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Objective: To test the hypothesis that caregivers' or adult participants' low ratings of provider communication are associated with more hospital admissions among adults and children with sickle cell disease (SCD), respectively. Secondarily, we determined whether there was an association between the caregivers' or participants' health literacy and rating of providers' communication. Methods: Primary data were collected from participants through surveys between 2014 and 2016, across six sickle cell centers throughout the U.S. In this cross-sectional cohort study, 211 adults with SCD and 331 caregivers of children with SCD completed surveys evaluating provider communication using the Consumer Assessment of Healthcare Providers and Systems (CAHPS), healthcare utilization, health literacy, and other sociodemographic and behavioral variables. Analyses included descriptive statistics, bivariate analyses, and logistic regression. Results: Participants with better ratings of provider communication were less likely to be hospitalized (odds ratio (OR) = 0.54, 95% confidence interval (CI) = [0.35, 0.83]). Positive ratings of provider communication were associated with fewer readmissions for children (OR = 0.23, 95% CI = [0.09, 0.57]). Participants with better ratings of provider communication were less likely to rate their health literacy as lower (regression coefficient (B) = -0.28, 95% CI = [-0.46, -0.10]). Conclusions: Low ratings of provider communication were associated with more hospitalizations and readmissions in SCD, suggesting the need for interventions targeted at improving patient-provider communication which could decrease hospitalizations for this population.

Outpatient care is critical in the management of chronic diseases, including sickle cell disease (SCD). Risk factors for poor adherence with clinic appointments in SCD are poorly defined. This exploratory study evaluated associations between modifying variables from the Health Belief Model and missed appointments.We surveyed adults with SCD (n = 211) and caregivers of children with SCD (n = 331) between October 2014 and March 2016 in six centres across the U.S. The survey tool utilized the framework of the Health Belief Model, and included: social determinants, psychosocial variables, social support, health literacy and spirituality.A majority of adults (87%) and caregivers of children (65%) reported they missed a clinic appointment. Children (as reported by caregivers) were less likely to miss appointments than adults (OR:0.22; 95% CI:(0.13,0.39)). In adults, financial insecurity (OR:4.49; 95% CI:(1.20, 20.7)), health literacy (OR:4.64; 95% CI:(1.33, 16.15)), and age (OR:0.95; 95% CI:(0.91,0.99)) were significantly associated with missed appointments. In all participants, lower spirituality was associated with missed appointments (OR:1.83; 95%CI:(1.13, 2.94)). The most common reason for missing an appointment was forgetfulness (adults: 31%, children: 26%). A majority thought reminders would help (adults: 83%, children: 71%) using phone calls (adults: 62%, children: 61%) or text messages (adults: 56%, children: 51%).Our findings demonstrate that modifying components of the Health Belief Model, including age, financial security, health literacy, spirituality, and lacking cues to action like reminders, are important in missed appointments and addressing these factors could improve appointment-keeping for adults and children with SCD.

Objective: Hospital admissions are significant events in the care of individuals with sickle cell disease (SCD) due to associated costs and potential for quality of life compromise. Methods: This cross-sectional cohort study evaluated risk factors for admissions and readmissions between October 2014 and March 2016 in adults with SCD (n = 201) and caregivers of children with SCD (n = 330) at six centres across the U.S. Survey items assessed social determinants of health (e.g. educational attainment, difficulty paying bills), depressive symptoms, social support, health literacy, spirituality, missed clinic appointments, and outcomes hospital admissions and 30-day readmissions in the previous year. Results: A majority of adults (64%) and almost half of children (reported by caregivers: 43%) were admitted, and fewer readmitted (adults: 28%; children: 9%). The most common reason for hospitalization was uncontrolled pain (admission: adults: 84%, children: 69%; readmissions: adults: 83%, children: 69%). Children were less likely to have admissions/readmissions than adults (Admissions: OR: 0.35, 95% CI: [0.23,0.52]); Readmissions: 0.23 [0.13,0.41]). For all participants, missing appointments were associated with admissions (1.66 [1.07, 2.58]) and readmissions (2.68 [1.28, 6.29]), as were depressive symptoms (admissions: 1.36 [1.16,1.59]; readmissions: 1.24 [1.04, 1.49]). In adults, difficulty paying bills was associated with more admissions, (3.11 [1.47,6.62]) readmissions (3.7 [1.76,7.79]), and higher spirituality was associated with fewer readmissions (0.39 [0.18,0.81]). Discussion: Missing appointments was significantly associated with admissions and readmissions. Findings confirm that age, mental health, financial insecurity, spirituality, and clinic attendance are all modifiable factors that are associated with admissions and readmissions; addressing them could reduce hospitalizations.

Sickle cell disease (SCD) results in neuropsychological complications that place adolescents at higher risk for limited educational achievement. A first step to developing effective educational interventions is to understand the impact of SCD on school performance. The current study assessed perceptions of school performance, SCD interference and acceptability of educational support strategies in adolescents with SCD. To identify potential risk factors, the relationships between school performance, SCD interference and demographics were also examined. Thirty adolescents aged 12 to 20 years completed demographics and SCD school performance questionnaires. Approximately 37% of participants reported receiving special education services, but more than 60% reported that SCD interfered with their school performance. Females reported that SCD impacted their schooling more than males (X2 (1, n = 30) = 5.00, p < .05). Study findings provide important insights into demographic risk factors and support the need for individualized health and educational plans for adolescents with SCD.

Practice guidelines have been developed for pediatric patients with hematologic disorders, and similar to guidelines for other diseases, adherence is variable. Quality improvement initiatives can move implementation of the guidelines from variable to frequent. For children with sickle cell disease (SCD), quality improvement interventions have significantly improved outcomes related to the effective and timely management of acute vaso-occlusive crises (VOC), reducing the frequency of VOC necessitating hospitalization by administration of hydroxyurea, prevention of stroke, and reducing infections such as influenza. Although there are guidelines for the care and treatment of children with hemophilia, quality improvement initiatives are in the early stages.

Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care.In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct.A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P=0.04).Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.).

Children with sickle cell anemia have a higher-than-expected prevalence of poor educational attainment. We test two key hypotheses about educational attainment among students with sickle cell anemia, as measured by grade retention and use of special education services: (1) lower household per capita income is associated with lower educational attainment; (2) the presence of a silent cerebral infarct is associated with lower educational attainment. We conducted a multicenter, cross-sectional study of cases from 22 U.S. sites included in the Silent Infarct Transfusion Trial. During screening, parents completed a questionnaire that included sociodemographic information and details of their child's academic status. Of 835 students, 670 were evaluable; 536 had data on all covariates and were used for analysis. The students' mean age was 9.4 years (range: 5-15) with 52.2% male; 17.5% of students were retained one grade level and 18.3% received special education services. A multiple variable logistic regression model identified that lower household per capita income (odds ratio [OR] of quartile 1 = 6.36, OR of quartile 2 = 4.7, OR of quartile 3 = 3.87; P = 0.001 for linear trend), age (OR = 1.3; P < 0.001), and male gender (OR, 2.2; P = 0.001) were associated with grade retention; silent cerebral infarct (P = 0.31) and painful episodes (P = 0.60) were not. Among students with sickle cell anemia, household per capita income is associated with grade retention, whereas the presence of a silent cerebral infarct is not. Future educational interventions will need to address both the medical and socioeconomic issues that affect students with sickle cell anemia.

Background : Approximately 100,000 persons with sickle cell disease (SCD) live in the United States, including 15,000 in the Midwest. Unfortunately, many patients experience poor health outcomes due to limited access to primary care providers (PCPs) who are prepared to deliver evidence-based SCD care. Sickle Treatment and Outcomes Research in the Midwest (STORM) is a regional network established to improve care and outcomes for individuals with SCD living in Indiana, Illinois, Michigan, Minnesota, Ohio, and Wisconsin. Methods : STORM investigators hypothesized that Project ECHO ® methodology could be replicated to create a low-cost, high-impact intervention to train PCPs in evidence-based care for pediatric and young adult patients with SCD in the Midwest, called STORM TeleECHO. This approach utilizes video technology for monthly telementoring clinics consisting of didactic and case-based presentations focused on the National Heart, Lung and Blood Institute (NHLBI) evidence-based guidelines for SCD. Results : Network leads in each of the STORM states assisted with developing the curriculum and are recruiting providers for monthly clinics. To assess STORM TeleECHO feasibility and acceptability, monthly attendance and satisfaction data are collected. Changes in self-reported knowledge, comfort, and practice patterns will be compared with pre-participation, and 6 and 12 months after participation. Conclusions : STORM TeleECHO has the potential to increase implementation of the NHLBI evidence-based guidelines, especially increased use of hydroxyurea, resulting in improvements in the quality of care and outcomes for children and young adults with SCD. This model could be replicated in other pediatric chronic illness conditions to improve PCP knowledge and confidence in delivering evidence-based care. Keywords: provider education; telementoring; continuing education; sickle cell disease (Published: 24 November 2016) Citation: Med Educ Online 2016, 21: 33616 - http://dx.doi.org/10.3402/meo.v21.33616

The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbSβ° thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P = .018), and male sex (P = .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761.

