterans. These findings emphasize that ethnicity should be taken into consideration in fear learning and extinction protocols.

A‐242

PHENOTYPING THE BLEEDING HISTORY OF NORMAL INDIVIDUALS USING AN ONTOLOGY‐BACKED, WEB‐BASED INSTRUMENT

Mauer AC ¹, Barbour EM¹, Khazanov N¹, Levenkova N¹, Mollah SA¹, Coller BS¹  ¹Rockefeller University, New York, NY, United States

OBJECTIVES: The bleeding history is vital to the evaluation of bleeding disorders but no standards exist for obtaining an optimal history. As a first step, we created a comprehensive questionnaire of bleeding symptoms, mapped it to an ontology, and developed a Web‐based Pheno‐type Recording Instrument (PRI). METHODS AND POPULATION: We used the PRI to collect bleeding symptoms from 500 healthy subjects: mean age 43 (range: 19‐86); 317 (63%) female; 187 (37%) African‐American, and 96 (19%) Hispanic. Logistic regression was used to investigate the influence of age, sex, race, and ethnicity on symptoms. RESULTS: The overall frequency of epistaxis was 24.8% and the reported frequency decreased with age (p<0.001). Women reported more easy bruising (23.7 vs. 7.1%, p<0.001) and venipuncture bruising (9.5 vs. 3.3%, p=0.013) than men. When compared to Caucasians, African‐Americans reported less epistaxis (17.6 vs. 28.6%, p=0.012), less eye bleeding (3.2 vs. 10.3%, p=0.007) and more trauma bleeding (23.3 vs. 9.9%, p=0.015), while Asians reported less menorrhagia (26.5 vs. 46.8%, p=0.029) and multiracial subjects reported more menorrhagia (88.9 vs. 46.8%, p=0.029). No symptoms varied with Hispanic ethnicity. SIGNIFICANCE OF STUDY: By participating in our IRB‐approved bleeding history data repository (http://ds9.rockefeller.edu/RUBHPSR/), investigators can access the PRI and our data on normal subjects, as well as upload their de‐identified clinical and laboratory data into a master database that they and others can query. We anticipate that combining data from multiple users using the PRI will increase the power to detect scientifically and medically important correlations.

A‐243

A TRIPLE DRUG REGIMEN FOR TRIPLE NEGATIVE BREAST CANCER

Maurer MA ¹, Hershman D¹, Parsons R¹  ¹Columbia University, New York, NY, United States

OBJECTIVES: Targeting the EGFR, PTEN and DNA damage pathways simultaneously with the EGFR inhibitor erlotinib, the TORC1 inhibitor temsirolimus, and cisplatin may provide therapeutic benefit in a definable subset of triple negative breast cancer (TNBC) patients. METHODS AND POPULATION: Before testing this hypothesis, preclinical testing and a Phase I trial must be performed. AIM 1: assess the triple drug combination for dose and schedule synergy and confirm effectiveness in xenograft mouse models; AIM 2: Phase I dose escalation trial in patients with advanced solid tumors: 1) characterize the combined toxicity and identify the maximal tolerated doses, 2) measure drug target inhibition from analysis of skin biopsies correlated with pharmacokinetic measurements and 3) perform proof‐of‐principle candidate biomarker measurements (EGFR, PI3K, KRAS, PTEN, p53, p63, p73). RESULTS: Preclinical testing may reveal the potential use of these medications in combination to inhibit TNBC tumor cell growth and delay outgrowth of resistant clones. Given that rash is the anticipated DLT, patients will be given prophylactic doxycycline. The anticipated MTDs are temsirolimus 25 mg given with cisplatin at 30 mg/m2 both on day 1 and 8 of 21 day cycles and erlotinib given daily at 100 mg. SIGNIFICANCE OF STUDY: Targeting EGFR has been a disappointment in TNBC patients, which is likely due to simultaneous inactivation of PTEN, which leads to the activation of PI3K and mTOR signaling. Preclinical studies show that 1) resistance to EGFR‐targeted therapy is reversed when PTEN signaling is restored with mTOR inhibition, and 2) TNBC cells with high expression of p63 and p73 and defects in BRCA1 pathway DNA repair are sensitive to cisplatin. Given their poor prognosis, understanding how targeted therapies interact with these tumors may have a significant impact.

A‐244

CATABOLISM OF ALZHEIMER'S AMYLOID‐BETA: IMPLICATIONS FOR BRAIN CLEARANCE AND PLAQUE DEPOSITION

McIntee FL ¹, Neubert T¹, Blais S¹, Ghiso J¹  ¹New York University School of Medicine, New York, NY, United States

OBJECTIVES: Alzheimer's disease (AD) is the leading cause of dementia and the most common form of amyloidosis in humans. Extensive extracellular deposition of amyloid‐β (Aβ), a 40‐42 amino acid degradation product of APP, is considered a hallmark feature of AD. Our attention is focused on the highly heterogeneous biochemical nature of the brain Aβ species. METHODS AND POPULATION: We have fractionated water‐soluble, detergent‐soluble and formic acid‐solube Aβ species from transgenic mouse models of amyloid deposition and AD cases. Subsequently, we applied a combination of biochemical techniques including immunoprecipitation followed by identification of Aβ fragments with a novel highly sensitive matrixassisted laser desorption/ionization time‐of‐flight mass spectrometry technique. RESULTS: Our biochemical data on the Aβ species present in sporadic and familial AD cases and in transgenic mouse models highlight the presence of similar N‐ and C‐terminally truncated fragments –likely reflecting the ability of multiple proteases to degrade Aβ in situ– and several post‐translational modifications with still unclear roles in the amyloidogenesis mechanism. Notably, not all the brain Aβ peptides have identical solubility properties. SIGNIFICANCE OF STUDY: In view of these findings and the growing evidence that an imbalance between Aβ production and clearance plays a major role in the process of Aβ deposition, we hypothesize that certain truncated and post‐translationally modified Aβ fragments have a distinct and opposite role in clearance and fibrillization mechanisms and that the spectrum and abundance of these species vary according to the magnitude of the amyloid load.

A‐245

INTACT NEURAL SPECIALIZATION FOR LETTERS BUT NOT FACES IN AUTISM

McPartland J ¹, Schultz R², Mayes L¹, Klin A¹  ¹Yale School of Medicine, New Haven, CT, United States, ²Children's Hospital of Philadelphia, Philadelphia, PA, United States

OBJECTIVES: Anomalies in face perception in autism may reflect reduced exposure to faces secondary to decreased social interest during development. This study contrasted neural and behavioral correlates of social and non‐social visual perception in autism and typical development. METHODS AND POPULATION: EEG was recorded from 36 children with autism and 18 typical peers while viewing social and non‐social “expert” vs. “non‐expert” stimuli (human faces vs. houses, Roman letters versus pseudoletters). Amplitude and latency were extracted for the N170 event‐related potential, and letter and face recognition were behaviorally assessed. RESULTS: In the right hemisphere, typical individuals displayed enhanced amplitude and decreased latency to faces compared to those with autism. Both groups showed comparably enhanced amplitude to familiar letters, with no between‐group differences. Children with autism exhibited impaired face recognition but comparable reading ability. SIGNIFICANCE OF STUDY: Children with autism exhibited slowed face processing and impaired face recognition. In contrast, they showed comparable performance and brain activity associated with letter perception. The observation of social perceptual deficits with intact non‐social functioning indicates focal dysfunction in social brain mechanisms. Results suggest preserved neural specialization when individuals with autism obtain sufficient exposure to a visual stimulus class. Findings support behavioral interventions designed to drive attention towards stimuli of relevance.

A‐246

HOST/VIRAL RISK FACTORS FOR HUMAN RHINOVIRUS INFANT ILLNESS SEVERITY

Miller E ¹, Williams JV¹, Gebretsadik T¹, Carroll K¹, Dupont W¹, Mohamed Y¹, Morin L¹, Heil L¹, Minton PA¹, Woodward K¹, Liu Z¹, Hartert TV¹  ¹Vanderbilt University Medical Center, Nashville, TN, United States

OBJECTIVES: Risk factors for severe human rhinovirus (HRV) associated illness in infants are not defined. METHODS AND POPULATION: We performed a prospective study of infants with acute upper(URI) or lower respiratory illness(LRI).The patient population included previously healthy term infants(≤12 months age)who required inpatient or outpatient care from Fall 2004‐May 2008.Illness severity was determined using an ordinal bronchiolitis severity score(BSS). Viral illness etiology was determined by realtime RTPCR for HRV and other viral etiologies;the VP4/VP2 gene from HRV positive specimens was sequenced to determine HRV species. RESULTS: Of 630 infants with LRTI or URI,159(26%) had rhinovirus detected among whom 118 had HRV alone;40% LRTI and 60% URI.Infant host factors associated with severity of HRV respiratory illness included maternal and family history of atopy(BSSmedian 3,IQR[1‐6.9]v1.2[0‐3.6],and BSSmedian 2.2[1‐6.9]v1.2[0‐3.0],respectively).Controlling for infant illness age,gestational age,race and gender,maternal history of atopy conferred an increase in bronchiolitis severity(OR=2.17,95%CI:1.10‐4.28).Among HRV‐positive specimens,35% were HRVA,5% HRVB,and 35% HRVC.Illness severity was not significantly different among HRV species. SIGNIFICANCE OF STUDY: HRV were detected frequently among previously healthy term infants with bronchiolitis or URI.Substantial genetic diversity was seen amongst the HRV detected,however,viral species was not found to be associated with illness severity.Host factors,including maternal atopy were associated with more severe infant HRV illness.

A‐247

MODAFINIL EFFECTS ON COGNITION IN SCHIZOPHRENIA: A DOSE‐RANGING STUDY

Minzenberg M ¹, Carter CS¹  ¹UC Davis, Sacramento, CA, United States

OBJECTIVES: Schizophrenia is characterized by deficits in various cognitive processes, which are modulated by central catecholamine systems, and strongly predict functional outcome in this illness. Therefore, pharmacologic agents which enhance dopamine and norepinephrine neurotransmission should have efficacy for these deficits. We addressed this question with a dose‐ranging study of modafinil, a combined norepinephrine/dopamine transport (NET/DAT) inhibitor, and compared different measures of cognition. METHODS AND POPULATION: 20 clinically‐stable outpatients with schizophrenia performed a within‐subjects test of single doses of 0, 100, 200 and 400 mg oral modafinil. Dose order was randomized and double‐blind. Subjects performed the cognitive battery between 2‐5 hours after dosing. RESULTS: To date, the patients show significant positive medication effects on performance on measures of working memory, episodic memory and cognitive control, in addition to practice effects observed on most of these cognitive measures. SIGNIFICANCE OF STUDY: Enhancement of catecholamine neurotransmission with transport inhibitors has efficacy in single doses for the cognitive deficits of schizophrenia. Further work is needed to address the relationship of single‐dose to sustained treatment effects, the specificity of cognitive processes involved (including their neural basis), and the best measures (both cognitive and neuroimaging) to detect these effects.

