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Background: We aimed to understand the effects of aspirin dose on outcomes in patients with peripheral artery disease (PAD) as well as their participation in a pragmatic randomized controlled trial. Methods: In a subanalysis of the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) study, we compared aspirin doses (81 vs 325 mg) among participants with PAD and study participation metrics in patients with and without PAD. The primary outcome composite was all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke. Results: Among 14,662 participants enrolled in ADAPTABLE with PAD status available, 3493 (23.8%) had PAD. Participants with PAD were more likely to experience the primary composite (13.76% vs 5.31%, p < 0.001), all-cause mortality (7.55% vs 3.01%, p < 0.001), myocardial infarction (5.71% vs 2.09%, p < 0.001), stroke (2.45% vs 0.86%, p < 0.001), and major bleeding (1.19% vs 0.44%, p < 0.001). A higher aspirin dose did not reduce the primary outcome in patients with PAD (13.68% vs 13.84% in 81 mg and 325 mg groups; OR 1.05, 95% CI 0.88–1.25). Participants with PAD were less likely to enroll via email (33.0% vs 41.9%, p < 0.0001), less likely to choose internet follow-up (79.2% vs 89.5%, p < 0.0001), and were more likely to change their aspirin doses (39.7% vs 30.7%, p < 0.0001). Conclusions: ADAPTABLE participants with PAD did not benefit from a higher dose of aspirin and participated in the study differently from those without PAD. These results reinforce the need for additional PAD-specific research and suggest that different trial strategies may be needed for optimal engagement of patients with PAD. (ClinicalTrials.gov Identifier: NCT02697916)

Conducting high-quality stroke trials is complex and costly. Often these trials compete for the attention of researchers and the availability of patients. Enrolling patients in more than one study concurrently has the potential to accelerate recruitment into individual studies. DISCOVERY is a multicenter, inception cohort study of cognitive impairment and dementia following ischemic or hemorrhagic stroke. At the request of site investigators, a DISCOVERY committee reviews individual studies for approval of possible concurrent co-enrollment into DISCOVERY. The purpose of this report is to summarize the characteristics and outcomes of studies reviewed by committee for possible co-enrollment.This analysis covers studies reviewed from 07/01/2020 to 04/26/2022 by the Site Management Committee (SMC) of the DISCOVERY Recruitment and Retention Core. Characterization of each study included study type, number and length of follow-up visits, and whether there were protocol-required blood draws, brain imaging studies, or cognitive tests. Studies were scored for patient burden and scientific overlap with Discovery. The primary outcome was SMC approval to co-enroll.59 studies were reviewed, and 69.5% (n = 41, 21 clinical trials; 20 observational studies) were found by the SMC to be appropriate for co-enrollment. Higher patient burden and greater scientific overlap with DISCOVERY reduced the rates of approval for co-enrollment.A large number of diverse stroke studies are being run concurrently across the DISCOVERY study network, however, about two-thirds of the studies were considered appropriate for consideration of co-enrollment. Future studies should study how co-enrollment might improve trial network efficiency.

Stroke is a leading cause of the adult disability epidemic in the United States, with a major contribution from poststroke cognitive impairment and dementia (PSCID), the rates of which are disproportionally high among the health disparity populations. Despite the PSCID’s overwhelming impact on public health, a knowledge gap exists with regard to the complex interaction between the acute stroke event and highly prevalent preexisting brain pathology related to cerebrovascular and Alzheimer disease or related dementia. Understanding the factors that modulate PSCID risk in relation to index stroke event is critically important for developing personalized prognostication of PSCID, targeted interventions to prevent it, and for informing future clinical trial design. The DISCOVERY study (Determinants of Incident Stroke Cognitive Outcomes and Vascular Effects on Recovery), a collaborative network of thirty clinical performance clinical sites with access to acute stroke populations and the expertise and capacity for systematic assessment of PSCID will address this critical challenge. DISCOVERY is a prospective, multicenter, observational, nested-cohort study of 8000 nondemented ischemic and hemorrhagic stroke patients enrolled at the time of index stroke and followed for a minimum of 2 years, with serial cognitive evaluations and assessments of functional outcome, with subsets undergoing research magnetic resonance imaging and positron emission tomography and comprehensive genetic/genomic and fluid biomarker testing. The overall scientific objective of this study is to elucidate mechanisms of brain resilience and susceptibility to PSCID in diverse US populations based on complex interplay between life-course exposure to multiple vascular risk factors, preexisting burden of microvascular and neurodegenerative pathology, the effect of strategic acute stroke lesions, and the mediating effect of genomic and epigenomic variation.

