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Background The 21st Century Cures Act has accelerated adoption of OpenNotes, providing new opportunities for patient and family engagement in their care. However, these regulations present new challenges, particularly for pediatric health systems aiming to improve information sharing while minimizing risks associated with adolescent confidentiality and safety. Objective Describe lessons learned preparing for OpenNotes across a pediatric health system during a 4-month trial period (referred to as “Learning Mode”) in which clinical notes were not shared by default but decision support was present describing the upcoming change and physicians could request feedback on complex cases from a multidisciplinary team. Methods During Learning Mode (December 3, 2020–March 9, 2021), implementation included (1) educational text at the top of commonly used note types indicating that notes would soon be shared and providing guidance, (2) a new confidential note type, and (3) a mechanism for physicians to elicit feedback from a multidisciplinary OpenNotes working group for complex cases with questions related to OpenNotes. The working group reviewed lessons learned from this period, as well as implementation of OpenNotes from March 10, 2021 to June 30, 2021. Results During Learning Mode, 779 confidential notes were written across the system. The working group provided feedback on 14 complex cases and also reviewed 7 randomly selected confidential notes. The proportion of physician notes shared with patients increased from 1.3% to 88.4% after default sharing of notes to the patient portal. Key lessons learned included (1) sensitive information was often present in autopopulated elements, differential diagnoses, and supervising physician note attestations; and (2) incorrect reasons were often selected by clinicians for withholding notes but this accuracy improved with new designs. Conclusion While OpenNotes provides an unprecedented opportunity to engage pediatric patients and their families, targeted education and electronic health record designs are needed to mitigate potential harms of inappropriate disclosures.

Thalassaemia is caused by genetic globin defects leading to anaemia, transfusion-dependence and comorbidities. Reduced survival and systemic organ disease affect transfusion-dependent thalassaemia major and thalassaemia intermedia. Recent improvements in clinical management have reduced thalassaemia mortality. The therapeutic landscape of thalassaemia may soon include gene therapies as functional cures. An analysis of the adult US thalassaemia population has not been performed since the Thalassemia Clinical Research Network cohort study from 2000 to 2006. The Centers for Disease Control and Prevention supported US thalassaemia treatment centres (TTCs) to compile longitudinal information on individuals with thalassaemia. This dataset provided an opportunity to evaluate iron balance, chelation, comorbidities and demographics of adults with thalassaemia receiving care at TTCs. Two adult cohorts were compared: those over 40 years old (n = 75) and younger adults ages 18-39 (n = 201). The older adult cohort was characterized by higher numbers of iron-related comorbidities and transfusion-related complications. By contrast, younger adults had excess hepatic and cardiac iron and were receiving combination chelation therapy. The ethnic composition of the younger cohort was predominantly of Asian origin, reflecting the demographics of immigration. These findings demonstrate that comprehensive care and periodic surveys are needed to ensure optimal health and access to emerging therapies.

The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial cochaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in RBC hemoglobinization, and the development of siderocytes and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene.

Background Medical errors in blood product orders and administration are common, especially for pediatric patients. A failure modes and effects analysis in our health care system indicated high risk from the electronic blood ordering process. Objectives There are two objectives of this study as follows:(1) To describe differences in the design of the original blood product orders and order sets in the system (original design), new orders and order sets designed by expert committee (DEC), and a third-version developed through user-centered design (UCD).(2) To compare the number and type of ordering errors, task completion rates, time on task, and user preferences between the original design and that developed via UCD. Methods A multidisciplinary expert committee proposed adjustments to existing blood product order sets resulting in the DEC order set. When that order set was tested with front-line users, persistent failure modes were detected, so orders and order sets were redesigned again via formative usability testing. Front-line users in their native clinical workspaces were observed ordering blood in realistic simulated scenarios using a think-aloud protocol. Iterative adjustments were made between participants. In summative testing, participants were randomized to use the original design or UCD for five simulated scenarios. We evaluated differences in ordering errors, time on task, and users' design preference with two-sample t-tests. Results Formative usability testing with 27 providers from seven specialties led to 18 changes made to the DEC to produce the UCD. In summative testing, error-free task completion for the original design was 36%, which increased to 66% in UCD (30%, 95% confidence interval [CI]: 3.9–57%; p = 0.03). Time on task did not vary significantly. Conclusion UCD led to substantially different blood product orders and order sets than DEC. Users made fewer errors when ordering blood products for pediatric patients in simulated scenarios when using the UCD orders and order sets compared with the original design.

