bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Pilot Intervention to Improve Hydroxyurea Adherence in Youth with Sickle Cell Disease through Community Health Workers: The "Habit" Study
Authors: Green Nancy S. , Manwani Deepa , Soto Luisa , Castillo Yina , Ireland Karen , Jin Zhezhen , Smaldone Arlene 
Published: November 2019

Abstract
Background: Chronic disease regimens for youth require self-management skills for a daily medication habit. Incomplete adherence to hydroxyurea (HU) is a treatment barrier for sickle cell disease (SCD) (Walsh KE, Pediatrics 2014). HU induction of fetal hemoglobin (HbF) is dose-dependent but not a standardized target (Ware RE, Hematology Am Soc Hematol Educ Program, 2015). In a previous 2-site retrospective analysis of youth with SCD, large deviation from historical personal best (PBest) HbF, a clinic-based form of maximum dose (Green NS, PBC, 2016), was common and correlated with increased acute hospital use. Here we hypothesized that: 1) A HU habit can develop through education and support of youth-parent dyads from a structured intervention of community health workers (CHW), augmented by text messaging; 2) Improved used will increase HbF; 3) The intervention is feasible and acceptable.
Methods: We conducted a 2-site R21-funded randomized controlled feasibility trial (RCT), "Hydroxyurea Adherence for Personal Best in Sickle Cell Treatment: HABIT" (Smaldone A, Contemp Clin Trials, 2016)." Youth- parent dyads (youth ages 10-18) were recruited for the 6-month intervention. Eligibility required a ≥15% drop from PBest HbF on stable HU dose over the preceding year. Intervention dyads received a 6-month structured intervention of education and support by CHWs with home visits and text messaging, versus educational materials. Primary outcomes were HbF, % deviation from PBest HbF and HU pharmacy refills.
Results: Using 2:1 randomization, 28 parent-youth dyads participated (18 intervention, 10 control): mean age 14.3±2.6 years, 42.9% female. At baseline, no differences were seen in HbF (10.5% vs. 13.4%, p=0.25), but deviation from PBest HbF was higher in the control group (-42.6%) than the intervention (18.1%, p=0.009). Using a growth model for % deviation from PBest HbF, the intervention group demonstrated a modest absolute improvement in deviation from PBest (2.2% per month higher in the intervention group), peaking at month 4 (p=0.31), and modest gain in mean HbF (3 versus 1.8). Four subjects exceeded their PBest. Compared to the year before intervention, pharmacy refills improved for the intervention group: 64.6% year prior, 80.7% (months 0 to 3), 85.9% (months >3 to 6), while the control group was unchanged (79.2% year prior, 83.6% months 0 to 3, 79.4% months >3 to 6). Intervention feasibility and acceptability by dyads were excellent.
Conclusions: The 6-month pilot RCT "HABIT" may improve HU adherence measured by improved HbF, deviation from PBest and pharmacy refill, was feasible and acceptable, and suggests utility as an intervention. Based on these findings, a multi-center HABIT RCT of 1-year duration powered to test efficacy is planned.
Funded by 5R21NR013745 (PIs Green, Smaldone)
Figure Figure.

Disclosures
No relevant conflicts of interest to declare.
Early Renal Disease in Children with Sickle Cell Disease from Malawi
Authors: Heimlich Jonathan Brett , Chipoka Godwin , Ellis Graham , Elsherif Laila , David Emeraghi , Kamthunzi Portia , Krysiak Robert , Majawa Yacinta , Mafunga Pilirani , Zhou Qingning , Cai Jianwen , Key Nigel S. , Gopal Satish , Ataga Kenneth I. 
Published: November 2019