Real-world evidence (RWE) is increasingly used to complement clinical trial data for regulatory decision-making and in certain cases utilized to establish the clinical effectiveness of a therapy. However, the use of RWE is not applicable for all regulatory submissions, and it can be challenging to identify appropriate use cases. An interactive tool was developed ("Decision Aid," https://sn.pub/TpDjZx ) to assist researchers, industry, and other stakeholders in identifying regulatory situations that can benefit from leveraging RWE by organizing precedent cases based on a given regulatory objective (new product approval, labeling expansion for new indication or additional clinical data, post-marketing requirement) and type of RWE study design (external control, observational study, pragmatic trial). Key success factors ensuring fit-for-purpose data and rigorous methods (e.g., clear endpoints, minimizing bias, data completeness) are also described. The tool allows the user to navigate through the precedent cases by selecting certain regulatory objectives and/or study designs. The Decision Aid supports regulatory activities in the RWE space and encourages further use of RWE in regulatory decision-making.

IMPORTANCE: Ischemic stroke is associated with increased risk of dementia, but the association of stroke severity and recurrence with risk of impaired cognition is not well known. OBJECTIVE: To examine the risk of dementia after incident ischemic stroke and assess how it differed by stroke severity and recurrence. DESIGN, SETTING, AND PARTICIPANTS: The Atherosclerosis Risk in Communities (ARIC) study is an ongoing prospective cohort of 15 792 community-dwelling individuals from 4 US states (Mississippi, Maryland, Minnesota, and North Carolina). Among them, 15 379 participants free of stroke and dementia at baseline (1987 to 1989) were monitored through 2019. Data were analyzed from April to October 2021. Associations between dementia and time-varying ischemic stroke incidence, frequency, and severity were studied across an average of 4.4 visits over a median follow-up of 25.5 years with Cox proportional hazards models adjusted for sociodemographic characteristics, apolipoprotein E, and vascular risk factors. EXPOSURES: Incident and recurrent ischemic strokes were classified by expert review of hospital records, with severity defined by the National Institutes of Health Stroke Scale (NIHSS; minor, ≤5; mild, 6-10; moderate, 11-15; and severe, ≥16). MAIN OUTCOMES AND MEASURES: Dementia cases adjudicated through expert review of in-person evaluations, informant interviews, telephone assessments, hospitalization codes, and death certificates. In participants with stroke, dementia events in the first year after stroke were not counted. RESULTS: At baseline, the mean (SD) age of participants was 54.1 (5.8) years, and 8485 of 15 379 participants (55.2%) were women. A total of 4110 participants (26.7%) were Black and 11 269 (73.3%) were White. A total of 1378 ischemic strokes (1155 incident) and 2860 dementia cases were diagnosed 1 year or more after incident stroke in participants with stroke, or at any point after baseline in participants without stroke, were identified through December 31, 2019. NIHSS scores were available for 1184 of 1378 ischemic strokes (85.9%). Risk of dementia increased with both the number and severity of strokes. Compared with no stroke, risk of dementia by adjusted hazard ratio was 1.76 (95% CI, 1.49-2.00) for 1 minor to mild stroke, 3.47 (95% CI, 2.23-5.40) for 1 moderate to severe stroke, 3.48 (95% CI, 2.54-4.76) for 2 or more minor to mild strokes, and 6.68 (95% CI, 3.77-11.83) for 2 or more moderate to severe strokes. CONCLUSIONS AND RELEVANCE: In this study, risk of dementia significantly increased after ischemic stroke, independent of vascular risk factors. Results suggest a dose-response association of stroke severity and recurrence with risk of dementia.

