bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Association of Iron Deficiency and Fatigue in Non-Anemic Females of Childbearing Age: An Nhanes Analysis
Authors: Akkad Mohamed , Shaik Mohammed , Al-Janadi Anas 
Published: October 2019

Abstract
Introduction:
Iron deficiency (ID) is the most common nutritional deficiency in the world and remains relatively common in at-risk groups in the United States. The development of (ID) is dependent upon the individual's iron stores which is a balance between iron absorption and loss. Commonly associated with (ID) is iron deficiency anemia (IDA) which has a well known association with fatigue. Fatigue is a common complaint in general, with a prevalence in population-based surveys in Great Britain and the United States of 6.0 and 7.5 % respectively. However it is not uncommon to have (ID) without subsequent anemia in females childbearing age group. Our study aims to evaluate the prevalence of ID in non anemic females of childbearing age and its association with fatigue.
Methods:
Data was obtained from continuous NHANES database, a nationally representative health survey conducted from 2005-2010. The data including age, race, complete blood count (CBC), ferritin and fatigue was obtianed from laboratory and questionnaire datasets, respectively. Subjects were further divided based on ferritin levels into two groups, Group A; ferritin ≤20 ng/mL and Group B; ferritin >20 ng/mL. The question regarding fatigue- "feeling tired or having little energy for past two weeks" was obtained from PHQ-9 scale. Univariate analysis was done comparing Group A and Group B using chi-square test and t-test for categorical and numerical variables, respectively. The effect of iron deficiency on fatigue was obtained using logistic regression to calculate odds ratio (OR) after adjusting for age and race.
Results:
Of 3230 female subjects( age 18yrs -49yrs), there were 809 with ID with no anemia. The weighted prevalence of iron deficiency in non-anemic women of childbearing age was 22.5% (95% CI 20.76-24.22). The weighted prevalence of fatigue in Group A and Group B was 61.8% (95% CI 56.4-67.2) and 59.7 % (95%CI 57-62.4) respectively (p=0.45)(table 1). In multivariate analysis, after adjusting for age and race, the odds ratio (OR) for fatigue with iron deficiency was 1.1 ( 95% CI 0.8-1.4).
Conclusion:
The prevalence of ID in non anemic females of childbearing age in the United States was 22.5 % .The percentage of subjects who reported fatigue was significantly high in both iron deficient and non-iron deficient subjects in this age group. There was no statistical difference in self-reported fatigue in both iron deficient and non-iron deficient women of childbearing age. Further studies are needed to validate our findings.
Table 1. Comparision of GpA and GpB Variables Ferritin≤ 20 ng/mL (GpA) Ferritin > 20 ng/mL Fatigue - Yes 512 1452 Fatigue - No 297 986 Total 809 2421

Disclosures
No relevant conflicts of interest to declare.
The Appropriateness of Heparin Antibody Testing. A Single Institution Retrospective Analysis
Authors: Landau Danny A. , Kholodnaya Nadezhda , CuestaFernandez Ana , PerezPerez Ariel 
Published: October 2019

Abstract
Background: Heparin-induced thrombocytopenia (HIT) is a drug-induced, immune-mediated prothrombotic disorder associated with thrombocytopenia and venous and/or arterial thrombosis.Up to 5% of patients exposed to heparin for at least one week develop HIT, and approximately 50% of them will have thrombosis. Diagnosis of HIT is suspected from the clinical picture based on the ''4 T's'' (Thrombocytopenia, Timing, Thrombosis, no other cause of platelet fall) or the HIT Expert Probability (HEP) scoring system. However, often these "4 T's" are ignored and testing is inappropriately ordered in low risk patients. This could lead to possible morbidity and increase length of hospital stay. We opted to look back at the appropriateness of testing done within our academic center.
Methods/ Design:
All hospitalized patients with thrombocytopenia who underwent HIT antibody testing (HIT ELISA) during February 2013 were screened using our internal electronic medical record.
Patients were subdivided to low, intermediate or high pretest probability group according to the 4Ts scoring system.
Appropriateness of testing was determined according ASH 2013 Clinical Practice Guideline on the Evaluation and Management of Adults with Suspected Heparin-Induced Thrombocytopenia (HIT). HIT Ab test is recommended to be tested when there is intermittent to high probability of HIT (4T's score above or equal to 4).
The percentage of appropriate/inappropriate testing was calculated.
The results were then subdivided by ordering physician group.
Results:
120 HIT ab tests were performed during February 2013 in our institution. Only 13 patients tested had a positive HIT Ab. Internal medicine ordered the majority of these tests. Of the 120 patients tested, 7 patients had high risk and another 50 had intermediate risk as per 4T's scoring. 61 patients were low risk and should not have been tested. (Table 1)
Table 1. HIT antibody test ordered per Service and probability of HIT. Service ordering test Low probability of HIT Intermediate/high probability of HIT TOTAL Internal Medicine 28 28 56 Cardiothoracic Surgery 13 11 24 Hematology Oncology 7 5 12 Cardiology 3 1 4 Surgery 1 4 5 Emergency medicine 0 1 1 Infectious disease 4 0 4 Pulmonary 0 1 1 Critical care 1 6 7 Nephrology 1 2 3 Ob Gyn 1 0 1 Family Medicine 2 0 2 TOTAL 61 59 120
Conclusions:
HIT testing has been overused within our institution. Low platelets, without other signs or symptoms of typical HIT were used as a trigger for testing the antibody. This has potential to cause harm due to increased bleeding risk, increased length of hospital stay, and the potential to utilize extended anticoagulation when not necessary. Better education on the appropriateness of the test can limit the potential harm of its use.