A‐248

THE ROLE OF MACROPHAGES AND T CELLS IN CARDIAC TRANSPLANT REJECTION

Moffatt‐Bruce SD ¹   ¹The Ohio State University Medical Center, Columbus, OH, United States

OBJECTIVES: Macrophages commonly present donor‐specific antigens via the indirect CD4 T cell pathway and produce chemokines which have poorly understood effects on T cell responses. Allograft rejection is likely a result of innate and adaptive processes. Our hypothesis is that macrophages are responsible for regulating the balance between T effector and T regulatory cell populations in acute cardiac rejection, ultimately resulting in allograft dysfunction. METHODS AND POPULATION: We will define the role of macrophages in regulating T cell infiltration in mouse cardiac allograft models of rejection. We will determine the requirement for chemokines for the infiltration of macrophages using KO mice, using laser capture microscopy and and blocking antibodies. The role of the innate immune system with respect to T cell mediated injury in human cardiac transplant recipients that experience both acute rejection and chronic rejection referred to as transplant related heart failure (TRHF) will also be determined. RESULTS: Using both an acute and a chronic cardiac allograft model we determined, using FACS, that macrophages are upregulated in the spleen when compared to naïve mice. Additionally, within the allograft there is significant macrophage staining in the acute rejection allografts and even more in the chronic rejection allografts. This increase correlated with a significant increase in MIG and IP‐10 in the acute rejection allografts and MIG in the chronic heart allografts. SIGNIFICANCE OF STUDY: Macrophages may be responsible for regulating the balance between T effector and T regulatory cell populations in allograft rejection. We intend to define the precise role of macrophages, the chemokines that mediate the process and the potential for manipulation, so to translate our findings to clinical heart transplantation.

A‐249

WTC PM2.5 STIMULATES A MORE INTENSE INFLAMMATORY RESPONSE IN HUMAN BAL CELLS THAN OTHER AMBIENT PM2.5 FROM NYC AND SURROUNDING ENVIRONS

Naveed B ¹, Weiden MD¹, Rom WN¹, Prezant DJ¹, Comfort A¹, Chen L¹, Kwon S¹, Chen Y¹, Gordon T¹, Nolan A¹  ¹New York University School of Medicine, New York, NY, United States

OBJECTIVES: Particulate matter (PM) exposure causes adverse health effects. The WTC collapse led to significant PM exposure and lung injury (Weiden et al. Chest 2009). The mechanism by which WTC PM causes pulmonary morbidity is not understood. We are investigating the differential cytokine effects on human alveolar cells, comparing ambient PM of WTC to ambient PM from NYC, South Bronx (SB) and Sterling Forest (SF), a rural area northwest of NYC. METHODS AND POPULATION: AM were obtained from Bronchoalveolar lavage (BAL) by adherence overnight. AM were exposed to 50μg/mL suspensions of WTC, SB, and SF PM2.5. Media alone was the negative control and 40 ng/mL of LPS was the positive control. After 24hrs, supernatants were collected and analyzed in duplicate using Human Cytokine Panel I (Millipore) on a Luminex‐200. RESULTS: Fold induction of mediators was expressed as ratios of PM exposure/media alone. Exposure to WTC PM was markedly more inflammatory than SB and SF. The most significant inductions were of the leukocyte growth factors (GM‐CSF, G‐CSF), a promoter of angiogenesis (VEGF), the chemokine (RANTES) and the potent multifunctional cytokine IL‐6. LPS caused a greater induction for all of the analytes when compared to WTC PM except for IL‐1ra. SIGNIFICANCE OF STUDY: WTC PM2.5 produces a marked inflammatory effect in comparison to PM2.5 from both NYC, SB and rural sites. The large number of cytokines induced by WTC PM may drive airway injury and may be biomarkers for lung injury. WTC PM has been observed in induced sputum obtained 9 months after 9/11/2001 and so the elaboration of cytokines may underlie the severe and long lasting health effects produced by exposure to WTC PM.

A‐250

CT‐BASED STRUCTURAL RIGIDITY ANALYSIS (CTRA) ALTERS THE COURSE OF TREATMENT IN PATIENTS WITH SKELETAL METASTASES

Snyder BD¹, Nazarian A ¹, Entezari V¹, Hipp JA², Calderon N², Damron TA³, Terek RM ⁴, Cheng EY⁵, Aboulafia AJ⁶, Anderson ME⁷, Gebhardt MC⁷

¹Beth Israel Deaconess Medical Sciences (BIDMC), Boston, MA, United States, ², Huston, TX, United States, ³, Syracuse, NY, United States, ⁴, Providence, RI, United States, ⁵, Minneapolis, MN, United States, ⁶, Baltimore, MD, United States, ⁷BIDMC, Boston, MA, United States

OBJECTIVES: Clinicians make subjective assessments regarding fracture risk using clinical guidelines now recognized to be inaccurate. We have developed and validated a CT‐based method to monitor the fracture risk associated with metastatic lesions. The aim of this study was to evaluate whether patient's treatment based on clinical guidelines was changed by CTRA. METHODS AND POPULATION: Axial, bending and torsional rigidities were calculated by summing the modulus‐weighted area of each pixel by its position relative to the centroid of the bone cross‐section. The orthopaedic oncologist was asked to select between observation, chemo/radiation, non‐invasive surgical stabilization, and intercalary allograft/prosthetic replacement based on the fracture risk assessment using Mirels’ score and then again after CTRA. RESULTS: Thirty patients (59.8 ± 13.7 y/o) with skeletal metastases to the appendicular skeleton were enrolled into the study. Treatment based on CTRA would have changed the initial treatment plan 50% of the time (16/32 cases). However, in 6 out of 16 cases, the clinician did not deviate from the original treatment plan although, CTRA indicated 5 of them were at high risk for fracture. SIGNIFICANCE OF STUDY: The results of the study suggest that CTRA will change treatment plan based on clinical guidelines half of the time. CTRA was most valuable in cases where bone destruction was moderate or osteoporosis coexisted.

A‐251

EXPLORATION OF DIABETES‐RELATED FACTORS IN NICARAGUAN ADULTS WITH OR AT‐RISK FOR DIABETES

Newlin K ¹, Melkus GD¹  ¹New York University, New York, NY, United States

OBJECTIVES: Although diabetes is the third leading cause of death in Nicaragua, few studies have examined diabetes‐related factors in Creole and Miskito adults with or at‐risk for type 2 diabetes (T2D) on the English‐speaking Atlantic coast. As part of a larger community‐based participatory research study, the purpose of this study was to explore diabetes‐related factors in adults with or at‐risk for T2D. METHODS AND POPULATION: Using a cross‐sectional design, a convenience sample of adults with or at‐risk for T2D was recruited. Measures of demographic (age, gender, and ethnicity); diabetes‐related (Pan American Health Organization Diabetes Survey and Risk Perception for Developing Diabetes); and clinical (A1c and BMI) factors were collected. Univariate statistics were computed. RESULTS: The sample (N=112) was comprised largely of Creoles (72.3%) and Miskitos (23.2%), who tended to be mid‐age (M=54.9, SD±16.4) women (77.8%). Most participants self‐reported a diagnosis of T2D (62.5%) and fewer T2D risk (27.5%). T2D participants had suboptimal glycemic control (M=10.6, SD±2.5) and elevated BMIs (M=31.7, SD±8.1). Most reported treatment (78%) to control their diabetes with medication exclusively (43%) or medication and lifestyle factors (35%). With respect to medication accessibility, most reported general availability of medications (78%) while a smaller percentage indicated affordability of medications (54%). Among those at‐risk for T2D, most tended to be obese (M=30.2, SD±6.0) with a majority indicating there is little to they can do to prevent diabetes (58%) and very modest control over risks to their health (83%). SIGNIFICANCE OF STUDY: Findings indicate introduction of diabetes self‐management and prevention education may help to effectively address the growing diabetes public health challenge on Nicaragua's Atlantic coast.

A‐252

ROLE OF THE IRF7 LOCUS IN HUMAN LUPUS

Salloum R¹, Franek BS¹, Kariuki SN¹, Rhee L¹, Mikolaitis RA², Jolly M², Utset TO¹, Niewold TB ¹  ¹University of Chicago, Chicago, IL, United States, ²Rush University Medical Center, Chicago, IL, United States

OBJECTIVES: Interferon alpha (IFN‐α) is a heritable risk factor for systemic lupus erythematosus (SLE). Studies have implicated genetic variation near interferon regulatory factor 7 (IRF7) in SLE susceptibility. SLE‐associated autoantibodies can stimulate IFN‐α production through the Toll‐like receptor/IRF7 pathway. We hypothesized that variants of IRF7 may cause risk of SLE by increasing IFN‐α production, and that autoantibodies may be important to this phenomenon. METHODS AND POPULATION: 511 SLE patients were studied, including 255 African‐American, 162 European‐American, and 94 Hispanic‐American patients. Serum IFN‐α was measured using a reporter cell assay. The rs4963128, rs12286521, rs702966, and rs2246614 SNPs in the IRF7/PHRF1 locus were genotyped. RESULTS: In European‐American subjects, rs702966C was associated with anti‐dsDNA antibodies (OR=1.81, p=0.030). The rs702966C allele was only associated with higher serum IFN‐α in European‐American and Hispanic‐American patients with anti‐dsDNA antibodies (p=0.0024 and p=0.0014 respectively). In African‐American subjects, anti‐Sm antibodies were associated with the rs4963128 SNP downstream of IRF7 (OR=1.92, p=0.0019). African‐American patients with anti‐Sm antibodies showed a dose‐response effect between rs4963128T and higher IFN‐α (p=0.0021). In African‐American patients lacking anti‐Sm antibodies, the anti‐dsDNA/rs702966C interaction upon serum IFN‐α was observed (p=0.0022), similar to the other ancestral backgrounds. SIGNIFICANCE OF STUDY: These data suggest that IRF7/PHRF1 genetic variants interact with SLE‐associated autoantibodies to result in higher serum IFN‐α, which subsequently results in risk of SLE.

A‐253

IL‐22 PRODUCING T CELLS ACCOUNT FOR UPREGULATED IL‐22 IN ATOPIC DERMATITIS DESPITE REDUCED TH17 CELLS

Nograles KE ¹, Zaba L¹, Shemer A², Duculan J¹, Cardinale I¹, Kikuchi T¹, Ramon M³, Bergman R³, Krueger JG¹, Guttman‐Yassky EG^1,4  ¹The Rockefeller University, New York, NY, United States, ²Tel‐Hashomer Medical Center, Ramat‐Gan, Israel, ³Rambam Medical Center and the Technion, Haifa, Israel, ⁴Cornell University, New York, NY, United States

OBJECTIVES: Atopic dermatitis (AD) and psoriasis vulgaris are common inflammatory skin diseases. While an upregulated Th17 signal has been demonstrated in psoriasis, the involvement of Th17 cells in AD has been unclear. We sought to compare the relative frequencies of T cell subsets in peripheral blood and skin lesions of patients with AD versus psoriasis. METHODS AND POPULATION: Skin biopsies and peripheral blood were collected from patients with chronic AD (n = 12) and psoriasis (n = 13), and examined by intracellular cytokine staining and flow cytometry. RESULTS: We found no significant difference between T cell subsets in peripheral blood of patients with atopic dermatitis versus psoriasis. In contrast, we found significantly increased frequencies of Th1 and Th17 cells in psoriatic lesions compared to AD, whereas Th2 cells were significantly elevated in AD. We found distinct IL‐22‐producing CD4+ and CD8+ T cells that were significantly increased in AD skin compared to psoriasis. IL‐22+CD8+ T cell frequencies correlated with AD disease severity. SIGNIFICANCE OF STUDY: IL‐22 is a cytokine commonly associated with Th17 cells. Our findings provide explanation for the elevated expression of IL‐22 in AD lesions despite decreased expression of IL‐17, and argue for a functional specialization of T cells such that Th17 and T22 cells may drive different features of epidermal pathology in inflammatory skin diseases. This may have important therapeutic implications as targeting T22 cells could potentially reverse epidermal hyperplasia and terminal differentiation observed in AD.