Objective: To assess health-related quality of life (HRQOL) in a large multicenter cohort of children and young adults with Marfan syndrome participating in the Pediatric Heart Network Marfan Trial. Study design: The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales were administered to 321 subjects with Marfan syndrome (5-25 years). PedsQL scores were compared with healthy population norms. The impact of treatment arm (atenolol vs losartan), severity of clinical features, and number of patient-reported symptoms on HRQOL was assessed by general linear models. Results: Mean PedsQL scores in children (5-18 years) with Marfan syndrome were lower than healthy population norms for physical (P ≤.003) and psychosocial (P

Background: Ectopic beats, defined by premature atrial contractions (PACs) and premature ventricular contractions (PVCs), are one of the most common findings on the electrocardiogram (ECG). Excess ectopic beats on ambulatory ECG monitoring are associated with atrial fibrillation (AF), stroke and death in symptomatic patients and in population-based studies. However, the repeatability of ECG-enumerated ectopic beats has not been sufficiently examined in a general population. Objectives: Characterize the repeatability of PACs and PVCs in a community-based population of older adults. Methods: Ambulatory, 48-hour ECG was measured in a subsample of the Atherosclerosis Risk in Communities Study (ARIC; 2011-2013) at two locales. Participants were randomly invited to participate in the repeatability study (n=92). Following an identical, standardized protocol, the participants wore a Holter monitor for two, 48-hour periods separated by a mean of 38 days (range: 11, 130 days) and completed a symptom questionnaire during each period. Each visit included new electrodes and Holter placement. All participants wore monitors for 48 hours and had recordings with Results: About 17% of the participants reported symptoms of dizziness, palpitations, or chest pain while wearing the monitor. During the 48-hour recordings, all participants had ≥1 PAC count and 2 participants had a 0 PVC count. The overall median (interquartile range (IQR)) was 266 counts (IQR: 80, 1,692.5) for PACs and 223 counts (IQR: 17.5, 1,085.5) for PVCs. The median between-visit difference (visit 2 - visit 1) was -12.5 counts for PACs (IQR: -154, 65) and 0 counts for PVCs (IQR: -78, 320). The between-visit, weighted kappa for count quartiles was 0.70 (95% confidence interval (CI): 0.61, 0.80) for PACs and 0.68 (95% CI: 0.58, 0.78) for PVCs. The kappa for counts >80th percentile was 0.56 (95% CI: 0.34, 0.78) for PACs and 0.71 (95% CI: 0.52, 0.90) for PVCs. Conclusion: Between-visit agreement is high to moderate for 48-hour, Holter-based PACs and PVCs quantiles, according to common interpretations for kappa coefficients. When paired with pending examination of how agreement varies over shorter duration recordings within the 48-hour monitoring period, the present results can facilitate epidemiologic and clinical applications in which knowledge of measurement error, variability and misclassification are needed to inform risk assessment.