This article describes the planning, implementation, and evaluation of Research and Education Day, an event designed to promote education and awareness of sickle cell disease (SCD), while also fostering and increasing participation by families in research studies. Quantitative and qualitative evaluation data (tracking of participant attendance and participation in research studies; program evaluation surveys) indicate that program goals were achieved. Results show that event attendance, research participation and retention, and community volunteerism has increased exponentially over the 8-year history of the event. Parents report that their top-rated reasons for attending are learning about research studies and participating in SCD-related educational activities. Data also show that families learn about the event in multiple ways (i.e., flyers, clinic staff, word of mouth, etc.). Research and Education Day is a model for educating participants with sickle cell and their families, engaging them in research studies, and enhancing community awareness and support.

Background Respiratory infections are associated with clinically significant illness in patients with sickle cell disease (SCD). The 2009 H1N1 pandemic was perceived as a significant threat to this population. Methods We undertook a chart review of all patients with SCD followed at our institution to identify those with confirmed H1N1 infection. Further chart and laboratory data was collected on affected patients to analyze clinical courses and the factors that correlated with disease severity. Results Approximately half of the patients with confirmed H1N1 infection were managed successfully on an outpatient basis with oseltamivir therapy. Among the patients admitted, the most common diagnosis was acute chest syndrome (ACS). Most admitted patients had uncomplicated clinical courses, with a median length of admission of 3 days and no mortality or requirement for mechanical ventilation. A past history of ACS or reactive airway disease correlated with a higher rate of admission and of ACS incidence during the acute illness. Chronic transfusion therapy or hydroxyurea therapy with high hemoglobin F levels had a strong inverse correlation with incidence of ACS. Conclusions Our results indicate that that in general the impact of the H1N1 influenza pandemic on patients with SCD was mild but that past clinical history correlated with the severity of illness. Additionally, effective hydroxyurea therapy and chronic transfusion therapy appeared to be protective against the incidence of ACS. Our results suggest guidelines for the management of patients with SCD during future influenza pandemics as well as during seasonal influenza epidemics. Pediatr Blood Cancer 2011; 57: 648–653. © 2011 Wiley-Liss, Inc.

In a phase-II multi-centre double-blinded trial, we evaluated haematological effects of oral hydroxycarbamide (HC) and magnesium (Mg) in patients with HbSC, aged 5-53 years old. Subjects were randomized to HC + placebo, Mg + placebo, HC + Mg, or placebo + placebo. The primary endpoint was the proportion of hyperdense red blood cells after 8 weeks. Thirty-six subjects were evaluable, but the study was terminated early because of slow enrollment. In the combined HC groups, mean cell volume and HbF were increased, but differences were not seen in hyperdense red cells or vaso-occlusive events. Mg had no effects. Further investigation of hydroxycarbamide as monotherapy in HbSC disease is warranted.

Background: Genetic transfer of an anti-sickling β87-globin lentiviral vector (LV) into hematopoietic stem cells (HSC) followed by myeloablative transplant has cured one child with sickle cell anemia (SCA) (NEJM 2017), although it was not successful in 7 subsequent adult SCA patients, and modifications to intensify ablative conditioning, improve HSC dose, gene transfer are underway (Blood 130 Suppl 1: 527, 2017). Based upon our preclinical data (Blood 2009), we embarked upon a Reduced Intensity Conditioning (RIC) Phase I/II Pilot Study on Gene Transfer in Patients with SCA with a modified γ-Globin LV (NCT02186418), hypothesizing this approach will be safe, feasible and efficacious; Moreover, RIC will have significantly less toxicity, costs, and be implementable in many transplant centers, including those in some of the resource-poor countries, where supportive therapies for myeloablative transplants are unavailable, and where majority of SCA patients exist. Methods: Adult patients with severe SCA deemed eligible were transfused/erythrocytapheresed prior to HSC collection and transfused for 6 months post-transplant (PT) to Hb>10g/dl and HbS~30%. CD34+ HSC were collected via bone marrow harvest (BMH) and/or plerixafor mobilized Peripheral Blood Stem Collection (PBSC), selected for CD34+ cells and transduced. Patients received a single dose of IV melphalan (140mg/m2 BSA) 36hr prior to infusion of γ-globin modified (GM)-HSC. Patients were monitored for adverse events (AE), engraftment, vector copy number (VCN), modified HbF (HbF*) expression and clinical features of SCA. Results: Two SCA patients (35yo and 25yo) with HbS-β0 thalassemia genotype were treated. CD34+ HSC were collected via multiple BMH (P1) and BMH+PBSC (P2). Follow up data are available for 6 and 12mo on P1 and P2. P1 received 1x106 CD34+ cells/kgbw [vector copy number (VCN) 0.22], and P2 received 6.9x106 CD34+ cells/kgbw [VCN 0.46]. Time to neutrophil engraftment (ANC ≥ 500) was day 9 and 7 post-transplant (PT) in P1 and P2, respectively, and time to Plt recovery (Plt>50K) was day 14 PT in both. Patients included in this trial had severe disease and continued to have pre-existing chronic pain requiring significant opiates; hence ~80% of the AEs were pain events; other AEs were anticipated transient laboratory AEs associated with melphalan. Following GM-HSC infusion, both patients showed a progressive rise in HbF* (a point mutation in the γ-globin LV allows distinction from endogenous HbF by HPLC) starting from day 30 PT. Since patients had transfused HbA containing RBCs in the initial 6 months, HbF*/(HbF*+HbS) was calculated, and was 20% and 21% in P1 and P2 at day 180 PT and VCN 0.2-0.4, detected in all lineages. Integration site analysis, performed on the infused products (Day 0), at day 30 PT on P1 and P2, and on day 180 PT on P1 demonstrated highly polyclonal pattern of integration. At 1 yr PT, P1 had 20% HbF* (2.1g/dl HbF*, total Hb 10.6) with a stable VCN of 0.2-0.4 in multiple lineages in bone marrow and peripheral blood. The baseline Hb of P1 was 7.5-8.5g/dL prior to transplant. In the preceding 2 years prior to transplant, both patients were admitted for pain crises/acute chest >5-6 times/yr, and had chronic pain requiring chronic opiates. Chronic pain persisted for 4-5 months PT in P1, after which P1 has not required IV opiates, negligible oral opiates and has had no hospital visits/admissions with acute sickle events. P2 has required decreasing amounts of oral opiates for chronic back pain. Conclusions: Early results from 2 SCA adults treated with a modified γ-globin LV modified autologous HSC following RIC transplant showed excellent safety, feasibility, with minimal post-transplant toxicity, rapid count recovery, and sustained stable genetically modified cells in peripheral blood and bone marrow. The first patient shows significant clinical amelioration of the SCA phenotype at 1 year PT, with 20% vector-derived HbF (HbF*) that has caused amelioration of anemia, near elimination of chronic pain and absence of acute sickle events. The second patient, although still early post-transplant shows a similar HbF* trajectory. Additional study data will demonstrate whether this level of HbF* will provide consistent clinical benefit to patients with severe SCA. These early results, especially following a RIC transpant, are extremely promising; and if sustained, will provide a 'transportable' safe and feasible gene therapy for SCA. Disclosures Malik: CSL Behring: Patents & Royalties. Quinn:Global Blood Therapeutics: Research Funding; Silver Lake Research Corporation: Research Funding; Amgen: Research Funding.

Background: Hydroxyurea is now the standard of care for children with sickle cell anemia (SCA). Results from the BABY HUG study and recommendations from the 2014 NHLBI Guidelines have led to early initiation (increasingly before 1 year of age) of hydroxyurea for many patients. Given the known variability in hydroxyurea pharmacokinetics (PK), treatment response (HbF%), and maximum tolerated dose (MTD), we hypothesized that individualized dosing would provide the optimal treatment approach. Methods: The Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154) is a prospective study of a personalized, PK-guided dosing model of hydroxyurea for children with SCA. Using population PK model-based Bayesian estimation, each participant's PK data are used to generate an individualized starting hydroxyurea dose that targets an area under the curve associated with actual MTD. Clinical follow-up and subsequent dose adjustments target MTD, usually defined by ANC Results:The analysis of children starting hydroxyurea before 2 years of age included 33 participants (of 47 total TREAT enrollments), who contributed a total of 59.5 patient-years of hydroxyurea therapy. The mean age (±SD) at hydroxyurea initiation was 1.0±0.4 years of age. The average PK-guided, individualized starting dose was 27.8±5.3 mg/kg/day, higher than conventional and BABY HUG initial dosing (20 mg/kg/day). For children who have completed 12 months of therapy (n=24), effects in hematologic laboratory data are remarkable with average 35.9±8.9% HbF and hemoglobin concentration of 10.2±1.1 g/dL after 12 months of therapy (compared to 29.3±8.8% and 9.2±1.3 g/dL at baseline). The majority (70%) of these participants have HbF>30% and almost half achieved HbF>40% after 12 months of hydroxyurea. This hematological response is more robust than what was observed in BABY HUG (HbF=22.4%, Hb=9.1 g/dL after two years of therapy, Wang WC et al. Lancet 2011). In the TREAT cohort, there were no episodes of dactylitis, acute splenic sequestration, or stroke. There were 111 emergency room or sick outpatient clinic visits for this young cohort; 107 ED/clinic visits (without subsequent hospitalization) were for fever, URI symptoms, GI illness, or other non-specific complaints unrelated to SCA, while only 4 (3.6%) visits were for pain. There were 38 hospitalizations in 17 participants, mostly for routine evaluation of fever (66%), but no positive blood cultures and no admissions for febrile neutropenia. The average length of hospitalization was 2.8±2.4 days with 81% of participants discharged within 72 hours of admission. There were 3 episodes of acute chest syndrome in 2 patients, two of whom required PRBC transfusion. Including all types of visits, there were only 6 pain events, equivalent to 10.1 pain events per 100 patient-years, which is much lower than the published 94 events per 100 patient-years in the hydroxyurea treatment arm of BABY HUG (Thornburg CD et al. Blood 2012). There were 37 TCD exams performed in 16 participants, all normal except for one patient with conditional velocities that normalized with hydroxyurea. There were no significant differences from baseline to month 12 in either RBC pit counts or cystatin C values. Conclusions: Hydroxyurea initiation at an early age using PK-guided dosing provides significant clinical benefits for young children with sickle cell anemia. These TREAT study data suggest that initiating hydroxyurea around one year of life using a personalized dosing strategy can provide better clinical and laboratory benefits than starting at the conventional 20 mg/kg/day weight-based dose. Very high HbF levels are observed at modest and well-tolerated doses of hydroxyurea, perhaps because treatment was initiated before the process of HbF inactivation is complete. Continued long-term follow-up of these patients will determine whether these will be sustained and able to prevent both short- and long-term complications of SCA. Disclosures Malik: CSL Behring: Patents & Royalties. Quinn:Silver Lake Research Corporation: Research Funding; Global Blood Therapeutics: Research Funding; Amgen: Research Funding. Ware:Biomedomics: Research Funding; Nova Laboratories: Consultancy; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Global Blood Therapeutics: Other: advisory board; Agios: Other: advisory board; Novartis: Membership on an entity's Board of Directors or advisory committees.

