bluuebunny/crossref_metadata_2025 huggingface dataset:
Opportunities From the Digital Revolution
Authors: Corti Louise , Fielding Nigel
Published: December 2016

In the 1990s, the term “online” research emerged as a new and vibrant suite of methods, focused on exploitation of sources not collected by traditional social science methods. Today, at least one part of the research life cycle is likely to be carried out “online,” from data collection through to publishing. In this article, we seek to understand emergent modes of doing and reporting qualitative research “online.” With a greater freedom now to term oneself a “researcher,” what opportunities and problems do working with online data sources bring? We explore implications of emerging requirements to submit supporting data for social science journal articles and question whether these demands might disrupt the very nature of and identity of qualitative research. Finally, we examine more recent forms of publishing and communicating research that support outputs where data play an integral role in elucidating context and enhancing the reading experience.
New Perspectives From Unstructured Interviews
Authors: Sutcliffe-Braithwaite Florence
Published: December 2016

In the early 1980s, Ray Pahl, a sociologist at the University of Kent, and PhD student Claire Wallace conducted interviews examining young people’s experiences of growing up, work, and unemployment on the Isle of Sheppey; these interviews are now deposited at the University of Essex, and this article examines how historians and others might reuse them to interrogate other subjects. The article examines one working-class young woman’s ideas about gender and sexuality in the early 1980s, using the Listening Guide method developed by psychologist Carol Gilligan to probe the individual subjectivity and emotion, as well as the cultural discourses at play in this interview. The interviewee was a young woman who was involved in a culture of casual sex with men “on the ships,” and the article focuses on how she saw the exchanges of money, drink, and gifts between them and herself, and how she avoided seeing her actions as “prostitution.” The analysis shows how in a particular locality in the early 1980s, a particular subculture could allow some young women to sidestep the dominant codes governing young, working-class women’s sexuality and go “on the ships” without seeing this as marking them as “prostitutes”’ or any related category. Thus, the article troubles the ontology of “prostitution” as a category. It also suggests how we can use a single individual’s narrative to offer a broader account of cultures or subcultures, by starting with the individual and examining how one subjectivity navigated and interacted with broader cultural discourses. Finally, this article also offers suggestions about some of the methodological and ethical issues with reusing archived sociological data but argues that it holds rich possibilities.
Conservative Treatment of Chronic Subdural Hematoma in HIV-Associated Thrombocytopenia with Tranexamic Acid
Authors: Kutty Raja K. , Peethambaran Anil Kumar , Sunilkumar  , Anilkumar M.
Published: December 2016

Chronic subdural hematomas (CSDHs) and its management comprise a majority work in a neurosurgical specialty. The effectiveness of surgery is beyond doubt and sometimes even lifesaving in severe cases. However, the straightforward surgery is sometimes complicated by the associated comorbidities of the patient. Comorbidities in the form of coagulopathies secondary to chronic liver diseases, drugs (warfarin, ecosprin, clopidogrel), thrombocytopenia secondary to systemic illness are always a challenge to deal with in patients with CSDH. The authors encountered a patient with thrombocytopenia secondary to systemic HIV infection who presented with CSDH. Her coagulation profile was severe enough to preclude surgery. She was managed conservatively with tranexamic acid and responded well. The authors present the challenges they faced in the course of successful management of this patient.
Acute promyelocytic leukemia: preventing early complications and late toxicities
Authors: Abedin Sameem , Altman Jessica K.
Published: December 2016

Acute promyelocytic leukemia (APL) is a unique subtype of acute myeloid leukemia (AML), which presents with a distinct coagulopathy. Therapeutic advances have made APL one of the true success stories in oncology, transforming this once lethal disease into the most curable form of AML. For many patients, cure will now be achieved without the use of chemotherapy. It is hoped that limiting chemotherapy will reduce mortality even further, particularly among more vulnerable older adults whose survival lagged behind that of younger patients. It should be noted that early death persists in patients with APL and continues to negatively affect survival. Further, among survivors treated with chemotherapy or even arsenic trioxide (ATO), there remains the potential for long-term toxicities that must be monitored. Understanding the management of these issues is an important complement to ensure maximal survival for patients with APL.
Prognostication of chronic lymphocytic leukemia in the era of new agents
Authors: Eichhorst Barbara , Hallek Michael
Published: December 2016