Background: Healthcare utilization analyses often are conducted with Centers for Medicare and Medicaid (CMS) data from fee-for-service (FFS) Medicare beneficiaries. Although use of preventive care services is greater among beneficiaries in managed care programs compared with those in FFS care, evidence of the effect of managed care enrollment on health outcomes is mixed. We compared the health status of ARIC cohort participants enrolled in FFS to those enrolled in managed care. Methods: Data for participants of the ARIC Study cohort were linked with CMS Medicare claims for the years 1991-2012 (N=14,695). Participants missing coverage start date or enrolled prior to 1991 were excluded from analyses (N=2,513). Enrollment in FFS and managed care was ascertained at the start of CMS Medicare coverage. Switch from initial FFS enrollment to managed care was ascertained in follow-up through December 31, 2012. Demographics and comorbidities were ascertained from ARIC clinical examination and follow-up data up to the coverage start date. Mortality was ascertained from start date of CMS Medicare coverage through December 31, 2012; rates were modeled using Poisson regression adjusted for age at time of coverage start. Cox proportional hazard regression models, adjusted for demographic characteristics and comorbidities, were used to examine the hazard ratio of all-cause mortality among those in FFS compared to those enrolled in managed care. Results: At the start of Medicare coverage, 10,983 and 1,087 ARIC participants were enrolled in FFS and managed care, respectively. In comparison with managed care beneficiaries, those in FFS at the start of coverage were more likely to be white (91% vs. 73.5%), male (43% vs. 38.5%) and have less than a high school education (20.4 vs. 11.8%). Comorbidity burden was greater among those enrolled in FFS compared to those in managed care. The age-adjusted rate of mortality (per 100,000 person-years; median follow-up 11.2 years) was 5.9 (95% CI 5.7, 6.1) among those in FFS and 3.5 (95% CI 2.9, 4.1) among those in managed care. The mortality hazard ratio, comparing FFS to managed care beneficiaries was 1.29 (95% CI 1.08, 1.55). During the time from coverage start to end of follow-up, 4,200 beneficiaries switched from FFS to managed care. With the exception of gender, education and proportion with a history of cancer, demographic characteristics and comorbidities of beneficiaries who switched vs. those who remained in FFS were comparable. The mortality hazard ratio, assessed from start of coverage through December 31, 2012, was 1.59 (95%CI 1.46, 1.74) among those remaining in FFS, as compared to those who switched to managed care. Conclusion: Generalizability of inferences from FFS CMS Medicare data may be limited by a greater observed mortality rate among FFS beneficiaries compared to those in managed care. Further analyses are needed to confirm this finding.

We assessed the relationships among severity measures of urinary incontinence in women with stress predominant symptoms enrolled in a randomized clinical trial comparing 2 surgical techniques (Burch colposuspension vs pubovaginal sling) for stress urinary incontinence.A total of 655 women underwent a standardized preoperative assessment that included the Medical, Epidemiological and Social Aspects of Aging questionnaire, Urogenital Distress Inventory, Incontinence Impact Questionnaire, 3-day voiding diary, 24-hour pad test, a supine empty bladder stress test and Valsalva leak point pressure measurements. Correlations were estimated using Spearman correlation coefficients and 95% confidence intervals. T tests at alpha=0.05 were conducted to compare the distributions of the continuous severity measure between patients with positive and negative supine empty bladder stress test.Baseline mean scores on Medical, Epidemiological and Social Aspects of Aging, Urogenital Distress Inventory and Incontinence Impact Questionnaire were 25.8, 151 and 171, respectively. Mean incontinence episode frequency and pad weight were 3.2 per day and 43.5 gm, respectively. Supine empty bladder stress test was positive in 218 patients, and 428 patients had valid Valsalva leak point pressure measurements with a mean Valsalva leak point pressure of 80 cm H(2)O. Weak to moderate correlations were observed between Medical, Epidemiological and Social Aspects of Aging, incontinence episode frequency, pad weight, Incontinence Impact Questionnaire and Urogenital Distress Inventory. On the other hand, Valsalva leak point pressure correlated poorly with all variables measured. The sensitivity and specificity of the supine empty bladder stress test to predict intrinsic sphincter dysfunction were 49% and 60%, respectively.Urinary incontinence severity measures correlate moderately with each other at best. While Medical, Epidemiological and Social Aspects of Aging demonstrated stronger correlations with the other measures of severity and quality of life, Valsalva leak point pressure did not. Supine empty bladder stress test did not demonstrate a clinically significant association among severity measures.