A‐254

CHARACTERISTICS OF NEUTROPHIL INFLAMMATORY MEDIATORS IN OLDER ASTHMA SUBJECTS

Nyenhuis S ^1,2, Schwantes E², Mathur SK²  ¹University of Illinois at Chicago, Chicago, IL, United States, ²University of Wisconsin, Madison, WI, United States

OBJECTIVES: We sought to assess age‐related changes in the function of the neutrophil in asthma. METHODS AND POPULATION: We recruited human subjects with mild to moderate asthma in two age groups: younger (20 to 40 years; n = 12) and older (50 to 70 years; n = 6). Baseline characterizations of lung function and sputum analysis were performed. Peripheral blood mononuclear cells (PBMCs) and neutrophils isolated from peripheral blood were stimulated with LPS and calcium ionophore (A23107) respectively and then examined by ELISA for interleukin‐8 (IL‐8), leukotriene B4 (LTB4), and neutrophil elastase activity (NE). Sputum samples were also analyzed for IL‐8, LTB4, and NE activity. Analysis of data was performed as a comparison between the younger and older age groups. RESULTS: Sputum analysis revealed a trend (p=0.08) towards a higher percentage of neutrophils in older asthma subjects. In vitro IL‐8, LTB4 production, and NE activity were comparable in both groups. Sputum analysis revealed a trend for higher NE activity (p=0.12) and IL‐8 levels (p=0.08). However, there was a significantly lower level of LTB4 (p=0.02) in the sputum of older asthma subjects. SIGNIFICANCE OF STUDY: We have defined an age‐related change in neutrophil function, specifically LTB4 production that may impact susceptibility to exacerbations in older asthma subjects.

A‐255

DIFFERENCES IN VASCULAR WALL PERMEABILITY BY MRI IN PRE‐MENOPAUSAL WOMEN WITH AND WITHOUT THE METABOLIC SYNDROME

Paramsothy P ¹, Knopp RH¹, Zhao X¹, Rue T¹, Gill EA¹, Kerwin W¹  ¹University of Washington, Seattle, WA, United States

OBJECTIVES: Cardiovascular disease (CVD) is the leading killer of American women. The Metabolic Syndrome (MetS) imparts a nearly 2 fold increased risk of CVD. MetS results in dyslipidemia and inflammation, both causal elements in the initiation and propagation of atherosclerosis. Atherosclerosis often takes decades before clinical manifestations are apparent and is not well understood in pre‐menopausal women with insulin resistance or MetS. Current knowledge is limited by an inability to see and understand early atherosclerosis in humans. The primary aim of the study is to determine if there are differences in vascular permeability, an early change in atherosclerosis, as measured by Ktrans ratio in MetS vs. metabolically normal pre‐menopausal women using Dynamic Contrast Enhancement Magnetic Resonance Imaging (DCE‐MRI). METHODS AND POPULATION: Pre‐menopausal women with and without MetS and without Diabetes Mellitus or CVD are being recruited. The carotid arteries of participants are imaged using high‐speed black‐blood DCE‐MRI sequence known as small Field‐of‐view quadruple inversion recovery (sfQIR). A standard blood curve of unit height is created allowing quantification of relative Ktrans in the vessel wall which is then divided by Ktrans of adjacent region of muscle to obtain a “Ktrans ratio.” Correlations of Ktrans ratio with serum markers of insulin resistance and inflammation will also be performed. RESULTS: We have completed 10/36 women. We anticipate that MetS will demonstrate increased Ktrans ratio compared to normal women. Ktrans ratio will correlate positively with markers of abdominal obesity, inflammation and insulin resistance. SIGNIFICANCE OF STUDY: If this pilot study is successful, the technology described will be used to evaluate changes over time and impact of treatment on vascular permeability prior to developing atherosclerosis and CVD.

A‐256

THE COMBINATION OF SUB‐MIC OF AMPICILLIN AND SUB‐MIC OF CLYS PHAGE LYSIN EFFECTIVELY KILLS METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS

Pastagia M ¹, Chahales P¹, Fischetti VA¹  ¹Rockefeller University, New York, NY, United States

OBJECTIVES: To test the synergistic effects of the staphylococci specific phage lysin, ClyS in vitro against MRSA strains in conjunction with resistant antibiotics. Our goal was to prove that the addition of sub minimum inhibitory concentrations (MIC) of ClyS to ampicillin could make it effective against MRSA strains. METHODS AND POPULATION: Activity of ClyS was tested via lytic assay in 96‐well microtiter plates using 2‐ fold dilutions of ClyS and MRSA cells with an optical density of 0.8. We studied the effects of ClyS in combination with ampi‐cillin in an in vitro agar plate model against MRSA cells. Overnight plating experiments and time kill assays were done on trypticase soy agar plates swabbed with MRSA cells 1x 10 to the eighth + ClyS (MIC 40 μg/ml) suspended in 20 mMol phosphate buffer. A control plate contained MRSA cells + equivalent volume of phosphate buffer alone. Additional agar plates were swabbed with MRSA and (i) ClyS + ampicillin, (ii) buffer + ampicillin. For the synergy studies, ClyS and ampicillin concentrations were 0.5 of their respective MIC. Plates were incubated overnight at 37 degrees C. RESULTS: ClyS alone was effective against MRSA strains as compared to buffer alone. At 0.5 MIC, the addition of ClyS to ampicillin resulted in MRSA colony count being diminished by 98% as opposed to the buffer + ampicillin combination. SIGNIFICANCE OF STUDY: ClyS alone shows good activity against MRSA. Using ClyS with ampi‐cillin, at sub‐MIC concentrations, conferred ampicillin susceptibility. The ability of ClyS to resensitize resistant antibiotics may be of great value clinically in the future. Studies are currently underway to determine the efficacy of ClyS in vivo.

A‐257

PROTEOMIC APPROACH TO ELUCIDATE MECHANISM OF STEROID RESISTANCE IN EOSINOPHILS IN THE COURSE OF SEVERE ASTHMA

Pazdrak K ¹, Straub C¹, Kurosky A¹  ¹University of Texas Medical Branch, Galveston, TX, United States

OBJECTIVES: Our long term objectives is firstly to elucidate mechanisms relating to the insensitivity of eosinophils to GC in the course of severe and/or steroid resistant asthma and secondly identify potential biomarkers of asthma phenotypes for the purpose of differential medical treatment. METHODS AND POPULATION: Our project will integrate clinical data obtained from asthmatic patients with proteomic data discovered in our proteomic facility and processed using bioinformatics tools. To this end we plan to use a proteomics approach to analyze phenotypes of eosinophils obtained from patients with steroid sensitive (mild to moderate) asthma and GC resistant (severe) asthma. RESULTS: We have recently identified the altered expression of the FPR2 receptor on eosinophils exposed to IL‐2 and IL‐4, two cytokines distinctively expressed in the airways of severe asthmatics. Since FPR2 transduces the anti‐inflammatory effects of GC, its downregulation upon IL‐2/4 stimulation, may provide new insights into mechanisms of steroid resistance. We have recently established a two‐dimensional proteome map of blood eosinophils and have indentified 3,141 proteins by matrix‐assisted laser desorption/ionization time‐of flight analysis, representing 426 nonreduntant distinct proteins. Of these, 268 were not previously reported to occur in eosinophils. Thus, our studies are designed to perform comparative proteomics of eosinophil activated in vivo. SIGNIFICANCE OF STUDY: This is an important systemic study that will set the stage for protein profiling of various phenotypes of asthma characterized by sensitivity to GC treatment. Our functional proteomic approach to delineate the mechanism of steroid resistance in eosinophils may identify novel biomarkers and therapeutic targets useful in management of severe asthma.

A‐258

WEIGHT LOSS BY DIETARY INTERVENTION REDUCES INFLAMMATION IN COLORECTAL MUCOSA OF OBESE INDIVIDUALS

Pendyala S ¹, Holt PR¹  ¹Rockefeller university, New York, NY, United States

OBJECTIVES: To evaluate for changes in markers of inflammation in rectosigmoid mucosa with weight loss to gain insight into potential mechanisms contributing to increased colorectal cancer in obesity. METHODS AND POPULATION: 10 obese premenopausal women were studied at Rockefeller University Hospital before and after weight loss induced by a very low calorie (800 kcal) diet. Inflammatory end points were studied in rectosigmoid biopsies and serum obtained at baseline and after weight loss. Cytokines were measured by human proin‐flammatory 9‐plex assay (Mesoscale Discovery, MD). Immunohistochemistry was performed with CD3 and CD163 mouse antihuman antibodies, and the signal was amplified with avidin‐biotin complex (ABC). Cells were counted using NIH image J software. RESULTS: Subjects lost an average of 10.1% of their baseline weight in a mean of 46.5 days. Weight loss markedly reduced proinflammatory cytokines in the mucosa including TNF‐alpha(p=0.04),IL‐6(p=0.06),IL1‐beta(p=0.04) and IL‐8(p=0.01). Immunohistochemistry showed significant reduction in CD3 positive T cells(p<0.01)and CD163 positive macrophages(p=0.02)after weight loss. Weight loss decreased circulating cytokines modestly(9.1%‐15%). SIGNIFICANCE OF STUDY: Weight loss by dietary intervention reduced multiple markers of inflammation in the rectosigmoid mucosa implying the presence of low grade inflammation in the colorectal mu‐cosa of obese individuals. Reducing inflammation might be a potential target for colorectal cancer prevention in obese individuals.

A‐259

N‐ACETYLASPARTATE AND RECOVERY IN CHILDREN WITH TRAUMATIC BRAIN INJURY

Benzinger T¹, Hicks TM¹, Day T¹, Song S¹, Pineda JA ¹  ¹Washington University, St. Louis, MO, United States

OBJECTIVES: Traumatic brain injury (TBI) is a leading cause of death and disability among children. N‐Acetylaspartate (NAA), one of the most concentrated molecules in the central nervous system, is decreased in children with TBI. The etiology of this finding remains controversial: brain tissue loss or, alternatively, transient tissue dysfunction has been postulated. As opposed to permanent tissue loss, brain tissue dysfunction could constitute a therapeutic target. Primary Hypothesis: Among children with TBI, brain NAA reductions detected with MRI spectroscopy are transient and parallel severity of injury and functional recovery. METHODS AND POPULATION: Repeated measures non‐randomized prospective case‐control study including children with TBI (mild, moderate, severe) and control patients. Severity of injury was measured with the Glasgow Coma Scale and functional outcome with the WeeFIM score. NAA spectra were acquired using a 3T Siemens Allegra MR system. RESULTS: This study was approved by the IRB at Washington University. Preliminary data suggests that brain NAA concentrations are reduced after TBI in children (all severities). Furthermore, initial trends suggest this reduction is transient, supporting the hypothesis that decreased NAA concentration represents transient cellular dysfunction rather than permanent tissue loss. SIGNIFICANCE OF STUDY: MRI methods that permit reliable quantification of brain NAA concentrations may provide insights into the mechanisms of brain dysfunction after TBI. For example, NAA is normally produced by neuronal mitochondria. This information may help delineate potential therapies addressing mitochondrial dysfunction in children with TBI.