The congenital sideroblastic anemias (CSAs) are a heterogeneous group of inherited disorders of erythropoiesis characterized by pathologic deposits of iron in the mitochondria of developing erythroblasts. Mutations in the mitochondrial glycine carrier SLC25A38 cause the most common recessive form of CSA. Nonetheless, the disease is still rare, there being fewer than 70 reported families. Here we describe the clinical phenotype and genotypes of 31 individuals from 24 families, including 11 novel mutations. We also review the spectrum of reported mutations and genotypes associated with the disease, describe the unique localization of missense mutations in transmembrane domains and account for the reoccurrence of several alleles in different populations.

We introduce a paradigm of completely non-invasive, on-demand diagnostics that may replace common blood-based laboratory tests using only a smartphone app and photos. We initially targeted anemia, a blood condition characterized by low blood hemoglobin levels that afflicts >2 billion people. Our app estimates hemoglobin levels by analyzing color and metadata of fingernail bed smartphone photos and detects anemia (hemoglobin levels, Anemia has a global prevalence of over 2 billion people and is diagnosed via blood-based laboratory test. Here the authors describe a smartphone app that can estimate hemoglobin levels and detect anemia by analyzing pictures of fingernail beds taken with a smartphone and without the need of any external equipment.

BACKGROUND HLA alloimmunization is a potential complication of red blood cell (RBC) transfusion with detrimental consequences for future organ or hematopoietic stem cell transplantation. STUDY DESIGN AND METHODS The study aimed to determine the prevalence and specificity of HLA antibodies among pediatric patients with thalassemia major (TM) and antibody changes over time while on leukoreduced chronic transfusion therapy. HLA antibodies were measured at two or more time points in children and young adults ages 3 to 21 years with TM. HLA Class I and II antibodies were measured by FlowPRA screening. Positive screening assays were confirmed with LabScreen single-antigen bead assays for antibody specificity. RESULTS HLA antibodies were detected in 10 of 19 (53%) subjects: seven of 19 (37%) with HLA Class I and II antibodies, two of 19 (11%) with only HLA Class I antibodies, and one of 19 (5%) with only HLA Class II antibodies. Subjects with HLA antibodies were older (14.6 years vs. 7.1 years, p = 0.05), predominantly male (80%), and more likely to have a remote history of nonleukoreduced transfusions (p = 0.057). Median time between testing was 3.7 years. De novo HLA antibodies were detected in two of 11 patients who initially had negative panel-reactive antibody screens, while one subject lost detection of Class II antibody. Two of seven patients with HLA antibodies had antibodies to self-HLA. CONCLUSION HLA antibodies have a high prevalence in TM patients and may be associated with nonleukoreduced transfusions and older age. For such patients, antibody identification will be useful if subsequent organ or stem cell transplantation is needed.

BACKGROUND. Anemia, or low blood hemoglobin (Hgb) levels, afflicts 2 billion people worldwide. Currently, Hgb levels are typically measured from blood samples using hematology analyzers, which are housed in hospitals, clinics, or commercial laboratories and require skilled technicians to operate. A reliable, inexpensive point-of-care (POC) Hgb test would enable cost-effective anemia screening and chronically anemic patients to self-monitor their disease. We present a rapid, standalone, and disposable POC anemia test that, via a single drop of blood, outputs color-based visual results that correlate with Hgb levels. METHODS. We tested blood from 238 pediatric and adult patients with anemia of varying degrees and etiologies and compared hematology analyzer Hgb levels with POC Hgb levels, which were estimated via visual interpretation using a color scale and an optional smartphone app for automated analysis. RESULTS. POC Hgb levels correlated with hematology analyzer Hgb levels (r = 0.864 and r = 0.856 for visual interpretation and smartphone app, respectively), and both POC test methods yielded comparable sensitivity and specificity for detecting any anemia (n = 178) (

Background Transfusions are the primary therapy for thalassemia but have significant cumulative risks. In 2004, the Centers for Disease Control and Prevention (CDC) established a national blood safety monitoring program for thalassemia. This report summarizes the population and their previous nonimmune and immune transfusion complications. Study Design and Methods The CDC Thalassemia Blood Safety Network is a consortium of centers longitudinally following patients. Enrollment occurred from 2004 through 2012. Demographics, transfusion history, infectious exposures, and transfusion and nontransfusion complications were summarized. Logistic regression analyses of factors associated with allo- and autoimmunization were employed. Results The race/ethnicity of these 407 thalassemia patients was predominantly Asian or Caucasian. The mean ± SD age was 22.3 ± 13.2 years and patients had received a mean ± SD total number of 149 ± 103.4 units of red blood cells (RBCs). Multiorgan dysfunction was common despite chelation. Twenty-four percent of transfused patients had previous exposure to possible transfusion-associated pathogens including one case of babesia. As 27% were immigrants, the infection source cannot be unequivocally linked to transfusion. Transfusion reactions occurred in 48%, including allergic, febrile, and hemolytic; 19% were alloimmunized. Common antigens were E, Kell, and C. Years of transfusion was the strongest predictor of alloimmunization. Autoantibodies occurred in 6.5% and were associated with alloimmunization (p

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.