Abstract
Sickle cell nephropathy (SCN) is a prevalent complication among adults with sickle cell disease (SCD) and has been observed in younger populations, suggesting potential early renal involvement in pediatric patients. Initial hyperfiltration and albuminuria followed by frank proteinuria, leading to declining GFR and eventual end stage renal disease is assumed to be the typical progression of SCN; however, few clinical biomarkers exist to identify early-stage renal disease. We describe the renal profile in 119 children with SCD at Kamuzu Central Hospital in Lilongwe, Malawi and propose a novel urinary biomarker for the identification of children with early renal disease. Among children with confirmed HbSS disease (females 47.9%; median age 9.0 years, IQR: 5, 11), 21.6% were found to have a urinary albumin to creatinine ratio (UACR) 30mg/g or above. Baseline laboratory and clinical parameters stratified by UACR are shown in Tables 1 and 2. Patients with increased levels of UACR were found to be significantly older, and have significantly elevated plasma levels of lactate dehydrogenase (LDH), total bilirubin, and indirect bilirubin when compared to those without albuminuria (p<0.05). No association was seen between albuminuria and either hemoglobin or plasma hemoglobin. Albuminuria was also significantly associated with elevated levels of nephrin, a urinary marker of glomerular injury (p<0.01). Multivariable logistic regression was used to investigate risk factors that are associated with albuminuria (UACR >= 30). Urine nephrin was significantly associated with albuminuria (regression coefficient estimate: 0.00188, SE: 0.000571, p = 0.0010). Additional analysis using a nephrin cut-point of 293 pg/mL, the median value in the cohort, revealed a 17.8 times greater odds of having albuminuria in children with nephrinuria above this value. These data taken together suggests that a significant proportion of children with SCD in Malawi exhibit renal involvement early in life and could be at risk for worsening nephropathy and end-stage renal disease as they grow older. Our data further indicates that urinary nephrin could be utilized as an early marker of glomerular disease in SCN and possibly prompt earlier intervention in these children. The discordant association of albuminuria with clinical markers of hemolysis suggests that hemolysis may not play a substantial role in the pathogenesis of albuminuria in this population. Increased surveillance of children with SCD for renal complications can ultimately inform management strategies to improve outcomes and increase life expectancy among children with SCD.

Disclosures
No relevant conflicts of interest to declare.
Termination and Frameshift Mutations in ELANE Are Associated with Adverse Outcomes in Patients with Severe Chronic Neutropenia
Authors: Dale David C. , Makaryan Vahagn , Kelley Merideth L. , Bolyard Audrey Anna , Boxer Laurence A. , Newburger Peter E. , Bonilla Mary Ann , Klimiankou Maksim , Skokowa Julia , Zeidler Cornelia , Welte Karl 
Published: November 2019

Abstract
Background: Mutations in ELANE are the most common cause for both cyclic and severe congenital neutropenia. We previously reported that some mutations, e.g., G214R and C151Y, are associated with more severe outcomes. (Makaryan, Zeidler, et al; Curr Op Hematol. 2015;22:3-11) We also found that termination and frameshift mutations are also associated with a high risk of MDS/AML, death from infection or need for transplantation. To aid in clinical care of SCN patients, we compared the clinical characteristics of patients with termination and frameshift who have or have not developed MDS/AML.
Methods: We reviewed clinical records for 403 patients with severe chronic neutropenia and mutations in ELANE. We identified 44 patients with termination or frameshift mutations, both categories predicted to lead to synthesis of mutant neutrophil elastase that is missing a number of terminal amino acids and causing distortion of the three dimensional structure of the protein.
Results:There are currently 11 cases of MDS/AML in the 44 patients with termination or frameshift mutations. Table 1 compares clinical characteristics of these two groups.
There was no significant relationship of baseline ANC values, G-CSF dose or duration of G-CSF treatment. There appeared to be a higher risk of AML for the female patients, but the difference was also not significant.
The leukemia cases occurred with mutations in exon 3 (1), exon 4 (1) and exon 5 (9). The mutations in the group without MDS/AML were in exon 4 (8) and exon 5 (25). To date, there have been six distinct frameshift mutations associated with MDS/AML. There have been 3 distinct termination mutations associated with MDS/AML; three unrelated patients have the identical mutation C223ter. All of the patients in the SCNIR database who have this specific mutation have developed MDS/AML.
Conclusion: Frameshift and termination mutations appear to convey a high risk of MDS/AML in patients with severe chronic neutropenia. We believe patients with these mutations should be on a "watch list" with particular attention to surveillance and regular bone marrow examinations. Mutation C223ter, together with G214R and C151Y, appear to be particularly high risk. We recommend that all patients with these mutations be considered for early HSCT.

