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The sudden infant death syndrome (SIDS), the leading cause of postneonatal infant mortality in the United States, is typically associated with a sleep period. Previously, we showed evidence of serotonergic abnormalities in the medulla (e.g. altered serotonin (5-HT)1A receptor binding), in SIDS cases. In rodents, 5-HT2A/C receptor signaling contributes to arousal and autoresuscitation, protecting brain oxygen status during sleep. Nonetheless, the role of 5-HT2A/C receptors in the pathophysiology of SIDS is unclear. We hypothesize that in SIDS, 5-HT2A/C receptor binding is altered in medullary nuclei that are key for arousal and autoresuscitation. Here, we report altered 5-HT2A/C binding in several key medullary nuclei in SIDS cases (n = 58) compared to controls (n = 12). In some nuclei the reduced 5-HT2A/C and 5-HT1A binding overlapped, suggesting abnormal 5-HT receptor interactions. The data presented here (Part 1) suggest that a subset of SIDS is due in part to abnormal 5-HT2A/C and 5-HT1A signaling across multiple medullary nuclei vital for arousal and autoresuscitation. In Part II to follow, we highlight 8 medullary subnetworks with altered 5-HT receptor binding in SIDS. We propose the existence of an integrative brainstem network that fails to facilitate arousal and/or autoresuscitation in SIDS cases.

Introduction: Post-traumatic stress disorder occurs in parents of infants with CHD, contributing to psychological distress with detrimental effects on family functioning and well-being. We sought to determine the prevalence and factors associated with post-traumatic stress disorder symptoms in parents whose infants underwent staged palliation for single ventricle heart disease. Materials and methods: A large longitudinal multi-centre cohort study evaluated 215 mothers and fathers for symptoms of post-traumatic stress disorder at three timepoints, including post-Norwood, post-Stage II, and a final study timepoint when the child reached approximately 16 months of age, using the self-report questionnaire Impact of Event Scale – Revised. Results: The prevalence of probable post-traumatic stress disorder post-Norwood surgery was 50% of mothers and 39% of fathers, decreasing to 27% of mothers and 24% of fathers by final follow-up. Intrusive symptoms such as flashbacks and nightmares and hyperarousal symptoms such as poor concentration, irritability, and sudden physical symptoms of racing heart and difficulty breathing were particularly elevated in parents. Higher levels of anxiety, reduced coping, and decreased satisfaction with parenting were significantly associated with symptoms of post-traumatic stress disorder in parents. Demographic and clinical variables such as parent education, pre-natal diagnosis, medical complications, and length of hospital stay(s) were not significantly associated with symptoms of post-traumatic stress disorder. Discussion: Parents whose infants underwent staged palliation for single ventricle heart disease often reported symptoms of post-traumatic stress disorder. Symptoms persisted over time and routine screening might help identify parents at-risk and prompt referral to appropriate supports.

The Norwood procedure with a right ventricular to pulmonary artery shunt (RVPAS) decreases early mortality, but requires a ventriculotomy, possibly increasing risk of ventricular arrhythmias (VAs) compared with the modified Blalock-Taussig shunt (MBTS). The effect of shunt and Fontan type on arrhythmias by 6 years of age in the SVRII (Single Ventricle Reconstruction Extension Study) was assessed. SVRII data collected on 324 patients pre-/post-Fontan and annually at 2 to 6 years included antiarrhythmic medications, electrocardiography (ECG) at Fontan, and Holter/ECG at 6 years. ECGs and Holters were reviewed for morphology, intervals, atrioventricular conduction, and arrhythmias. Isolated VA were seen on 6-year Holter in50% of both cohorts (MBTS 54% vs RVPAS 60%), whereas nonsustained ventricular tachycardia was rare and observed in RVPAS only (2.7%). First-degree atrioventricular block was more common in RVPAS than MBTS (21% vs 8%, p = 0.01), whereas right bundle branch block, QRS duration, and QTc were similar. Antiarrhythmic medication usage was common in both groups, but most agents also supported ventricular function (e.g., digoxin, carvedilol). Of the 7 patients with death or transplant between 2 and 6 years, none had documented VAs, but compared with transplant-free survivors, they had somewhat longer QRS (106 vs 93 ms, p = 0.05). Atrial tachyarrhythmias varied little between MBTS and RVPAS but did vary by Fontan type (lateral tunnel 41% vs extracardiac conduit 29%). VAs did not vary by Fontan type. In conclusion, at 6-year follow-up, benign VAs were common in the SVRII population. However, despite the potential for increased VAs and sudden death in the RVPAS cohort, these data do not support significant differences or increased risk at 6 years. The findings highlight the need for ongoing surveillance for arrhythmias in the SVR population.

Few data exist regarding predictors of rapid aortic root dilation and referral for aortic surgery in Marfan syndrome (MFS). To identify independent predictors of the rate of aortic root (AoR) dilation and referral for aortic surgery, we investigated the data from the Pediatric Heart Network randomized trial of atenolol versus losartan in young patients with MFS. Data were analyzed from the echocardiograms at 0, 12, 24, and 36 months read in the core laboratory of 608 trial subjects, aged 6 months to 25 years, who met original Ghent criteria and had an AoR z-score (AoRz) > 3. Repeated measures linear and logistic regressions were used to determine multivariable predictors of AoR dilation. Receiver operator characteristic curves were used to determine cut-points in AoR dilation predicting referral for aortic surgery. Multivariable analysis showed rapid AoR dilation as defined by change in AoRz/year > 90th percentile was associated with older age, higher sinotubular junction z-score, and atenolol use (R2 = 0.01) or by change in AoR diameter (AoRd)/year > 90th percentile with higher sinotubular junction z-score and non-white race (R2 = 0.02). Referral for aortic root surgery was associated with higher AoRd, higher ascending aorta z-score, and higher sinotubular junction diameter:ascending aorta diameter ratio (R2 = 0.17). Change in AoRz of 0.72 SD units/year had 42% sensitivity and 92% specificity and change in AoRd of 0.34 cm/year had 38% sensitivity and 95% specificity for predicting referral for aortic surgery. In this cohort of young patients with MFS, no new robust predictors of rapid AoR dilation or referral for aortic root surgery were identified. Further investigation may determine whether generalized proximal aortic dilation and effacement of the sinotubular junction will allow for better risk stratification. Rate of AoR dilation cut-points had high specificity, but low sensitivity for predicting referral for aortic surgery, limiting their clinical use. Clinical Trial Number ClinicalTrials.gov number, NCT00429364.

Background Data routinely captured in clinical registries may be leveraged to enhance efficiency of prospective research. The quality of registry data for this purpose has not been studied, however. We evaluated the completeness and accuracy of perioperative data within congenital heart centers' local surgical registries. Methods Within 12 Pediatric Heart Network (PHN) sites, we evaluated 31 perioperative variables (and their subcategories, totaling 113 unique fields) collected via sites' local clinical registries for submission to The Society of Thoracic Surgeons Database, compared with chart review by PHN research coordinators. Both used standard STS definitions. Data were collected on 10 subjects for 2 to 5 procedures/site and adjudicated by the study team. Completeness and accuracy (agreement of registry data with medical record review by PHN coordinator, adjudicated by the study team) were evaluated. Results A total of 56,500 data elements were collected on 500 subjects. With regard to data completeness, 3.1% of data elements were missing from the registry, 0.6% from coordinator-collected data, and 0.4% from both. Overall, registry data accuracy was 98%. In total, 94.7% of data elements were both complete/non-missing and accurate within the registry, although there was variation across data fields and sites. Mean total time for coordinator chart review per site was 49.1 hours versus 7.0 hours for registry query. Conclusions This study suggests that existing surgical registry data constitute a complete, accurate, and efficient information source for prospective research. Variability across data fields and sites also suggest areas for improvement in some areas of data quality.