Activity of nuclear receptors is regulated by their nuclear localization. Liver X receptors (LXR) alpha and beta are nuclear receptors that regulate transcription of genes for cholesterol metabolism, cholesterol transport, and lipogenesis. While LXR alpha and beta are very similar in structure and exhibit similar ligand binding properties, their physiological roles are quite different. Since the LXRs fall into a class of receptors that move between the nucleus and cytoplasm, experiments were conducted to determine whether LXR alpha and LXR beta show differences in their nuclear localization pattern. To determine the location of each receptor, cell lines stably expressing yellow fluorescent protein (YFP) chimeras with either LXR alpha or LXR beta were examined. Retention in the nucleus of the chimeric proteins in the presence or absence of ligands was assessed using fluorescence microscopy coupled with digitonin permeabilization assays. Surprisingly, differences were found between LXR alpha and LXR beta. Whereas unliganded LXR alpha was retained in the nucleus, unliganded LXR beta was partially exported. Mutations were then introduced into putative nuclear localization sequences (NLS) to determine which sequences are important for nuclear localization and function. Mutation in one such sequence abolished nuclear localization of LXR alpha, whereas the analogous change in LXR beta had a much less dramatic effect. Mutations in analogous putative NLS also differentially affected transcriptional activation by LXR alpha and LXR beta. These data demonstrate for the first time that nuclear retention and localization as well as function of LXR alpha and LXR beta are differentially regulated.

HLA alloimmunization is a potential complication of red blood cell (RBC) transfusion with detrimental consequences for future organ or hematopoietic stem cell transplantation.The study aimed to determine the prevalence and specificity of HLA antibodies among pediatric patients with thalassemia major (TM) and antibody changes over time while on leukoreduced chronic transfusion therapy. HLA antibodies were measured at two or more time points in children and young adults ages 3 to 21 years with TM. HLA Class I and II antibodies were measured by FlowPRA screening. Positive screening assays were confirmed with LabScreen single-antigen bead assays for antibody specificity.HLA antibodies were detected in 10 of 19 (53%) subjects: seven of 19 (37%) with HLA Class I and II antibodies, two of 19 (11%) with only HLA Class I antibodies, and one of 19 (5%) with only HLA Class II antibodies. Subjects with HLA antibodies were older (14.6 years vs. 7.1 years, p = 0.05), predominantly male (80%), and more likely to have a remote history of nonleukoreduced transfusions (p = 0.057). Median time between testing was 3.7 years. De novo HLA antibodies were detected in two of 11 patients who initially had negative panel-reactive antibody screens, while one subject lost detection of Class II antibody. Two of seven patients with HLA antibodies had antibodies to self-HLA.HLA antibodies have a high prevalence in TM patients and may be associated with nonleukoreduced transfusions and older age. For such patients, antibody identification will be useful if subsequent organ or stem cell transplantation is needed.