Disclosures
Dale: Amgen: Consultancy, Honoraria, Research Funding. Boxer:Amgen: Equity Ownership.
Involvement of NFAT Transcription Factors in NK Cell Reactivity
Authors: Rothfelder Kathrin , Märklin Melanie , Wild Julia , Dörfel Daniela , Kanz Lothar , Müller Martin R , Salih Helmut R. 
Published: November 2019

Abstract
NK cells are lymphoid components of innate immunity and play an important role in tumor immunosurveillance. One of the major transcriptional regulators in lymphoid cells is NFAT (Nuclear Factor of Activated T Cells), as highlighted by its important role in T and B cell development and function. With regard to NK cells, available data indicate that NFAT is dispensable for development. However, several lines of evidence including the observation that the immunosuppressive drugs cyclosporin A and tacrolimus, which mediate their effects through inhibition of calcineurin and consecutively NFAT, influence NK reactivity implicate a role of this family of transcription factors in NK cell reactivity and function. Here we employed different genetic mouse models on the C57BL/6 background to directly study the functional role of NFAT in NK cells.
We found that except for NFAT3 mRNA and protein of all family members (NFAT 1, 2, 4 and 5) was expressed in resting NK cells of wild type (WT) mice with NFAT1, 2 and 4 being most abundantly detectable. When we employed NK cells with knockout (KO) of NFAT 1, 2, and 4 in comparative in vitro analyses, we surprisingly found that lack of NFAT resulted in enhanced NK cell activation, degranulation and release of immunomodulatory cytokines like IFN-γ after co-culture with YAC-1 target cells as well as increased production of granzyme B and perforin after cytokine activation. The inhibitory effect of NFAT on NK cell effector function was further confirmed in vivo by employing WT and germ line NFAT KO animals in the syngeneic B16 melanoma model, which revealed a significantly reduced metastatic burden in NFAT KO mice. Depletion of NK cells in this model system in turn resulted in increased metastasis, however, with WT animals displaying significantly higher metastatic burden compared to NFAT KO mice. As this pointed to the fact that NFAT influences metastasis via both NK-dependent and independent mechanisms, we further generated mice with a NK cell-specific (conditional Ncr1-Cre dependent) NFAT2 KO. When these animals were employed again in analyses of B16 lung metastasis, comparative analyses with WT animals confirmed the inhibitory effect of NFAT on NK tumor immunosurveillance.
Taken together, these results provide the first direct evidence for the functional involvement of NFAT in NK cell antitumor reactivity and, in contrast to T and B cells, identify NFAT as a negative regulator of NK cell function.

Disclosures
No relevant conflicts of interest to declare.
Quinine-Induced Thrombotic Microangiopathy (Q-TMA): Frequency, Presenting Features, Outcomes
Authors: Page Evaren E , Vesely Sara K. , George James N. 
Published: November 2019

Abstract
Q-TMA is an acute, severe, immune-mediated, drug-induced disorder. Q-TMA is suspected when symptoms suddenly begin within hours following quinine (Q) exposure. Diagnosis of Q-TMA is established by the history of recurrent acute symptoms following recurrent Q exposures and/or by documentation of Q-dependent antibodies reactive with platelets and/or neutrophils. The Oklahoma TTP-HUS Registry enrolls all patients for whom plasma exchange (PEX) is requested for suspected TTP or HUS. Since 1995, when routine measurement of ADAMTS13 activity began, the Registry has diagnosed 78 patients with acquired TTP (ADAMTS13 <10%). During this time we have also diagnosed 17 patients with Q-TMA; 2 additional patients were diagnosed before 1995. Seventeen of these 19 patients were tested for Q-dependent antibodies; all were positive. Nine patients had a history of recurrent acute symptoms with recurrent Q exposure, including the 2 patients not tested for Q-dependent antibodies. Q exposure was a pill in 18 patients, tonic water in one. Remarkably, 18 patients were women; all 19 patients were white. Common presenting symptoms were fever, chills, nausea and vomiting. No patients had focal neurologic abnormalities. All patients had microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and acute kidney injury. Eight patients had elevated serum alanine aminotransferase (231-1345 U/L). Three patients had neutropenia (absolute neutrophil counts, 184-486). Two patients had coagulation abnormalities suggesting disseminated coagulation (DIC).
One patient died from complications of the central venous catheter insertion, performed for PEX and dialysis; all other patients recovered normal platelet counts. Three of the 18 surviving patients had end-stage renal disease (2 had kidney transplants). The median estimated glomerular filtration rate (GFR) for the other 15 patients, at 2.7-19.2 years (median, 10.2) after recovery, was 36 ml/min (range, 19-98). Only two patients had normal GFR (≥90 ml/min). Eleven patients had chronic kidney disease, defined by GFR <60 ml/min. Seven of 18 patients have died 4.1-12.7 years (median, 7.8) following recovery at ages 59-87 years. Conclusion. Quinine can cause severe immune-mediated toxicities involving multiple organ systems (Am J Hematol 2016; 91: 461). Q-TMA is an acute disorder causing severe kidney injury and, in some patients, also liver toxicity, neutropenia, and/or DIC. Q-TMA is not rare. During 20 years, we enrolled 17 Q-TMA patients compared to 78 patients with acquired TTP. Chronic kidney disease is a common long-term outcome. Explicit questions are required to discover the association of systemic symptoms with quinine ingestion.
Table Table.