BACKGROUND: The reliability of LV systolic functional indices calculated from blinded echocardiographic measurements of LV size has not been tested in a large cohort of healthy children. The objective of this study was to estimate interobserver variability in standard measurements of left ventricular (LV) size and systolic function in children with normal cardiac anatomy and qualitatively normal function. METHODS: The Pediatric Heart Network Normal Echocardiogram Database collected normal echocardiograms from healthy children ≤18 years old distributed equally by age, gender, and race. A core lab used 2-dimensional echocardiograms to measure LV dimensions from which a separate data coordinating center calculated LV volumes and systolic functional indices. To evaluate interobserver variability, two independent expert pediatric echocardiographic observers re-measured LV dimensions on a subset of studies, while blinded to calculated volumes and functional indices. RESULTS: Of 3215 subjects with measurable images, 552 (17%) had a calculated LV shortening fraction (SF)

BACKGROUND: Retrospective studies suggested that storage age of RBCs is associated with inflammation and thromboembolism. The Red Cell Storage Duration Study (RECESS) trial randomized subjects undergoing complex cardiac surgery to receive RBCs stored for shorter versus longer periods, and no difference was seen in the primary outcome of change in multiple organ dysfunction score. STUDY DESIGN AND METHODS: In the current study, 90 subjects from the RECESS trial were studied intensively using a range of hemostasis, immunologic, and nitric oxide parameters. Samples were collected before transfusion and on Days 2, 6, 28, and 180 after transfusion. RESULTS: Of 71 parameters tested, only 4 showed a significant difference after transfusion between study arms: CD8+ T-cell interferon-γ secretion and the concentration of extracellular vesicles bearing the B-cell marker CD19 were higher, and plasma endothelial growth factor levels were lower in recipients of fresh versus aged RBCs. Plasma interleukin-6 was higher at Day 2 and lower at Days 6 and 28 in recipients of fresh versus aged RBCs. Multiple parameters showed significant modulation after surgery and transfusion. Most analytes that changed after surgery did not differ based on transfusion status. Several extracellular vesicle markers, including two associated with platelets (CD41a and CD62P), decreased in transfused patients more than in those who underwent surgery without transfusion. CONCLUSIONS: Transfusion of fresh versus aged RBCs does not result in substantial changes in hemostasis, immune, or nitric oxide parameters. It is possible that transfusion modulates the level of platelet-derived extracellular vesicles, which will require study of patients randomly assigned to receipt of transfusion to define.

Background: Interpretation of pediatric ECGs is limited by lack of accurate sex- and race-specific normal reference values obtained with modern technology for all ages. We sought to obtain contemporary digital ECG measurements in healthy children from North America, to evaluate the effects of sex and race, and to compare our results to commonly used published datasets. Methods: Digital ECGs (12-lead) were retrospectively collected for children ≤18 years old with normal echocardiograms at 19 centers in the Pediatric Heart Network. Patients were classified into 36 groups: 6 age, 2 sex, and 3 race (white, black, and other/mixed) categories. Standard intervals and amplitudes were measured; mean±SD and 2nd/98th percentiles were determined by age group, sex, and race. For each parameter, multivariable analysis, stratified by age, was conducted using sex and race as predictors. Parameters were compared with 2 large pediatric ECG data sets. Results: Among ECGs from 2400 children, significant differences were found by sex and race categories. The corrected QT interval in lead II was greater for girls compared with boys for age groups ≥3 years ( P ≤0.03) and for whites compared with blacks for age groups ≥12 years ( P P P ≤0.006), and greater compared with a commonly used public data set for age groups ≥12 years ( P Conclusions: In this large, diverse cohort of healthy children, most ECG intervals and amplitudes varied by sex and race. These differences have important implications for interpreting pediatric ECGs in the modern era when used for diagnosis or screening, including thresholds for left ventricular hypertrophy.

Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, .6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of UCB recipients discontinued systemic immunosuppression by 2 years. Six patients who had Pesaro risk class 2 (n = 5) and class 3 (n = 1) died of GVHD (n = 3), viral pneumonitis (n = 2) and pulmonary hemorrhage (n = 1). Outcomes after this RIC compared favorably with URD HSCT outcomes for TDT and supported engraftment in 32 of 33 patients. Efforts to reduce GVHD and infectious complications are being pursued further.

Background— Published nomograms of pediatric echocardiographic measurements are limited by insufficient sample size to assess the effects of age, sex, race, and ethnicity. Variable methodologies have resulted in a wide range of Z scores for a single measurement. This multicenter study sought to determine Z scores for common measurements adjusted for body surface area (BSA) and stratified by age, sex, race, and ethnicity. Methods and Results— Data collected from healthy nonobese children ≤18 years of age at 19 centers with a normal echocardiogram included age, sex, race, ethnicity, height, weight, echocardiographic images, and measurements performed at the Core Laboratory. Z score models involved indexed parameters (X/BSA α ) that were normally distributed without residual dependence on BSA. The models were tested for the effects of age, sex, race, and ethnicity. Raw measurements from models with and without these effects were compared, and α ) were selected for each measurement. Multivariable regression revealed statistically significant effects by age, sex, race, and ethnicity for all outcomes, but all effects were clinically insignificant based on comparisons of models with and without the effects, resulting in Z scores independent of age, sex, race, and ethnicity for each measurement. Conclusions— Echocardiographic Z scores based on BSA were derived from a large, diverse, and healthy North American population. Age, sex, race, and ethnicity have small effects on the Z scores that are statistically significant but not clinically important.

BACKGROUND: Heart failure results in significant morbidity and mortality for young children with hypoplastic left heart syndrome (HLHS) following the Norwood procedure. METHODS: We studied subjects enrolled in the prospective Single Ventricle Reconstruction (SVR) trial who survived to hospital discharge after the Norwood operation and were followed up to age 6 years. The primary outcome was heart failure, defined as heart transplant listing after Norwood hospitalization, death attributable to heart failure or symptomatic heart failure (NYHA class IV). Multivariate modeling was undertaken using Cox regression methodology to determine variables associated with heart failure. RESULTS: Of the 461 subjects discharged to home following Norwood procedure, 66 (14.3%) met criteria for heart failure. Among these, 15 died from heart failure, 39 were listed for transplant (22 had a transplant, 12 died after listing and 5 were alive and not yet transplanted), and 12 had NYHA Class IV heart failure but were never listed. The median age at heart failure identification was 1.28 yrs (interquartile range 0.30 - 4.69 years). Factors associated with heart failure included post-Norwood lower fractional area change, need for ECMO, non-Hispanic ethnicity, Norwood perfusion type and total support time (p

ObjectiveChildren with hypoplastic left heart syndrome are at a risk for neurodevelopmental delays. Current guidelines recommend systematic evaluation and management of neurodevelopmental outcomes with referral for early intervention services. The Single Ventricle Reconstruction Trial represents the largest cohort of children with hypoplastic left heart syndrome ever assembled. Data on life events and resource utilisation have been collected annually. We sought to determine the type and prevalence of early intervention services used from age 1 to 4 years and factors associated with utilisation of services.MethodsData from 14-month neurodevelopmental assessment and annual medical history forms were used. We assessed the impact of social risk and geographic differences. Fisher exact tests and logistic regression were used to evaluate associations.ResultsAnnual medical history forms were available for 302 of 314 children. Greater than half of the children (52–69%) were not receiving services at any age assessed, whereas 20–32% were receiving two or more therapies each year. Utilisation was significantly lower in year 4 (31%) compared with years 1–3 (with a range from 40 to 48%) (pConclusionDespite significant neurodevelopmental delays, early intervention service utilisation was low in this cohort. As survival has improved for children with hypoplastic left heart syndrome, attention must shift to strategies to optimise developmental outcomes, including enrolment in early intervention when merited.