A‐260

ELECTROCARDIOGRAM‐BASED SLEEP SPECTROGRAM MEASURES OF SLEEP STABILITY AND GLUCOSE DISPOSAL IN SLEEP DISORDERED BREATHING

Pogach MS ¹, Punjabi NM², Thomas N¹, Thomas RJ²  ¹Beth Israel Deaconess Medical Center, Boston, MA, United States, ²Johs Hopkins University, Baltimore, MD, United States

OBJECTIVES: Sleep‐disordered breathing (SDB) is independently associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Experimental sleep fragmentation has been shown to impair insulin sensitivity. Conventional EEG‐based sleep quality measures have been inconsistently associated with indices of glucose metabolism. This analysis explored associations between glucose metabolism and an EEG‐independent measure of sleep quality, the sleep spectrogram, which maps coupled oscillations of heart rate variability and ECG‐de‐rived respiration. METHODS AND POPULATION: Non‐diabetic subjects with and without SDB (n = 118) underwent the frequently sampled intravenous glucose tolerance test (FSIVGTT) and a full‐montage polysomnography (PSG). The sleep spectrogram was generated from the ECG. RESULTS: Standard PSG stages (N1, N2, N3, and REM) were not associated with measures derived from the FSIVGTT including insulin sensitivity, acute insulin response to glucose, or the disposition index. In contrast, spectrographic high frequency coupling (a marker of stable sleep) was positively correlated, and very low frequency coupling (a marker of wake/REM/transitions) was negatively correlated with the disposition index after adjusting for age, gender, apnea hypopnea index and body mass index. Glucose effectiveness and the glucose effectiveness at zero insulin also correlated with very low frequency proportion and duration. SIGNIFICANCE OF STUDY: ECG‐derived sleep spectrogram measures of sleep stability are associated with alterations in glucose‐insulin homeostasis across the spectrum of SDB. This alternate mode of estimating sleep fragmentation may improve understanding of sleep and SDB effects on glucose metabolism.

A‐261

CAVEOLIN‐1, INSULIN RESISTANCE AND VASCULAR DYSFUNCTION IN HYPERTENSION

Pojoga L ¹, Underwood P¹, Williams J¹, Williams GH¹, Weiss ST¹, Adler GK¹  ¹Brigham and Women's Hospital/Harvard Medical School, Boston, MA, United States

OBJECTIVES: The genetic underpinnings of the association between insulin resistance (IR) and hypertension (HTN) are yet to be discovered. Caveolin‐1 (cav‐1) is involved in regulating intracellular pathways that affect insulin signaling and vascular function. Moreover, the cav‐1 gene was identified as a QTL for HTN and IR in humans, while cav‐1 deficient mice display HTN and altered insulin signaling. We hypothesize that the cav‐1 gene locus may contribute to the association of IR and HTN. The aims of this study were : (1) To determine whether the human cav‐1 gene variant rs926198 is associated with IR and vascular dysfunction; (2) To determine if cav‐1 ablation associates with IR and vascular dysfunction. METHODS AND POPULATION: Insulin and HOMA levels and angiotensin II‐induced changes in renal blood flow (ΔRBF) were assessed in 333 hypertensive and 144 normotensive non‐diabetic Caucasians. Multivariate associations with rs926198 were tested using a general linear model adjusted for potential confounders (age, gender, BMI). WT and cav‐1 KO mice were subjected to a glucose tolerance test (GTT). Two days later, animals were sacrificed and vascular reactivity was assessed in aortic rings. RESULTS: Hypertensive but not normotensive carriers of the rs926198 minor allele displayed higher HOMA and insulin levels and lower ΔRBF. As compared to WT, cav‐1 KO mice displayed exacerbated GTT responses, as well as significantly altered vasoreac‐tivity. SIGNIFICANCE OF STUDY: Hypertensive carriers of the cav‐1 rs926198 minor allele are associated with IR and vascular dysfunction. Cav‐1 ablation in mice is associated with IR and altered vasoreactivity. These data support the hypothesis that cav‐1 is involved in the etiology of both IR and HTN, likely by modulating signaling pathways in vascular cells and insulin sensitive tissues.

A‐262

A GENETIC DETERMINANT OF THE STRIATAL DOPAMINE RESPONSE TO ALCOHOL

Ramchandani VA ¹, Umhau J¹, Pavon F¹, Ruiz‐Velasco V¹, Margas W¹, Issa J¹, Sun H¹, Damadzic R¹, Eskay R¹, Schoor M¹, Thorsell A¹, Schwandt M¹, Sommer W¹, George DT¹, Parsons L¹, Herscovitch P¹, Hommer D¹, Heilig M¹

¹NIAAA, Bethesda, MD, United States

OBJECTIVES: Dopamine release in ventral striatum is critical for drug reward, but alcohol has a complex pharmacology, and humans vary greatly in their alcohol responses. The objective of this study was to determine if a functional mu‐opioid receptor polymorphism (OPRM1 A118G) influences dopamine response to alcohol. METHODS AND POPULATION: Healthy male social drinkers were screened to obtain two groups: (1) subjects homozygous for the major 118A allele (118AA); and (2) subjects carrying 1 or 2 copies of the variant 118G allele (118GX). Subjects were challenged in separate session with alcohol and placebo under pharmacokinetically‐controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]‐raclopride displacement. To directly establish the causal role of OPRM1 A118G variation, two humanized mouse lines carrying the respective human sequence variant were generated. Brain microdialysis was performed following alcohol challenge in these mice to evaluate differences in dopamine release. RESULTS: The 118GX group, but not the 118AA group, showed significant decreases in 11C‐raclopride binding potential in striatal regions, indicating greater dopamine release, following alcohol compared to placebo. The striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. Brain microdialysis in mice showed a four‐fold greater peak dopamine response to an alcohol challenge in h/mOPRM1‐118GG than in h/mOPRM1‐118AA mice. SIGNIFICANCE OF STUDY: OPRM1 A118G genotype is a determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward.

A‐263

SPHERICAL SILICON NANOPARTICLES DO NOT ENTER THE FETAL CIRCULATOIN DURING PREGNANCY

Refuerzo J ¹, Ramin S¹, Ferrari M¹  ¹University of Texas Health Science Center at Houston, Houston, TX, United States

OBJECTIVES: To determine whether spherical silicon nanoparticles (SSP) restrict its distribution to only the maternal circulation and thereby inhibit its entrance into the fetal circulation. METHODS AND POPULATION: Timed‐pregnant Sprague Dawley rats on GD20 were administered either SSP at 1.2 x 109 concentration or saline in 1 ml volume via jugular vein injection. The SSP are 1 micron diameter in size and tagged with fluorescein. Four hours later, la‐parotomy was performed and maternal organs, placentas and fetuses were retrieved. Silicon levels were measured in each organ using inductively coupled plasma atomic emission spectrometer. Silicon was qualitatively measured using fluorescence microscopy identifying the absence or presence of silicon within each organ. RESULTS: Six pregnant rats received the SSP and 4 received saline. Silicon concentrations were significantly higher in maternal liver in the SSP group compared to control, [SSP 64.95 ± 8.90 vs. Control 0.081 ± 0.02 mcg per 100 mg, p=0.0006]. Although the results are not available, similarly we expect there to be significantly increased silicon levels in the maternal heart, lung, spleen, kidney and uterus of the SSP group compared to control. In contrast, we anticipate similar silicon levels in the fetus of the SSP group and control. Qualitatively, we expect to visualize the SSP only within the maternal organs, and not the placental or fetal tissue using fluorescence microscopy. SIGNIFICANCE OF STUDY: SSP do not cross the placenta to the fetus and remain within the maternal circulation. These nanoparticles can therefore function as a vehicle to administer medications needed to treat pregnancy complications that are currently considered teratogenic.

A‐264

RNA DYSREGULATION IN MAJOR TDP‐43 DISEASES

Renwick N ¹, Akat K¹, Hafner M¹, Tuschl T¹  ¹Rockefeller University, New York, NY, United States

OBJECTIVES: Aim 1: Identify RNA targets and determine RNA regulatory functions of wild‐type and mutant TDP‐43 proteins in Flp‐In HEK‐293 and SH‐SY5Y cell lines. Aim 2: Assess miRNA regulatory networks in major TDP‐43 disease tissues and Flp‐In cell lines. Aim 3: Estimate sequence variation in TDP‐43 RNA‐binding regions and TDP‐43 and/or miRNA‐ targeted sites in persons with and without major TDP‐43 diseases. METHODS AND POPULATION: Study Populations: (1) 98 postmortem brain tissues obtained from 28 persons with major TDP‐43 diseases and 70 controls (2) genomic DNA from 1,411 persons with or at risk for Alzheimer Disease. Methods for each aim: (1) Identify RNA targets of TDP‐43 through Photoactivatible Ribonucleoside‐Crosslinking and Immunoprecipitation (PAR‐CLIP) and bioinformatic analyses. (2) Profile and quantify miRNA expression in major TDP‐43 disease and control tissues, and TDP‐43 Flp‐In cell lines. Perform miRNA in situ hybridization (ISH). Identify miRNA‐targeted transcripts using AGO‐CLIP. (3) Sequence the TARDBP gene and a PAR‐CLIP defined gene with hyperconserved target regions using nested multiplex PCR with barcoded pyrosequencing. RESULTS: (Aim 1) PAR‐CLIP has been performed on Flp‐In HEK‐293 cells that express wild‐type TDP‐43. (Aim 2) We have developed a barcoded small RNA sequencing method for simultaneous profiling of miRNAs in 20 clinical samples. (Aim 3) We developed a nested multiplex PCR assay with barcoded pyrosequencing to assess sequence variation in multiple DNA samples. SIGNIFICANCE OF STUDY: RNA dysregulation is likely a key pathogenetic mechanism in major TDP‐43 diseases, given that TDP‐43 is an RBP and involved in miRNA biogenesis. Identification of TDP‐43 and miRNA‐targeted transcripts and delineation of genetic determinants that contribute to RNA dysregulation are essential for understanding pathogenesis.

A‐265

THE DUKE TRANSLATIONAL RESEARCH INSTITUTE “RESEARCH SUPPORT SYSTEMS SURVEY” OF DUKE FACULTY TO IDENTIFY STRATEGIES FOR SUCCESS IN T1 RESEARCH

Reynolds B ¹, Sullenger B¹  ¹Duke University School of Medicine, Durham, NC, United States

OBJECTIVES: The goal of this project is to examine and delineate cultural and systemic measures that effectively support T1 research to maximize productivity and professional satisfaction. METHODS AND POPULATION: DTRI created a comprehensive on‐line, 130‐question survey to evaluate the research environment of Duke scientists. We surveyed the entire faculty of the Duke School of Medicine in clinical and basic sciences. The survey had faculty rate their agreement with a statement such as, “I receive ample mentoring” and the importance of each parameter. Despite the survey length, more than 50% of faculty responded (over 850 responses). Inclusion of names and affiliations was optional and respondents understood that data would only be reported in aggregate, which contributed to the high response rate. To evaluate many aspects of work culture, the survey was divided into Demographics, Professional Alignment, Collegial Relations, Departmental Leadership, Mentoring, Duke Medicine (Medical School leadership), Duke University (University leadership), and Work Segmentation to help understand responses in context. Free text sections allowed for comments on any topic. RESULTS: We anticipate that this approach will allow DTRI to understand the cultural and professional levers that promote job satisfaction and success in T1 research. It is hoped that insight gained will promote effective recruitment/retention of high‐impact T1 faculty and guide development of metrics to monitor T1 research effectiveness. SIGNIFICANCE OF STUDY: By implementing improvements recommended by the faculty, we feel that T1 research productivity, job satisfaction and retention will increase. The survey will be provided to CTSA members so that a general picture of the national T1 research environment can be assessed with possible Federal implications.