Disclosures
No relevant conflicts of interest to declare.
To Push or Not to Push: The Benefit of Administering Anti-Emetics By Intravenous Push
Authors: Arumugam Raajasekar Arun Kumar , Barola Sindhu , Tehrani Lynne , Chandra Abhinav B 
Published: October 2019

Abstract
Background
Prevention of chemotherapy-induced nausea and vomiting is crucial for maintaining the quality of life of cancer patients. Granisetron and dexamethasone are commonly used medications prior to chemotherapy to minimize these adverse effects. There are no well-defined guidelines on the route of administration of medications that are administered prior to chemotherapy. With the ever increasing cost of cancer care, innovative methods need to be employed to maximize utilization of resources.
Methods
A retrospective chart review was performed to identify patients who received granisetron and dexamethasone prior to emetogenic chemotherapy. The primary study site was the cancer center of a tertiary care community hospital. Over a two month period there were 1552 instances when patients received dexamethasone or granisetron prior to emetogenic chemotherapy. Patients either received medications by intravenous piggyback (IVPB) or intravenous push (IVP). The time spent on delivering medication by the two routes and the rate of occurrence of nausea and vomiting requiring the administration of rescue medications were compared.
Results
Patients who received granisetron and dexamethasone by IVPB had a 2.8% rate of adverse effect rate requiring rescue medications (n=806) and patients who received the medication by IVP had a 2.9% rate of adverse effects requiring rescue medications (n=746). There was no statistical significance in the occurrence of nausea and vomiting requiring rescue medications between the two groups (p>0.80). The total average duration for administration of granisetron and dexamethasone by IVPB was 30 minutes and two minutes by IVP. The average cost of an IVP is $57 as compared to $161 for IVPB based on national average costs.
Conclusions
An average of 28 minutes of chemotherapy chair time is saved on each patient for each session of chemotherapy by administering granisetron and dexamethasone by IVP. Approximately $167,000 would have been saved if the above IVPB group received medications by IVP. This sum excludes nursing costs, chemotherapy chair costs and other disposable charges. The route of administration of the medications did not affect the rate of occurrence of adverse effects requiring rescue medications. The utilization of the intravenous push route will save the patient time and reduce nursing hours without compromising on the effectiveness of the drugs while adding to sizeable cost savings.

Disclosures
No relevant conflicts of interest to declare.
Molecular Diagnosis of Hereditary Spherocytosis By Multi-Gene Target Sequencing in Korea
Authors: Choi Qute , Kim Jung Ah , Im Kyong Ok , Park Si Nae , Park Yoomi , Kim Ju Han , Jung Hye Lim , Kim Seon Young , Shin Hee Young , Lee Dong Soon 
Published: October 2019

