bluuebunny/crossref_metadata_2025_split huggingface dataset:
JMML genomics and decisions
Authors: Niemeyer Charlotte M. 
Published: April 2019

Abstract
Juvenile myelomonocytic leukemia (JMML) is a unique clonal hematopoietic disorder of early childhood characterized by hyperactivation of the RAS signal transduction pathway. Approximately 90% of patients harbor molecular alteration in 1 of 5 genes (PTPN11, NRAS, KRAS, NF1, CBL), which define genetically and clinically distinct JMML subtypes. Three subtypes, PTPN11- , NRAS-, and KRAS-mutated JMML, are characterized by heterozygous somatic gain-of-function mutations in non syndromic children, while two subtypes, JMML in neurofibromatosis type 1 and in JMML in children with CBL syndrome, are characterized by germ line RAS disease and acquired biallelic inactivation of the respective tumor suppressor genes in hematopoietic cells. In addition to the initiating RAS pathway lesion, secondary genetic alterations within and outside of the RAS pathway are detected in about half the patients. Most recently, genome-wide DNA methylation profiles identified distinct methylation signatures correlating with clinical and genetic features and highly predictive of outcome. JMML is a stem cell disorder, and most JMML patients require allogeneic stem cell transplantation for long-term survival. However, spontaneous disease regression is noted in the majority of children with CBL-mutated JMML and in some NRAS-mutated cases. In the absence of 1 of the 5 canonical RAS pathway alteration, rare mutations in other RAS genes and non-JMML myeloproliferative disorders need to be excluded. Understanding the genetic basis of myeloproliferative disorders in early childhood will greatly improve clinical decision making.
Beyond transfusion therapy: new therapies in thalassemia including drugs, alternate donor transplant, and gene therapy
Authors: Porter John 
Published: April 2019

Abstract
Transfusion combined with chelation therapy for severe β thalassemia syndromes (transfusion-dependent thalassemia [TDT]) has been successful in extending life expectancy, decreasing comorbidities and improving quality of life. However, this puts lifelong demands not only on the patients but also on the health care systems that are tasked with delivering long-term treatment and comprehensive support. Prevention programs and curative approaches are therefore an important part of overall strategy. Curative treatments alter the dynamic of a patient's health care costs, from financial commitment over 50 years, into a potential “one-off” investment. Since the 1980s, this has usually been available only to the 30% or so of young children with matched sibling donors. By improving the safety of matched related donors and haploidentical hematopoietic stem cell transplants, the potential size of the donor pool for curative therapies may be increased. Recent advances in gene therapy demonstrate that even patients lacking a matched donor can be rendered transfusion independent with an autograft of genetically modified autologous stem cells, with a low short-term risk. Noncurative treatments are also of potential value by decreasing use of blood and chelators and decreasing hospital visits. An example is luspatercept, an activin-receptor trap that modifies transforming growth factor-β signaling, thereby increasing the efficiency of erythropoiesis. This has entered phase 3 clinical trials for TDT and non-TDT and, usefully increases in both Hb and quality of life in non-TDT as well as decreasing transfusion requirements in TDT. Other novel noncurative treatments are entering clinical trials such improvement of erythropoiesis through pharmacological manipulation of hepcidin and iron metabolism.
Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria
Authors: Merrill Samuel A. , Brodsky Robert A. 
Published: April 2019

Abstract
Atypical hemolytic uremic syndrome (aHUS); hemolysis, elevated liver function tests, and low platelets syndrome; and transplant-associated thrombotic microangiopathy are related conditions, in that many patients harbor germline heterozygous mutations in genes that regulate the alternative pathway of complement (APC). Penetrance is variable because development of clinically significant disease appears to require supervention of a process such as inflammation. Complement activation on the endothelial surfaces leads to endothelial damage, platelet consumption, microthrombi, and a mechanical hemolytic anemia with schistocytes. Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic disease caused by expansion of a stem cell that harbors a somatic mutation in PIGA. PIGA mutant blood cells are deficient in the complement regulator proteins CD55 and CD59, making them susceptible to intravascular hemolysis due to a failure to regulate the APC on erythrocytes. Eculizumab is a monoclonal antibody that binds to C5 and inhibits terminal complement by interfering with the cleavage of C5 by the C5 convertases. The drug is approved by the US Food and Drug Administration for the treatment of aHUS and PNH; however, a new generation of complement inhibitors that block C5 and other components of the complement cascade is showing promise in preclinical and clinical trials.
Autoimmune hemolytic anemia
Authors: Hill Anita , Hill Quentin A. 
Published: April 2019