Thalassaemia is characterized by ineffective erythropoiesis and anaemia, which can precipitate bone marrow expansion and extramedullary haematopoiesis. The mainstays of treatment are blood transfusion and chelation therapy, which can cause an array of complications. Only recently, however, has pain been recognized as a clinical component of thalassaemia (Trachtenberg, et al 2010). Sixty-nine per cent of 265 participants in the Thalassaemia Clinical Research Network (TCRN) Thalassaemia Longitudinal Cohort reported bodily pain (Trachtenberg, et al 2010). Additionally, 34% of transfused thalassaemia patients participating in the TCRN Low Bone Mass Observational Study reported that transfusions helped reduce or eliminate their pain (Vogiatzi, et al 2009). We hypothesized that the effects of ineffective erythropoiesis are mitigated by transfusion and thus incidence of pain will vary throughout the transfusion cycle. The Assessment of Pain Survey study, conducted by the TCRN, was initiated to address increasing reports of pain. The primary aim of this substudy was to assess whether reports of pain vary over the transfusion cycle. Secondary aims were to assess whether the length of the transfusion cycle affects the level of pain and whether pain varies by pre-transfusion haemoglobin (Hb) level and reticulocyte count. The TCRN of the National Heart, Lung and Blood Institute is a clinical research network, funded by the National Institutes of Health (Appendix 1). The protocol was approved by the TCRN Data and Safety Monitoring Board and by the ethical review boards of all TCRN institutions. All participants signed informed consent. Transfusion-dependent subjects (≥8 transfusions within the last 12 months) with β-thalassaemia or Hb E β-thalassaemia participating in the Assessment of Pain Survey study who reported at least mild pain in the last month as measured by Brief Pain Inventory (BPI; Cleeland 2009) were enrolled. The BPI provides information on the intensity of pain and the degree to which pain interferes with function. It has been used previously to assess pain in osteoporotic thalassaemia patients and its use has been validated in cancer patients (Cleeland 2009; Dworkin, et al 2005; Keller, et al 2004; Tan, et al 2004). Subjects were stratified into two cohorts: age 18–29 years vs. 30+ years. Stratification was chosen based on observation that patients aged 30+ years tend to have more pain than younger patients (Haines, et al 2013). Target enrolment was 25–35 subjects. Subjects completed a daily pain assessment during three non-consecutive transfusion cycles, separated by at least three months and no more than four months apart. Subjects were transfused according to their clinical need; cycles lasted two to four weeks. Transfusion cycles were not altered for participation. Daily pain was assessed using the BPI Short Form (BPI-SF) by daily telephone call provided by Interactive Performance Technologies in association with Telecare Management of Pain (Cambridge, MA). The BPI-SF consists of 10 questions in which participants rate their worst, least and average pain in the past 24 h on a scale of 0–10 where 0 is “No pain” and 10 is “Pain as bad as you can imagine”. Variation over the transfusion cycle was modelled with repeated measures logistic regression (for pain prevalence) or regression (for pain severity) of time in pain, controlling for age, sex and transfusion cycle. An autoregressive [AR(1)] variance structure was assumed. Time was measured as percentage of transfusion cycle completed and quadratic effects of time were utilized. Length of transfusion cycle, pre-transfusion Hb level and reticulocyte counts were added to the model. Repeated measures models, controlling for age, were used to test for differences in reported causes of pain between patients reporting frequent (≥50% of study days) vs. infrequent pain. Thirty-two subjects enrolled, 56% were female, the mean age was 31.8 years (range, 18 – 55), and 59% were Caucasian. The average pre-transfusion Hb was 101 g/l (range, 73–128 g/l) and the average length of transfusion cycle was 23 days. Pain prevalence and severity increased with age (p 0.4), or differences over the three transfusion cycles (p>0.5). Thirty-four per cent of subjects reported pain on at least 50% of study days, confirming that pain is an important problem. Table I Pain prevalence, severity, and treatment over the thalassaemia transfusion cyclea. There was a non-significant trend towards lower prevalence of pain midway through the transfusion cycle compared to immediately pre-transfusion (31.3 vs. 42.2%, p=0.14; Figure 1, Table I). Pain reduction was more pronounced among subjects transfused less frequently (>4 weeks) (13.6 vs. 40.9%, p=0.026 for effect of length of transfusion cycle; Table I) whilst, there was no apparent variation among subjects transfused more frequently (≤2 week cycle); Table I). As fluctuation in Hb levels is greater with longer transfusion cycles, these effects may reflect improvement in anaemia and/or ineffective erythropoiesis. Figure 1 Pain prevalence over the thalassaemia transfusion cycle. Unexpectedly, prevalence of pain correlated with higher, not lower, pre-transfusion Hb (p=0.013) and also a lower reticulocyte count (p=0.05). Subjects transfused more frequently also reported more severe average pain compared to those with a longer transfusion cycle (3.8/10 for ≤2 week cycles vs. 0.7/10 for >4 weeks; p=0.031 for length of cycle). Although higher Hb could contribute to pain, it is also possible that patients are transfused more frequently in response to chronic pain or other complications. Nevertheless, it is likely that pain is multifactorial. Use of pain medications/treatments varied from 25–35% over the transfusion cycle (15–18% for those aged 18–29 years, 35–51% aged 30+ years; 14–32% for those transfused frequently, 40–50% transfused infrequently). Furthermore, midway through the transfusion cycle, pain severity was greater among subjects with frequent pain (5.1/10 vs. 0/10, p

Background:Because of internet searches, advice from friends, and pharmaceutical advertising, especially direct-to-consumer advertising, patients are increasingly activated to request medications during a physician encounter.Objectives:To estimate the effect of patient requests for medications on ph

Background— Multiple echocardiographic methods are used to measure left ventricular size and function. Clinical management is based on individual evaluations and longitudinal trends. The Pediatric Heart Network VVV study (Ventricular Volume Variability) in pediatric patients with dilated cardiomyopathy has reported reproducibility of several of these measures, and how disease state and number of beats impact their reproducibility. In this study, we investigated the impact of observer and sonographer variation on reproducibility of dimension, area, and volume methods to determine the best method for both individual and sequential evaluations. Methods and Results— In 8 centers, echocardiograms were obtained on 169 patients prospectively. During the same visit, 2 different sonographers acquired the same imaging protocol on each patient. Each acquisition was analyzed by 2 different observers; first observer analyzed the first acquisition twice. Intraobserver, interobserver, interacquisition, and interobserver-acquisition (different observers and different acquisition) reproducibility were assessed on measurements of left ventricular end-diastolic dimension, area, and volume. Left ventricular shortening fraction, ejection fraction, mass, and fractional area change were calculated. Percent difference was calculated as (interobservation difference/mean)×100. Interobserver reproducibility for both acquisitions was better for both volume and dimension measurements ( P ≤0.002) compared with area measurements, whereas intraobserver, interacquisition (for both observers), and interobserver-acquisition reproducibilities (for both observer-acquisition sets) were best for volume measurements ( P ≤0.01). Overall, interobserver-acquisition percent differences were significantly higher than interobserver and interacquisition percent differences ( P Conclusions— In pediatric patients with dilated cardiomyopathy, compared with dimension and area methods, left ventricular measurements by volume method have the best reproducibility in settings where assessment is not performed by the same personnel. Clinical Trial Registration— URL: https://www.clinicaltrials.gov . Unique identifier: NCT00123071.

This exploratory study assessed apoptosis in peripheral blood leucocytes (PBL) from β-thalassaemia patients receiving chronic transfusions and chelation therapy (deferasirox or deferoxamine) at baseline, 1, 6, and 12 months. At baseline, thalassaemic PBLs presented 50% greater levels of Bax (BAX), 75% higher caspase-3/7, 48% higher caspase-8 and 88% higher caspase-9 activities and 428% more nucleosomal DNA fragmentation than control subjects. Only neutrophils correlated significantly with apoptotic markers. Previously, we showed that over the treatment year, hepatic iron declined; we now show that the ratio of Bax/Bcl-2 (BCL2), (-27·3%/year), and caspase-9 activity (-13·3%/year) declined in both treatment groups, suggesting that chelation decreases body iron and indicators of PBL apoptosis.