Congenital sideroblastic anemias (CSAs) are uncommon inherited diseases resulting from defects in heme biosynthesis, mitochondrial translation or mitochondrial iron-sulfur cluster (ISC) assembly. CSAs are characterized by pathological mitochondrial iron deposits in bone marrow erythroblasts. Recently, mutations in mitochondrialheat shock protein 70 (HSPA9), a critical chaperone involved in mitochondrial ISC assembly, have been reported as a cause of non-syndromic CSA. Human heat shock cognate protein 20 (HSCB), a highly conserved mitochondrial co-chaperone, is the primary binding partner of HSPA9. HSCB allows the transfer of nascent ISC to HSPA9 and stimulates its ATPase activity, promoting ISC transfer to target proteins. To identify novel genes responsible for CSA, we performed whole exome sequencing on more than 75 CSA probands and their family members. In one patient, a young woman, with pancytopenia characterized by a normocytic anemia with numerous bone marrow ringed sideroblasts, we identified two variants in HSCB : a paternally-inherited promoter variant (c.-134C>A) predicted to disrupt a conserved ETS transcription factor binding site, and a maternally-inherited frameshift (c.259dup, p.T87fs*27). A fibroblast cell-line derived from the proband showed a decrease in HSCB expression, but normal HSPA9 expression compared to healthy, unrelated controls. Impairment of ETS1-dependent transcriptional activation of the promoter variant was demonstrated in K562 cells transfected with an HSCB-luciferase reporter construct. K562 cells were also employed to determine if reduced expression of HSCB could result in impaired erythroid metabolism, maturation, or proliferation. K562 cells infected with shRNA directed against HSCB were deficient in multiple mitochondrial respiratory complexes, had abnormal iron metabolism and a defect of protein lipoylation, all consistent with defective ISC metabolism. In addition, both IRP1 and IRP2 expression were decreased and cell surface transferrin receptor 1 (TFR1) expression was enhanced, suggesting disturbed cellular iron metabolism. Nevertheless, cells lacking HSCB partially retained an ability to respond to iron chelation and iron overload. Cells lacking HSCB lose their ability to hemoglobinize in response to sodium butyrate treatment (Figure 1A). This defect was confirmed in vivo using a morpholino strategy in zebrafish, as fish lacking HSCB are also unable to hemoglobize (Fig 1B). We generated an Hscb conditional mouse to better elucidate the underlying pathophysiology of the disease. Heterozygous (Hscb+/-) animals have no discernable phenotype; however, null animals die prior to embryonic day E7.5. Thus, to avoid this lethality, we employed Vav-cre animals (Tg(Vav1-cre)1Graf) to evaluate the loss of HSCB specifically in the hematopoietic compartment. Hscbc/- Vav-cre+ pups are pale and growth retarded compared to control littermates and die at approximately p10 with severe pancytopenia. To assess the loss of HSCB specifically in the erythroid lineage, we bred conditional animals to EpoR-cre (Eportm1(EGFP/cre)Uk) mice. Hscbc/- EpoR-cre+ mice die at approximately E12.5 due to a complete failure of erythropoiesis (Figure 1C). Finally, temporally inducible, hematopoietic-specific deletion animals were generated by transplantation of fetal livers from Mx-Cre (Tg(Mx1-cre)1Cgn) positive Hscbc/- animals. After polyinosinic:polycytidylic acid (pIpC) induction, global defects of hematopoiesis were observed in Mx-Cre+ animals, leading to their death 3-weeks post-induction from profound pancytopenia. A transient siderocytosis was seen in the peripheral blood between days 6-8 post-pIpC. Flow cytometry using FSC-TER119-CD44 gating strategy confirmed the defect in erythropoiesis. Taken together, these data demonstrate that HSCB is essential for hematopoiesis; both whole animal and in vitro cell culture models recapitulate the patient's phenotype, suggesting that the two patient mutations are likely disease-causing. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Transfusions are the primary therapy for thalassemia but have significant cumulative risks. In 2004, the Centers for Disease Control and Prevention (CDC) established a national blood safety monitoring program for thalassemia. This report summarizes the population and their previous nonimmune and immune transfusion complications.The CDC Thalassemia Blood Safety Network is a consortium of centers longitudinally following patients. Enrollment occurred from 2004 through 2012. Demographics, transfusion history, infectious exposures, and transfusion and nontransfusion complications were summarized. Logistic regression analyses of factors associated with allo- and autoimmunization were employed.The race/ethnicity of these 407 thalassemia patients was predominantly Asian or Caucasian. The mean ± SD age was 22.3 ± 13.2 years and patients had received a mean ± SD total number of 149 ± 103.4 units of red blood cells (RBCs). Multiorgan dysfunction was common despite chelation. Twenty-four percent of transfused patients had previous exposure to possible transfusion-associated pathogens including one case of babesia. As 27% were immigrants, the infection source cannot be unequivocally linked to transfusion. Transfusion reactions occurred in 48%, including allergic, febrile, and hemolytic; 19% were alloimmunized. Common antigens were E, Kell, and C. Years of transfusion was the strongest predictor of alloimmunization. Autoantibodies occurred in 6.5% and were associated with alloimmunization (p 0.0001). Local institutional policies, not patient characteristics, were major determinants of blood preparation and transfusion practices.Hemosiderosis, transfusion reactions, and infections continue to be major problems in thalassemia. New pathogens were noted. National guidelines for RBC phenotyping and preparation are needed to decrease transfusion-related morbidity.