AbstractThe diagnosis of autoimmune hemolytic anemia (AIHA) can be made with a stepwise approach that aims to identify laboratory and clinical evidence of hemolysis and then determine the immune nature of hemolysis with the direct anti-globulin test. Once alternative causes for these findings have been excluded, AIHA is established, and the clinician must search for secondary causes, as well as identify the type of AIHA. Rituximab is now the preferred second-line treatment for primary warm AIHA and first-line treatment for primary cold agglutinin disease (CAD), either as monotherapy or combined with bendamustine. Complement inhibitors have shown utility in stabilizing AIHA patients with acute severe hemolysis. Future prospects are discussed and include the C1s inhibitor BIVV009 (sutimlimab) that is now entering phase 3 studies for CAD.
Management of thrombosis in children and neonates: practical use of anticoagulants in children
Authors: Monagle Paul , Newall Fiona 
Published: April 2019

AbstractVenous thrombosis (VTE) in children and neonates presents numerous management challenges. Although increasing in frequency, VTE in children and neonates is still uncommon compared with adults. The epidemiology of VTE is vastly different in neonates vs children vs adolescents vs adults. In reality, pediatric thrombosis should be viewed as a multitude of rare diseases (eg, renal vein thrombosis, spontaneous thrombosis, catheter-related thrombosis, cerebral sinovenous thrombosis), all requiring different approaches to diagnosis and with different short- and long-term consequences, but linked by the use of common therapeutic agents. Further, children have fundamentally different physiology in terms of blood flow, developmental hemostasis, and, likely, endothelial function. The American Society ofHematology 2017 Guidelines for Management of Venous Thromboembolism: Treatment of Pediatric VTE provides up-to-date evidence-based guidelines related to treatment. Therefore, this article will focus on the practical use of therapeutic agents in the management of pediatric VTE, especially unfractionated heparin, low-molecular-weight heparin, and oral vitamin K antagonists, as the most common anticoagulants used in children. Direct oral anticoagulants (DOACs) remain in clinical trials in children and should not be used outside of formal trials for the foreseeable future.
Pediatric ITP: is it different from adult ITP?
Authors: Despotovic Jenny M. , Grimes Amanda B. 
Published: April 2019

AbstractImmune thrombocytopenia (ITP) has historically been thought to occur in 2 distinct forms: childhood ITP and adult ITP. This division is based largely on the presumption that childhood ITP is often benign and self-limited, whereas ITP in adults tends to be more chronic and difficult to treat. Although data exist to justify a different approach to the diagnosis and treatment in young children and the elderly, ITP in older children, adolescents, and younger adults is likely to share more similar pathology. This article will highlight the most recent data describing the natural history, diagnostic approach, management strategies, and disease-related outcomes in children and adults with ITP. These data reveal many unexpected similarities between the 2 groups, while confirming some of the more well-described differences. Discussion of these findings aims to highlight similarities and differences between ITP in children and adults, which will underscore important areas of future research and/or changes in management guidelines.
New insights into the pathophysiology and development of novel therapies for sickle cell disease
Authors: Moerdler Scott , Manwani Deepa 
Published: April 2019