The prognosis of chronic lymphocytic leukemia (CLL) is very heterogeneous. Therefore, a plethora of prognostic factors has been identified to allow a better prediction of the individual prognosis of a given patient. The clinical staging systems by Rai and Binet have been the backbone of clinical management for several decades. The advent of genetic and biochemical markers, as well as next-generation sequencing has provided several markers that can predict the prognosis of patients with CLL. Using this knowledge, several scores have been created to improve predicting overall survival and/or treatment-free survival. These prognostic scores were developed in the era of chemotherpay/chemoimmunotherapy. Therefore, they now need to be tested with novel agents. However, despite tremendously improved therapeutic options, CLL patients with TP53 dysfunction or a complex karyotype remain at very high risk and seem to have a shorter (treatment-free) survival. The recently published international prognostic index (CLL IPI) incorporates most of these factors and provides a tool to analyze outcome in the modern era of targeted therapies.
Treatment of blastic plasmacytoid dendritic cell neoplasm
Authors: Sullivan Jill M. , Rizzieri David A.
Published: December 2016

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare myeloid malignancy with no defined standard of care. BPDCN presents most commonly with skin lesions with or without extramedullary organ involvement before leukemic dissemination. As a result of its clinical ambiguity, differentiating BPDCN from benign skin lesions or those of acute myeloid leukemia with leukemia cutis is challenging. BPDCN is most easily defined by the phenotype CD4+CD56+CD123+lineage–MPO–, although many patients will present with variable expression of CD4, CD56, or alternate plasmacytoid markers, which compounds the difficulty in differentiating BPDCN from other myeloid or lymphoid malignancies. Chromosomal aberrations are frequent, and the mutational landscape of BPDCN is being rapidly characterized although no obvious molecular target for chemoimmunotherapy has been identified. Chemotherapy regimens developed for acute myeloid leukemia, acute lymphoid leukemia, and myelodysplastic syndrome have all been used to treat BPDCN. Relapse is frequent, and overall survival is quite poor. Allogeneic transplantation offers a chance at prolonged remission and possible cure for those who are eligible; unfortunately, relapse remains high ranging from 30% to 40%. Novel therapies such as SL-401, a diphtheria toxin conjugated to interleukin-3 (IL-3) is commonly overexpressed in BPDCN and other aggressive myeloid malignancies and has shown considerable promise in ongoing clinical trials. Future work with SL-401 will define its place in treating relapsed or refractory disease as well as its role as a first-line therapy or bridge to transplantation.
The value of quality of life assessment in chronic myeloid leukemia patients receiving tyrosine kinase inhibitors
Authors: Efficace Fabio , Cannella Laura
Published: December 2016

The development of the oral tyrosine kinase inhibitors (TKIs) to treat chronic myeloid leukemia (CML) is one of the great triumphs of cancer research. Although the efficacy of TKIs has dramatically improved the disease-specific overall survival rate, the prevalence of CML is increasing worldwide. Currently, CML patients receive prolonged (even lifelong) treatment, and over the last decade, clinical decision making has become challenging. Therefore, consideration of the effects of TKI therapies on patients’ quality of life (QoL) and symptom burden (ie, patient-reported outcomes [PROs]) is now critical to more robustly inform patient care and improve health care quality. Over the last 5 years, a number of studies have generated valuable PRO data, for example, on long-term QoL effects of imatinib therapy or symptom burden of patients switching from imatinib to second-generation TKIs. PRO findings are important, as they provide a unique patient perspective on the burden of the disease and treatments effects. We will review main evidence-based data on the use of PROs in clinical research and highlight the importance of methodological rigor of PRO assessment. Also, we will describe the potential value of using PRO assessment in routine clinical practice, for example, to facilitate timely management of side effects. Areas for future research will also be discussed.
Thrombosis in the setting of obesity or inflammatory bowel disease
Authors: Lentz Steven R.
Published: December 2016