Patients with thalassemia have low circulating levels of many nutrients, but the contribution of dietary intake has not been assessed.Our objective was to assess dietary intake in a large contemporary sample of subjects with thalassemia.A prospective, longitudinal cohort study using a validated food frequency questionnaire was conducted.Two hundred and twenty-one subjects (19.7±11.3 years, 106 were female) were categorized into the following age groups: young children (3 to 7.9 years), older children/adolescents (8 to 18.9 years), and adults (19 years or older); 78.8% had β-thalassemia and 90% were chronically transfused. This study took place at 10 hematology outpatient clinics in the United States and Canada.We conducted a comparison of intake with US Dietary Reference Intakes and correlated dietary intake of vitamin D with serum 25-OH vitamin D and dietary iron with total body iron stores.Intake was defined as inadequate if it was less than the estimated average requirement. χ(2), Fisher's exact, and Student's t test were used to compare intake between age categories and logistic regression analysis to test the relationship between intake and outcomes, controlling for age, sex, and race.More than 30% of subjects consumed inadequate levels of vitamin A, D, E, K, folate, calcium, and magnesium. The only nutrients for which90% of subjects consumed adequate amounts were riboflavin, vitamin B-12, and selenium. Dietary inadequacy increased with increasing age group (P0.01) for vitamins A, C, E, B-6, folate, thiamin, calcium, magnesium, and zinc. More than half of the sample took additional supplements of calcium and vitamin D, although circulating levels of 25-OH vitamin D remained insufficient in 61% of subjects. Dietary iron intake was not related to total body iron stores.Subjects with thalassemia have reduced intake of many key nutrients. These preliminary findings of dietary inadequacy are concerning and support the need for nutritional monitoring to determine which subjects are at greatest risk for nutritional deficiency. Future research should focus on the effect of dietary quality and nutritional status on health outcomes in thalassemia.

An elevated tricuspid regurgitant jet velocity (TRV) is associated with hemolysis and early mortality in sickle cell disease, yet risk factors, clinical parameters, and mortality associated with this biomarker in thalassemia are poorly defined. This report summarizes the prevalence of an elevated TRV in 325 patients screened by Doppler echocardiography in the Thalassemia Clinical Research Network. A documented TRV was reported in 148 of 325 (46%) of patients. Average age was 25.9 years (range, 5-56 years) and 97% were transfusion-dependent. Mean TRV was 2.3 ± 0.4 m/s (range, 0.2-3.5 m/s). An abnormal TRV ≥ 2.5 m/s was identified in 49 of 148 (33%) of patients with a documented TRV, 5% (8/148), with a TRV ≥ 3.0 m/s, suggesting significant PH risk. Older age was strongly associated with a high TRV; however, 16% of children had a TRV ≥ 2.5 m/s. A history of splenectomy, hepatitis C, smoking, or high white blood cell count was associated with TRV elevation. In summary, an elevated TRV is noted in one-third of transfusion-dependent thalassemia patients with a documented value and develops in both children and adults. Age, splenectomy, hepatitis C, and smoking are significant univariate risk factors, with splenectomy surfacing as the dominant risk factor over time. Mortality was low in this cohort. Prospective longitudinal studies are needed. This study is registered at http://www.clinicaltrials.gov as NCT00661804.

Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary β(2) -microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.

Red blood cell (RBC) transfusion is the primary treatment for severe forms of thalassaemia. Pre-storage screening has resulted in decreased transfusion-transmitted infections, but anti-RBC antibodies remain a major problem. We report on 697 participants who had ever received transfusions. Allo- and autoantibody rates were compared with respect to splenectomy status, ethnicity, diagnosis, duration of transfusions, treatment centre, and age at transfusion initiation, together with rates before and after 1990, when leucoreduction methods were routine at thalassaemia treatment centres. Allo- and autoantibodies were reported in 115 (16·5%) and 34 (4·9%) subjects, respectively. Splenectomized patients were more likely to have alloantibodies [odds ratio (OR) = 2·528, P ≤ 0·0001], or autoantibodies (OR = 2·590, P = 0·0133). Alloantibodies occurred in 19 of 91 (21%) splenectomized subjects who started transfusion after 1990, and only 18 of 233 (7·7%) nonsplenectomized subjects (P < 0·001). Data from this study demonstrate that RBC antibodies continue to develop in chronically transfused thalassaemia patients at a high rate. Splenectomy preceded the development of antibodies in most cases. Increased rates of RBC sensitization among splenectomized patients is concerning and deserves further study.

Thalassemia is an inherited blood disorder that requires lifelong adherence to a complicated and burdensome medical regimen which could potentially impact emotional functioning of patients. The importance of understanding and promoting healthy emotional functioning is crucial not only to psychological well-being, but also to physical health as it has been shown to impact adherence to medical regimens [1-4]. The current study aimed to [1] determine the prevalence of depressive and anxiety symptoms in adolescent and adult patients with thalassemia; and [2] explore possible demographic, medical, and psychosocial correlates of these symptoms in 276 patients (14-58 years old, M age = 27.83; 52% female). Overall, most patients did not report experiencing significant symptoms of anxiety and depression (33% of participants indicated experiencing symptoms of anxiety and 11% symptoms of depression). Females and older patients were more likely to experience these symptoms than males and younger patients. Symptoms of anxiety and depression were positively associated with self-report of difficulty with adherence and negatively associated with quality of life. Given these findings, regular screening for anxiety and depression symptoms could help to identify at-risk individuals to provide them with appropriate psychological support with the goal of improving both emotional and physical health.

Advances in the management of thalassemia have resulted in increased life expectancy and new challenges. We conducted the first survey of education and employment status of people with thalassemia in North America.A total of 633 patients (349 adults and 284 school age children) enrolled in the Thalassemia Clinical Research Network (TCRN) registry in Canada and the U.S. were included in the data analysis. Predictors considered for analysis were age, gender, race/ethnicity, site of treatment (Canada vs. United States), transfusion and chelation status, serum ferritin, and clinical complications.Seventy percent of adults were employed of which 67% reported working full-time. Sixty percent had a college degree and 14% had achieved some post-college education. Eighty-two percent of school age children were at expected grade level. In a multivariate analysis for adults, Whites (OR = 2.76, 95% CI: 1.50-5.06) were more likely to be employed compared to Asians. Higher education in adults was associated with older age (OR = 1.67, 95% CI: 1.29-2.15), female gender (OR = 2.08, 95% CI: 1.32-3.23) and absence of lung disease (OR = 14.3, 95% CI: 2.04-100). Younger children (OR = 5.7 for 10-year increments, 95% CI: 2.0-16.7) and Canadian patients (OR = 5.6, 95% CI: 1.5-20) were more likely to be at the expected education level. Neither transfusion nor chelation was associated with lower employment or educational achievement.Individuals with thalassemia in North America can achieve higher education; however, full-time employment remains a problem. Transfusion and chelation do not affect employment or education status of this patient population.