Abstract
Although the seminal event in sickle cell disease is the polymerization of abnormal hemoglobin, the downstream pathophysiology of vasoocclusion results from heterotypic interactions between the altered, adhesive sickle cell red blood cells, neutrophils, endothelium, and platelets. Ischemia reperfusion injury, hemolysis, and oxidant damage all contribute to heightened inflammation and activation of the hemostatic system. These various pathways are the focus of emerging treatments with potential to ameliorate disease manifestations. This review summarizes the considerable progress in development of these agents despite challenges in selection of study end points and complex pathophysiology.
TTP: long-term outcomes following recovery
Authors: George James N. 
Published: April 2019

Abstract
Although risk for relapse may be the greatest concern following recovery from acquired, autoimmune thrombotic thrombocytopenic purpura (TTP), there are multiple other major health issues that must be recognized and appropriately addressed. Depression may be the most common disorder following recovery from TTP and may be the most important issue for the patient’s quality of life. Severe or moderate depression has occurred in 44% of Oklahoma Registry patients. Recognition of depression by routine screening evaluations is essential; treatment of depression is effective. Minor cognitive impairment is also common. The recognition that cognitive impairment is related to the preceding TTP can provide substantial emotional support for both the patient and her family. Because TTP commonly occurs in young black women, the frequency of systemic lupus erythematosus, as well as other autoimmune disorders, is increased. Because there is a recognized association of TTP with pregnancy, there is always concern for subsequent pregnancies. In the Oklahoma Registry experience, relapse has occurred in only 2 of 22 pregnancies (2 of 13 women). The frequency of new-onset hypertension is increased. The most striking evidence for the impact of morbidities following recovery from TTP is decreased survival. Among the 77 patients who survived their initial episode of TTP (1995-2017), 16 (21%) have subsequently died, all before their expected age of death (median difference, 22 years; range 4-55 years). The conclusion from these observations is clear. Following recovery from TTP, multiple health problems occur and survival is shortened. Therefore, careful continuing follow-up is essential.
Drug-associated thrombocytopenia
Authors: Bakchoul Tamam , Marini Irene 
Published: April 2019

AbstractMany drugs have been implicated in drug-induced immune thrombocytopenia (DITP). Patients with DITP develop a drop in platelet count 5 to 10 days after drug administration with an increased risk of hemorrhage. The diagnosis of DITP is often challenging, because most hospitalized patients are taking multiple medications and have comorbidities that can also cause thrombocytopenia. Specialized laboratory diagnostic tests have been developed and are helpful to confirm the diagnosis. Treatment of DITP involves discontinuation of the offending drug. The platelet count usually starts to recover after 4 or 5 half-lives of the responsible drug or drug metabolite. High doses of intravenous immunoglobulin can be given to patients with severe thrombocytopenia and bleeding. Although in most cases, DITP is associated with bleeding, life-threatening thromboembolic complications are common in patients with heparin-induced thrombocytopenia (HIT). Binding of antiplatelet factor 4/heparin antibodies to Fc receptors on platelets and monocytes causes intravascular cellular activation, leading to an intensely prothrombotic state in HIT. The clinical symptoms include a decrease in platelet counts by >50% and/or new thromboembolic complications. Two approaches can help to confirm or rule out HIT: assessment of the clinical presentation using scoring systems and in vitro demonstration of antiplatelet factor 4/heparin antibodies. The cornerstone of HIT management is immediate discontinuation of heparin when the disease is suspected and anticoagulation using nonheparin anticoagulant. In this review, we will provide an update on the pathophysiology, diagnosis, and management of both DITP and HIT.
Challenges and implications of genomics for T-cell lymphomas
Authors: Jacobsen Eric D. , Weinstock David M. 
Published: April 2019