Hypothesis: We hypothesized that outpatient management of patients at risk for a HF hospitalization is associated with lower mortality following an incident HF hospitalization. Methods: Patterns of outpatient visits prior to incident HF hospitalization were assessed among CMS Medicare beneficiaries with continuous fee-for-service eligibility residing during 2003-2006 in four geographic areas of CVD surveillance conducted by the ARIC Study. Incident HF hospitalization was defined as hospitalization with ICD9 code 428.x with no HF hospitalizations in preceding 2 years. Outpatient visits to primary care physicians, general internists, or cardiologists were identified from Carrier files. A comorbidity score was calculated from ICD9 codes at the time of incident HF hospitalization. Cox proportional hazard models adjusted for age, comorbidity score, gender, and race were used to estimate mortality. Results: Mean age among beneficiaries with observed incident HF hospitalization (n=2006; 90.4% white, 45.1% male) was 79.8 years (SD 7.4). Mean comorbidity score was 3.6 (SD 1.9). Mean number of outpatient physician visits occurring in two years preceding the incident HF hospitalization, was 9.6 (SD 9.0); 19.6% beneficiaries had no observed prior outpatient physician visits. Risk of death within one year of incident HF hospitalization was greater among those with no preceding outpatient physician visits as compared to those with at least one physician visit (adjusted HR=1.81 (95% CI 1.50, 2.18); Figure). Adjustment for the presence of an outpatient visit within 2 weeks following the HF hospitalization attenuated the risk of death (HR=1.56 (1.29, 1.89)). Conclusion: Lack of outpatient care in two years prior to a HF-related hospitalization is associated with increased mortality within one year following hospitalization. Further inquiry is warranted to assess whether the association reflects diversity in causes/manifestations of HF, ambulatory care received in ED settings, or benefits associated with outpatient care.

Introduction: Among older adults with diabetes, cognitive dysfunction is of particular concern as it has implications for treatment adherence and diabetes self-management. The prevalence of cognitive dysfunction has not been well characterized in this population. Methods: We conducted a cross-sectional analysis of 5509 participants (1815 with diabetes) from visit 5 (2011-2013) of the ARIC Study. Diabetes was defined based on self-reported physician diagnosis, diabetes medication use, or HbA1c ≥ 6.5%. Cognitive function was measured using 8 neuropsychological tests, which were grouped into three cognitive domains representing memory, executive function, and language. Participants were categorized as having cognitive dysfunction if test scores were more than 1.5 standard deviations below age-, race-, and education-adjusted scores derived from a cognitively healthy population. We calculated crude prevalence estimates and used Poisson regression to estimate adjusted prevalence ratios (PRs), comparing cognitive dysfunction in persons with and without diabetes. We adjusted for demographic and clinical characteristics. Results: The mean age of participants was 75 years, 59% were female, 79% were white, and 33% had diabetes. In each domain, the prevalence of cognitive dysfunction among persons with diabetes ranged from 14% to 27%. Persons with diabetes were more likely than persons without diabetes to have dysfunction in multiple domains (PR = 1.29, 95% CI: 1.12, 1.49). Prevalence of cognitive dysfunction was significantly higher in persons with versus without diabetes for memory (PR=1.13, 95% CI: 1.02, 1.25), language (PR=1.24, 95% CI: 1.09, 1.45), and executive function (PR=1.10, 95% CI: 1.00, 1.22)(Figure). PRs were similar in crude models. Conclusions: The prevalence of cognitive dysfunction among older adults with diabetes is high. These results have implications for how physicians educate patients in appropriate self-management practices and for the prevention of diabetes-related complications.