Abstract
Background: Hereditary spherocytosis (HS) is the most common cause of hereditary hemolytic anemia. Spherocytes formed by defective membrane proteins are selectively captured in the spleen and destroyed, leading to hemolytic anemia. Current tests used to diagnose HS focus on the detection of hemolysis or indirectly assess protein defects. Direct methods to detect protein defects are complicated and difficult to implement. Recent next-generation sequencing (NGS) methods enable large-scale gene mutation analyses to be used for such diagnoses. In this study, we investigated the patterns of genetic variation associated with HS to determine the molecular mechanisms underlying the condition. Specifically, we analyzed mutations in red blood cell membrane protein-encoding genes in Korean HS patients using NGS.
Methods: In total, 60 patients with HS were enrolled in this study. Targeted sequencing of 43 genes (17 membrane protein-encoding genes, 20 enzyme-encoding genes, and 6 additional candidate genes) was performed using the Illumina HiSeq platform and variants were called according to a data-processing pipeline.
Results: Of the 60 patients, 50 (83%) had one or more significant variants in a membrane protein gene. A total of 54 significant variants (8 previously reported and 46 novel) were detected in 6 membrane protein-encoding genes, i.e., SPTB, ANK1, SPTA1, SLC4A1, EPB41, and EPB42. The most variants (28) were detected in SPTB. Four significant variants, all of which were previously reported, were detected in genes encoding enzymes (ALDOB, G6PD, GAPDH, and GSR). Additionally, 5 previously reported variants were detected in UGT1A1. These results suggest 35 primer sets that can be used to diagnose HS.
Conclusion: This was the first large-scaled genetic study of Korean HS patients. These results clarify the pattern of genetic variation associated with HS in Korean patients. They will enable easier, more rapid diagnosis of HS.

Disclosures
No relevant conflicts of interest to declare.
Gene Editing with Crispr-Cas9 for Treating Beta-Hemoglobinopathies
Authors: Lee Ciaran , Bao Gang , Porteus Matthew H. , Cornu Tatjana , Miccio Annarita , Cradick Thomas , Cathomen Toni , Lundberg Ante , Mavilio Fulvio 
Published: October 2019

Abstract
CRISPR/Cas9 systems provide a powerful tool for precision genome editing due to their highly efficient targeting of specific DNA sequences in a genome. We have designed CRISPR single-guide RNAs (sgRNAs) containing the guide and tracr RNAs to selectively edit the human globin locus for potential therapeutic benefit in treating sickle cell anemia and beta-thalassemia. Multiple sgRNAs have been identified and tested across key sites in the human globin locus, and the gene modification frequencies quantified in 293T, K562 and CD34+ hematopoietic progenitor cells. The nuclease cutting efficiency was determined by the rate of insertions, deletions or mutations (indels) from NHEJ-directed repair. The indel rates for these sgRNAs ranged from <1% to ~70%. We found that there was only a weak correlation between indel rates and deletion frequencies, and the gene modification efficiency varied between cell lines/cell types. Although bioinformatics tools are available for sgRNA design, determining the optimal sgRNAs is still largely empiric and system-dependent, thus better bioinformatics tools are needed. Our results demonstrate that, with careful design and optimization of sgRNAs, efficient genome editing can be achieved with high specificity, which promises effective treatment of beta-hemoglobinopathies.

Disclosures
Porteus: CRISPR Therapeutics: Consultancy, Equity Ownership. Cornu:CRISPR Therapeutics: Research Funding. Miccio:CRISPR Therapeutics: Research Funding. Cradick:CRISPR Therapeutics: Employment. Cathomen:CRISPR Therapeutics: Consultancy, Research Funding. Lundberg:CRISPR Therapeutics: Employment. Mavilio:CRISPR Therapeutics: Consultancy, Research Funding.
Successful Therapy of a Patient with a Novel STAT1 Gain of Function Mutation and Life-Threatening Cytopenias with Janus Kinase Inhibitor Ruxolitinib
Authors: Weinacht Katja G. , Charbonnier Louis m , Plant Ashley , Torgerson Troy , Rosenzweig Sergei , Fleisher Thomas , Notarangelo Luigi Daniele 
Published: October 2019