The purpose of this study was to examine perceived barriers to clinic attendance and strategies to overcome these barriers for adolescents with sickle cell disease.This was a 2-phased study, which used focus groups (n=13) and individual semistructured interviews (n=32) with adolescent patients (aged 13 to 21 y) from 3 pediatric sickle cell clinics in the Midwest.Adolescents identified competing activities, health status, patient-provider relationships, adverse clinic experiences, and forgetting as barriers to clinic attendance. Calendars/reminders and parent reminders were the most commonly reported strategies to facilitate clinic attendance. Adolescents also reported the need for flexible scheduling and improved patient-provider communication.Adolescents with sickle cell disease and their families may benefit from ongoing education about the importance of attending routine clinic visits. Adherence to clinic appointments for adolescents may be enhanced by developing interventions to decrease forgetting (eg, phone call reminders or text messaging) and increase patient satisfaction with clinic visits. Scheduling appointments to accommodate busy schedules/scheduling conflicts (eg, late clinic hours), providing teen-friendly clinic environments, and using technology may also facilitate attendance.

Keywords: sickle cell disease; atypical haemolytic uraemic syndrome; eculizumab; thrombotic microangiopathy; complement mutations

Iron-overload associated endocrinopathy is the most frequently reported complication of chronic transfusion therapy in patients with thalassaemia (Thal). This study compared iron-overloaded subjects with Thal (n = 142; 54%M; age 25.8 +/- 8.1 years) and transfused sickle-cell disease (Tx-SCD; n = 199; 43%M, 24.9 +/- 13.2 years) to non-transfused SCD subjects (non-Tx-SCD; n = 64, 50%M, 25.3 +/- 11.3 years), to explore whether the underlying haemoglobinopathy influences the development of endocrinopathy. Subjects were recruited from 31 centres in the USA, Canada and the UK. Subjects with Thal had more evidence of diabetes (13% vs. 2%, P < 0.001), hypogonadism (40% vs. 4%, P < 0.001), hypothyroidism (10% vs. 2%, P =

Objective To investigate the relationship between neuropsychological functioning and radiographic findings in children with sickle cell disease (SCD) with no history of clinical neurological events. Methods Thirty-one patients with SCD randomly selected from a regional treatment center underwent neuropsychological and disease severity assessments. Of these, 22 also had structural magnetic resonance imaging and magnetic resonance perfusion studies performed. Results Forty-five percent of the imaged subgroup showed imaging abnormalities that were found to be correlated with disease severity but not neuropsychological level of performance indices. A significant relationship, however, was found between imaging abnormalities and increased variability in neuropsychological performance. Conclusions These results corroborate the high rate of rheologic and vascular pathology in SCD and underscore the importance of representing neuropsychological functioning in multiple ways.

Objective To investigate the feasibility and efficacy of a randomized clinical pilot trial comparing routine services (RS) with a school intervention program (SIP) for children with sickle cell anemia (SCA). Method Twenty-four children (ages 8-12 years) with SCA were randomized to RS or SIP. General disease knowledge, consumer satisfaction, self-concept, and school absences were evaluated. Results Compared with children receiving RS, children and teachers receiving SIP evidenced more accurate information about their disease, and children with SCA had significantly fewer absences. Teachers receiving SIP reported higher consumer satisfaction. Conclusions A modest educational curriculum can increase knowledge of SCA, is associated with lower absence rates, and yields high consumer satisfaction ratings.

Elevated plasma homocysteine levels have been shown to be a risk factor for endothelial cell damage and thrombosis, which are implicated in sickle cell disease (SCD)-related vaso-occlusion. The aim of this study was to determine the prevalence of hyperhomocysteinemia in SCD. Fasting and postmethionine load (PML) homocysteine, red cell folate, and the MTHFR C677T mutation were determined in 77 patients with SCD and 110 African-American controls. Plasma methylmalonic acid and pyridoxine levels were determined in 54 patients and all controls. For analysis, the subjects were divided into two age groups (2-10 years and 10.1-21 years). In both age groups, median PML homocysteine levels were significantly elevated in patients with SCD compared with controls. Fasting homocysteine levels were elevated in patients with SCD versus controls only in those older than 10 years. Hyperhomocysteinemia was noted in 38% of patients versus 7% in controls. Folate levels were higher among patients than controls and showed a significant negative correlation with PML homocysteine levels in patients with SCD. Pyridoxine levels in patients with SCD were significantly lower than in controls and showed a negative correlation with PML homocysteine levels. Among patients with SCD, pyridoxine deficiency was more common (62%) among those with hyperhomocysteinemia compared with those with normal homocysteine levels (30%). Homozygosity for the MTHFR C677T mutation was rare. These data suggest that children with SCD have significant hyperhomocysteinemia, associated with pyridoxine and relative folate deficiencies.

Background: Although increase prevalence of airway hyper-reactivity (AHR) has been detected in children, and even adults with sickle cell disease (SCD) using methacholine provocative challenge test (MCT), AHR was not been found to be associated with clinical asthma.Hence, the clinical implications of AHR in SCD are unknown. Furthermore, AHR studies in SCD patients using MCT lack comparisons with a control population. We recently showed that increased placenta growth factor (PlGF) levels in sickle mice causes AHR by upregulating leukotriene synthesis and inflammation. We therefore designed a prospective study to determine the prevalence of AHR in children and young adults with SCD, and in unaffected siblings living in the same household as a control population, and also determine the biochemical and clinical implications of AHR in SCD. Methods: A total of 67 patients with SCD and 14 unaffected siblings of the patients enrolled on to the study for determining baseline AHR (ClinicalTrials.gov Identifier: NCT00448370). Chief eligibility criteria included a diagnosis of SCD (HbSS, HbSC or HbS b-thalassemia) confirmed by hemoglobin electrophoresis or gene sequencing, ages 5.5 years to 30 years who were able to complete pulmonary function testing and were at baseline/steady state (no acute sickle events 3 weeks prior or acute chest syndrome (ACS) 4 weeks prior). Excluded were patients taking anti-leukotriene medications within 30 days prior, although patients with SCD who had a known history of asthma but not on leukotriene inhibitors were eligible. Patients with chronic transfusions, congenital lung or heart condition, or other medical condition that could affect the pulmonary function testing were also ineligible. Unaffected siblings of the 67 enrolled SCD patients living in the same household were offered enrollment for MCT and those consenting were enrolled. Results: 64 SCD patients and 14 siblings underwent a MCT; 3 of 67 SCD patients had FEV116mg/mL; borderline AHR=PC20 4-16mg/mL; mild AHR=PC20 1-3mg/mL and moderate-severe AHR=PC20 Conclusions: There was a higher prevalence of mild to severe AHR (51%) in patients with SCD, compared to a 14% prevalence of mild AHR in siblings living in the same household. The higher degree of AHR was associated with increased SCD morbidity - increased rates of admission from ACS and pain crisis, when compared to those with no AHR. AHR was associated with higher leukotrienes and a trend towards higher PlGF target gene induction. Together, our data suggests that AHR may be a biomarker for SCD morbidity, and may also be a therapeutic target, since blockade of PlGF or leukotriene synthesis in patients with severe AHR may reduce SCD morbidity. Disclosures No relevant conflicts of interest to declare.