A‐266

INTEGRATING TECHNOLOGY TO IMPROVE THE COMMUNICATION PROCESS OF SUDDENLY SPEECHLESS HOSPITALIZED PATIENTS

Rodriguez CS ¹   ¹University of Florida, Gainesville, FL, United States

OBJECTIVES: To describe translational research concepts relevant to a research program directed to improve the communication process between suddenly speechless patients and hospital staff. METHODS AND POPULATION: Suddenly spechless hospitalized patients. RESULTS: Development of technology tailored to the needs of suddenly speechless hospitalized patients. SIGNIFICANCE OF STUDY: Hospitalized patients can become suddenly speechless (sudden inability to speak; SS) as a result of conditions such as head and neck surgery or trauma, tracheal intubation, or brain damage. In these situations familiar face‐to‐face communication methods are ineffective to communicate and result in significant challenges and frustration for both patients and hospital staff. Currently, hospitals do not have reliable and consistent methods to assist hospitalized SS patients with their communication challenges. These challenges may be solved effectively with the use of a speech generating device with features unique to the hospitalized SS patient. Translational research concepts relevant to the goal of improving the communication process between SS patients and hospital staff are described as followed: “bench to beside and back”‐information generated from preclinical studies related to the feasibility of integrating a technology oriented communication intervention to assist speechless patients in the hospital setting; development of technology and testing of ability and effectiveness to improve communication between SS patients and hospital staff (SBIR Phase 1 & 2); “ integration of best practices in the community”‐ adoption of evidence based guidelines/communication intervention in the acute care setting, and evaluation of the impact of the communication intervention in practice and other populations at risk.

A‐267

TISSUE FACTOR PRE‐MRNA UNDERGOES SPLICING BY ACTIVATED PLATELETS DURING SEPSIS

Rondina M ¹, Schwertz H¹, Harris E¹, Kraemer BF¹, Zimmerman G¹, Weyrich A¹  ¹University of Utah, Salt Lake City, U T, United States

OBJECTIVES: The transcriptome of human platelets includes the pre‐mRNA for Tissue Factor (TF). Upon activation, platelets demonstrate TF pre‐mRNA splicing to form a mature mRNA. Here we hypothesized that agonists present in the septic milieu activate platelets, inducing TF pre‐mRNA splicing and a procoagulant phenotype. METHODS AND POPULATION: We characterized platelet activation, TF pre‐mRNA, mature mRNA, and procoagulant activity in platelets from healthy subjects or septic patients and activated with bacteria, toxins, or platelet activating factor (PAF). RESULTS: Live bacteria adhered to platelets. Furthermore, agonists present in sepsis, including E. coli and S.aureus, α‐toxin, LPS, and PAF induced platelet activation and TF pre‐mRNA splicing in platelets isolated from healthy subjects. Membranes isolated from toxin‐stimulated platelets accelerated TF‐dependent clotting; this response was blocked with a TF pre‐mRNA splicing inhibitor or anti‐TF antibody. In parallel clinical studies, we also found that consistent with our in vitro data, platelets from 52% of septic patients expressed spliced TF mRNA. The odds of expressing spliced TF mRNA were higher in septic patients ≥ 65, with an APACHE II score > 20, bacteremia, and who did not survive their sepsis. TF‐dependent procoagulant activity was higher in platelets from septic patients compared to healthy controls. SIGNIFICANCE OF STUDY: Activation of splicing pathways in platelets by bacterial or host factors induces post‐transcriptional expression of TF mRNA and TF‐dependent coagulant activity. The septic milieu induces TF pre‐mRNA splicing in platelets in vivo and may be a novel marker for platelet activation in this syndrome.

A‐268

A LONGITUDINAL ASSESSMENT OF FGF23 MODULATION IN X‐LINKED HYPOPHOSPHATEMIC RICKETS

Ruppe M^1,2  ¹University of Texas Medical School at Houston, Houston, TX, United States, ²Shriners Hospital for Children, Houston, TX, United States

OBJECTIVES: The objective of the study was to create a prediction model of Fibroblast Growth Factor‐23 (FGF23) levels in an X‐linked hypophosphatemic rickets (XLH) cohort. METHODS AND POPULATION: Subjects with XLH were recruited. At outpatient visits, a history was taken, a clinical examination was performed and laboratory evaluation was obtained. Data on mutational status, inheritance pattern, kindred membership, sex, growth velocity, medication doses along with measurements of serum calcium, creatinine, phosphorus, alkaline phosphatase, intact parathyroid hormone level and urinary calcium, creatinine and phosphorus were obtained. FGF23 levels were measures using an intact assay (Kainos). A mixed effects model with nested clustering was developed. RESULTS: To date, thirty‐one subjects from 22 kindreds have been included. At the time of initial recruitment, there were 9 males and 22 females ranging in age from 18 months to 17 years and 6 months. Utilizing the developed statistical model, this preliminary investigation revealed a significant relationship between serum phosphorus (p= < 0.001) and inheritance status (p= 0.02). There was a predicted increase in FGF23 of 262 pg/mL (95% confidence interval 151‐373 pg/mL) for every unit increase in serum phosphorus. SIGNIFICANCE OF STUDY: XLH, the most common genetic form of renal phosphate wasting, is a disease of great clinical diversity with some patients having severe bone disease and extreme short stature while others are only mildly affected. FGF23 has been implicated as a leading contributor to the renal phosphate wasting but its regulation in XLH is poorly understood. Taken together these factors highlight our need to better understand the complex pathophysiology of XLH. This study will explore the clinical regulators of FGF23.

A‐269

VIRULENCE OF EMERGING STREPTOCOCCUS PNEUMONIAE SEROTYPE 6C IN EXPERIMENTAL OTITIS MEDIA

Sabharwal V ¹, Figueira M¹, Pelton SI¹, Pettigrew M²  ¹Boston University Medical Center, Boston, MA, United States, ²Yale University School of Public Health, New Haven, CT, United States

OBJECTIVES: To compare the capacity of Streptococcus pneumoniae serotypes 6C, 19A, and 15B/C to produce Experimental otitis media (EOM) in chinchilla animal model. METHODS AND POPULATION: Several 6C, 19A and15BC carriage and invasive isolates recovered from Massachusetts children were used in our EOM model, which employs initial nasopharyngeal colonization followed by barotrauma. The proportion of chinchillas that developed culture positive EOM, density of middle ear infection and proportion of chinchillas with bacteremia were compared. RESULTS: EOM was found in 28/82 (34%) ears challenged with 6C compared to 13/18(72.2%) challenged with 19A [p=0.0003] or 15B/C 38/47(81%) [p<0.0001]. Disease due to 6C was characterized by low density infection (∼10E2) when compared to 15B/C and 19A (∼10E4). Bacteremia was significantly less common in chinchillas challenged with 6C (5/41) compared to 15B/C (16/33)[p=0.001]. SIGNIFICANCE OF STUDY: Increases in colonization with nonvaccine serotypes have been observed among children immunized with the 7‐valent conjugate vaccine. Approximately 3% of children < 7 yrs are now colonized with serotype 6C. Limited data are available regarding the ability of 6C to cause acute otitis media. Our findings show that challenge with serotype 6C results in EOM less frequently compared to serotypes 19A and 15B/C. Infection with 6C is characterized by lower bacterial density (middle ear) and less frequent bacteremia. Serotype 6C has a lower capacity to produce EOM in our model.

A‐270

DEVELOPMENT OF AN INDOLEAMINE 2,3‐DIOXYGENASE (IDO) DEFICIENT MOUSE MODEL OF PREECLAMPSIA

Santillan M ¹, Pelham C¹, Ketsawatsomkron P¹, Santillan D¹, Yang B¹, Hunter S¹, Sigmund C¹  ¹University of Iowa, Iowa City, IA, United States

OBJECTIVES: In placentas of preeclamptic mothers, a deficiency in immunoactive indoleamine 2,3‐dioxygenase (IDO), is linked to placental dysfunction. IDO deficiency may contribute to vascular dysfunction as IDO utilizes superoxide anion to catabolize tryptophan. The objective of this study was to develop an IDO‐deficient mouse strain and to then to assess the cardiovascular effects of IDO‐deficiency. METHODS AND POPULATION: IDO‐/‐ mice were generated by ES cell gene targeting and then established on the C57BL/6 and 129SvEv background. C57 IDO‐/‐ females were mated with C57 IDO‐/‐ males. At gestational day 17 (GD 17), a 24h urine collection was performed to measure total protein concentration by BCA assay. At GD 18, the dams were sacrificed and aortic dose dependent vasodilatory responses to acetylcholine (Ach) and sodium nitroprusside (SNP) were determined utilizing an ex vivo vascular function assays. Syngeneically crossed C57 IDO+/+ females and males served as controls. RESULTS: C57 IDO‐/‐ (4333 ± 101 mcg/mL, n = 4) dams exhibited a significantly higher 24h urine protein concentration in comparison to pregnant C57 IDO+/+ (2976 ± 160, n = 3) dams (p<0.001). We observed a significant dose dependent reduction in the aortic vasodilatory response to Ach in C57 IDO‐/‐ dams.(n = 4) vs C57 IDO+/+ dams (n = 2). No difference in the response to SNP was observed. SIGNIFICANCE OF STUDY: IDO deficiency results in proteinuria and aortic endothelial dysfunction in pregnancy. We are examining the blood pressure in syngeneic and allogenic crosses of this model. These findings provide a basis to further investigate the IDO‐/‐ mice as an immunologically based model for preeclampsia.

A‐271

EVALUATION OF MICRORNAS IN CROHN'S DISEASE PATIENTS

Schaefer J ¹, Streckfus C¹, Graham D^2,3, Klein J¹  ¹The University of Texas Dental Branch at Houston, Houston, TX, United States, ²Baylor College of Medicine, Houston, TX, United States, ³Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, United States

OBJECTIVES: The inflammatory bowel diseases, Chrohn's Disease (CD) and ulcerative colitis (UC), are chronic inflammatory conditions characterized by an inability to regulate the immune response in the intestine, particularly within the colon. Several cytokines (IL‐17A) and cytokine receptors (IL‐23 receptor) are dysregulated in patients and mouse models of IBD. In patients, confirmation of diagnosis usually involves a combination of invasive procedures, thus illustrating the need for a more complete screening tool. The importance of microRNAs (miRNA), a class of small non‐coding RNA molecules that regulate gene expression via target gene post‐translational repression or degradation, in both normal and disease processes has been accumulating over the past few years. Dysregulated expression of some miRNAs has been linked to some diseases, both within the diseased tissue itself and the blood plasma; however, the role of miRNAs within CD colonic tissue and peripheral blood leukocytes (PBLs) is not well‐known. This is important because it validates that screening of PBL or plasma could be a diagnostic tool to ascertain disease presence, progression, or treatment efficacy. Therefore, evaluation of miRNAs could aid in the diagnosis and/or treatment of CD patients. METHODS AND POPULATION: Quantitative real‐time PCR has been used to examine miRNA expression in CD patients to determine if miRNA could be used as a diagnostic marker. RESULTS: We have identified several miRNAs that are dysregulated in both colon and PBL specimens from CD patients. SIGNIFICANCE OF STUDY: Findings from these studies are expected to lead to improved techniques for diagnosis and therapy of CD.