Background: A seasonal periodicity, winter peaks and summer troughs, of coronary heart disease (CHD) mortality has been identified by several investigations in various parts of the world using vital statistics. However, population-based studies describing seasonal patterns of validated incident non-fatal and fatal myocardial infarction (MI) are sparse. Thus, we aim to characterize the monthly distribution of acute MI incidence using data from the community surveillance component of the Atherosclerosis Risk in Communities (ARIC) Study. Methods: We estimated monthly rates of incident hospitalized acute MI from community-wide surveillance of 35 to 84 year old residents of the 4 ARIC Study communities (415,000 base population) from 2006 to 2010. Diagnostic classifications of all hospitalized MI events were independently validated using standardized algorithms applied to data on chest pain history, electrocardiographic evidence and cardiac biomarkers obtained from medical record abstraction. Age adjusted event rates (95% confidence intervals) per 10,000 persons stratified by ARIC community were calculated using population denominators estimated from United States census data. Analyses were weighted to account for the underlying sampling scheme. Results: From 2006 - 2010, a total of 8,578 estimated hospitalized MI events occurred, on the basis of 3,692 hospitalizations sampled. Of these, 71% [6,090 of 8,578] were in persons with no recorded history of MI. Overall, rates of incident MI varied across the months. Distributions of incident MI by month differed between ARIC communities, ranging from a monthly rate of 13.5/10,000 to 45.1/10,000 persons. In Forsyth, NC, we observed the highest monthly rates of incident MI in June [41.1 (23.0, 59.2)] and July [37.3 (26.5, 48.2)], and the lowest rates in September [26.2 (19.0, 33.5)] and March [27.8 (19.1, 36.4)]. Within Jackson, MS, event rates ranged from minimums of 27.1 (18.2, 35.9) and 28.2 (15.4, 40.9) in January and June to maximums of 45.1 (30.4, 59.8) and 39.9 (27.2, 52.7) in May and August. In Minneapolis, MN, the highest monthly rates of incident MI occurred in June [30.0 (19.8, 40.2)] and December [25.3 (12.6, 38.0)], and the lowest rates in October [13.5 (8.4, 18.6)] and September [15.5 (10.5, 20.5)]. Within Washington County, MD, rates of incident MI peaked in April [29.2 (18.3, 40.1)] and November [27.2 (15.8, 38.6)], and reached lows in August [14.7 (9.9, 19.4)] and January [17.0 (11.3, 22.8)]. Conclusions: From 2006 - 2010, monthly distributions of incident MI rates differed between ARIC communities. Across the climatologically diverse ARIC sites, we did not observe seasonal patterns of MI incidence typically reported of CHD mortality (i.e. winter peaks and summer troughs). Triggers for incident MI events are complex and these data suggest they may involve factors not predominately tied to seasonal transitions in these communities.

Background: Anemia has been associated with increased mortality in heart failure patients. The prevalence and outcomes of anemia in patients hospitalized with acute decompensated heart failure (ADHF) in population-based settings are unknown. Methods: Hospitalizations related to heart failure among black and white residents 55 years and older were sampled by stratified design from 4 US communities (total population age 55+ =177,000), January 1, 2005 -December 31,2008 in the Atherosclerosis Risk in Communities (ARIC) Study. Events were validated by physician review of medical records, and linked to mortality files. Those classified as definite or probable ADHF were included in the analysis; chronic, stable heart failure and hospitalizations not for heart failure were excluded. ADHF was further classified as heart failure with preserved (≥50%) or reduced ( Results: Over four years, 13,554 (weighted) hospitalized events for definite or probable ADHF occurred, based on 2,804 sampled events. Comorbidities of ADHF included: hypertension (84%), coronary heart disease (55%), chronic bronchitis or COPD (34%), diabetes (48%), and chronic kidney disease (eGFR < 60 mL/min/1.73m 2 ) (73%). Prevalence of anemia was 77% (95%CI: 75-79%) overall and did not differ by race (p=0.6), gender (p=0.1) or by subtype of heart failure based on preserved or reduced ejection fraction (p=0.09). Anemia was more common in patients over age 75 (80%; 95%CI: 78-83%) than patients aged 55-74 (73%; 95% CI: 70-76%); p Conclusion: Among patients hospitalized for ADHF in these 4 US areas, anemia was common, particularly for those over age 75, and was associated with a longer length of hospital stay and higher 1-year mortality.