Morbidity and mortality in thalassemia are associated with iron burden. Recent advances in organ-specific iron imaging and the availability of oral deferasirox are expected to improve clinical care, but the extent of use of these resources and current chelation practices have not been well described. In the present study, we studied chelation use and the change in iron measurements in 327 subjects with transfusion-dependent thalassemia (mean entry age, 22.1 ± 2.5 years) from 2002-2011, with a mean follow-up of 8.0 years (range, 4.4-9.0 years). The predominant chelator currently used is deferasirox, followed by deferoxamine and then combination therapies. The use of both hepatic and cardiac magnetic resonance imaging increased more than 5-fold (P < .001) during the study period, leading to an 80% increase in the number of subjects undergoing liver iron concentration (LIC) measurements. Overall, LIC significantly improved (median, 10.7 to 5.1 mg/g dry weight, P < .001) with a nonsignificant improvement in cardiac T2* (median, 23.55 to 34.50 ms, P = .23). The percentage of patients with markers of inadequate chelation (ferritin > 2500 ng/mL, LIC > 15 mg/g dry weight, and/or cardiac T2* < 10 ms) also declined from 33% to 26%. In summary, increasing use of magnetic resonance imaging and oral chelation in thalassemia management has likely contributed to improved iron burden.

Thalassemia is one of the most common monogenic diseases of man, prevalent in tropical and subtropical regions of the world. Population migration during the past decades has led to increasing numbers of these patients being encountered in all parts of the world, including in the United States. A

Abstract 340 Transfusions are the primary therapy for thalassemia (thal) but have significant cumulative risks. The Thalassemia Clinical Research Network recently highlighted the increased rate of alloimmunization in this population1. In 2004, the CDC established a national blood safety monitoring program for thal. The goals of the program were to monitor blood safety and strategies for the management of complications. This report focuses on immune and non-immune transfusion reactions. Methods: The CDC Thalassemia Blood Safety Network is a consortium of thal centers that follow patients longitudinally to determine the transfusion-related complications. Serial demographic, physical, and laboratory data are collected along with blood samples analyzed at the CDC. Data collected includes ethnicity, genotype, phenotype, transfusion data, immunizations, type of red cell product, degree of antigen matching, and chelation therapy. Chronically transfused (CT) patients were defined as requiring at least 8 transfusions annually. Intermittently transfused (IT) patients received less than 8 transfusions annually. Statistical analyses included continuous variables, logistic regression, and multivariant analysis. Results: There were 407 patients including 327 CT patients and 80 IT patients. The genotype of chronically transfused patients included: TM (81%), TI (6%), E-Beta-Thal (6%), and Hemoglobin H/CS (4%). The average age of CT patients was 22.3 years ± 13 and 21.4 years ± 17 in IT patients. The average units CT patients received was 149 ± 103. Hemosiderosis occurred in both patient groups and correlated with transfusion history. The average ferritin (m/L) in each group, respectively, was 2261 and 689. 78% of the total population has received chronic chelation therapy. Multiple organ dysfunction was common in the population, including cardiac disease (13%), gonadal failure (17%), growth hormone deficiency (8%), hypothyroidism (8%), hypoparathyroidism (1.2%), diabetes (10%), and thrombotic events (5.4%). 45% of the population was splenectomized. Transfusion reactions occurred in 48% of patients, including allergic (45%), multiple etiologies (32%), febrile (17%), and hemolytic (5%). Transfusion-associated infection included 58 cases of Hepatitis-C and 4 cases of HIV. Two Hepatitis-C cases occurred after specific blood testing was initiated. Recent cases of bacteremia, malaria, and Babesiosis have been documented. 21% of CT patients and 13% of IT patients developed an alloantibody. The most common antigen specificity included E (25%), Kell (13%), C (9%), Jka (5%), Kpa (4%), HLA (4%), V (3%), c (3%), D (2.5%), WA-1 (2.5%), and S (2.5%). 45% of alloimmunized patients had multiple antibodies. Race, transfusion burden, age and splenectomy predicted alloimmunization. Alloimmunization was found in 31% of splenectomized patients vs. 10% of non-splenectomized patients (p Autoantibodies occurred in 6.5% of the population and increased with age and splenectomy. Alloimmunization increased the risk of autoantibodies: 26% of patients with an alloantibody had an autoantibody whereas only 2% of patients without alloantibodies had an autoantibody (p Local institutional policies were the major determinant in the type of units administered. In the last year, 32% of the units were washed and 80% radiated. 40% of patients received standard ABO matching, 47% limited phenotypic matching, and 12% full extended matching. Conclusion: Transfusion-related morbidity is a major problem in thal. Hemosiderosis immunologic and non-immunologic reactions are common. Transfusion-related infections have decreased but new, emerging pathogens have been noted. Disclosures: No relevant conflicts of interest to declare.