Objective. To conduct intensive pain management skills training (IST) in children with sickle cell disease (SCD) and their parents and to comprehensively evaluate pain, coping, and daily functioning in children pre, immediately post, and 3 months following treatment. Methods. Three children who received IST in nonpharmacological and pharmacological pain management strategies completed a Coping Strategies Questionnaire (CSQ) at pre, post, and follow-up assessments, and daily pain and activity diaries for 18 weeks, spanning from 1 week pretreatment to 11 weeks posttreatment. Results. From pre- to posttreatment, 1 child receiving IST indicated increased report of active coping attempts and all 3 children indicated decreased report of negative thinking on the CSQ. Participants in IST used coping skills on 90% of days with pain and reported the skills to be moderately helpful on the daily diaries. For daily activities such as eating dinner, playing with friends, and hours slept, children participated similarly on days with pain and days without pain during the posttreatment period. Given the small number of participants in this study, individual cases are discussed to highlight similarities and differences in how participants responded to the treatment and during the 3-month follow-up period. Conclusions. In this pilot study, each participant showed improvement in coping and daily functioning after completing the IST program. Individual differences in response to treatment indicate the need for more targeted intervention programs that incorporate pharmacological and nonpharmacological components. The results of this study highlight both the promise and the complications of conducting comprehensive pain intervention and functional outcome studies in children with SCD.

Recently, a mild to moderate elevation in the plasma homocysteine (Hcy) level has been found to be an important risk factor for stroke. Homozygosity for a common mutation (C677T) in the gene encoding for the enzyme methylenetetrahydrofolate reductase (MTHFR) involved in Hcy metabolism has been associated with increased levels of Hcy. To determine the role of hyperhomocysteinemia in the pathogenesis of stroke in children with sickle cell disease (SCD), Hcy levels and C677T MTHFR genotype were determined in 40 patients homozygous for hemoglobin SS and compared with 197 healthy children. Eleven of 40 patients with SCD had a history of stroke. The prevalence of homozygosity for the C677T MTHFR variant was 5% in the patients with SCD. The median Hcy level was 5.8 micromol/L in the patients versus 5.4 micromol/L in the controls (Fisher's, P > 0.05). There was no correlation of Hcy levels with the MTHFR genotype in patients with SCD. In patients with SCD and stroke, the median Hcy level was 4.8 micromol/L versus 6.0 micromol/L in those without stroke (P = 0.44, Mann-Whitney rank sum test). There was no difference in the proportion of patients with SCD with or without stroke who were homozygous for the C677T MTHFR mutation (0/11 versus 2/29; Fisher's, P = 1.000). In conclusion, this study failed to demonstrate an elevation in plasma Hcy levels in children with SCD compared with normal controls. Furthermore, hyperhomocysteinemia did not seem to be a significant factor in the pathogenesis of stroke in children with SCD.

Cutis marmorata telangiectatica congenita is an uncommon, congenital cutaneous condition typified by persistent cutis marmorata and other associated abnormalities. Progressive neurologic complications are generally not a feature of the disorder. A case is reported of cutis marmorata telangiectatica congenita associated with diffuse cerebrovascular infarcts at 7 months of age. Moyamoya-like vascular abnormalities were demonstrated in addition to the factor V Leiden mutation, a congenital hypercoagulable disorder. This novel case illustrates the importance of evaluating children with strokes for congenital thrombophilic disorders.

Objective: To obtain caregiver and medical professional opinions regarding the child-rearing practices of caregivers of children with sickle cell diseases (SCD). Methods: We obtained self-reports of parenting practices from 48 caregivers of children with SCD and 48 caregivers of matched classroom comparison peers using the Child-Rearing Practices Report (CRPR). CRPR ratings were also obtained from 12 experts in pediatric SCD regarding their predictions of how a parent of a child with SCD would respond. The experts predicted differences in protectiveness, discipline, and excessive worry. Objective interim and lifetime illness severity scores were obtained for the children with SCD. Resultr: Caregivers showed similarity between the two groups, disagreement with the experts, and minimal relationship to illness severity. Conclusions: Experts who work with children with chronic illnesses such as SCD seem to have stereotyped ideas that do not correspond with parental reports of their child-rearing practices, suggesting the need for careful clinical evaluations.

OBJECTIVES: (1) To determine serotype-specific IgG antibody responses to reimmunization with pneumococcal polysaccharide vaccine at age 5 years in children with sickle cell anemia and (2) to determine whether continued penicillin prophylaxis had any adverse effects on these responses. STUDY DESIGN: Children with sickle cell anemia, who had been treated with prophylactic penicillin for at least 2 years before their fifth birthday, were randomly selected at age 5 years to continue penicillin prophylaxis or to receive placebotreatment. These children had been immunized once or twice in early childhood with pneumococcal polysaccharide vaccine and were reimmunized at the time of randomization. RESULTS: Serotype-specific IgG antibody responses to reimmunization varied according to pneumococcal serotype but in general were mediocre or poor; the poorest response was to serotype 6B. The antibody responses were similar in subjects with continued penicillin prophylaxis or placebo treatment, and in subjects who received one or two pneumococcal vaccinations before reimmunization. The occurrence of pneumococcal bacteremia was associated with low IgG antibody concentrations to the infecting serotype. CONCLUSIONS: Reimmunization of children with sickle cell anemia who received pneumococcal polysaccharide vaccine at age 5 years induces limited production of serotype-specific IgG antibodies, regardless of previous pneumococcal vaccine history. Continued penicillin prophylaxis does not interfere with serotype-specific IgG antibody responses to reimmunization. (J Pediatr 1996;129:828-35)

Comparisons with measures of peer relationships and emotional well-being were made between youngsters with sickle cell disease (SCD) and same-classroom comparison peers. Relative to the comparison subjects, females with SCD were perceived by peers as being less sociable and less well accepted; males with SCD were perceived as being less aggressive than comparison peers. For both males and females with SCD, no other differences were identified on numerous measures of emotional well-being. None of the multiple measures of illness severity were significantly related to measures of psychological adjustment. The common side effects of SCD, chronic fatigue and small physical size, may divert males with the illness from manifesting difficulties related to aggressive behavior with peers. For females with the illness, the common side effects of the illness may hinder the development of normal social relationships. Despite chronic exposure to numerous stressful life events associated with SCD, the youngsters with the illness were remarkably similar to comparison peers, showing evidence of considerable hardiness.

The case of a patient with sickle cell disease is presented in which neuropsychological and magnetic resonance imaging studies were completed prior to and after a right hemispheric stroke. The contribution of a new MR perfusion technique in understanding the neurological complications in this patient is discussed. This case illustrates the complex pathophysiology of neuropsychological deficits in SCD and underscores the need to develop models that better reflect this complexity.

Objective : To evaluate the consequences of discontinuing penicillin prophylaxis at 5 years of age in children with sickle cell anemia who had received prophylactic penicillin for much of their lives. Design : Randomized, double-blind, placebo-controlled trial. Setting : Eighteen teaching hospitals throughout the United States. Patients : Children with sickle cell anemia (hemoglobin SS or hemoglobin S β 0 -thalassemia) who had received prophylactic penicillin therapy for at least 2 years immediately before their fifth birthday and had received the 23-valent pneumococcal vaccine between 2 and 3 years of age and again at the time of randomization. Of 599 potential candidates, 400 were randomly selected and followed for an average of 3.2 years. Interventions : After randomization, patients received the study medication twice daily-either penicillin V potassium, 250 mg, or an identical placebo tablet. Patients were either seen in the clinic or contacted every 3 months thereafter for an interval history and dispensing of the study drug. A physical examination was scheduled every 6 months. Main outcome measures : The primary end point was a comparison of the incidence of bacteremia or meningitis caused by Streptococcus pneumoniae in children continuing penicillin prophylaxis versus those receiving the placebo. Results : Six children had a systemic infection caused by S. pneumoniae , four in the placebo group (2.0%; 95% confidence interval 0.5%, 5.0%) and two in the continued penicillin prophylaxis group (1.0%; 95% confidence interval 0.1%, 3.6%), with a relative risk of 0.5 (95% confidence interval 0.1, 2.7). All invasive isolates were either serotype 6(A or B) or serotype 23F. Four of the isolates were penicillin susceptible, and two (one from each treatment group) were penicillin and multiply antibiotic resistant. Adverse effects of the study drug were reported for three patients (nausea, vomiting, or both), one of whom was in the placebo group. Conclusion : Children with sickle cell anemia who have not had a prior severe pneumococcal infection or a splenectomy and are receiving comprehensive care may safely stop prophylactic penicillin therapy at 5 years of age. Parents must be aggressively counseled to seek medical attention for all febrile events in children with sickle cell anemia. (J PEDIATR 1995;127:685-90)