Summary This study aimed to determine differences in the rates of growth, endocrine- and calcium-related abnormalities in the various thalassemia syndromes in North America treated with current therapies. Medical history, physical examinations and blood and urine collections were obtained from patients with all thalassemia syndromes age 6 years and older in the Thalassemia Clinical Research Network. 361 subjects, 49% male, mean age 23·2 years (range 6·1–75 years) were studied. Approximately 25% of children and adults, regardless of the thalassemia syndrome, had short stature. Overall growth in children was mildly affected. Final height was close to midparental height (z = −0·73 ± 1·24). Patients with beta thalassemia major (TM) had higher rates of hypogonadism, multiple endocrinopathies, worse hyperglycaemia, subclinical hypoparathyroidism and hypercalciuria. Hypogonadism remained the most frequent endocrinopathy and was frequently under-treated. 12·8% of the subjects had 25 vitamin D concentrations less than 27 nmol/l and 82% less than 75 nmol/l, regardless of the thalassemia syndrome. Adolescents had lower 25 vitamin D levels than children and adults. Compared to patients with other thalassemia syndromes, those with beta TM suffered from higher rates of multiple endocrinopathies, abnormal calcium metabolism and hypercalciuria. Vitamin D abnormalities were high among adolescents.

Improved survival in thalassemia has refocused attention on quality of life, including family planning. Understanding the issues associated with infertility and adverse pregnancy outcomes may impact clinical care of patients with thalassemia. We report the number and outcomes of pregnancies among subjects enrolled in Thalassemia Clinical Research Network (TCRN) registries and examine variables associated with successful childbirth. We identified 129 pregnancies in 72 women among the 264 women, age 18 years or older in our dataset. Over 70% of pregnancies resulted in live births and 73/83 (88%) of live births occurred at full term. Most pregnancies (78.2%) were conceived without reproductive technologies. Most (59.3%) pregnancies occurred while on chronic transfusion programs, however only 38.9% were on iron chelation. Four women developed heart problems. Iron burden in women who had conceived was not significantly different from age- and diagnosis-matched controls that had never been pregnant. There was also no difference in pregnancy outcomes associated with diagnosis, transfusion status, diabetes or Hepatitis C infection. Pregnancies occurred in 27.3% of women with thalassemia of child-bearing age in the TCRN registries, a notable increase from our previous 2004 report. With optimal health maintenance, successful pregnancies may be achievable.

Pulmonary hypertension (PH) commonly develops in thalassaemia syndromes, but is poorly characterized. The goal of this study was to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassaemia at risk for PH. A case-control study of thalassaemia patients at high versus low PH-risk was performed. A single cross-sectional measurement for variables reflecting cardiopulmonary status and biological pathophysiology were obtained, including Doppler-echocardiography, 6-minute-walk-test, Borg Dyspnea Score, New York Heart Association functional class, cardiac magnetic resonance imaging (MRI), chest-computerized tomography, pulmonary function testing and laboratory analyses targeting mechanism of coagulation, inflammation, haemolysis, adhesion and the arginine-nitric oxide pathway. Twenty-seven thalassaemia patients were evaluated, 14 with an elevated tricuspid-regurgitant-jet-velocity (TRV) ≥2.5m/s. Patients with increased TRV had a higher frequency of splenectomy, and significantly larger right atrial size, left atrial volume and left septal-wall thickness on echocardiography and/or MRI, with elevated biomarkers of abnormal coagulation, lactate dehydrogenase levels and arginase concentration, and lower arginine-bioavailability compared to low-risk patients. Arginase concentration correlated significantly to several echocardiography/MRI parameters of cardiovascular function in addition to global-arginine-bioavailability and biomarkers of haemolytic rate, including lactate dehydrogenase, haemoglobin and bilirubin. Thalassaemia patients with a TRV ≥2.5m/s have additional echocardiography and cardiac-MRI parameters suggestive of right and left-sided cardiac dysfunction. In addition, low arginine bioavailability may contribute to cardiopulmonary dysfunction in β-thalassaemia.

Thalassemia, a chronic blood disease, necessitates life-long adherence to blood transfusions and chelation therapy to reduce iron overload. We examine stability of health-related quality of life (HRQOL) in thalassemia and adherence to chelation therapy over time, especially after changes in chelator choice.Thalassemia Longitudinal Cohort participants in the USA, UK, and Canada completed the SF-36v2 (ages 14+) and the PF-28 CHQ (parents of children14 years). Chelation adherence was defined as self-reported percent of doses administered in the last 4 weeks.Two hundred and fifty-eight adults/adolescents (mean 29.7 years) and 133 children (mean 8.5 years) completed a mean of 2.8-years follow-up. Children made few chelator changes, whereas a mean of 2.2 changes was observed among the 37% of adults/adolescents who made chelator changes, mainly due to patient preference or medical necessity. Physical HRQOL improved among those with lower iron burden (better health status) at baseline who made a single change in chelator, but declined among participants with multiple changes and/or high iron burden (worse health status). Mental health improved among participants with lower iron burden, but iron overload was negatively associated with social functioning. Adherence did not significantly change over follow-up except for an increase after a change from deferoxamine (DFO) infusion to oral deferasirox (p = 0.03). Predictors of lower adherence for adults/adolescents at follow-up included side effects, smoking, younger age, problems preparing DFO, increased number of days per week DFO prescribed, and lower physical quality of life .Strategies to balance medical needs with family, work, and personal life may assist in adherence.

Pulmonary hypertension is a common but often overlooked complication associated with thalassemia syndromes. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. We, therefore, designed a 12-week, open-label, phase 1/2, pilot-scale, proof-of-principle trial of sildenafil therapy in 10 patients with β-thalassemia and at increased risk of pulmonary hypertension based on an elevated tricuspid regurgitant jet velocity >2.5 m/s on Doppler-echocardiography. Variables compared at baseline and after 12 weeks of sildenafil treatment included Doppler-echocardiographic parameters, 6-minute walked distance, Borg Dyspnea Score, New York Heart Association functional class, pulmonary function, and laboratory parameters. Treatment with sildenafil resulted in a significant decrease in tricuspid regurgitant jet velocity by 13.3% (3.0±0.7 versus 2.6±0.5 m/s, P=0.04), improved left ventricular end systolic/diastolic volume, and a trend towards a improved New York Heart Association functional class. No significant change in 6-minute walked distance was noted. Sildenafil was well tolerated, although minor expected adverse events were commonly reported. The total dose of sildenafil (mg) was strongly correlated with percent change in nitric oxide metabolite concentration in the plasma (ρ=0.80, P=0.01). There were also significant increases in plasma and erythrocyte arginine concentrations. Our study suggests that sildenafil is safe and may improve pulmonary hemodynamics in patients at risk of pulmonary hypertension; however, it was not demonstrated to improve the distance walked in 6 minutes. Clinical trials are needed to identify the best treatment strategy for pulmonary hypertension in patients with β-thalassemia. (clinicaltrials.gov identifier: NCT00872170)

Background Established heart failure in thalassaemia major has a poor prognosis and optimal management remains unclear. Methods A 1 year prospective study comparing deferoxamine (DFO) monotherapy or when combined with deferiprone (DFP) for patients with left ventricular ejection fraction (LVEF)

Pain reports have become increasingly common and problematic in thalassemia. As patients are living longer,there is a growing need to study pain and to explore its impact on patient lives. The Brief Pain Inventory(BPI) was used quarterly to assess pain and pain interference in patients with thalassemia in North America.The Medical Outcomes Study 36-Item Short Form Health Survey and the Hospital Anxiety and Depression Scale were used to assess quality of life, anxiety and depression. Of the 252 participants, 56% reported pain at least once over the course of this study, with 32% reporting severe pain (≥7/10); 16% reported pain at all four visits. Increased pain severity significantly interfered with daily life (P0.001; regression analysis) and participants with more sites of pain showed an increase in the amount of daily activities affected by pain(P50.001). Participants reporting more visits with pain reported a significantly higher impact on affective and physical function (P0.001). Physical quality of life decreased with increasing numbers of visits with pain (P0.001). Those who reported one or more sites of pain showed increased symptoms of both depression(P0.001) and anxiety (P50.003). Participants reporting at least two visits with pain had higher symptoms of anxiety (P50.002) and those with at least three visits reported higher symptoms of depression(P50.003). Pain is prevalent in thalassemia and is often a chronic condition that interferes with life. The study highlights the significance of pain in thalassemia and its impact, which should be considered in future research and treatments.