Abstract 257 Background. Advances in treatment of thalassemia have led to increased life expectancy for patients making outcomes such as health related quality of life (HRQOL) an important consideration of therapy. Little has been published about the HRQOL of pediatric patients with thalassemia. There are limited reports on how this illness impacts the family. Because the familial situation is the starting point for how patients learn to live with their condition, it is important to document this effect and how it changes over time. This report looks at changes in parental reported HRQOL from baseline (BL) to year 1 (Y1) in the Thalassemia Clinical Research Networks (TCRN) Thalassemia Longitudinal Cohort (TLC) study. Patients and Methods. The TCRN is a NIH-sponsored network of 16 major thalassemia centers in the US, Canada and London. We report here on the results from 77 patients under the age of 14 who completed BL and assessments at Y1. Overall the patients were 47% male with a mean age of 9 years (range 5–13). 94% were chronically transfused, and 69% had β-thalassemia, and 12% were E-β thalassemia patients. 57% used an oral chelator, while 29% were on desferoxamine (DFO). HRQOL was measured by self-report with the Children Health Questionnaire (CHQ), 28-item Parental Form (PF28). The 28 items derive 12 subscales that assess physical and psychosocial health. 2 summary scales assess overall physical health and psychosocial health. We defined a clinically significant change as a difference of at least 2 points on any subscale. Results. Clinical Changes: 45% saw a reduced number of transfusions from BL to year 1 (32% showed no change). 73% did not change chelator, while 18% changed from DFO to oral (2.6% other way). 5% began a chelation regimen. Only one percent of patients developed new secondary complications. 63% showed no change in their general adherence rate; 25% showed a decrease. HRQOL changes: As a population, mean HRQOL remained stable over the 1 year study period. Age appears to be significant for CHQ assessment of child's self esteem and behavior (and overall psychosocial assessment), but gender, country and ethnicity do not appear to be significant. The average number of scales with significant changes was eight. Only one CHQ assessment does not show any significant changes on any CHQ scale, while three reports showed changes on all 14 scales. The psychosocial scales showed more significant changes than physical health assessments. Figure 1 illustrates the reported changes by scale. Measures of overall general health, parental emotions and child behavior showed the most changes. Assessment of the child's physical and psychosocial roles and family cohesion showed the least change. The physical health assessments of function and pain showed lower significant changes than the psychosocial health assessments. More psychological health measures show a significant drop than familial assessments. When we examine scale changes by age groups, the youngest age group (5-7) showed modestly better physical and psychosocial scale changes. The 8–10 age group saw more than twice the number of parents seeing a decline in a physical or psychosocial health scale. The oldest age group (11-14) showed the fewest changes, with mainly higher physical health scale changes, but lower scores on the psychosocial scales. Clinical Associations: Changes in number of transfusions and adherence do not appear to impact CHQ assessment. However, changes in chelator appear to be significant for parental time (P=0.048) and the psychosocial summary scale (p=0.04). Changes in secondary complication appear to be associated with changes in the CHQ assessment of the child's behavior (p=.04). Conclusions. The dearth of clinical changes suggests that patients enrolled in TCRN are receiving optimized health care. The lack of changes on the CHQ's physical health scales is to be expected given the low number of clinical changes, and the reported changes in CHQ do not appear to be related to clinical changes. At this stage of data analysis, CHQ assessment in thalassemia appears to be associated with the normal effects a growing child has on the family. This would be the desired result of effective clinical intervention in thalassemia. Further analyses of changes are needed to understand the relationship between changes in HRQOL and specific changes in clinical measures. Disclosures: Neufeld: Novartis, Inc: Research Funding; Ferrokin, Inc: Research Funding.