A‐272

MATERNAL IMMUNIZATION AND INFANT IMMUNITY TO INFLUENZA

Shakib JH ¹, Pavia AT¹, Varner MW¹, Byington CL¹  ¹University of Utah, Salt Lake City, UT, United States

OBJECTIVES: Determine whether the timing of influenza immunization or history of influenza infection in the mother affect the efficiency of maternal‐infant influenza antibody transport or duration of influenza antibody in the infant. METHODS AND POPULATION: We will conduct surveys of pregnant women at the University of Utah Obstetric and Gynecology Clinics at the 28‐week prenatal visit and at delivery regarding specific maternal factors, including history and timing of influenza immunization or infection. Influenza hemagglutina‐tion inhibition (HAI) titer levels for seasonal and novel H1N1 influenza A will be quantified in these pregnant women at 28 weeks and at delivery, and in their infants at delivery, 2 months, and 4 months of age. Infant influenza A HAI titers will be compared with maternal antibody levels at delivery to determine efficiency of maternal‐infant antibody transport. The duration of infant influenza A antibody will be correlated with maternal immunization or infection status. Our recruitment goal is 100 mother‐infant pairs. RESULTS: We anticipate that pregnant women who have had influenza immunization or infection in the second or third trimester of pregnancy will 1) have higher influenza antibody titers; 2) transfer these antibodies more efficiently to their infants, and 3) deliver infants with a longer duration of influenza antibodies compared with women without an immunization or infection history. SIGNIFICANCE OF STUDY: Young infants are at high risk for influenza and immunization strategies to protect them are a national priority. Alternative immunization strategies to protect infants younger than 6 months have not been thoroughly investigated. The results of this study will expand our understanding of transplacental immunity and inform future immunization trials.

A‐273

AUTONOMIC CONTRIBUTION TO OBESITY‐ASSOCIATED HYPERTENSION IN AFRICAN‐AMERICAN FEMALES

Shibao C ¹, Gamboa A¹, Diedrich A¹, Biaggioni I¹  ¹Vanderbilt University, Nashville, TN, United States

OBJECTIVES: Obesity affects nearly 30% of the US population and is a risk factor for hypertension. Those most affected, with the higher prevalence of obesity and hypertension, are African‐Americans, particularly women. Increased sympathetic activation has been associated with obesity and it may contribute to obese‐related hypertension, however blood pressure is poorly controlled with sympatholytics agents in hypertensive African‐Americans. We tested the hypothesis that the autonomic nervous system contributes less to blood pressure regulation in obese African‐Americans as compared to obese Caucasians. METHODS AND POPULATION: A total of 17 obese healthy females were studied (9 Caucasians, Age 37±4 years, BMI 35±1.2 Kg/m2, BP 125±5/74±4 mm Hg, and 8 African Americans, Age 35±2 years, BMI 34±0.9 Kg/m2,BP 126±7/74±4 mm Hg, P<0.05). The ganglionic blockade, trimethaphan, was infused at doses of 4 mg/min until complete autonomic blockade was achieved. RESULTS: Complete autonomic blockade with trimethaphan decreased mean arterial blood pressure (MAP) more in Caucasians (‐19±4 mm Hg as compared to African Americans (‐8±2 mm Hg, Figure 1). Intrinsic MAP, in the absence of autonomic influences, was higher in African Americans (83±6 vs 72±3 mm Hg in Caucasians, P=0.124). The decreased in MAP was negatively associated with the androgen to gynecoid ratio (A/G), an index of abdominal fat distribution (R=‐0.6, P<0.03). SIGNIFICANCE OF STUDY: We conclude that the autonomic nervous system contributes less to blood pressure regulation in African Americans as compared to Caucasians obese women.

A‐274

A NOVEL NON‐INVASIVE 3D ULTRASOUND IMAGING MODALITY FOR THE FUNCTIONAL ASSESSMENT OF THE RIGHT VENTRICLE USING 3D CORRELATION‐BASED SPECKLE TRACKING

Tripathy S¹, Simon MA ¹, Sacks MS¹, Brigham JC¹, Kim K¹  ¹University of Pittsburgh, Pittsburgh, PA, United States

OBJECTIVES: To validate a recently developed 3‐dimensional (3D) ultrasound (US) elasticity imaging (UEI) algorithm using 3D synthesized US data based on a cardiac mechanical model. METHODS AND POPULATION: A numerical approach was performed to validate the developed 3D UEI. A two‐chamber cardiac mechanical model was created using finite element (FE) techniques. This cardiac model was combined with a 3D US radio frequency (RF) data generation program for a typical cardiac US probe. The 3D UEI on synthesized 3D US volume images were quantitatively analyzed and compared to 2D UEI. RESULTS: Strain calculated by 3D UEI compares excellently with the FE model with averaged error of less than 2.5%. Significant improvement of 30%‐50% was also achieved compared to 2D UEI, especially where out‐of‐plane motion (13% wrt elevational full width at half maximum ∼ 1 mm) is demonstrated due to cardiac torsion. SIGNIFICANCE OF STUDY: Functional assessment of the right ventricle (RV) is essential for the prognosis and treatment of various cardiac diseases such as pulmonary hypertension and heart failure. Current RV evaluation methods are either invasive or limited, mainly due to complex 3D geometry and deformation. Most of the 2D imaging techniques assume erroneous planar deformation, while available 3D imaging techniques have limited functional assessment. A 3D UEI algorithm using 3D correlation‐based speckle tracking technique provides both anatomical and functional information such as mechanical property changes of the cardiac walls. With these encouraging preliminary results, we expect that 3D UEI may assess regional mechanical property changes of the RV wall with high accuracy, sensitivity and spatial resolution.

A‐275

PREFRONTAL PATHWAYS UNDERLYING SUCCESSFUL DELAY OF GRATIFICATION: A MULTI‐LEVEL MEDIATION ANALYSIS

Sripada C ¹, Gonzalez R¹, Phan K¹, Liberzon I¹  ¹University of Michigan, Ann Arbor, MI, United States

OBJECTIVES: Delaying gratification, the ability to forgo earlier rewards in order to achieve larger rewards later, may be abnormal in ADHD and substance use disorders. Medial pre‐frontal cortex (mPFC) represents the value of rewards, but it remains unknown whether the mPFC valuation signal is modulated by brain regions such as dorsolateral prefrontal cortex (DLPFC), involved in top‐down regulatory processing. We used a new mediation analysis method to investigate whether DLPFC (the ‘predictor’) contributes to choices to delay gratification (the ‘outcome’) by influencing mPFC (the ‘mediator’). METHODS AND POPULATION: During fMRI scanning, healthy participants (n = 20) made choices (n = 80) between dollar amounts ($4.05 to $48.80) delivered with varying amounts of delay. Mediation analysis was conducted using custom software based on Wager et al (2008), with significance set at p<0.005, uncorrected. RESULTS: Using DLPFC as a predictor seed, whole brain search revealed mPFC [‐3, 57, 3] positively mediates the relationship between the DLPFC seed and choices for later rewards. Using the mPFC valuation region as a mediator seed, whole brain search revealed DLPFC [36, 39, 42], as well as cingulate cortex, as predictor regions whose contribution to delayed choice is mediated by the mPFC seed. SIGNIFICANCE OF STUDY: This study was first to use mediation analysis to study prefrontal pathways contributing to successful delay of gratification. Our results demonstrate that mediation modeling can delineate interactions between brain regions during decision‐making, and can illuminate the neural basis of impulsivity.

A‐276

EVALUATION OF BETA‐CATENIN EXPRESSION IN SPONTANEOUS DEVELOPING CANINE OSTEOSARCOMA, A MODEL FOR HUMAN OSTEOSARCOMA

Stein TJ ¹, Holmes K¹, Muthuswamy R¹, Thompson V¹, Huelsmeyer M¹  ¹University of Wisconsin‐Madison, Madison, WI, United States

OBJECTIVES: Determine the frequency of cytoplasmic/nuclear accumulation of β‐catenin in canine osteosarcoma (OSA). METHODS AND POPULATION: Immunohistochemical (IHC) staining for β‐catenin in canine OSA was performed using a monoclonal antibody against β‐catein on canine OSA and normal bone. A cumulative IHC score was given to all samples based on the percentage of positive‐stained OSA cells and stain intensity. Three OSA cell lines, one human (SaOS‐2) and two canine (D17 and Abrams), were used to evaluate the specificity of the β‐catenin antibody on canine tissues. Finally, sequencing of β‐catenin exon 3 was to be performed on DNA isolated from paraffin‐embedded tissue of representative cases of canine OSA and normal bone. RESULTS:β‐catenin was detected in thirty of thirty‐seven (81%) primary OSA specimens and in two of three (66%) metastatic OSA specimens. All thirty positive‐staining primary OSAs displayed cytoplasmic staining, nine of thirty (30%) had membranous staining, and three of thirty (10%) had nuclear staining. β‐catenin staining score had no correlation with survival. Exon 3 sequencing results are currently not available. SIGNIFICANCE OF STUDY: Our results indicate cytoplasmic accumulation of β‐catenin in canine OSA is a frequent event. This is similar to β‐catenin accumulation in human OSA, thereby strengthening the relevancy of canine OSA as a model for human OSA. The exon 3 sequencing results will aid in determining if aberrant accumulation of β‐catenin is due to mutations in this region. Future studies will determine the contribution of aberrant β‐catenin expression to OSA using canine OSA cell lines.

A‐277

MENTORING, TEAM BUILDING AND TENURE AND PROMOTION ASSISTANCE FOR T1 SCIENTISTS

Sullenger B ¹, Reynolds B¹  ¹Duke University, Durham, NC, United States

OBJECTIVES: To develop programs that enhance the personal and professional growth, success and job satisfaction of T1 scientists through interactions with mentors, colleagues, collaborators and AP and T committee members. METHODS AND POPULATION: Fifteen detailed face‐to‐face interviews were conducted with faculty identified by clinical department chairs as leaders in T1 research. The interviews were designed to elicit comments about efforts that may enhance the experience and success of T1 scientists. A recurring theme was a lack of mentors/effective mentoring. We identified a department in which each interviewee was quite satisfied with their mentoring program and their chair and noted his efforts as a possible best‐practice. We interviewed the chair to gain insight into his methodologies. He has assembled a mentoring committee to assign mentors to each faculty member. He also meets with each faculty yearly to discuss progress and develop 1‐ and 5‐year plans for their work. The AP and T representative for their department meets yearly with each faculty to help them improve their AP and T portfolios. Many mandatory events were held to enrich and broaden faculty in various research areas and to increase their knowledge of the work of other faculty. Labs were built in an open format that provided maximum exposure of faculty to each other to facilitate idea sharing. RESULTS: The approaches described above served to energize an already busy faculty and, more so than in other departments, gave them the sense that their chair was actively invested in their success and satisfaction. SIGNIFICANCE OF STUDY: By documenting this set of methods and sharing them with leadership, we hope to disseminate the information to other departments to spread this set of best‐practices. We anticipate that similar positive impacts will result in these departments enhancing productivity, job satisfaction and retention.