Assessment of the size and function of a functional single ventricle (FSV) is a key element in the management of patients after the Fontan procedure. Measurement variability of ventricular mass, volume, and ejection fraction (EF) among observers by echocardiography and cardiac magnetic resonance imaging (CMR) and their reproducibility among readers in these patients have not been described. From the 546 patients enrolled in the Pediatric Heart Network Fontan Cross-Sectional Study (mean age 11.9 +/- 3.4 years), 100 echocardiograms and 50 CMR studies were assessed for measurement reproducibility; 124 subjects with paired studies were selected for comparison between modalities. Interobserver agreement for qualitative grading of ventricular function by echocardiography was modest for left ventricular (LV) morphology (kappa = 0.42) and weak for right ventricular (RV) morphology (kappa = 0.12). For quantitative assessment, high intraclass correlation coefficients were found for echocardiographic interobserver agreement (LV 0.87 to 0.92, RV 0.82 to 0.85) of systolic and diastolic volumes, respectively. In contrast, intraclass correlation coefficients for LV and RV mass were moderate (LV 0.78, RV 0.72). The corresponding intraclass correlation coefficients by CMR were high (LV 0.96, RV 0.85). Volumes by echocardiography averaged 70% of CMR values. Interobserver reproducibility for the EF was similar for the 2 modalities. Although the absolute mean difference between modalities for the EF was small (2%), 95% limits of agreement were wide. In conclusion, agreement between observers of qualitative FSV function by echocardiography is modest. Measurements of FSV volume by 2-dimensional echocardiography underestimate CMR measurements, but their reproducibility is high. Echocardiographic and CMR measurements of FSV EF demonstrate similar interobserver reproducibility, whereas measurements of FSV mass and LV diastolic volume are more reproducible by CMR.

Abstract 3075 Multiple sclerosis (MS) is an autoimmune disease which in most patients presents as defined relapses followed by remissions (relapsing-remitting (RR)). Over time the clinical course evolves to a gradual but irreversible loss of neurological function to which a neurodegenerative process likely contributes. Previous studies of high-dose immunosuppressive therapy (HDIT) and autologous hematopoietic cell transplantation (HCT) were done in patients with advanced progressive MS and many patients continued to lose neurological function. To investigate the potential benefit of HDIT/HCT to halt the evolution of MS and prevent the development of the neurodegenerative processes, HDIT/HCT was studied in RRMS. A phase II clinical trial of HDIT (BCNU, etoposide, ara-C and melphalan (BEAM) and antithymocyte globulin (ATG)) and autologous HCT was conducted in patients with highly active RRMS who had failed conventional therapy to determine if sustained remissions could be induced. Eligibility criteria required Expanded Disability Status Scale (EDSS) 3.0 (moderate disability, fully ambulatory) -5.5 (severe disability, ambulatory only 100 meters without aids) and ≥2 relapses on MS treatment with EDSS worsening over the previous 18 months. Hematopoietic progenitor cells were mobilized with G-CSF and a 10-day course of prednisone. The graft was CD34-selected (Baxter, Isolex). The primary endpoint was treatment-failure defined as a composite endpoint of 1) mortality 2) relapse 3) new lesions on MRI or 4) progression in disability ≥1.0 EDSS point. Adverse events (AE) were recorded according to NCI-CTCAE v3.0. Twenty-five patients at a median age of 38(27–53) years had autologous hematopoietic stem cells collected. There were 7 Grade 3 non-hematopoietic AEs during mobilization; mostly line-associated thromboses and infections. There was 1 Grade 4 AE with pretransplant withdrawal from study; a pulmonary embolus associated with heparin-induced thrombocytopenia and pre-existing arteriovenous malformation in the brain. During mobilization, a MS flare occurred in one patient who was non-compliant with the prednisone prophylaxis. Twenty-four patients proceeded to transplant. Median follow-up is 80(52–232) weeks. Patients were infused with a median of 4.58(2.95–9.73) × 106 CD34+ cells/kg. Neutrophil recovery occurred at a median of +11(9–15) days. In the 1st year after transplant, there were 17 Grade 3 and 4 Grade 4 non-hematopoietic, non-GI AEs. The Grade 4 AEs were suicide attempt (recorded as 2 separate events), hypokalemia and increase in ALT. At baseline (n=24), one (n=23) and two (n=8) years after HDIT/HCT, the mean EDSS (SD) was 4.42(+/−0.637), 3.78(+/−0.951) and 4.13(+/−0.916) respectively. There was only one case with gadolinium-enhancing lesions after 6 months (at Year 3) (Table 1). T2 lesion volume decreased and T1 lesion volume increased from baseline to Month 12. Despite the decrease in T2 lesion volume, there was early posttransplant loss in brain volume. Four patients failed by the composite endpoint (relapses at +22 and +96 weeks; new MRI brain lesions at +197 weeks and progression of disability/death at +82/138 weeks). Event-free survival at 1 and 2 years was 95.8(90% CI :73.9, 99.4)% and 76.7(90% CI :41.1, 92.4)% respectively. 22/24 patients were without progression of disability at last follow-up.Table 1:Brain MRI: Changes in first year after transplant.Baseline n=24Month 2 n=24Month 6 n=24Month 12 n=23Total Gd+ lesions [n (%)]014 (58%)19 (90%)22 (96%)22 (100%)14 (17%)0 (0%)1 (4%)0 (0%)2+6 (25%)2 (10%)0 (0%)0 (0%)T2 lesion volume change (cc)*n202320Median(min, max)-0.13 (-6.51,1.26)-0.60 (-6.46,1.73)-0.58 (-5.14,0.97)1T1 lesion volume change (cc)*n202320Median (min, max)-0.002 (-1.10, 0.87)0.02 (-0.87, 0.99)0.11 (-0.40,1.74)2Brain volume change (%)*n202419Mean (SD)-0.91 (0.73)3-1.19 (0.86)-1.28 (1.01)*Change from baselineWilcoxon signed rank test: 1) p=0.0014; 2) p=0.0186 3) t-test: p High-dose immunochemotherapy was well-tolerated with few serious early complications. Early control of highly active RRMS was obtained post transplant but has not been complete in all patients. Patient follow-up is planned for 5 years to determine durability of responses. Disclosures: Stuve: Teva Neuroscience, EMD Serono, Roche, Novartis, Genzyme: Consultancy, Honoraria; Teva Neuroscience, EMD Serono, Roche, Novartis, Genzyme: Honoraria; Teva Neruoscience: Research Funding. Arnold:NeuroRx Research: Equity Ownership. Wundes:Biogen Idec: Consultancy, Research Funding, Speakers Bureau; Teva pharmaceutics: Consultancy.