Obesity and inflammatory bowel disease (IBD) are systemic inflammatory disorders that predispose to arterial and venous thrombosis through similar prothrombotic mechanisms. Obesity and IBD are chronic risk factors that lead to a persistently elevated risk of thrombosis, although the thrombotic risk with IBD appears to wax and wane with disease severity. Because of the lack of high-quality evidence to guide management decisions, approaches to the prevention and treatment of thrombosis in patients with obesity or IBD are based on extrapolation from general guidelines for antithrombotic therapy. Obesity alters the pharmacokinetics of some anticoagulant drugs, and IBD patients present the added management challenge of having a high risk of gastrointestinal bleeding while taking anticoagulants. An extended duration of anticoagulant therapy is often recommended for obese or IBD patients with unprovoked venous thromboembolism unless there is a high risk of bleeding, although more data and better biomarkers are needed to determine whether anticoagulation can be safely stopped in a subset of IBD patients during remission of active disease. Most patients with obesity or IBD require thromboprophylaxis in conjunction with hospitalization or surgery, with adjustment of anticoagulant dosing in patients with severe obesity.
Therapy-related myeloid neoplasms: does knowing the origin help to guide treatment?
Authors: Heuser Michael
Published: December 2016

Therapy-related myeloid neoplasms (t-MN) combine t-MDS and therapy related acute myeloid leukemia (t-AML) patients in one entity because of their similar pathogenesis, rapid progression from t-MDS to t-AML, and their equally poor prognosis. Treatment with epipodophyllotoxins like etoposide has been associated with a short interval between treatment and development of t-AML, with fusion oncogenes like KMT2A/MLL-MLLT3 and a better prognosis. In contrast, treatment with alkylating agents has been associated with a longer latency, an initial MDS phase, adverse cytogenetics, and a poor prognosis. The pathogenesis of t-MN can be explained by direct induction of an oncogene through chromosomal translocations, induction of genetic instability, or selection of a preexisting treatment-resistant hematopoietic stem cell clone. Recent evidence has highlighted the importance of the last mechanism and explains the high frequency of TP53 mutations in patients with t-MN. After previous cytotoxic therapy, patients present with specific vulnerabilities, especially evident from the high nonrelapse mortality in patients with t-MN after allogeneic hematopoietic cell transplantation. Here, the prognostic impact of currently known risk factors and the therapeutic options in different patient subgroups will be discussed.
Platelets in liver and renal disease
Authors: Lambert Michele P.
Published: December 2016

This review will discuss how 2 common and morbid conditions, renal disease and liver disease, alter platelet number and function. It will review the impact of thrombocytopenia on bleeding complications in patients with these disorders and whether the low platelet count actually correlates with bleeding risk. Emerging data also suggest that platelets are much more than bystanders in both renal and liver disease, but instead play an active role in the pathobiology of these disorders. This review will briefly cover the emerging information on novel roles of platelets in the biology of renal and liver disease.
Response-adapted frontline therapy for Hodgkin lymphoma: are we there yet?
Authors: Johnson Peter W. M.
Published: December 2016

Treating Hodgkin lymphoma by using chemotherapy with or without radiotherapy is highly successful, with substantially fewer deaths from lymphoma than from other causes in recent studies of both early-stage and advanced-stage disease. Long-term toxicity is a major consideration in this context, and recent trials have used functional imaging with [18F]fluorodeoxyglucose (FDG) positron emission tomography early in the course of treatment (interim PET) to assess response and modulate subsequent therapy. In early-stage disease, this has allowed omission of consolidation radiotherapy after a good response to doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy, and trials have shown that this can be done without detriment to overall survival, despite a small increase in rates of recurrence of ∼5%. Conversely, escalation to more intensive chemotherapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) for those with positive interim PET scans seems to be an effective strategy with improved disease control. In advanced-stage disease, several groups have elected to start treatment with ABVD and escalate to BEACOPP or myeloablative therapy for patients who remain PET positive after 2 cycles, which gives rates of disease control of ∼65%. De-escalation by omission of bleomycin and consolidation radiotherapy after a negative interim PET scan seems safe with no increase in recurrence rate, but the performance of interim PET after ABVD is suboptimal, especially for those with very advanced disease at presentation; recurrence rates after a negative scan are ∼15%. The negative predictive value of PET is higher after escalated BEACOPP chemotherapy, and the approach of initially treating with BEACOPP and de-escalating to ABVD for those with negative interim PET scans shows promising early results. Response-adapted therapy has yielded important results for patients with Hodgkin lymphoma and is becoming established as a standard approach.
Fitness in the elderly: how to make decisions regarding acute myeloid leukemia induction
Authors: Rao Arati V.
Published: December 2016