A‐278

ROLE OF ARTERIAL STIFFNESS IN PULMONARY HYPERTENSION

Tan W ¹   ¹University of Colorado, Aurora, CO, United States

OBJECTIVES: Pulmonary arterial hypertension (PAH) is an important determinant of morbidity and mortality in children. Despite efforts on chronic treatment to reduce pulmonary vascular resistance (PVR), children with PAH can still develop functional and structural remodeling. Recently, pulmonary vascular stiffness (PVS) is identified as an additional factor that determines the severity and outcome of PAH, but its role in the PAH progression is unex‐amined. We hypothesize that increased PVS increases pulse pressure and flow pulsatility in distal pulmonary artery (PA) accelerating PA structural alterations. To test this, we perform a translational study which involves clinical measurement and mechanistic determination of PVS and pulse pressure in the hierarchical PA. METHODS AND POPULATION: Measurements of pressure in various PA segments are performed on pediatric patients. Subjects are divided into 2 groups with no PA H or PAH, 15 subjects in each group. The patients are catheterized to measure resistance, cardiac output, ultrasound and Doppler imaging for impedance and pressure‐diameter curves in large arteries as well as pressure waves and vessel diameters in hierarchical PA system. To establish a mechanistic relationship between PVS and variations of pulse pressure and pulsatile flow in distal PA, we develop a numerical model based on parametric measures. RESULTS: Measurements on two PAH pediatric patients showed that the child with more severe hypertension has higher PVS and higher pulse pressure in PA. Quantitatively, the first three harmonics of pressure in the more normotensive patient decayed 24%, 63%, and 76% when compared to the more hypertensive patient. Numerical modeling results showed that PVS increase is a major contributor to increased pulse pressure, flow pulsatility and pulsatile power in distal PA. SIGNIFICANCE OF STUDY: PVS may have a critical role in PAH.

A‐279

IS ANTIPHOSPHOLIPID SYNDROME AN UNDERLYING CAUSE OF ASPIRIN RESISTANCE?

Toma I ¹, Fallahi P¹, Katz R¹, Li R¹, Reiner J¹, Rebling F¹, Chauhan L¹, Carpio L¹, Marshall L¹, Lian Y¹, Fu SW¹, McCaffrey TA¹  ¹George Washington University, Washington, DC, United States

OBJECTIVES: Aspirin is a widely used prophylactic for thrombotic disorders due to low cost and efficient antiplatelet effect. A substantial proportion of subjects (6‐25%) do not exhibit a full inhibition of platelet aggregation, termed ‘aspirin resistance’ (AR). The aim of our study was to examine the gene expression profile in AR patients. METHODS AND POPULATION: Whole blood microarray gene expression profile was performed under GWU IRB approved study in patients with and without AR as measured by whole blood aggregation. Differentially expressed genes were identified by statistically significant changes of greater than 2‐fold. RESULTS: Our study revealed a 124‐gene signature strongly correlated with inadequate response to aspirin therapy and a strong association of the expressed genotype for MHC class II genes HLA‐DRB4 and ‐DQA1, suggesting an autoimmune component to AR. SIGNIFICANCE OF STUDY: HLA‐DRB4 and –DQA1 genotypes have been linked to a number of autoimmune disorders, particularly primary antiphospholipid (Hughes) syndrome (PAPS) in which autoanti‐bodies to phospholipid/protein complexes can trigger platelet activation and a procoagulant state. Consistent with PAPS, AR patients exhibited mild (30%) thrombocytopenia despite enhanced platelet aggregation. Detection of nonresponders based on a genetic test would allow preventing major complications in patients taking aspirin. Additional studies should evaluate whether AR subjects exhibit immunogenicity to any of the PAPS biomarkers. Clinical screening for aspirin‐insensitive platelet hyperreactivity may identify patients with asymptomatic PAPS and elevated risk of developing “second‐hit” triggered vascular events.

A‐280

IDENTIFYING MOLECULAR DETERMINANTS OF METASTATIC DISEASE IN MELANOMA

Tran H ¹, Tavazoie SF¹  ¹Rockefeller University, New York, NY, United States

OBJECTIVES: Metastasis is the major cause of mortality in cancer patients, including those with melanoma. By better understanding how metastases develop in melanoma, we will have a greater likelihood of developing new therapeutics that can effectively treat this disease process. Our goal is to identify the molecular determinants that regulate metastasis development in melanoma. Our aims are: 1)To identify the molecular determinants that regulate the development of metastasis in melanoma; 2)To determine the clinical relevance of these molecular determinants as prognostic markers; 3)To define the mechanism of regulation of these molecular determinants for possible drug development. METHODS AND POPULATION: Using an in vivo metastasis mouse model system, we have identified molecular determinants that may be involved in metastasis. These determinants will be analyzed using multiple approaches to determine the roles they play in the development of metastasis. To assay their potential for use as prognostic markers, we will screen for the presence of these molecular determinants in primary melanoma tissue samples of patients who develop metastasis and those who do not. This will allow us to correlate these molecular determinants with the risk of developing metastasis and therefore validate them for use as prognostic markers. RESULTS: We anticipate that the molecular determinants that we have identified will be able to stratify patients with primary melanoma into those who will likely metastasize and those who will not. SIGNIFICANCE OF STUDY: The importance of identifying these molecular determinants of metastatic disease in melanoma patients is multi‐fold. It will not only allow us to stratify patients into relatively more homogeneous subgroups for more aggressive monitoring and tailored therapeutic interventions but will also identify targets that may be candidates for therapeutic development.

A‐281

PROOF OF A NOVEL ULTRASOUND‐BASED TRIGGER FOR PROSPECTIVELY‐GATED CARDIAC COMPUTED TOMOGRAPHIC ANGIOGRAPHY

Tridandapani S ¹   ¹Emory University, Atlanta, GA, United States

OBJECTIVES: Our goal is to prove that Ultrasound (US) can more reliabily identify quiescent phases within the cardiac cycle than electrocardiography (ECG) for the purposes of triggering cardiac computed tomography (CCT). METHODS AND POPULATION: US images of the heart along with simultaneous ECG will be obtained from 20 subjects in both the subxiphoid and parasternal approaches. The US data will be range‐gated and only the data from the left ventricular wall will be evaluated. Beat‐to‐beat cross‐correlation will be performed for 10 beats and averaged. Periods which have a correlation of ≥ 0.8 between successive beats will be considered. RESULTS: For two preliminary patients that we have scanned with nearly equal heart rates (58 and 62), the quiescent periods do not appear at the same point in the cardiac cycle and also have different durations. In addition, the quiescent period for each subject within a cardiac cycle is different when imaging near the base of the heart using the subxiphoid approach than when imaging near the apex using the parasternal approach. We expect that these quiescent periods will be even further apart particularly when patients with different heart rates and arrhythmias are included. SIGNIFICANCE OF STUDY: CCT is an emerging alternative to invasive catheter angiography for evaluating the patency of coronary arteries. The current approach, ECG‐based gating of CCT, is limited because ECG does not describe the real‐time mechanical location and motion of the heart. US on the other hand is real‐time, just like ECG, but also describes the mechanical properties of cardiac motion. If an US‐based technique for triggering cardiac CT can be perfected, it will lead to a cheaper, non‐invasive, reliable alternative to catheter coronary angiography while also decreasing radiation dosage.

A‐282

GENETIC POLYMORPHISMS IN LIVER TRANSPLANT RECIPIENTS WITH RENAL DYSFUNCTION

Tuteja S ¹, Ploessl C¹, Voigt M¹, Reed A¹, Murray J¹  ¹University of Iowa, Iowa City, IA, United States

OBJECTIVES: To determine if polymorphisms in the ABCB1 gene and CYP3A5 gene are risk factors for development of posttransplant renal dysfunction in liver transplant recipients. METHODS AND POPULATION: Liver transplant recipients from 1990‐2008 will be contacted to obtain saliva for DNA extraction and genotyping for the following SNPs: CYPA3A5(22893A‐G), ABCB1 (1236 C>T),(2677 G>T,A),(3435 C>T). Retrospective review of medical records will be conducted to collect data on clinical risk factors for renal dysfunction. Time to renal dysfunction will be calculated according to the Kaplan‐Meier method including CYP3A5 and ABCB1 genotypes as covariates. RESULTS: Sample collection and clinical data extraction is ongoing. SIGNIFICANCE OF STUDY: Calcineurin inhibitor (CNI) based im‐munosuppressive therapy in transplantation has dramatically improved short‐term outcomes by decreasing rates of acute rejection. Nephrotoxicity is the most frequent and most severe adverse event following treatment with CNI and occurs in liver (52%), heart (20‐75%) and kidney (76‐94%) transplant recipients. Long‐term studies of adult liver transplant recipients estimate the incidence of end‐stage renal disease (ESRD) to be 10% by 10 years. Little data exist as to which patients may have increased susceptibility to calcineurin‐inhibitor induced nephrotoxi‐city. Calcineurin inhibitors are substrates for CYP450 3A and for the multidrug resistance (ABCB1) gene product Pgp, and are predominantly metabolized by CYP3A4/5 in the liver. Since CYP3A5 and Pgp are also found in renal tubules, available evidence suggests that they modulate the risk of developing nephrotoxicity secondary to the calcineurin inhibitors.

A‐283

AMINO ACID TRANSPORTER EXPRESSION IS INCREASED IN THE SKELETAL MUSCLE OF YOUNG AND OLDER HUMANS FOLLOWING RESISTANCE EXERCISE

Drummond M¹, Fry CS¹, Glynn EL¹, Timmerman KL¹, Volpi E ¹, Rasmussen BB¹  ¹The University of Texas Medical Branch at Galveston, Galveston, TX, United States

OBJECTIVES: The purpose of this study was to evaluate if aging influences the expression level of amino acid transporters following a single bout of heavy resistance exercise. METHODS AND POPULATION: Young (n = 8) and older (n = 6) male subjects participated in a bout of resistance exercise and muscle biopsies were sampled at Basal, 3, 6, and 24h post‐exercise. Amino acid transporter mRNA expression was measured by real‐time PCR. RESULTS: LAT1 mRNA increased at 3 and 6h in both age groups while CD98 mRNA only increased at 6h post‐exercise in the young. PAT1 mRNA increased at 6h in the young and older subjects while there was a group difference at 3h post‐exercise in favor of higher expression in older subjects. CAT1 mRNA increased at 6 and 24h in the young but was only increased at 6h post‐exercise in the older subjects. SNAT2 mRNA expression was unchanged in both age groups. SIGNIFICANCE OF STUDY: These data support a rapid upregulation of amino acid transporters expression which may serve as a mechanism of adaptation to support enhanced protein synthesis following future exercise bouts. Aging does not appear to induce major changes in the transcription of amino acid transporters, suggesting that in older adults resistance exercise produces an anabolic signal sufficient to stimulate amino acid transporter expression to levels comparable to those seen in younger individuals. Supported by ACSM Research Endowment Grant, NIH/NIA P30 AG024832, and NIH/NIAMS R01 AR049877

A‐284

LEVELS OF PLGF AND ET‐1 IN ADULTS WITH SCD ARE LINKED TO MARKERS OF HEMOLYSIS, INFLAMMATION, IRON OVERLOAD AND PULMONARY HYPERTENSION

Wang X ¹, Mendelsohn L¹, Allen D¹, Minniti C¹, Taylor JG¹, Kato GJ¹  ¹NIH, Bethesda, MD, United States

OBJECTIVES: 1. Determine the PlGF levels and ET‐1 levels in adult SCD plasma; 2. Evaluate the association between PlGF and ET‐1,and the correlation between PlGF levels, ET‐1 levels and TRV, and intravascular hemolysis markers. METHODS AND POPULATION: We m e a s ‐ured the levels of PlGF and ET‐1 in plasma samples from 123 adults with SCD, and evaluated statistical correlations with standard clinical laboratory markers. RESULTS: We find in plasma specimens from adults with SCD that the two are significantly correlated (p<0.01). Interestingly, our results have shown that both PlGF and ET‐1 levels are correlated with tricuspid regurgitant jet velocity (TRV)(p<0.001 for both), a Doppler echocardiography marker of PH. Furthermore, ET‐1 also correlates with a second marker of PH, plasma NT‐proBNP (p<0.05). These results implicate the PlGF‐ET‐1 pathway in PH in SCD. In addition, the level of PlGF is linked with several markers of hemolysis, iron overload and hepatic dysfunction that are re‐producibly linked to PH in SCD: low Hb (p<0.01) and transferrin (p<0.001); and high serum LDH (p<0.05), direct bilirubin (p<0.05), ferritin (p<0.001), and transferrin saturation (p<0.01). PlGF also is correlated to leukocyte count (p<0.05) and CRP (p<0.01), which are inflammatory markers that contribute to the risk of atherosclerosis, another proliferative vasculopathy with mechanistic parallels to PH in patients with SCD. SIGNIFICANCE OF STUDY: ET‐1 appears to be a mediator of elevated pulmonary artery pressures as estimated by echocar‐diography in patients with SCD. Its expression is related in part to PlGF, the associations of which match the established profile of the average SCD patient with PH. The potential therapeutic benefit of ET‐1 receptor antagonists merits further clinical trials.