Abstract 2016 Poster Board I-1038 BACKGROUND: Pulmonary hypertension (PH) contributes to heart disease, the leading cause of death in thalassemia. PH in thalassemia is multifactorial, including oxidative stress, hemolysis, thrombosis, splenectomy, abnormal arginine-nitric oxide bioavailability, and iron overload. Despite the high mortality rate associated with PH, no intervention studies in thalassemia have been completed. This report summarizes the prevalence of elevated tricuspid regurgitant jet velocity (TRV) as a proxy for PH in patients clinically screened by Doppler echocardiography (echo) in the Thalassemia Clinical Research Network (TCRN). PATIENTS AND METHODS: The TCRN is an NIH-sponsored network of major thalassemia centers in the US, Canada and London, UK. This analysis is part of the Thalassemia Longitudinal Cohort (TLC), which collects longitudinal data from 428 patients at 16 centers. We report results from 303 patients (71%) who were assessed by echo at least once. Predictors considered for analysis were age, gender, splenectomy, hepatitis C, WBC, ferritin, hemoglobin, liver function, creatinine, chronic transfusion status, number of transfusions, chelation status, and hydroxyurea use. Multivariate effects of predictors significant in univariate analysis were modeled using logistic regression for elevated TRV. RESULTS: Measurable TRV jet was detectable in 144/303 (48%) of patients. Average age of the cohort with a detectable TRV was 25.8 years (range 5-56 years); half were female.. 97% of the patients studied 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 45/144 (31%) of patients screened, 18% (8/45) of whom had a TRV ≥ 3.0 m/s suggesting significant PH. Older age was strongly associated with PH (r = 0.38, p CONCLUSIONS: Elevated TRV is noted in at least 1/3 of transfusion-dependent thalassemia patients with measurable TR jets. We observed elevated TRV in both children and adults. Less than half of patients screened by echo had a measurable TRV, suggesting that technical diligence is needed to increase the fraction of echos with a measured TRV to better identify patients at risk of PH. Age, splenectomy and history of hepatitis C are significant univariate risk factors in this population, with age remaining an independent risk factor in multiple regression analysis. Ongoing assessment in the TLC and specific prospective longitudinal studies of PH in thalassemia are needed to understand the natural history and pathophysiology in thalassemia in order to determine optimal therapy. Interventional trials for PH in thalassemia are needed. Disclosures: No relevant conflicts of interest to declare.

Abstract 1371 Poster Board I-393 The study examines the quality of life (QOL) of pediatric thalassemia patients and their families enrolled in the Thalassemia Longitudinal Cohort (TLC) study of the NHLBI-sponsored Thalassemia Clinical Research Network, which comprises 17 centers in the US, Canada, and London, UK. The study evaluates 99 baseline responses to the Children's Health Questionnaire (CHQ) PF28, a self-administered survey filled out by the parent or guardian of patients age 5 y and older. The CHQ utilizes 12 scales that can be grouped into parental assessments of the child's physical well-being; mental, emotional and behavioral health; and the familial context. We previously showed that compared to the US population, the thalassemia population is significantly different on 7 of the 12 scales. Here we evaluate these data by patient gender, race, age, and chelator type. The mean age of the population was 9.7 y (range 5.0-13.8 y), with 48% male, and 65% non-white. While parents assessed males to have a lower QOL than females, the only significant difference was in their assessment of the child's emotional role/behavior (school or friends). When comparing white to non-white (predominantly Asian) patients, with the exception of bodily pain, non-white thalassemia patients reported poorer PF28 scores. However, only the reported impact on parental time and emotion are significant. These variances appear to mirror the US population. Figure 1 shows PF28 summary scores by age in thalassemia compared to the general US population. Parents evaluate their child with thalassemia with lower physical health than US norms (p Finally, when CHQ PF28 assessments are compared by chelator type (subcutaneous deferoxamine vs. oral deferasirox), parents report that children receiving deferoxamine have generally lower QOL than the rating for those receiving Deferasirox. However, the only significant differences are with perceived physical function, impact on family activities, and the overall physical summary scale. The CHQ PF28 data provides important insight into the impact the child with thalassemia has on the family. Although psychosocial QOL is similar, children, and especially adolescents, with thalassemia have lower physical QOL, especially those on chelation with Deferoxamine. Because PF28 takes the parents' point of view, it can't be determined from these data alone whether the reported difference between parenteral and oral chelator would hold true for direct patient assessments. The gender of the child also appears to affect parental expectation of the child's QOL. These data validate the observational evidence that a child with thalassemia has a significant impact on the family. Figure 1 TLC CHQ PF28 Summary Scales compared to US norms Figure 1. TLC CHQ PF28 Summary Scales compared to US norms Disclosures: Odame: Novartis: Consultancy, Speakers Bureau. Thompson: Novartis: Research Funding. Neufeld: Novartis: Research Funding.