Sickle Treatment and Outcomes Research in the Midwest (STORM) is a regional sickle cell network, funded by the Health Resources and Services Administration Treatment Demonstration Project (HRSA U1EMC27863), established to improve outcomes for individuals with sickle cell disease (SCD) living in Indiana, Illinois, Michigan, Minnesota, Ohio and Wisconsin. The STORM network is led by pediatric and adult hematologists who coordinate network activities in each state, along with a Regional Coordinating Center that organizes efforts throughout the Midwest. The goal of the STORM network is to increase the number of pediatric and adult primary care providers (PCP) who are knowledgeable about the management and treatment of SCD, and who are willing to prescribe and manage hydroxyurea therapy as a means to improve medical care for the approximately 15,000 individuals living with SCD in the Midwest. One PCP engagement strategy that has been implemented to increase provider knowledge in the region is replication of the Project ECHOTM (Extension for Community Healthcare Outcomes) telementoring model. Project ECHO was developed by the University of New Mexico to utilize low-cost, high-impact video technology to link expert inter-disciplinary specialist teams with primary care providers to improve management of chronic diseases. This guided practice telementoring model delivers complex specialty medical care to underserved areas, reduces health disparities, and increases workforce capacity. Project ECHO's methodology is based on 1) using telehealth technology to build healthcare resources where they are scarce; 2) sharing best practices to reduce variation in clinical care; 3) utilizing practice-based learning to develop specialty expertise among providers; and 4) monitoring and evaluating provider outcomes. Project ECHO has demonstrated improved healthcare outcomes in Hepatitis C and several other chronic diseases, and is now being piloted by STORM to test its feasibility and applicability for SCD by using a regional approach with CME accreditation. STORM network site physician leads in each state are recruiting multi-disciplinary primary care teams to participate as "spokes" in monthly SCD TeleECHO clinics. The "hub" led by the STORM Regional Coordinating Center, located at Cincinnati Children's Hospital Medical Center, coordinates implementation and evaluation of the telementoring clinics, delivered through monthly teaching sessions. STORM TeleECHO participants log onto an internet-based virtual meeting site, using a webcam to interact during the session. STORM TeleECHO clinics include brief didactic presentations from nationally-recognized SCD content experts with topics and curriculum based on the National Heart Lung and Blood Institute Evidence-Based Management of Sickle Cell Disease guidelines released in 2014. TeleECHO teaching clinics also include 1-2 de-identified, HIPAA protected case discussions (pediatric and adult) presented by providers who would like medical and psychosocial feedback on management of challenging clinical scenarios. Providers participating in the STORM TeleECHO complete an initial survey assessing knowledge and comfort levels, practice behaviors (including hydroxyurea prescribing practices) and clinic demographics. Satisfaction surveys are sent to participants after each session as part of the CME-credit evaluation. Follow-up surveys at 6 months and 1 year will assess satisfaction, knowledge, comfort level and changes in practice. STORM's TeleECHO was launched in March 2016. Preliminary data indicate an interest in STORM TeleECHO teaching sessions by both pediatric and adult providers across the Midwest region. Future efforts will expand the network to more PCPs in the region, while improving the applicability and utility of STORM TeleECHO in SCD through provider assessment. Disclosures Ware: Global Blood Therapeutics: Consultancy; Biomedomics: Research Funding; Bristol Myers Squibb: Research Funding; Addmedica: Research Funding; Nova Laboratories: Consultancy; Bayer Pharmaceuticals: Consultancy.

Background: Hydroxyurea is the primary disease modifying therapy for patients with sickle cell anemia (SCA). The clinical and laboratory benefits of hydroxyurea are the greatest when escalated to the maximum tolerated dose (MTD). The process of dose escalation to MTD requires expertise and can be tedious, often taking 6-12 months to titrate to the optimal dose. In addition, due in part to inter-patient variability in hydroxyurea pharmacokinetics (PK), the MTD varies among patients with a range of 15-35 mg/kg/day. We utilized a population PK model in combination with Bayesian estimation and a sparse sampling strategy, to individualize dosing of children starting hydroxyurea treatment. Methods: The Therapeutic Response Evaluation and Adherence Trial (TREAT, ClinicalTrials.gov NCT02286154) is a prospective study of hydroxyurea for children with SCA. The primary objective is to develop and evaluate a population PK-based model to predict hydroxyurea MTD through an individualized dosing strategy. A sparse sampling approach was developed to allow practical sampling from young children with SCA. The sampling strategy includes administering a single oral 20 mg/kg dose followed by collection of small quantities of blood (~100uL) at three post-dosing time points (15-20 minutes, 50-60 minutes, and ~3 hours). Baseline labs (including liver and renal function) are typically collected by venipuncture, while the other two samples are drawn by fingerstick or heelstick. Plasma hydroxyurea concentrations are measured using HPLC using an internal standard of methylurea. Using the population PK model with Bayesian estimation and hydroxyurea concentrations measured at the three specified time points, hydroxyurea exposure is estimated using specialized therapeutic drug monitoring software (MWPharm, Mediware, Prague, Czech Republic). Using the area under the curve (AUC0-inf) estimated by the model, we calculate a starting dose that is predicted to achieve an AUC of 115 ug*h/mL, which was the mean AUC value at MTD for a large cohort of children from a previous study (Dong M et al. Br J Clin Pharmacol 2016). The primary objective is to select a starting dose that is close to actual MTD, to reduce the time to maximum therapeutic effect and need for dose modifications before achieving MTD. Results: From December 2014 through June 2016, 20 children taking taking hydroxyurea for the first time were enrolled in TREAT. Seventeen of the 20 participants had all 3 post-treatment PK samples collected and processed to allow calculation of an individualized PK-based dose, while 3 had difficulties in sampling or processing that prevented a safe PK-guided dose recommendation. These 3 participants were started at the standard hydroxyurea dose of 20 mg/kg/day. The Table summarizes baseline characteristics for the initial study population, notable for a very young starting age with 13/20 (65%) less than two years of age. Twelve children with PK-based initial dosing have been treated with hydroxyurea for at least six months. Despite the young starting age, after six months of hydroxyurea, children have documented increases in total Hb (1.4+/-1.9 g/dL), HbF (11.3+/-6.4%), and MCV (15+/-8 fL) and decreases in absolute reticulocyte count (-217+/-128 x 109/L) and absolute neutrophil count (-1.0+/-1.9 x 109/L). In 9 of 12 participants, the PK-guided initial dose remained the best clinical dose at six months without significant dose changes except for minor adjustments for weight. Two patients required a single dose escalation due to inadequate marrow suppression, while one required a dose hold and decrease due to neutropenia during and following a viral infection. Conclusions: These data demonstrate that a sparse sampling approach, requiring only 3 blood samples over 3 hours, is able to accurately estimate hydroxyurea exposure in children with SCA. Hydroxyurea exposure, as defined by AUC, was similar with this sparse sampling approach as previous studies that relied upon a more standard and prolonged PK sampling approach. This population PK model is then able to predict a safe starting dose of hydroxyurea that approximates the actual MTD, with clinically significant improvements in laboratory parameters following six months of therapy. This individualized PK-guided dosing regimen should simplify hydroxyurea dosing and reduce the time interval to reach MTD and maximal clinical benefits. Table Table. Disclosures Kalfa: Baxter/Baxalta/Shire: Research Funding. Quinn:Silver Lake Research Corporation: Consultancy; Amgen: Research Funding; Eli Lilly: Research Funding. Ware:Nova Laboratories: Consultancy; Addmedica: Research Funding; Global Blood Therapeutics: Consultancy; Bayer Pharmaceuticals: Consultancy; Biomedomics: Research Funding; Bristol Myers Squibb: Research Funding.

Examined the peer relationships of siblings of children with SCA (N = 37), comparing them to a matched group of classroom comparison children who were the same race/gender, closest date of birth. Social reputation was examined from the perspective of teacher and peers; peer ratings and nominations of social acceptance were obtained; and information was obtained about the sibling's own view of their peer relationships. No differences were found between the two groups, suggesting that the overall functioning of this group of siblings was comparable to peers in their classrooms. Findings are discussed in terms of professional biases, the lack of empirical data relevant to the issue of sibling competence, and resilience.

Research indicates that the quality of the adherence assessment is one of the best predictors for improving clinical outcomes. Newer technologies represent an opportunity for developing high quality standardized assessments to assess clinical outcomes such as patient experience of care but have not been tested systematically in pediatric sickle cell disease (SCD). The goal of the current study was to pilot an interactive web-based tool, the Take-Charge Program, to assess adherence to clinic visits and hydroxyurea (HU), barriers to adherence, solutions to overcome these barriers, and clinical outcomes in 43 patients with SCD age 6–21 years. Results indicate that the web-based tool was successfully integrated into the clinical setting while maintaining high patient satisfaction (>90%). The tool provided data consistent with the medical record, staff report, and/or clinical lab data. Participants reported that forgetting and transportation were major barriers for adherence to both clinic attendance and HU. A greater number of self-reported barriers(P<.01)and older age(P<.05)were associated with poorer clinic attendance and HU adherence. In summary, the tool represents an innovative approach to integrate newer technology to assess adherence and clinical outcomes for pediatric patients with SCD.

with SCD and comparison caregivers were found on self-reported psychological distress or family conflict. Distress in primary caregivers was related to perceived family conflict, but not to the presence of a child with SCD or to measures of social support. No evidence was found for a main effect or a buffering effect of social support. These results suggest similar psychological morbidity for caregivers of youth with SCD and healthy children, and highlight the role of family conflict.