Pain is not a symptom generally associated with thalassaemia. However, providers have noted increasing patient reports of pain, creating an impetus for this prospective, observational assessment of pain in thalassaemia patients. The primary study goals were to assess pain prevalence, severity, location, and potential risk factors. This was a multicentre, prospective study of thalassaemia patients receiving care at 12 Thalassaemia Clinical Research Network sites. Pain was assessed using the Brief Pain Inventory. Two hundred and fifty-two thalassaemia patients ranging in age from 12 to 71 years (mean 28.8) were enrolled. Sixty-four per cent reported experiencing pain during the last 4 weeks, 22% of whom reported pain on a daily basis. Ordinal regression analysis of pain ratings demonstrated significant (P < 0.001) correlation of increased age with increased pain, irrespective of diagnosis, transfusion status, gender, bone density, chelator type or iron overload. Eighty-one per cent reported having pain for 1 year or longer and 31% reported pain for five or more years. Pain is a major cause of morbidity and an unrecognized problem for patients with thalassaemia. Age is the strongest predictor of frequency and severity. Little else is known about the aetiology and predictors of this pain syndrome.

Ineffective erythropoiesis, the hallmark of β-thalassemia, is a result of α/non-α globin chain imbalance.1 One strategy to redress globin-chain imbalance is to induce γ-globin gene (HBG) expression. Repression of HBG in adult erythroid cells involves DNA methylation and other epigenetic changes. Therefore, the cytosine analog decitabine, which can deplete DNA methyltransferase 1 (DNMT1), can potentially activate HBG. In 5 patients with β-thalassemia intermedia, a dose and schedule of decitabine intended to deplete DNMT1 without causing significant cytotoxicity (0.2 mg/kg subcutaneous 2 times per week for 12 weeks) increased total hemoglobin from 7.88 ± 0.88 g/dL to 9.04 ± 0.77 g/dL (P = .004) and absolute fetal hemoglobin from 3.64 ± 1.13 g/dL to 4.29 ± 1.13 g/dL (P = .003). Significant favorable changes also occurred in indices of hemolysis and red blood cell densitometry. Consistent with a noncytotoxic, differentiation altering mechanism of action, the major side effect was an asymptomatic increase in platelet counts without erythrocyte micronucleus or VDJ recombination assay evidence of genotoxicity. This study was registered at www.clinicaltrials.gov as #NCT00661726.

The Thalassemia Clinical Research Network collected adherence information from 79 patients on deferoxamine and 186 on deferasirox from 2007 to 2009. Chelation adherence was defined as percent of doses administered in the last 4 weeks (patient report) out of those prescribed (chart review). Chelation history since 2002 was available for 97 patients currently on deferoxamine and 217 on deferasirox, with crude estimates of adherence from chart review. Self-reported adherence to both deferoxamine and deferasirox were quite high, with slightly higher adherence to the oral chelator (97 vs. 92%). Ninety percent of patients on deferasirox reported at least 90% adherence, compared with 75% of patients on deferoxamine. Adherence to both chelators was highest in children, followed by adolescents and older adults. Predictors of lower deferoxamine adherence were smoking in the past year, problems sticking themselves (adults only), problems wearing their pump, and fewer transfusions in the past year. Predictors of lower deferasirox adherence were bodily pain and depression. Switching chelators resulted in increased adherence, regardless of the direction of the switch, although switching from deferoxamine to deferasirox was far more common. As adherence to deferoxamine is higher than previously reported, it appears beneficial for patients to have a choice in chelators.

Little is known about the effects of thalassaemia on the kidney. Characterization of underlying renal function abnormalities in thalassaemia is timely because the newer iron chelator, deferasirox, can be nephrotoxic. We aimed to determine the prevalence and correlates of renal abnormalities in thalassaemia patients, treated before deferasirox was widely available, using 24-h collections of urine. We calculated creatinine clearance and urine calcium-to-creatinine ratio and measured urinary β2-microglobulin, albumin, and protein. We used multivariate modelling to identify clinical, therapeutic, and laboratory predictors of renal dysfunction. One-third of thalassaemia patients who were not regularly transfused had abnormally high creatinine clearance. Regular transfusions were associated with a decrease in clearance (P = 0·004). Almost one-third of patients with thalassaemia had hypercalciuria, and regular transfusions were associated with an increase in the frequency and degree of hypercalciuria (P < 0·0001). Albuminuria was found in over half of patients, but was not consistently associated with transfusion therapy. In summary, renal hyperfiltration, hypercalciuria, and albuminuria are common in thalassaemia. Higher transfusion intensity is associated with lower creatinine clearance but more frequent hypercalciuria. The transfusion effect needs to be better understood. Awareness of underlying renal dysfunction in thalassaemia can inform decisions now about the use and monitoring of iron chelation.

Red blood cell (RBC) transfusion is the primary treatment for severe forms of thalassaemia. Pre-storage screening has resulted in decreased transfusion-transmitted infections, but anti-RBC antibodies remain a major problem. We report on 697 participants who had ever received transfusions. Allo- and autoantibody rates were compared with respect to splenectomy status, ethnicity, diagnosis, duration of transfusions, treatment centre, and age at transfusion initiation, together with rates before and after 1990, when leucoreduction methods were routine at thalassaemia treatment centres. Allo- and autoantibodies were reported in 115 (16.5%) and 34 (4.9%) subjects, respectively. Splenectomized patients were more likely to have alloantibodies (Odds Ratio [OR] = 2.528, p =

Thalassemia is a chronic, inherited blood disorder, which, in its most severe form, causes life-threatening anemia. Advances in treatment have led to increased life expectancy however the need for chronic blood transfusions and chelation therapy remains a significant burden for patients. Our study compared health related quality of life (HRQOL) from the Thalassemia Clinical Research Network's (TCRNs) Thalassemia Longitudinal Cohort (TLC) study to US norms and assessed association with clinical variables. There were 264 patients over age 14 who completed the Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF36v2) baseline assessment. When compared to US norms, TLC patients had statistically significant (P < 0.05) worse HRQOL on five of the eight subscales (physical functioning, role-physical, general health, social functioning, and role-emotional) and on both summary scales (physical component summary and mental component summary). Women, older patients, and those with more disease complications and side effects from chelation reported lower HRQOL. In general, adolescents and adults with thalassemia report worse HRQOL than the US population, despite contemporary therapy. The SF-36 should become a standard instrument for assessing HRQOL in thalassemia to determine predictors of low HRQOL which may be better addressed by a multidisciplinary team.

Thalassemia is a congenital blood disorder often requiring chronic blood transfusions and iron chelation therapy [1,2]. While advances in treatment have resulted in increased life expectancy [3], extended life spans have exposed previously unidentified issues, including bodily pain. The aim of this study was to examine the prevalence, severity, predictors, and effects of pain in 265 adults/adolescents and 103 children with thalassemia. Overall, 69% of adults/adolescents reported bodily pain on the SF-36v2 health survey, with 28% reporting at least moderate pain. Parents reported pain in 56% of children using the PF-28 child health questionnaire, with only 11% reporting pain fairly often. There were no significant differences in pain in children with thalassemia compared with the general population. In adults/adolescents, pain increased significantly with age (P = 0.005), more so than in the general population. This study highlights the fact that children and young adults with thalassemia experience pain comparable to the general population, whereas older adults (aged 35+) experience greater pain. Our findings show that increased pain is associated with decreased quality of life and increased anxiety and depression.