Abstract
Treatment outcomes for patients with peripheral T-cell lymphomas (PTCLs) and advanced-stage cutaneous T-cell lymphomas (CTCLs) remain poor. The past few years have witnessed an explosion in our understanding of the genetics of these diverse malignancies. Many subtypes harbor highly recurrent mutations, including single-nucleotide variants, insertions/deletions, and chromosomal rearrangements, that affect T-cell receptor signaling, costimulatory molecules, JAK/STAT and phosphatidylinositol 3-kinase pathways, transcription factors, and epigenetic modifiers. An important subset of these mutations is included within commercially available, multigene panels and, in rare circumstances, indicate therapeutic targets. However, current preclinical and clinical evidence suggests that only a minority of mutations identified in TCLs indicate biologic dependence. With a few exceptions that we highlight, mutations identified in TCLs should not be routinely used to select targeted therapies outside of a clinical trial. Participation in trials and publication of both positive and negative results remain the most important mechanisms for improving patient outcomes.
Visit-to-visit fasting plasma glucose variability is an important risk factor for long-term changes in left cardiac structure and function in patients with type 2 diabetes
Authors: Tang Xixiang , Zhong Junlin , Zhang Hui , Luo Yanting , Liu Xing , Peng Long , Zhang Yanling , Qian Xiaoxian , Jiang Boxiong , Liu Jinlai , Li Suhua , Chen Yanming 
Published: April 2019

Abstract
Background
To investigate the effect of visit-to-visit fasting plasma glucose (FPG) variability on the left cardiac structure and function in patients with type 2 diabetes mellitus (T2DM).

Methods
In this prospective cohort study, 455 T2DM patients were included and follow-up for a median of 4.7 years. FPG measured on every hospital visit was collected. FPG variability was calculated by its coefficient of variation (CV-FPG). Left cardiac structure and function were assessed using echocardiography at baseline and after follow-up. Multivariable linear regression analyses were used to estimate the effect of FPG variability on the annualized changes in left cardiac structure and function. Subgroup analysis stratified by mean HbA1c levels (< 7% and ≥ 7%) were also performed.

Result
In multivariable regression analyses, CV-FPG was independently associated with the annualized changes in left ventricle (β = 0.137; P = 0.031), interventricular septum (β = 0.215; P = 0.001), left ventricular posterior wall thickness (β = 0.129; P = 0.048), left ventricular mass index (β = 0.227; P < 0.001), and left ventricular ejection fraction (β = − 0.132; P = 0.030). After additionally stratified by mean HbA1c levels, CV-FPG was still independently associated with the annualized changes in the above parameters in patients with HbA1c ≥ 7%, while not in patients with HbA1c < 7%.

Conclusions
Visit-to-visit variability in FPG could be a novel risk factor for the long-term adverse changes in left cardiac structure and systolic function in patients with type 2 diabetes.
Trial registration ClinicalTrials.gov (NCT02587741), October 27, 2015, retrospectively registered.
The changing landscape of professional practice in podiatry, lessons to be learned from other professions about the barriers to change – a narrative review
Authors: Harrison‐Blount Michael , Nester Christopher , Williams Anita 
Published: April 2019

AbstractBackgroundThe delivery of healthcare is changing and aligned with this, the podiatry profession continues to change with evidence informed practice and extending roles. As change is now a constant, this gives clinicians the opportunity to take ownership to drive that change forward. In some cases, practitioners and their teams have done so, where others have been reluctant to embrace change. It is not clear to what extent good practice is being shared, whether interventions to bring about change have been successful, or what barriers exist that have prevented change from occurring. The aim of this article is to explore the barriers to changing professional practice and what lessons podiatry can learn from other health care professions.Main bodyA literature search was carried out which informed a narrative review of the findings. Eligible papers had to (1) examine the barriers to change strategies, (2) explore knowledge, attitudes and roles during change interventions, (3) explore how the patients/service users contribute to the change process (4) include studies from predominantly primary care in developed countries.Ninety‐two papers were included in the final review. Four papers included change interventions involving podiatrists. The barriers influencing change were synthesised into three themes (1) the organisational context, (2) the awareness, knowledge and attitudes of the professional, (3) the patient as a service user and consumer.ConclusionsMinimal evidence exists about the barriers to changing professional practice in podiatry. However, there is substantial literature on barriers and implementation strategies aimed at changing professional practices in other health professions. Change in practice is often resisted at an organisational, professional or service user level. The limited literature about change in podiatry, a rapidly changing healthcare workforce and the wide range of contexts that podiatrists work, highlights the need to improve the ways in which podiatrists can share successful attempts to change practice.
HistoQC: An Open-Source Quality Control Tool for Digital Pathology Slides
Authors: Janowczyk Andrew , Zuo Ren , Gilmore Hannah , Feldman Michael , Madabhushi Anant 
Published: April 2019