Abstract
Monoallelic gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity. The immunodeficiency is caused by impaired IL-17 immunity and typically presents with chronic mucocutaneous candidiasis, variably associated with other opportunistic infections. The autoimmune manifestations due to exaggerated responsiveness to interferon are more diverse and include SLE, thyroiditis, hepatitis, and alopecia areata. The phenotypic spectrum of STAT1 GOF mutations is extremely wide, ranging from intermittent localized disease to chronic systemic illness and fatality. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor, leaving a void for alternate long-term strategies to control the disease and maintain remission. Recently, we diagnosed a patient suffering from chronic mucocutaneous candidiasis and life-threatening autoimmune cytopenias with a novel monoallelic mutation in the linker domain of STAT1 (c.1633G>A; p.E545K). The mutation caused a profound increase in STAT1 phosphorylation in response to type 1 and 2 interferon without affecting dephosphorylation kinetics, which is mechanistically distinct from all reported STAT1 GOF mutations to date. The potential of naïve patient CD4+ T cells to become IFN- γ or IL-17 producing cells was investigated under TH0 (anti-CD3/28), TH1 (anti-CD3/28, IL-12) and TH17 (anti-CD3/28, IL6, IL-23, TGF-β1) conditions and revealed that patient CD4+ T cells are biased to produce IFN-γ irrespective of polarizing conditions, and resistant to TH17 induction upon stimulation with IL6, IL-23 and TGF-β1. In addition, the patient's proportion of T follicular helper cells (TFH) relative to regulatory T cells (Treg) was increased. Treatment with the Janus Kinase (JAK) 1/2 inhibitor Ruxolitinib reduced the hyperresponsiveness to interferon, normalized the TH1 response, enabled naïve T cells to differentiate into TH17 cells and decreased the TFH to Treg ratio. Under therapeutic dose Ruxolitinib the patient maintained clinical remission with respect to both autoimmunity and mucocutaneous candidiasis.
Conclusion: Clinical vigilance for an underlying immune dysregulation syndrome due to abnormal JAK-STAT signaling is critical when evaluating patients with autoimmunity combined with opportunistic infections as JAK-inhibitors represents an effective targeted therapy for long-term disease control even in severely affected patients for whom hematopoietic stem cell transplantation is not available.

Disclosures
Off Label Use: Ruxolitinib use for STAT1 GOF mutation.
Standardized Ultrasonography (HEAD-US) of Joints and First Correlation with Function in Haemophilic Arthropathy: Results of a Clinical Trial and Potential Importance of Joint-Ultrasound for an Individualized Prophylaxis in Haemophiliacs
Authors: Sigl-Kraetzig Michael , Bauerfeindt Stefan , Wildner Amanda , Seuser Axel 
Published: October 2019

Abstract
Background: Sonography is applied in patients with bleeding disorders. By ultrasonography the extent of synovitis is detected as a sign of the activity of an existing hemophilic arthropathy, as a sign of progression are defects of articular cartilage and bony structures quantifiable. In 2013 an easy-to-use standardized ultrasound protocol (HEAD-US) for examination of early joint changes in Hemophilic Arthropathy was published. Correlation between functional and structural changes in Haemophilic Arthropathy was not published before.
Aims: The sonographic quantification of the arthropathy by haemophilia-treaters could be the basis for better individualized haemophilia therapy in young patients.
Methods: For this purpose, highly reproducible sonographic standard section planes and an examiner-independent ultrasound score (HEAD -US) were published by C. Martinoli in 2013. After a preliminary study of 27 patients now we have included 177 young german patients (children and young adults) with haemophilia A, haemophilia B or von-Willebrand- disease from different German hemophilia treatment centers in the HaemarthroSonoPilot study (DRKS00004483).
After informed consent sonography of the elbow, knee and ankle joints with a Zonare " z.one ultra " ultrasound device (Linear probe L14 -5w ) was performed. Simultaneously an orthopedic clinical examination with clinical scoring and 3D motion analysis of the lower limbs for detecting early function defects were performed with an ultrasonic topometer (developed by the University of Bonn, Germany).
Results: Already in the previous investigation of the pilot study on a small cohort yielded promising results depending on age. The investigations in the presented pilot study showed correlation of the sonographic diagnostics with the measurement of a clinical orthopedic examination in haemophilic arthropathy. Through the joint sonography changes were even partially already seen before that stood out in the clinical investigation.
Conclusion: It may be useful if haemophilia treaters in future apply this method to individualize the therapy under close control and evaluation of joint changes.