The purpose of this study was to assess the relationship between baseline caries experience and the restoration replacement rate in children.The 5-year New England Children's Amalgam Trial recruited 534 6- to 10-year-old children with 2 or more carious posterior teeth. The association between decoy and longevity of restorations was assessed. Restorations with no follow-up (N = 391) were excluded from analysis.The average follow-up was 3.0 +/- 1.6 years in 489 children. Restorations with follow-up (N = 3,604) were placed in mouths with a median of 15 dfs/DFS and 8 dft/DFT. The need for replacement increased significantly (Por = .001) with increasing numbers of dfs/DFS and dft/DFT. After 5 years of follow-up, at least 15% of restorations in a mouth withor = 14 dfs/DFS needed replacement, compared to 9% for 2 to 5 dfs/DFS. Comparing dft/DFT after 5 years of follow-up, there was a 23% replacement rate foror = 12 dft/DFT compared to 10% for 2 to 3 dft/DFT. Decoy in the mouth had a greater association with the need for replacement due to new caries compared to replacement due to recurrent caries.Children with more decoy at the time of restoration placement were at higher risk for replacement of restorations.

The New England Children's Amalgam Trial (NECAT) was a five-year randomized trial of 534 6- to 10-year-old children that compared the neuropsychological outcomes of those whose caries were restored using dental amalgam with the outcomes of those those whose caries were restored using mercury-free resin-based composite. The primary intention-to-treat analyses did not reveal significant differences between the treatment groups on the primary or secondary outcomes of the administered psychological tests: Full-Scale IQ score on the Wechsler Intelligence Scale for Children-Third Edition, General Memory Index of the Wide Range Assessment of Memory and Learning, and Visual-Motor Composite of the Wide Range Assessment of Visual Motor Abilities.To determine whether treatment group assignment, a dichotomous measure of exposure, was sufficiently sensitive to detect associations between mercury exposure and these outcomes, the authors conducted analyses to evaluate the associations between the primary and secondary outcomes and two continuously distributed indexes of potential exposure, surface-years of amalgam and urinary mercury excretion.Neither index of mercury exposure was significantly associated with any of the three outcomes.The authors found no evidence that exposure to mercury from dental amalgam was associated with any adverse neuropsychological effects over the five-year period after placement of amalgam restorations.Analyses of the outcomes of the NECAT study indicate that use of dental amalgam was not associated with an increase in children's risk of experiencing neuropsychological dysfunction.

Limited information is available from randomized clinical trials comparing the longevity of amalgam and resin-based compomer/composite restorations. The authors compared replacement rates of these types of restorations in posterior teeth during the five-year follow-up of the New England Children's Amalgam Trial.The authors randomized children aged 6 to 10 years who had two or more posterior occlusal carious lesions into groups that received amalgam (n=267) or compomer (primary teeth)/composite (permanent teeth) (n=267) restorations and followed them up semiannually. They compared the longevity of restorations placed on all posterior surfaces using random effects survival analysis.The average+/-standard deviation follow-up was 2.8+/-1.4 years for primary tooth restorations and 3.4+/-1.9 years for permanent tooth restorations. In primary teeth, the replacement rate was 5.8 percent of compomers versus 4.0 percent of amalgams (P=.10), with 3.0 percent versus 0.5 percent (P=.002), respectively, due to recurrent caries. In permanent teeth, the replacement rate was 14.9 percent of composites versus 10.8 percent of amalgams (P=.45), and the repair rate was 2.8 percent of composites versus 0.4 percent of amalgams (P=.02).Although the overall difference in longevity was not statistically significant, compomer was replaced significantly more frequently owing to recurrent caries, and composite restorations required seven times as many repairs as did amalgam restorations.Compomer/composite restorations on posterior tooth surfaces in children may require replacement or repair at higher rates than amalgam restorations, even within five years of placement.

To examine the connection between patients' trust and their attitudes toward seeking care, participating in medical decision making, and adhering to treatment recommendations.Data were collected from a national telephone survey of English-speaking adults (N=553) in 1999. Eligibility requirements were some type of public or private health care coverage and having seen a physician or other health professional at least twice in the past 2 years. Five questions on preferred role in medical care were asked. Trust in physicians and satisfaction with care were separately measured using validated scales.The most significant predictor of patients' preferred role in medical care is trust in the medical profession. Views also varied by sex, age, health, education, income, number of visits/years with physician, past dispute with a physician, and satisfaction with care, but many of these bivariate associations were no longer significant in multivariate regression models. Views varied slightly by trust in the specific physician. There were no racial differences.A strong connection exists between patients' preferred involvement in medical care and trust in the medical profession, but only a slight connection with trust in their own physician. Increased trust in physicians generally is associated with greater willingness to seek care, to follow recommendations of physicians, and to grant them decisional authority. Higher trust in a specific physician is strongly associated only with greater reported adherence. Although higher trust in the medical profession appears to entail a more deferential role by patients, higher trust is also consistent with more active patient roles such as seeking care and adhering to treatment regimens.

Background HCT cures thalassemia major (TM). In the absence of a family donor, marrow or less frequently umbilical cord blood (UCB) from unrelated donors (URD) has been used. Due to risks of graft rejection, myeloablative preparative regimens are primarily utilized. URD marrow and UCB HCT have 65-90% and 21-74% event free survival (EFS) and rejection rates of 9-17% and 17-57% respectively. The URTH trial was developed in collaboration with the Thalassemia Clinical Research Network (TCRN), National Heart, Lung and Blood Institute (NHLBI), Pediatric Blood and Marrow Transplant Consortium (PBMTC) and New England Research Institutes (NERI) to explore URD HCT for TM as a strategy to expand availability of HCT. It employed reduced intensity conditioning (RIC) as a means to decrease early and late toxicities. The study tested our hypothesis that an immunosuppressive RIC regimen was sufficient for engraftment in children with TM (age > 1 year to < 17 years) after URD HCT. The primary objective was to determine EFS at 1 year after URD marrow or UCB HCT. Methods Patients with transfusion dependent beta thalassemia and a suitable URD (matched at 8/8 HLA-alleles in marrow donors or 5 to 6/6 HLA antigens in UCB donors) were conditioned with hydroxyurea (30mg/kg x 30 days) (day -50 to -21), alemtuzumab (48 mg) (-22 to -19), fludarabine (150 mg/m2) (-8 to -4), thiotepa (8mg/kg) (-4), and melphalan (140mg/m2) (-3). Patients received tacrolimus or cyclosporine with methotrexate and methylprednisone (marrow) or mycophenolate mofetil (UCB) after HCT to prevent graft-versus-host disease (GVHD). Suitable UCB units were defined as having a pre-thaw total nucleated cell content >4.0x10E7/Kg recipient weight. Patients were eligible irrespective of Pesaro classification but the presence of liver fibrosis by histology was an exclusion criterion. Results Twenty-three patients from 11 US centers (11M: 12F) with a median age of 10 years (2–17 years) received unrelated donor allografts: marrow (14) or UCB matched at 6/6 (1) or 5/6 HLA antigens (8). The median follow up time was 12 months (range 120 days-2 years). The median time to neutrophil engraftment was 13 days (range 10-25) and 34 days (range 12-46) after marrow and UCB HCT respectively. The median time to platelet engraftment after marrow and UCB HCT was 24 days (range 18-34) and 54.5 days (range 32-234) respectively. Primary graft rejection occurred in 1 patient (4% of all patients) following UCB HCT and was accompanied by autologous hematopoietic recovery 35 days after HCT. All others had >90% donor chimerism and achieved transfusion independence. There were no late graft rejections. The overall and EFS probabilities were 82% and 78% respectively at the most recent encounter. One patient developed mild VOD which resolved uneventfully. Of 15 patients who had CMV reactivation, 13 responded to pre-emptive therapy and had no progression to CMV disease. The probabilities of grade II-IV and grade III-IV acute GVHD were 30% and 9% respectively. Limited chronic GVHD was noted in 35% of the cohort; 9% developed extensive cGVHD. Four patients died on days 25, 86, 106 and 366. The causes of death included 1) pulmonary hemorrhage associated with CMV, adenovirus, and Pneumocystis jiroveci infections, 2) diffuse alveolar pulmonary hemorrhage, 3) cGVHD with pneumonia associated with CMV and adenovirus infections, and 4) cGVHD with pulmonary failure associated with CMV and EBV infections and presumed central nervous system post-transplantation lymphoproliferative disease. Conclusion HCT after RIC for thalassemia is feasible and sufficient for engraftment after URD marrow and UCB transplantation with survival exceeding 80%. The principal transplant- related complications we observed were early opportunistic viral reactivations; otherwise the preparative regimen was tolerated well with very little early toxicity. Fatal and late viral infections were noted only in the setting of severe GVHD. Patients should be monitored carefully and treated promptly for infectious complications after HCT until there is adequate immune reconstitution. The risk of severe GVHD was low despite unrelated and mismatched (UCB) donor sources. Longer follow up will determine if this regimen can reduce late toxicities. An extension of this trial is ongoing and currently recruiting patients to evaluate additional HCT related and quality of life measures. Disclosures: Neufeld: Shire: Consultancy. Kwiatkowski:Resonance Health: Research Funding; Shire: Consultancy. Thompson:Novartis: Consultancy, Research Funding; ApoPharma: Consultancy, Honoraria; Glaxo Smith Kline: Research Funding; Eli Lilly: Research Funding; Amgen: Research Funding; bluebird bio: Research Funding.