A‐285

THE IMPACT OF COMORBIDITIES ON IMMUNOLOGIC DERANGEMENTS AND OUTCOMES IN SARCOIDOSIS

Westney GE ¹   ¹Morehouse, Atlanta, GA, United States

OBJECTIVES: Sarcoidosis is a multi‐system, granulomatous inflammatory disease of unknown etiology Immune modulating molecules appear to parallel the disease course.Comorbid illnesses, may influence the course and outcome. The specific aim is to ascertain the pattern of inflammatory cytokine expression in patients with sarcoidosis alone (Group 1), sarcoidosis & diabetes mellitus (Group 2), and sarcoidosis & asthma (Group 3). METHODS AND POPULATION: Patients with sarcoidosis had serum and bronchoalveolar lavage fluid (BALF) obtained. Multiplexed immunoassay using Luminex xMAP technology was used to measure the serum and BALF levels of TH1 versus TH2 cytokines. Data are expressed as the mean + the standard deviation or as frequencies and proportions where applicable. The mean TH1 and TH2 cytokine levels for the controls and comorbidity groups were compared using Student's t‐test with significance at p < 0.05. RESULTS: Preliminary data was obtained for 15 African American sarcoidosis patients (M=5, F= 10) who were 47±8 yrs of age. For the total study group, cytokine levels (in pg/ml) were highest for IL‐6 and IL‐8 in serum. Cytokine levels in BAL fluid were highest for INF7, TNFa and IL‐10. Control serum had cytokine levels were highest for TNFa and IL‐4 while control BAL fluid had highest cytokine levels for IL‐8 and IL‐6. Significant differences between the controls and study groups were observed in four TH1 and TH2 serum cytokines and only in BAL fluid IL‐8 levels. SIGNIFICANCE OF STUDY: Conclusion: Although sample size is small, specific cytokines may contribute to differing immune profiles between the serum and BAL fluid compartments in sarcoidosis patients with diabetes or asthma diagnoses. Subsequent studies evaluating specifically IL‐6 and IL‐8 are needed to clarify the role of these cytokines in sarcoidosis.

A‐286

VIRTUAL CRC‐CTSA AND MEDICAL IGNORANCE EXPLORATORIUM (MIEX): TRANSLATING TRANSLATION

Witte MH ¹, Crown PC¹, Hall JR¹, Bernas MJ¹, Daley SK¹, Garcia FA¹, Joyner MJ¹  ¹University of Arizona, Tucson, AZ, United States, Mayo Medical School, Rochester, MN, United States

OBJECTIVES: Access to a user‐friendly virtual CRC/CTSA would serve to showcase and advance clinical research, networking, subject recruitment, and training internationally. The UAz NCRR SEPA aims to develop an interactive virtual platform presenting translational research with a unifying “medical ignorance” theme as an engaging inquiry‐driven collaborative learning environment. METHODS AND POPULATION: A web‐based application went through multiple iterations with user feedback to create a Campus with text input archived for subsequent analysis and multiple pathways through the virtual experience for user individualization. Targeted for high school students and science teachers it is adaptable to higher level trainees, general public and media. RESULTS: Visitors to the Virtual Campus navigate through a Resource Library offering translational research video presentations, “Questionarium” with exercises in asking research questions, Multimedia Presentation Space, and ToolBox of clinical and core laboratory technologies. Links are available for Think Tank conferences and remote outreach. MIEx features on‐line activities highlighting the Curriculum on Medical Ignorance (“Ig‐noramics”)‐the unanswered questions driving research, as viewed from beginner to multidisciplinary expert perspectives. Evaluation employs online assessment of student questioning, search strategies, research skills, and career pathways, critical elements in national science literacy benchmarks. SIGNIFICANCE OF STUDY: VCRC/MIEx contributes to NIH Roadmap in building diverse clinical research teams, expanding technology infrastructure, and explaining and expediting bidirectional translation of advances from bench to bedside to community.

A‐287

A GCH1 HAPLOTYPE ASSOCIATED WITH SUSCEPTIBILITY TO VASOOCCLUSIVE PAIN AND IMPAIRED VASCULAR FUNCTION IN SICKLE CELL ANEMIA

Youngblood V ¹, Belfer I², Darbari D¹, Desai K¹, Freeman L¹, Kato GJ¹, Goldman D³, Max MB², Taylor, VI JG¹  ¹NHLBI, NIH, Bethesda, MD, United States, ²University of Pittsburg, Pittsburg, PA, United States, ³NIAAA, NIH, Rockville, MD, United States

OBJECTIVES: The underlying mechanism for painful vasoocclusive (VOC) episodes in sickle cell anemia (SCA) has not been elucidated. We hypothesized that genetic variation in GCH1 results in uncoupled BH4‐dependent enzymes that may modulate complications of SCA, especially those complications associated with nitric oxide (NO) deficiency. METHODS AND POPULATION: We examined GCH1 markers against phenotypes including pulmonary hypertension (PH) defined by echocardiography and hospitalizations for pain among 188 SCA subjects at NIH. Forearm blood flow studies were performed on 21 subjects. Functional studies utilized cell lines from the Yoruban Hapmap population. RESULTS: A GCH1 haplotype defined by 3 SNPs (rs8007267, rs2878172, rs7147286) was associated with frequent painful episodes (odds ratio 2.13, 95% CI 1.21‐3.78, P=0.007), but surprisingly not with PH. Cell lines homozygous for these markers had significantly higher GCH1 mRNA (P=0.02) and protein after stimulation compared to variant homozygotes. In vivo, the GCH1 pain haplotype was associated with diminished vasodilation in response to infused ACh (P=0.03), but not with ni‐troprusside or L‐NMMA infusions. SIGNIFICANCE OF STUDY: Taken together, we show an association between pain and a GCH1 haplotype that is linked to endothelial‐dependent vascular function in SCA. The association with impaired vascular function does not appear to be associated with NO based upon the L‐NMMA results and the absence of a strong association with PH. Additional studies are needed to determine if polymorphisms in GCH1 and variability in BH4 synthesis modulates SCA pain, and if polymorphisms of GCH1 should be accounted for in pain prevention clinical trials.

A‐288

BIOLOGIC PROFILING OF BURN PATIENTS WITH DIABETES: MATRIX METALLOPROTEINASE 9 (MMP‐9) IN THE EARLY POST‐INJURY PERIOD

Schwartz S¹, Yuen D ¹, Yurt R ¹, Barron‐Vaya Y¹  ¹Weill Cornell Medical College, New York, NY, United States

OBJECTIVES: Impaired healing is a well‐recognized complication of diabetes. In spite of ongoing efforts to characterize its defects, identifying therapeutic targets remains elusive. Since chronic wounds originate as acute insults, we have been interested in determining if, among diabetics, acute burns prone to dysrepair are identifiable via biologic characterization of the patient & his/her wound in the initial days post‐admission. We examined MMP‐9, a proteolytic enzyme with an important role in normal repair as well as in chronic wound pathogenesis. METHODS AND POPULATION: Venous samples were serially collected from diabetic (db) and non‐diabetic (ndb) burn patients enrolled in an ongoing observational study up to 72 hours post study entry. Total sera concentrations of MMP‐9 (ng/ml) were determined via ELISA. We correlated this data to the study's main outcome measure‐ time to 100% wound closure as well as to other clinical variables, including; burn size (<25%TBSA); A1C%; graft need; & wound/graft complications. Study cohort: 24 patients, 16 db (67%); male (67%); age 22‐93 years (db mean 56; ndb mean 44); 6.8% av TBSA for db & ndb. RESULTS: Circulating MMP‐9 levels within 72h between ndb's and db's were 648.5 ng/mL and 649.2 ng/mL respectively, p = 0.99; and MMP‐9 levels with respect to time to wound closure had a 0.25 correlation, p = 0.30. SIGNIFICANCE OF STUDY: Circulating MMP‐9 within initial 72h post‐burn showed no significant difference between non‐diabetics and diabetics. Also, there was no significant correlation between initial MMP‐9 and time to would closure. Since MMP‐9 expression varies temporally during healthy repair, extending analyses beyond 72 hours, i.e., during protracted healing, might yield contrasting findings as a late marker of poor healing.

A‐289

MENDELIAN GENETIC DEFECTS IN TLR3‐INTERFERON PATHWAY PROVIDE PREDISPOSITION TO HERPES SIMPLEX ENCEPHALITIS IN CHILDHOOD

Zhang S ¹, Abel L¹, Casanova J¹  ¹The Rockefeller University, New York, NY, United States

OBJECTIVES: Herpes simplex encephalitis (HSE) is the most common sporadic viral encephalitis in the Western world. The pathogenesis of HSE, which affects a small minority of HSV‐1‐infected individuals, has long remained elusive. Mendelian defects in the TLR3‐inter‐feron (IFN) and IFN‐responsive pathways were recently shown to predispose to HSE, at least in some children. Autosomal recessive STAT‐1 deficiency and X‐linked NEMO deficiency were found in children with both mycobacterial disease and HSE. Autosomal recessive UNC‐93B deficiency and autosomal dominant TLR3 deficiency were described as the first two genetic etiologies of isolated HSE in children. We are now intending to test our hypothesis that childhood HSE by a rule results from single gene inborn errors of interferon (IFN)‐mediated immunity. METHODS AND POPULATION: We are following a hypothesis‐based candidate gene approach and a hypothesis‐generating genome‐wide screening approach, aiming to identify novel genetic etiologies of HSE. RESULTS: Our recent investigations led to the identification of other children with impaired IFN response to TLR3‐activations in skin‐derived fibroblast cells, including one child with autosomal recessive TLR3 deficiency. SIGNIFICANCE OF STUDY: These discoveries provided proof‐of‐principle that HSE may result from a novel group of single‐gene inborn errors of IFN immunity. The TLR3‐UNC‐93B‐dependent production of IFN‐alpha/beta and IFN‐lambda is essential to confer protective immunity to HSV‐1 in the central nervous system (CNS) during the course of primary infection in childhood, at least in some children.

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ACRT‐SCTS Scholar Abstracts

CLINICAL EPIDEMIOLOGY

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ETHICS

HEALTH SERVICES RESEARCH

OUTCOMES RESEARCH

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ACTIONS

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