Objective To assess the effects of chronic erythrocyte transfusions on prevalence of sonographic incidence of organ damage in children with sickle cell anemia (SCA). Study design Children (N = 148; mean age, 13.0 years) with SCA, receiving chronic transfusions (average, 7 years), underwent abdominal sonography at 25 institutions. After central imaging review, spleen, liver, and kidney measurements were compared with published normal values. Potential relations between ultrasound, clinical, and laboratory data were explored via analysis of variance, Student t test, and Cochran-Mantel-Haenzel tests of non-zero correlation. Results Average spleen length was similar to normal children, but over one-third had spleen volumes >300 mL, 15 had previous splenectomy for splenomegaly, and 24 had abnormal splenic echotexture. Two-thirds had hepatobiliary disease; 37 had prior cholecystectomy, 46 had gallstones, and 16 had gallbladder sludge. Gallbladder disease correlated with older age ( P = .002), longer liver length ( P P = .034), and higher total bilirubin ( P P P ≤ .005) were larger than published norms. Conclusions In children with SCA, long-term transfusion therapy may not prevent development or progression of abdominal organ dysfunction.

In a phase-II multi-centre double-blinded trial, we evaluated haematological effects of oral hydroxycarbamide (HC) and magnesium (Mg) in patients with HbSC, aged 5-53 years old. Subjects were randomized to HC + placebo, Mg + placebo, HC + Mg, or placebo + placebo. The primary endpoint was the proportion of hyperdense red blood cells after 8 weeks. Thirty-six subjects were evaluable, but the study was terminated early because of slow enrollment. In the combined HC groups, mean cell volume and HbF were increased, but differences were not seen in hyperdense red cells or vaso-occlusive events. Mg had no effects. Further investigation of hydroxycarbamide as monotherapy in HbSC disease is warranted.

A 7-year-old girl with HbSE experienced fever and pain in her legs and back while on a car trip with her family, but did not seek medical attention. She complained of sudden respiratory distress and then collapsed. An emergency squad responded within minutes, and the child was evacuated by helicopter to a local tertiary care pediatric emergency room, where she was admitted in full cardiopulmonary arrest. After prolonged attempts at resuscitation, she was pronounced dead. An autopsy was performed. Hemoglobin E (HbE) is a beta chain variant characterized by lysine substitution for glutamic acid at amino acid 26 [b] [1]. The GAG to AAG mutation in the b-globin exon 1 also results in abnormal RNA splicing that produces an unstable mRNA [2], resulting in a mild thalassemic phenotype in individuals with homozygous HbE and a more severe phenotype when combined with beta thalassemia (HbE/beta thal) [3–7]. Due to a weakened interface between the a-globin and b-globin chains, HbE is also unstable [8], causing hemolysis that may be exacerbated by fever or oxidant stress [9]. HbE is common in Southeast Asia, where the gene frequency may be as high as 60% in some localities [8]. HbS is widely distributed in Africa and to a lesser degree in the eastern Mediterranean and India [10]. Compound heterozygosity for HbE and HbS (HbSE) is relatively rare, but there are a significant number of individuals with HbSE in India [11] and in Arab countries such as Oman [12]. With population admixture and racial intermarriages, the incidence of HbSE is increasing in the West [3,7,13]. The current literature generally associates HbSE with a benign clinical course, although vaso-occlusive complications have been reported [3–7]. The child in this case was born to an African-American father and a mother of mixed Cambodian and European descent, with no family history of sickle cell anemia, bleeding or clotting disorders, or pulmonary embolism. A newborn screen performed showed HbSE. Records of counseling the family received at the time of diagnosis are not available; however, they believed that the condition was benign and did not require follow-up care. The patient was not seen by a hematologist and was not placed on penicillin prophylaxis in infancy. At the age of five the child was referred to a pediatric orthopedic surgery clinic for complaints of intermittent leg pain that had begun six months earlier. A bone scan showed mildly increased uptake in the physis of the left tibia and femur (not shown). MRI evaluation revealed two areas of abnormal signal within the mid and distal left femoral diaphysis (see Fig 1), interpreted as most consistent with bone infarction. Review of her medical records at that time revealed the diagnosis of HbSE, and she was referred to a comprehensive sickle cell center. When first seen in the hematology clinic at age 5 [1/2], she appeared well, with growth parameters in the 50th percentile. Physical examination was normal, except for a palpable spleen tip. There was no jaundice and no cardiac murmur. Over the next 2 years, the patient’s hemoglobin averaged 11.4 gm/dl (114 gm/L) ranging from 10.5 to 11.5 gm/dl. Reticulocyte count was slightly elevated, typically 1.5–1.7% (ranging from 1.1 to 3.0%). Bilirubin was 0.9 to 1.4 mg/dL (normal: 0.0–1.1) and urine urobilinogen typically was 1.0 to 2.0 mg/dL (normal: 0.2–1.0). These findings suggested slight, but variable hemolysis; LDH was not measured. The red blood cells were microcytic, with a mean cell volume ranging from 68.8 to 74.2 fL (nl 77.0– 95.0 fL) and with mean cell hemoglobin averaging 26.4 pg. (nl 25.0–33.0 pg) Blood smear showed microcytosis, occasional target cells, rare sickle cells, mild hypochromia, and mild polychromasia, no Howell–Jolly bodies. Platelet counts ranged from 180,000 to 220,000 per lL. Electrolytes and urinalysis were normal. Quantification of hemoglobin by high performance liquid chromatography showed 55% HbS, 31% HbE, and 1.3% HbF, with normal amounts of hemoglobin A2 and minor hemoglobins. Between the ages of 5 [1/2] and 7 [1/2] years, the child was hospitalized twice for pain management of vaso-occlusive events. On one of these occasions, a repeat bone scan revealed decreased uptake in the proximal and distal left femur and distal right femur consistent with a new bone infarction (not shown). Cerebral MRI/MRA was normal (not shown). She was treated with narcotics and nonsteroidal anti-inflammatory agents for pain relief. During several comprehensive care visits over this time, she exhibited no jaundice or splenomegaly on physical exam. In the days before her death the patient complained intermittently of pain in her back and legs. By parental report, the patient was febrile the day she died, but it is not clear when the fever began. The onset of respiratory distress was acute and severe, and loss of consciousness occurred very shortly thereafter. On arrival

Chronic transfusions to maintain haemoglobin S (HbS) < or =30% are the mainstay of treatment for children with sickle cell anaemia (SCA) and previous stroke. This HbS target is often hard to maintain, however, and values achieved in current practice are unknown. In preparation for the Phase III Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial, we collected data on 295 children with SCA and stroke who received transfusions at 23 institutions. The overall average pre-transfusion %HbS was 35 +/- 11% (institutional range 22-51%). Receiving scheduled transfusions on time was the most predictive variable for maintaining HbS at the < or =30% goal.

Hereditary spherocytosis (HS) is a genetically and phenotypically heterogeneous hemolytic anemia caused by deficiency in red blood cell (RBC) cytoskeleton proteins leading to disruptions in the vertical association of the cytoskeleton with the RBC lipid bilayer. Monoallelic mutations in the genes encoding ankyrin (ANK1), beta-spectrin (SPTB) and band 3 (SLC4A1) or biallelic mutations in the genes encoding alpha-spectrin (SPTA1), ankyrin, and protein 4.2 (EPB42) result in HS. Autosomal recessive HS due to compound heterozygous defects in SPTA1 is typically severe and diagnosis based on phenotypic assays like RBC morphology, osmotic fragility or ektacytometry is complicated by transfusion dependence resulting in most of the circulating RBCs to be of donor origin. We have developed a rapid comprehensive next-generation sequencing-based assay that evaluates 27 genes with published disease-causing mutations for RBC cytoskeletal disorders, enzymopathies, and CDAs. We describe here patients with hemolytic anemia due to SPTA1 mutations, identified utilizing this assay, and their phenotype-genotype correlation. Each of these cases, when possible, has been also evaluated with ektacytometry and immunoblotting of RBC ghosts for alpha-spectrin quantitation. Wichterle et al in 1996 had estimated that alphaLEPRA(Low Expression PRAgue) mutation (c.4339-99C>T) occurs in SPTA1 gene in about 5% of Caucasians. This mutation leads to activation of an alternate acceptor splice site at position -70 of intron 30, causing frame shift and premature termination, thereby leading to decrease in alpha-spectrin production in this allele to about 16% of normal. We have found a cohort of three transfusion-dependent hereditary hemolytic anemia cases where a nonsense mutation in SPTA1 gene has occurred in trans to alphaLEPRA mutation, resulting in premature termination (see Table 1). Transfusion dependence was alleviated in two of these patients after splenectomy; the third one did not have splenectomy yet. RBC phenotype explored after splenectomy revealed an ektacytometry curve indicating spherocytosis (Figure 1A) and severely decreased alpha-spectrin on immunoblotting along with significant decrease of the associated beta-spectrin (Figure 1B). A patient with moderately severe form of HS, maintaining a hemoglobin value greater than 7 g/dL and requiring only occasional transfusions during periods of illness or stress, was found to have alphaLEPRA occurring in trans to an intronic splicing mutation c.1351-1G>TG where there is substitution at nucleotide-1 of intron positioned between nucleotides 1350 and 1351 of the SPTA1 mRNA. This splicing mutation may allow for some expression of functional alpha-spectrin protein from this allele in contrast to no protein expression in the previous cases of premature termination. Alternatively, other gene mutations, not identified by the next-generation sequencing panel we used, may contribute to this patient's milder phenotype. A couple with history of two fetal losses associated with hydrops fetalis seeked genetic counseling and gave consent to have diagnostic evaluation of genes associated with non-immune hemolytic anemia using targeted next-generation sequencing. Results of the panel revealed a heterozygous frameshift SPTA1 mutation in each of the parents (c.4206delG in the father and c.4180delT in the mother). These mutations in compound heterozygous state in the offspring likely caused total absence of alpha spectrin and fatal hemolytic anemia by the time of birth. Hereditary Spherocytosis is characterized by wide phenotypic variability that will be better understood with studies of genotype-phenotype association. While complete absence of alpha-spectrin expression due to null mutations of both SPTA1 alleles is incompatible with life, a nonsense or splicing SPTA1 mutation in trans to an alphaLEPRA low expression allele causes severe or moderately severe recessive HS, respectively. Targeted next-generation sequencing can be an effective diagnostic tool particularly for patients requiring frequent transfusions that preclude meaningful phenotypical testing of their red blood cells. Figure 1. SPTA1 null mutations occurring in trans to alpha-LEPRA causing severe HS Figure 1. SPTA1 null mutations occurring in trans to alpha-LEPRA causing severe HS Figure 2. Figure 2. Disclosures Begtrup: GeneDx: Employment.