Disclosures
No relevant conflicts of interest to declare.
Pharmacokinetics of Subcutaneously Administered CB2679d/ISU304 in Wild-Type and Hemophilia B Mice
Authors: Hong Seung-Beom , Levy Howard , Jung Jae Yong , Park Minkyung , Seo A Rim , Seo So Hyeon , Madison Ed 
Published: November 2019

Abstract
The rapid clearance of factor IX (FIX) necessitates frequent intravenous IV administrations to achieve effective prophylaxis for patients with hemophilia B (HB). Subcutaneous (SC) administration would be a preferred route of administration but has been limited by low bioavailability and potency of the marketed FIX products. CB2679d/ISU304 with enhanced biological properties was developed using a rational protein design approach and has resistance to inhibition by ATIII, increased affinity for FVIIIa, increased catalytic activity and resultant 20-fold enhanced potency in vitro (clotting activity) and in vivo (the tail clip model) and 8-fold increased duration of aPTT activity in vivo compared to recombinant wild-type FIX dosed at the same mass.
ISU304 (4622 IU/mg) was injected into HB mice SC with a single dose ISU304 at 0.02, 0.05 or 0.15 mg/kg and sampled at 4, 6, 8, 24 hours. Groups of wild-type mice received ISU304 0.02, 0.05 or 0.15 mg/kg SC and BeneFIX (273 IU/mg) 0.15 mg/kg SC, and sampled at 0.25, 1, 4, 8, 24, 48, 72, and 96 hours. Daily SC injection in HB mice of ISU304 at 0.05 mg/kg was sampled at 24, 48, 72 and 96 hours. FIX antigen was measured using a sandwich ELISA and FIX activity was measured using a one-stage clotting assay on Stago Compact. Pharmacokinetics of FIX was performed using PKSolver.
There was a dose-dependent increase of plasma FIX antigen with SC ISU304. Mass-based pharmacokinetic profiles of ISU304 (t1/2, 18 hours; Tmax,8 hours, Bioavailability, 19-22%) were similar to those of BeneFIX (t1/2, 20 hours; Tmax, 8 hours, Bioavailability, 16%). Due to ISU304 high specific activity, SC dose of ISU304 yields much higher FIX activities in mouse plasma compared with the same mass dose of BeneFIX.
Daily SC dosing of ISU304 230 IU/kg reached steady-state plateau FIX 8% activity after three injections.
The bioavailability and increased potency of CB2679d/ISU304 facilitates the initiation of the Phase 1 subcutaneous dosing study in individuals with hemophilia B.
Figure 1 Figure 1. Table 1 Table 1. Figure 2 Figure 2.

Disclosures
Hong: ISU Abxis: Employment. Levy:Catalyst Biosciences: Employment. Jung:ISU Abxis: Employment. Park:ISU Abxis: Employment. Seo:ISU Abxis: Employment. Seo:ISU Abxis: Employment. Madison:Catalyst Biosciences: Employment, Equity Ownership, Patents & Royalties.
Identification and Characterization of a New Mutation in Coagulation Factor VII (Carmel mutation), with Different Reactivity Towards Tissue Factors of Different Origin
Authors: Cassel Aliza , Rosenberg Nurit , Muhammad Emad , Dazdik Rima , Berl Miriam , Preis Meir 
Published: November 2019