Abstract 4056 Poster Board III-991 BACKGROUND Survival in thalassemia is strongly influenced by iron burden and adherence to chelation therapy. Deferoxamine (DFO) is an effective chelator, in use since the 1970s, but the parenteral mode of administration hinders adherence. Deferasirox (DFX), taken orally, became commercially available in the US in Jan. 2006, and deferiprone (DFP) is only available in North America (N.A.) through research or compassionate use. The impact of expanded chelation options on iron burden in thalassemia patients has not been studied. The goals of this study were to assess the chelator choices among patients with thalassemia and to compare efficacy and treatment adherence among chelators. METHODS The TCRN is a NHLBI-sponsored clinical trial network of Thalassemia Centers in N. A. and London, U.K. The Thalassemia Longitudinal Cohort (TLC) study of the TCRN was launched in 2006. Baseline data collection included a five-year retrospective component, with clinical, radiographic, and laboratory data from 2002 onward. This is followed by annual prospective data collection thereafter. The current analyses include data from the retrospective portion through baseline assessment. The dates of data collection span the initiation of DFX, first in clinical trials and then in routine clinical use. RESULTS Of the 404 enrolled subjects, 317 had ever received chelation therapy. Mean age was 21.2 ± 12.1y, and 46.4% were male. Genotype distribution included beta-thal major (79.2%), beta-thal intermedia (6.6%), chronically transfused HbE-beta-thal (9.5%), Hb E-beta-thal, not chronically transfused (1.6%), chronically transfused alpha-thal syndromes (2.3%), and other (1%). The median ferritin level was 1431 ng/mL (range, 122-23712 ng/mL) and mean liver iron content (LIC) was 10.8 mg/g dw (0.3-43.3 mg/g dw). Current choices are: DFO (27%), DFX (58%), DFP (1%), combination DFO+DFP (5%), DFO+DFX (3%), and no chelation (7%). Among chelated patients, 65 (21%, mean age 19.1y) chose to continue DFO and never used DFX, while 192 (61%, mean age 21.9y) have taken DFX (p=0.1). The mean current doses of DFO and DFX were 39 mg/kg/day and 25 mg/kg/day, respectively. Compared to those who switched to DFX, patients who continued DFO had lower initial ferritin levels (1499 DFO v. 2144 ng/mL DFX, p=0.02), but similar LICs (14.1 v 13.9 mg/g dw, p=0.9). Reasons for switching to DFX included: participation in clinical trials before 2006 (26%), commercial availability of drug (27%), patient/family preference (22%), high iron burden (15%), and other (10%). Conversely, 32 subjects who tried DFX switched back to DFO for the following reasons: patient/family preference (38%), high iron burden on DFX (16%), renal dysfunction (6%), elevated alanine aminotransferase (3%), and other (37%). Over the 5-year period, patients currently receiving DFX had a significant reduction in LIC (13.3 to 10.9 mg/g dw, p=0.02) and a trend towards reduction in ferritin level (2198 to 2027 ng/mL, p=0.06), while those receiving DFO had no significant change in LIC (12.2 to 10.4 mg/g dw. P=0.17) but had a significant decrease in ferritin levels (1881 to 1516 ng/mL, p=0.04). Self-reported treatment adherence was higher in the DFX group than in the DFO group, with 89% compared with 76.5% reporting adherence at least 75% of the time (p=0.02). Twenty-seven percent of patients on DFO at study entry and 30% of patients on DFX have ferritin >2500 ng/mL and/or LIC >15 mg/g d.w., indices of inadequate chelation. CONCLUSIONS DFX is currently the predominant chelator choice among patients with thalassemia in the TCRN. LIC appeared to improve among patients who have switched to DFX between 2002 and baseline TLC studies in 2007-2009, although ferritin remained stable. In the same time period, for DFO treated patients, ferritin significantly decreased but the LIC did not change. Nevertheless, the final LIC was similar between DFO and DFX treated groups. Inadequate control of iron burden was observed in a significant subset of patients receiving either chelator; thus, close monitoring of iron burden and encouragement and support of adherence are essential. Disclosures: Thompson: Novartis: Consultancy, Honoraria. Mueller:Novartis: Site principal investigator. Odame:Novartis: Consultancy, Speakers Bureau. Giardina:Novartis: Research Funding. Vichinsky:Novartis: Consultancy, Research Funding. Porter:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Vifor International: Membership on an entity's Board of Directors or advisory committees. Coates:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Neufeld:Novartis: Research Funding.

Ten patients had repeated measurements of the their midventricular T2* imaging, and an additional 8 patients had measurements at three slice locations (9/18 males, median age 19.3 years, range 11.2-23.6 years). For the initial 10 patients, the median T2* value was 21.3 ms (range 6.336.0), with a median standard deviation of 1.5 ms (range 0.1-4.4) at the mid-ventricular level. Two of ten patients had values that spanned the clinically accepted cut-point of 20 ms, indicating they could have been classified as either normal or mildly abnormal depending on which image was selected for analysis. For the 8 patients with multiple slice locations analyzed, the median T2* values were 29.5 ms (9.5-47.2), 25.9 (12.5-37.3), and 22.7 (9.933.7) for the apex, mid, and basilar levels respectively. While the median standard deviations for each slice location were low (0.6, 0.9, and 0.5 respectively), the differences between the slice locations resulted in 1 patient having values both above and below 20 ms, and 2 additional patients with values above and below the “severely abnormal” cut-point of 10 ms. Conclusions