To determine if rituximab, an anti-CD20 monoclonal antibody, reduces cerebrospinal fluid (CSF) B-cell expansion in opsoclonus-myoclonus syndrome (OMS) and results in clinical improvement.Sixteen children with OMS and increased % CD20 B-cells in CSF received 4 rituximab infusions (375 mg/m IV) as add-on therapy to corticotropin (ACTH), intravenous immunoglobulins, or both, and were reevaluated 6 months later. Outcome measures were clinical (motor function, behavior, sleep) and immunologic (CSF and blood immunophenotype and Ig levels). Controls were 16 age-matched and sex-matched children, who did not have OMS.After rituximab, 81% of OMS had a lower motor severity score, and 44% improved one severity category. Mean total score decreased by 44% (P = 0.0005). Rituximab reduced rage score, nighttime awakenings, and the number of children with opsoclonus, action myoclonus, drooling, gait ataxia, and rage. Despite a 51% reduction in ACTH dose, 9 of 11 children on ACTH did not relapse. The percentage of CSF CD19 (and CD20) B-cells was lowered in all children (undetectable in 6), with a 90% reduction in the group mean (P = 0.00003). CSF B-cells were no longer expanded compared with controls. In blood, CD19 B-cells decreased (-90%, P = 0.0003), as did the CSF:blood CD19 B-cell ratio (P = 0.00003). Serum IgM fell by 69% (below reference range), with no statistically significant change in IgG or IgA.Rituximab seems efficacious and safe as adjunctive therapy for OMS. Selective targeting of CSF B lymphocytes represents a novel and valuable paradigm shift in the therapy for centrally mediated paraneoplastic disorders.

To conduct a randomized prospective trial of immune globulin treatment for 105 Rh+ children with newly-diagnosed immune thrombocytopenic purpura and a platelet count20,000/microL, to determine whether anti-D immune globulin (anti-D) is as effective as intravenous immune globulin (IVIg).Eligible patients received either a single intravenous dose of 50 microg/kg anti-D (anti-D50), 75 microg/kg anti-D, (anti-D75), or 0.8 g/kg IVIg, (IVIg). Patients were monitored for response to treatment and adverse events.By 24 hours after treatment 50%, 72%, and 77% of patients in the anti-D50, anti-D75, and IVIg groups, respectively, had achieved a platelet count20,000/microL (P=.03). By day 7, hemoglobin concentrations decreased by 1.6 g/dL, 2 g/dL, and 0.3 g/dL in the anti-D50, anti-D75, and IVIg groups, respectively. Headache, fever, or chills occurred least often in the anti-D50 group.A single 75 microg/kg dose of Anti-D raised the platelet count in children with newly diagnosed immune thrombocytopenic purpura more rapidly than standard-dose anti-D and as effectively as IVIg, with an acceptable safety profile.

Objective: To conduct a multidimensional assessment of pain in children with sickle cell disease (SCD). Variables included parent and child reports of pain location and intensity, qualitative descriptors of pain, perceptions regarding the seriousness and severity of SCD, and environmental and emotional factors associated with pain. Methods: We replicated previous SCD pain research and applied advanced assessment methodology and research design to a population of pediatric SCD patients and their caregivers. Results: Convergence of data supports the utility of multidimensional pain assessment with parents and children with SCD. SCD pain is experienced as intense and severe in home and hospital environments. Conclusions: Findings support including children as reporters in clinical assessment of SCD pain. Integration of assessment strategies into home-based pain management may improve health outcomes. Future research should target biobehavioral treatment for pediatric SCD pain.

Introduction Disease-specific patient portals use technology to provide patients with easy access to health information and have been shown to promote healthy behaviors, encourage self-care, and assist with informed decision-making. Most of the available studies, however, have failed to examine the feasibility of patient portals with adolescent/young adult, vulnerable or underrepresented populations. As a first step toward enhancing patient access to medical information and better understanding how to engage adolescent/ young adult, diverse and vulnerable populations in using a patient portal, we designed and refined a disease-specific version of an existing patient portal (MyChart) for use with adolescents and young adults with sickle cell disease (SCD). We then piloted the patient portal with the goal of understanding the impact of the intervention on quality of life and transition readiness outcomes. We hypothesized that the patient portal would be rated as feasible, accurate and useful, and that use of the patient portal would be positively associated with transition readiness and increased quality of life. Methods Patients were recruited from a Comprehensive Sickle Cell Center at an urban pediatric medical center in the Midwest through letters, at clinic visits and at SCD-related events. The current study reports data from a sample of participants who have been followed 6 months post-intervention. At each time point (Baseline, Post, 3, 6 Months Post-Intervention), participants completed a series of measures including the Pediatric Quality of Life Inventory (PedsQLTM) and an item asking about their readiness to transition to the adult healthcare system. The patient portal intervention consisted of four assignments to facilitate familiarity with the portal (e.g. graphing a test result). All participants completed these assignments over the 6-week intervention. Results All participants in the study were African American (N=20; 60% male) with a mean age of 19.4 years (SD = 2.08). Ninety percent had HbSS (5% HbSC; 5% HbSB+Thal). At the post-intervention time point, the portal was rated as feasible (M = 3.3/5) and useful (M = 4.3/5). Data indicated that participants viewed/used the following portal features most often: 1) Lab results, 2) Medications, 3) Messaging, and 4) Appointment Review. Patients logged in an average of 6.59 times over six months (range: 0-39). Portal use was analyzed categorically as non-users (with zero independent logins after the intervention period) and users (with one or more independent logins after the intervention period). Sixty percent (n=12) of participants were users, whereas 40% were non-users. Portal patients reported increasing readiness to transition over the follow-up period (Post M = 2.3/5; 3-month M = 3/5; 6-month M = 3.6/5). Finally, a repeated measures ANOVA determined that Total PedsQLTM scores increased significantly over time, (F(3) = 2.98, p = .05). Post hoc tests using Bonferroni correction revealed the largest increase in Total PedsQL scores between the post-intervention and 3-month time points. Although this increase was not statistically significant, there was a significant correlation between transition readiness and Total PedsQL scores at the 3-month time point. Discussion Study results suggest that participants found the disease-specific patient portal easy to use and beneficial to their overall health management. Participants also showed improvements in quality of life across the post-intervention time period, suggesting that use of a patient portal may have served to bolster quality of life in this sample. Study participants further reported increased readiness to transition, which was positively associated with quality of life at 3 months post- intervention. Despite the small sample size, results of this study help to increase our understanding of the relationship between portal use and health and transition outcomes. This intervention shows promise in engaging SCD adolescent/ young adult patients in clinical care and disease management that can ultimately be evaluated in a larger multi-site study. This study was funded in part by NHLBI Grant#: 1K07HL108720-03 and the Cincinnati Children's Hospital Medical Center Place Outcomes Award. Disclosures: No relevant conflicts of interest to declare.