Abstract
Inherited factor VII (FVII) deficiency is a rare autosomal recessive disorder manifested by bleeding tendency in homozygotes or compound heterozygotes. The bleeding tendency is variable and does not always correlate with the measured amount of FVII. More than 30 mutations causing FVII deficiency have been identified. The aim of this study was to identify the molecular defect in a family with FVII abnormality and to characterize the functional defect and its clinical consequences.
An 80 year old woman showed various prolonged prothrombin time (PT) dependent on the origin of tissue factors (TF) in the reagents, in the range of 5-18%. FVII activity measured using placenta human TF was ~4% and less than 1% using recombinant human TF or rabbit brain TF. Direct sequencing of PCR-amplified FVII genomic DNA exons demonstrated a single homozygous nucleotide exchange G>A in exon 6 predicting missense mutation Tyr164Cys, in close vicinity to the active site of the protease and to the binding site of FX.
Sequencing of exon 6 in six members of the family comprising three generations was performed. All of them exhibited low activity of FVII. Direct sequencing of PCR-amplified exon 6 demonstrated that her son, daughter and grand-daughter are heterozygote to the novel mutation, Tyr164Cys, henceforth, Carmel mutation. The grand -daughter (third generation) was identified as a compound heterozygote carrying in addition an Ala244Val mutation along with a Arg353Gln polymorphism, a well-known linkage previously characterized in the Israeli population, inherited from the paternal side. Her FVII activity was 3-7% and 8% FVII antigen. In the individuals heterozygote for Tyr164Cys we detected 41-54% activity and 46-66% antigenic FVII.
The measurement of VIIa in the proband and her grand-daughter could not demonstrate any activity in plasma, possibly because of perturbation of the interaction between the mutated FVII and TF or FX which are part of the assay. The heterozygote for Tyr164Cys showed approximately 30% FVIIa of normal controls .
Despite the dramatic laboratory presentation, the clinical manifestation of the Tyr164Cys genotype is very mild, suggesting that a low level of FVII is sufficient to prevent bleeding. The homozygous patient reached an old age, gave birth to two children and did not suffer any major bleedings during her life. The compound heterozygote presents a similar phenotype with slightly higher FVII activity and antigen, no measurable FVIIa activity and mild clinical presentation. Further investigation into this novel mutation is needed in order to characterize the interaction of the FVII with TF, phospholipids and FX and to understand the reason for such low amount of FVII protein in plasma.

Disclosures
No relevant conflicts of interest to declare.
Late Effects in Survivors of Infantile Acute Leukemia Are Less Severe Than Expected: A Study of the L.E.a Program
Authors: Gandemer Virginie , Bonneau Jacinthe , Oudin Caroline , Berbis Julie , Bertrand Yves , Tabone Marie-Dominique , Ducassou Stephane , Chastagner Pascal , Brethon Benoit , Dalle Jean-Hugues , Thouvenin Sandrine , Poiree Maryline , Plantaz Dominique , Kanold Justyna , Sirvent Nicolas , Lutz Patrick , Hamidou Zeinab , Baruchel Andre , Leverger Guy , Auquier Pascal , Michel Gerard 
Published: November 2019

Abstract
Purpose
The long-term impact of treatment in infants with acute leukemia (AL) is poorly understood and of concern.
Patients and methods
We analyzed the incidence, in the L.E.A. cohort, of and risk factors for late sequelae in the survivors of infant AL diagnosed before the age of one year, according to group: type of AL, transplantation, sex, and age ≤ or > 6 months. Of 113 survivors, 55 had had lymphoblastic AL and 58 myeloblastic AL. The median follow-up was 11.7 years [1.9-34.7]. Sixty-three were treated with chemotherapy only (and four with central nervous system irradiation) and 50 received transplantation (with a chemotherapy-based regimen except for three).
Results
The most frequently observed sequelae included problems of height, body mass index, and gonadal or thyroid function (Figure 1). We found a mean of 1.3 +/-0.1 sequelae per patient. In multivariate analysis, treatment after the age of six months significantly decreased the incidence of major growth failure (OR 0.38, p = 0.04) and low weight (OR 0.3, p = 0.02) (Figure 2). Transplants performed in first remission did not affect the occurrence of late effects (p = 0.2) (Figure 3). Parent-reported child quality of life (QoL) scores were similar among groups and to the normative population. Adults had diminished QoL as measured by psychosocial subscales relative to French norms but with no difference between groups.
Conclusion
Altogether, these results highlight the need for comprehensive follow-up with hormone replacement therapy and psychological intervention. Our results in a large cohort with very limited use of irradiation, did not show an increased risk of late sequelae relative to older children. We conclude, that transplantation should be considered when warranted, as there is no increased risk of late effects.

Disclosures
No relevant conflicts of interest to declare.