Background Atopic dermatitis (AD) is the most common inflammatory skin disorder in the general population worldwide, and the majority of patients are colonized with Staphylococcus aureus . Eczema herpeticum is a disseminated herpes simplex virus infection that occurs in a small subset of patients. Objectives The goal was to conduct proteomic profiling of patients with AD based on S aureus colonization status and history of eczema herpeticum. We hoped to identify new biomarkers for improved diagnosis and prediction of eczema herpeticum and S aureus susceptibility and to generate new hypotheses regarding disease pathogenesis. Methods Skin taping was performed on nonlesional skin of nonatopic control subjects and on lesional and nonlesional skin of patients with AD. Subjects were classified according to the history of eczema herpeticum and S aureus colonization. Proteins were analyzed by using mass spectrometry; diagnostic groups were compared for statistically significant differences in protein expression. Results Proteins related to the skin barrier (filaggrin-2, corneodesmosin, desmoglein-1, desmocollin-1, and transglutaminase-3) and generation of natural moisturizing factor (arginase-1, caspase-14, and gamma-glutamyl cyclotransferase) were expressed at significantly lower levels in lesional versus nonlesional sites of patients with AD with and without history of eczema herpeticum; epidermal fatty acid–binding protein was expressed at significantly higher levels in patients with methicillin-resistant S aureus . Conclusion This noninvasive, semiquantitative profiling method has revealed novel proteins likely involved in the pathogenesis of AD. The lower expression of skin barrier proteins and enzymes involved in the generation of the natural moisturizing factor could further exacerbate barrier defects and perpetuate water loss from the skin. The greater expression of epidermal fatty acid–binding protein, especially in patients colonized with methicillin-resistant S aureus , might perpetuate the inflammatory response through eicosanoid signaling.

Abstract 2643 Children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities receive chronic transfusion therapy in an effort to prevent a primary stroke. Typically the goal is maintaining sickle hemoglobin (HbS) Disclosures: Off Label Use: It will include the use of hydroxyurea in children with sickle cell anemia.