Background Understanding patients’ views about medication is crucial to maximize adherence. Thalassemia is a congenital blood disorder requiring chronic blood transfusions and daily iron chelation therapy. Methods The Beliefs in Medicine Questionnaire (BMQ) was used to assess beliefs in chelation in thalassemia patients from North America and London in the Thalassemia Longitudinal Cohort (TLC) of the Thalassemia Clinical Research Network (TCRN). Chelation adherence was based on patient report of doses administered out of those prescribed in the last four weeks. Results Of 371 patients (ages 5-58y, mean 24y), 93% were transfused and 92% receiving chelation (26% deferoxamine (DFO; a slow subcutaneous infusion via portable pump), 63% oral, 11% combination). Patients expressed high “necessity” for transfusion (96%), DFO chelation (92%) and oral chelation (89%), with lower “concern” about treatment (48%, 39%, 19% respectively). Concern about oral chelation was significantly lower than that of DFO (p Conclusions Despite their requirement for multimodal therapy, thalassemia patients have positive views about medicine, more so than in other disease populations. Patients may benefit from education about the tolerability of chelation and strategies to effectively cope with side effects, both of which might be beneficial in lowering body iron burden. Clinicaltrials.gov identifier NCT00661804

Abstract 2122 Introduction: Pulmonary hypertension (PH) commonly develops in thalassemia syndromes, but is poorly characterized. Since limited data are available we set out to provide a comprehensive description of the cardiopulmonary and biological profile of patients with thalassemia at-risk for PH. Methods: We designed a case-control study of thalassemia patients at-risk for PH, defined by a tricuspid-regurgitant-jet velocity (TRV)≥2.5m/s on Doppler-echocardiography (echo) compared to those with low PH-risk, define by a TRV Results: Twenty-seven thalassemia patients with a mean TRV=2.5±0.6m/s (range:1.0–4.9m/s) were evaluated, 14 with a TRV≥2.5m/s. Mean age was 35±12 years, 70% were male, 74% were splenectomized, and 67% had thalassemia major (TM). Patients with PH-risk (mean TRV=3.1±0.7m/s) had a significantly higher frequency of splenectomy (OR:11.1 [95% CI: 1.11–112.0], p=0.04), higher NYHA functional class, Borg Dyspnea Score after 6MWT, and significantly larger right atrial size, left atrial volume, and left septal-wall thickness on echo and/or MRI, with elevated biomarkers of coagulation abnormalities, lactate dehydrogenase (LDH) levels, arginase concentration (5.7±7 vs. 78.7±108 ng/ml, p=0.003) and arginase activity, and lower arginine-bioavailability compared to low-risk patients (mean TRV=2.1±0.4m/s). Arginase concentration and activity correlated significantly to several echo/MRI parameters of cardiovascular function including cardiac index (r=0.75, p Conclusions: Thalassemia patients with a TRV≥2.5m/s have additional echo and MRI parameters suggestive of PH-risk. Dysregulation of the arginine metabolome and the consequences of excess plasma arginase are associated with cardiopulmonary complications in thalassemia and warrants further study. Disclosures: Taher: Novartis: Research Funding, Speakers Bureau.

Abstract 1023 Introduction. Pulmonary hypertension (PH) is a complication associated with thalassemia syndromes, particularly thalassemia intermedia. There are limited data on the safety and efficacy of selective pulmonary vasodilators in this at-risk population. Methods. We evaluated the safety and efficacy of a 12-week prospective, phase 1/2 pilot scale study of sildenafil (100 mg TID) in ten b-thalassemia patients with elevated TRV on Doppler-echocardiography ≥ 2.5 m/s suggestive of PH risk. Patients were evaluated at baseline and at weeks 2, 4, 8 and 12 of sildenafil therapy, and six minute walk distance (6MWD), biomarkers of hemolysis, coagulation, inflammation and adhesion were assessed. Results. Our study population had an average age of 37±12.3 years, 8/10 were male, and 50% were thalassemia intermedia. Splenectomy prevalence was high (90%), and only 30% of patients were transfused since infancy. The mean pre-transfusion hemoglobin was 10.4±1.5 g/dL. A 12-week open-label trial resulted in a significant decrease in TRV by 13.3% (3.0±0.7 vs. 2.6±0.5m/s, p=0.04, Figure 1), improvements in left ventricular end systolic/diastolic volume (p≤0.02), diffusion capacity for carbon monoxide (DLCO, p=0.003) and a trend towards a reduced Borg Dyspnea Score and improved NYHA Functional class. No significant change in 6MWD was noted, although 6MWD correlated strongly with DLCO (ρ=0.72, p=0.03) suggesting that oxygen diffusion across the alveolar-capillary membrane was an important determinant of exercise capacity. Sildenafil was generally well tolerated, but most patients experienced anticipated transient headaches and visual/color disturbances associated with sildenafil use. One patient withdrew from the study due to worsening dyspnea. No other serious adverse events were reported. A strong direct correlation between total dose of sildenafil (mg) taken and % change in plasma NO metabolite concentration was observed (ρ =0.80, p=0.01). A significant increase in plasma and erythrocyte arginine concentration occurred, without an associated change in plasma arginase activity/concentration, nitric oxide metabolites or vascular endothelial growth factor. However arginase concentration was elevated in this cohort similar to prior reports, and correlated inversely to hemoglobin (ρ=-0.41, p=0.01), and directly to ALT (ρ=0.40, p=0.004), AST (ρ=0.38, p=0.04), left ventricular end systolic volume (ρ=0.77, p=0.001), and end-diastolic volume (ρ=0.79, p=0.001). Conclusion. Our study suggests that sildenafil is safe and may improve cardiopulmonary hemodynamics in patients at risk for PH, however improved exercise capacity as reflected by an improved 6MWD was not observed. The reduction in left ventricular dimensions is promising, and could reflective of either increased inotropy or chronotropy, or decreased systemic afterload. This is also the first report of an influence of sildenafil on diffusion capacity of the lungs in patients with thalassemia and the first description of increased plasma and erythrocyte arginine concentration after sildenafil therapy. Given the association of arginine bioavailability with long-term survival in cardiovascular disease, this is an unexpected effect of sildenafil that warrants further investigation. These data support the need for further clinical trials evaluating the use of sildenafil in thalassemia. Disclosures: Taher: Novartis: Research Funding, Speakers Bureau.