PURPOSE Digital pathology (DP), referring to the digitization of tissue slides, is beginning to change the landscape of clinical diagnostic workflows and has engendered active research within the area of computational pathology. One of the challenges in DP is the presence of artefacts and batch effects, unintentionally introduced during both routine slide preparation (eg, staining, tissue folding) and digitization (eg, blurriness, variations in contrast and hue). Manual review of glass and digital slides is laborious, qualitative, and subject to intra- and inter-reader variability. Therefore, there is a critical need for a reproducible automated approach of precisely localizing artefacts to identify slides that need to be reproduced or regions that should be avoided during computational analysis. METHODS Here we present HistoQC, a tool for rapidly performing quality control to not only identify and delineate artefacts but also discover cohort-level outliers (eg, slides stained darker or lighter than others in the cohort). This open-source tool employs a combination of image metrics (eg, color histograms, brightness, contrast), features (eg, edge detectors), and supervised classifiers (eg, pen detection) to identify artefact-free regions on digitized slides. These regions and metrics are presented to the user via an interactive graphical user interface, facilitating artefact detection through real-time visualization and filtering. These same metrics afford users the opportunity to explicitly define acceptable tolerances for their workflows. RESULTS The output of HistoQC on 450 slides from The Cancer Genome Atlas was reviewed by two pathologists and found to be suitable for computational analysis more than 95% of the time. CONCLUSION These results suggest that HistoQC could provide an automated, quantifiable, quality control process for identifying artefacts and measuring slide quality, in turn helping to improve both the repeatability and robustness of DP workflows.
Successful Implementation of a Multidisciplinary Chemotherapy Efficiency Initiative at a Community Hospital
Authors: Parkes Amanda , Nusrat Maliha , Di Tomasso Pamela Maree , Davis LaToya , Ogbonnaya Sunny , Iwuorie Martina , Patel Shilpa , Abraham Thega Grace , Mack Rita , Bhadkamkar Nishin A. , Ma Hilary , Nazario L. Arlene , Ramondetta Lois , Rosenstock Aron , Rieber Alyssa G. 
Published: April 2019

PURPOSE: Long wait times at chemotherapy infusion centers adversely affect patients’ perception of quality of care and result in patient dissatisfaction. We conducted a quality improvement initiative at a busy community hospital to improve infusion center efficiency and reduce patient wait time, while maintaining patient safety and avoiding chemotherapy waste. METHODS: We used a coordinated and collaborative effort between providers, infusion center nurses, and pharmacists to ensure completion of orders, review of laboratory data, and prepreparation of chemotherapy 1 day ahead of each patient’s scheduled infusion center appointment. Monthly Plan-Do-Study-Act cycles were conducted for 6 months beyond the pilot month to refine and sustain the intervention. RESULTS: The average patient cycle time, measured as time from patient check-in to check-out from the infusion chair, decreased from 252 minutes to 173 minutes in the last 4 months evaluated (30% decrease) after the intervention. Similarly, the average chemotherapy turnaround time, measured as time from chemotherapy request by nursing to pharmacy delivery, improved from 90 minutes to 27 minutes after the intervention (70% decrease). Infusion center capacity was unaffected by the intervention. The cost of wasted chemotherapy was minimal after the first postintervention month. Surveys revealed extremely high patient and employee satisfaction with the new system. CONCLUSION: A strategy involving prepreparation of chemotherapy on the day before the scheduled infusion is feasible to implement at a busy community hospital infusion center and is associated with significant improvement in infusion center efficiency as well as patient and employee satisfaction.