Disclosures
Sigl-Kraetzig: Pfizer Deutschland GmbH: Research Funding. Bauerfeindt:Pfizer Deutschland GmbH: Honoraria, Research Funding. Seuser:BAXALTA Deutschland GmbH: Honoraria, Research Funding.
Molecular Basis for Distinct, Antagonistic, Regulatory Functions of Ribosomal Protein Paralogs Rpl22 and Rpl22-Like1 (Like1) in Hematopoiesis
Authors: Wang Minshi , Zhang Yong , Rao Shuyun , Rhodes Jennifer , Rhodes Michele 
Published: October 2019

Abstract
The prevailing view of ribosomal proteins (RP) is that they act to facilitate the core function of the ribosome in synthesizing proteins. However, emerging evidence suggests that some RP perform regulatory functions outside of the context of the ribosome ("extra-ribosomally"). Indeed, our laboratory demonstrated that ribosomal protein, Rpl22 and its paralog Rpl22l1 (Like1), are dispensable for ribosome assembly and translation, yet they perform critical regulatory functions in hematopoiesis that are mediated by binding selected RNA targets and controlling their translation. Despite their high degree of homology, Rpl22 and Like1 antagonistically control the emergence of hematopoietic stem cells (HSC) by regulating the translation of the key transcription factor, Smad1, with Rpl22 repressing its translation and Like1 acting to oppose that translation. Here, we seek to establish the molecular basis for how such highly homologous proteins perform distinct and opposing functions. Since both Rpl22 and Like1 share highly conserved RNA-binding domains in the central core of the proteins, we hypothesize that their unique regulatory functions are likely to reside in their termini. To systematically test this hypothesis, we employed a domain-swapping approach, creating a series of Rpl22:Like1 chimeric proteins to assess which changes would confer on Like1, the Rpl22 function of blocking HSC emergence. In doing so, we utilized zebrafish as a model organism. During embryonic zebrafish development, the enforced expression of Rpl22, but not Like1, represses Smad1 expression and blocks HSC) emergence. Interestingly, our analysis of the Rpl22:Like1 chimeras revealed that transfer of the N-terminal amino acids of Rpl22 to Like1 was sufficient to confer upon Like1 the Rpl22 function of blocking HSC emergence. Moreover, this Rpl22:Like1 N-terminal chimera also was able to restore the block in T lymphocyte development observed upon loss of Rpl22, indicating that Rpl22 function in another hematopoietic process, supporting T lymphocyte development, can be conferred upon Like1 by the N-terminal sequences of Rpl22. Together, these data suggest that the unique and opposing functions of Rpl22 and Like1 reside in their N-termini. How these newly identified N-terminal amino acid sequences confer distinct biological functions on these two paralogs is unclear at present, but may involve the association with distinct co-factors. This possibility is currently under investigation. This study demonstrates that relative minor changes in amino acid sequence can have profound effects on the functions of these RP paralogs, enabling them to play divergent regulatory roles in controlling hematopoiesis.

Disclosures
No relevant conflicts of interest to declare.
A Tailor-Made Protein Synthesis Program Drives Erythroid Development and Disease
Authors: Forester Craig M , Shi Zhen , Barna Maria , Ruggero Davide 
Published: October 2019

Abstract
Erythropoiesis constitutes the largest demand on the hematopoietic system due to its extraordinary production on a daily basis. The erythroid proteome requires an integration of multiple external cues to coordinate programs of differentiation as well as maintenance of erythroid precursors. The biomedical relevance of this critical process is underscored by recent findings showing impaired ribosome function in an entire class of clinical disorders with severe impairments in erythroid differentiation, known as ribosomopathies, which remain poorly understood. One of the main signaling pathways controlling post-transcriptional gene expression during erythropoiesis is the mTOR pathway. mTOR activation downstream of SCF/Epo in erythroid progenitors controls the activity of the major cap-binding protein eIF4E. However, the functional role of eIF4E during erythropoiesis and protein synthesis control in this cell type remains unexplored. Here we show that eIF4E activity, through mTOR-dependent phosphorylation of its inhibitory protein 4EBP1, unexpectedly undergoes a dynamic switch between early erythroid precursor populations and during terminal erythrocyte maturation, where eIF4E becomes progressively silenced. Employing a unique eIF4E transgenic mouse model, we strikingly show that overexpression of eIF4E in the bone marrow compartment results in an early accumulation of erythrocyte precursors and a block in erythrocyte differentiation. Surprisingly, this new role of eIF4E in erythropoiesis is independent from control of global protein synthesis but instead may promote a specialized program of translation control that is customized for erythroid cell function. Employing state of the art unbiased proteomics, our work is uncovering distinct networks of proteins, whose expression levels are controlled by eIF4E dosage during specific phases of erythrocyte maturation. Together, our research highlights a novel molecular program linking exquisite regulation of eIF4E activity to specialized translational control underlying erythroid development, providing unprecedented insight into the etiology of erythroid dysfunction in ribosomopathies.

Disclosures
No relevant conflicts of interest to declare.