Background Tanabe and colleagues (2010) highlighted the importance of engaging patients with Sickle Cell Disease (SCD) in disease self-management activities to improve health outcomes. Specifically, they recommended interventions that address disease self-efficacy, patient-provider communication, healthy lifestyle behaviors, future planning, and advocacy. The Stanford Chronic Disease Self-Management Program (CDSMP) is a six-week, structured intervention for adults with a chronic disease that helps them develop self-management skills in all of these areas. The CDSMP has been implemented with adults with a variety of chronic diseases (e.g., arthritis, Type II diabetes), and outcome data has shown improvements in health utilization, health status and self-management behaviors for participants six-months post participation in the CDSMP (Lorig et al. 2001). There is limited data available on the effectiveness of the CDSMP for adults with SCD, particularly young adults and adolescents. As a first step in examining the effectiveness of the CDSMP in adolescents with SCD, we conducted two CDSMP intervention groups with SCD patients 16-24 years of age. Objective The objective of the study was to assess: 1) the feasibility, acceptability and utility of the CDSMP with this population, and, 2) changes in disease self-efficacy, quality of life (QOL), and self-management behaviors from pre to 6-months after participation in the CDSMP. Methods Patients were eligible if they: 1) had a diagnosis of SCD; 2) were followed by the University of Cincinnati Health Complex or Cincinnati Children’s Hospital Medical Center (CCHMC) sickle cell clinics; 3) were between the ages of 16 -24; and, 4) had no significant cognitive limitations. Participants received a letter followed by a phone call inviting them to participate in the CDSMP and were compensated at the end of each weekly session. Results Eighteen adolescents completed the CDSMP (i.e., attended four of the six sessions) and have completed their 6-month follow-up. The majority of patients were female (56%) and had Hb SS (SS 67%; SC 28%; Sβ+Thal 5%); the mean age for participants was 19.06 (SD = 2.44). Acceptability data indicated that sessions 2 and 6 (physical activity and exercise, managing difficult emotions, working with your healthcare provider, and planning for the future) were the most beneficial. Overall participant satisfaction with the CDSMP was high, M=8.88 (SD=1.67) on a scale of 1-10 (10=totally satisfied). Qualitative comments suggest that the participants enjoyed interacting with other patients and learning skills to help manage their illness. Repeated measures ANOVAs were used to examine the QOL and disease self-efficacy data. There was not a significant improvement on PedsQL total scores over time. Patient-reported disease self-efficacy scores showed a positive trend (F(1.572, 9.432) = 3.442, P = .083). Participants reported continuing to use a number of the self-management skills/strategies they learned during the intervention such as better breathing (86.7%), problem solving (73.3%), and action planning (66.7%). Discussion Initial Results from this small pilot suggest that the CDSMP may have some promising benefits as an intervention for adolescents and young adults with SCD given its feasibility, acceptability, and potential impact on disease self-efficacy and utilization of skills learned. In addition to participants being satisfied with the content, structure, and opportunity to interact with other participants, they also reported that they continued to use the self-management skills that they had developed. Disease self-efficacy also trended upwards for participants over the course of the intervention. Although improvements in quality of life were not observed at six-months post-intervention, the small sample size likely had an impact. The next steps will be to examine these outcomes for the duration of the post-intervention period (i.e., nine and twelve-month follow-ups) to determine whether the improvements in disease self-efficacy are maintained and whether we see quality of life improving once analyses are completed with a more complete sample size. Disclosures: No relevant conflicts of interest to declare.

Sickle cell disease (SCD) is associated with a high prevalence of airway hyperreactivity (AHR) and chronic inflammation at a steady state in the absence of infection or acute sickle events; SCD patients have also been reported to have increased circulating leukotrienes (LT) (Setty et al, 2002; Jennings et al, 2008): both the pro-inflammatory LT-B4 and cysteinyl leukotrienes (cys-LTs; LT-C4, -D4 and -E4), known to promote AHR. We sought to explore the mechanisms of increased AHR in SCD. Five-lipoxygenase (5LO) is a key enzyme in LT-B4 and cysLT synthesis, we have recently reported that expression of 5LO is significantly increased in blood mononuclear cells (MNCs) in patients with SCD (Patel et al 2009). Zileuton is a specific inhibitor of 5LO that decreases LT production, is licensed for asthma and is now available in BID dosing (Zyflo CR, Cornerstone Therapeutics), but has never been tested in patients with SCD. We performed a phase 1 clinical trial to determine the safety and pharmacodynamics (PK) of twice daily administration of ZL (Zyflo CR, the study drug was provided by Cornerstone Therapeutics) in patients with SCD after obtaining an IND from the FDA. The primary objective of this study was to determine a safe and tolerable dose of ZL using a 3x3 dose escalation design of twice daily ZL for 6 weeks, with monitoring of blood counts, serum and urine chemistries, echo, EKG and clinical events. Patients 7-30 years of age with SCD at steady state that were not on hydroxyurea or chronic transfusions were enrolled. A total of 14 subjects were consented and screened for the ZL trial; 4 failed screening and 11 subjects received the study drug; 2 subjects were withdrawn due to acute sickle events. The 1200 mg BID dose that is approved for asthma was well tolerated by 3 patients; the dose was then escalated to 3000 mg/day. We found that 1800 mg alternating with 1200 mg of ZL was a safe and clinically well tolerated dose in 6 patients. No clinically significant changes of any of the clinical/laboratory safety parameters were observed from baseline values that were attributable to ZL. PK, another primary objective of this study was performed using a D-optimal sampling strategy (day 1 through week 6) and data analyzed by nonlinear mixed effects modeling (NONMEM). ZL plasma concentrations were determined by validated LC-MS/MS assay. The Cmax of ZL were 2445 ± 795 ng/ml and 2510 ± 489 ng/ml at 2400 mg/d and 3000 mg/d and the minimum zileuton exposure as measured by predose troughs were 445.0 ± 137.7 ng/ml and 703.7 ± 172.2 ng/ml at 2400 mg/d and 3000 mg/d respectively. PK details will be presented. The secondary objective was to determine the pharmacodynamics (PD) of ZL in patients with SCD. PD end points were 1. CysLT levels before and after ZL administration for 6 weeks, 2. circulating levels of inflammatory biomarkers: sVCAM, sICAM, IL-6, IL-13 and macrophage chemoattractant protein-1 (MCP-1), 3. Methacholine challenge test (MCT) for AHR and 4. fetal hemoglobin. MCT was negative in 5 of 9 of patients; It is to be noted that exclusion of patients on hydroxyurea and chronic transfusions excluded the majority of patients with moderate to severe SCD that predominantly have AHR; 4 patients had a positive MCT, 2 of them became negative after receiving ZL while there was no change in the other 2 patients. LT and inflammatory markers are under analysis. There was no increase in HbF, F cells/F-retics in any of the patients, unlike results reported in vitro in erythroid cultures (Haynes et al, Blood 2004). Our study shows the safety and PK of ZL in SCD and that a higher dose of ZL (than used for asthma) was safely tolerated by SCD patients with good compliance. This phase I trial may form the basis of a phase II/III trial of zileuton in SCD. Clinicaltrial.gov # NCT01136941. Disclosures: No relevant conflicts of interest to declare.

This study was designed to determine the incidence of thoracic bone infarction in patients with sickle cell diseases who were hospitalized with acute chest or back pain above the diaphragm and to test the hypothesis that incentive spirometry can decrease the incidence of atelectasis and pulmonary infiltrates.We conducted a prospective, randomized trial in 29 patients between 8 and 21 years of age with sickle cell diseases who had 38 episodes of acute chest or back pain above the diaphragm and were hospitalized. Each episode of pain was considered to be an independent event. At each hospitalization, patients with normal or unchanged chest radiographs on admission were randomly assigned to treatment with spirometry or to a control nonspirometry group. Each patient in the spirometry group took 10 maximal inspirations using an incentive spirometer every two hours between 8 a.m. and 10 p.m. and while awake during the night until the chest pain subsided. A second radiograph was obtained three or more days after admission, or sooner if clinically necessary, to determine the incidence of pulmonary complications. Bone scanning was performed no sooner than two days after hospital admission to determine the incidence of thoracic bone infarction.The incidence of thoracic bone infarction was 39.5 percent (15 of 38 hospitalizations). Pulmonary complications (atelectasis or infiltrates) developed during only 1 of 19 hospitalizations of patients assigned to the spirometry group, as compared with 8 of 19 hospitalizations of patients in the nonspirometry group (P = 0.019). Among patients with thoracic bone infarction, no pulmonary complications developed in those assigned to the spirometry group during a total of seven hospitalizations, whereas they developed during five of eight hospitalizations in the nonspirometry group (P = 0.025).Thoracic bone infarction is common in patients with sickle cell diseases who are hospitalized with acute chest pain. Incentive spirometry can prevent the pulmonary complications (atelectasis and infiltrates) associated with the acute chest syndrome in patients with sickle cell diseases who are hospitalized with chest or back pain above the diaphragm.

Bone marrow transplantation (BMT) is the only curative therapy available for hemoglobinopathies. BMT was performed on a young child with sickle cell anemia (SCA) after approximately 9 months of transfusion therapy following her initial stroke. The patient received a matched sibling donor (sickle trait) BMT. The conditioning regimen consisted of busulfan 4 mg/kg/day x 4, cyclophosphamide 50 mg/kg/day x 4. Graft vs. host disease prophylaxis was daily cyclosporine for 6 months. There were no significant complications during BMT. Engraftment occurred on day +17 and the patient was transfusion independent since day +45. Pre-BMT cerebral arteriography showed multiple stenotic cerebral vessels and a moya-moya pattern. Perfusion MRI demonstrated reduced capillary perfusion. Approximately 170 days after BMT the patient experienced episodes of transient left-sided weakness and speech problems. Neuroimaging revealed progression of large vessel pathology by angiography despite significant improvement in cortical perfusion (MR perfusion scan). Molecular analysis by PCR and DNA fingerprinting confirmed absence of mixed mosaicism. Rheologic evaluation showed normal corrected bulk viscosity. It is possible that progression of large vessel pathology and return of clinical symptoms in the face of normal rheologic parameters may be due to worsening of the already damaged cerebral vessels by the BMT conditioning regimen. Further evaluations of patients with SCA undergoing BMT after a stroke are needed to answer this question.