Acute myeloid leukemia (AML) is a disease of the elderly, but less than half of these patients are offered therapy despite the evidence of better survival with treatment in this patient population. Assessing fit, vulnerable, and frail older adults with AML remains a challenge for the treating oncologist. A majority of AML patients are elderly and often have significant comorbidities, lack of social support, and older caregivers. Performance status (PS), a subjective measure of how a patient will tolerate cancer chemotherapy, has been strongly correlated with mortality in older AML patients. However, a large portion of older adults have poor PS as a result of their underlying AML, and these patients may end up being undertreated. Conversely, some patients with excellent PS unexpectedly end up with excessive toxicity and mortality. The treating physician thus needs a more objective and comprehensive method to differentiate patients along the fit-frail spectrum irrespective of their chronological age. For more than a decade, comprehensive geriatric assessment has been shown to improve routine oncology assessment by adding information about the functional, emotional, cognitive, and social status of older patients with cancer. In addition to the chronological and functional age, there is an attempt to quantify a patient’s biological age to aid in better decision making. This chapter attempts to review the clinical challenges of AML treatment in the elderly population and to highlight the current literature and future research required to be able to assess fitness and maximize therapeutic options in this heterogeneous patient population.
Primary central nervous system lymphoma
Authors: Batchelor Tracy T.
Published: December 2016

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma (NHL) confined to the brain, leptomeninges, eyes, or spinal cord. The majority of PCNSL cases occur in the immunocompetent host, the focus of this review. The prognosis of PCNSL is inferior to that of other NHL subtypes including other organ-specific subtypes of extranodal NHL. The 5- and 10-year survival proportions for PCNSL are 29.3% and 21.6%, respectively. The diagnosis and management of PCNSL differs from that of other primary brain cancers and NHL in other parts of the body.
Walking a tightrope: clinical use of ibrutinib in mantle cell lymphoma in the elderly
Authors: Ruella Marco , Soubeyran Pierre
Published: December 2016

Representative clinical case. A 74-year-old male patient was diagnosed with stage 3 mantle cell lymphoma in 2012. Because he was ineligible for intensive treatment (age, previous myocardial infarction [MI]), he received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemoimmunotherapy for 6 cycles (reaching complete response) and then rituximab maintenance (RM) for 2 years. One year after the end of RM, he relapsed with disseminated disease. He was started on ibrutinib 560 mg/day. Two weeks after the start of ibrutinib, he developed grade 3 diarrhea that required interruption of ibrutinib. Two weeks after the regular dose was restarted (month 3), the patient had repeated bleeding (patient was receiving aspirin for previous MI) and had to stop ibrutinib again. Because the patient was in partial response (PR) with lack of disease-associated symptoms, he was restarted on ibrutinib 280 mg/day with no further adverse events, and he had maintained PR at last follow-up (month 9 on ibrutinib).
Minimal residual disease in mantle cell lymphoma: insights into biology and impact on treatment
Authors: Hoster Eva , Pott Christiane
Published: December 2016

Despite the recent substantial improvement of clinical outcome in mantle cell lymphoma (MCL), resistance to immunochemotherapy and common relapses are challenges for long-term tumor control. The assessment of minimal residual disease (MRD) by real-time quantitative polymerase chain reaction has emerged as a widely feasible and standardized tool for direct assessment of therapy-induced reduction of tumor burden and regrowth after cytotoxic treatment in MCL, with much improved sensitivity compared with conventional staging procedures. Several studies have shown that intensification of initial treatment, which has resulted in improved clinical outcome, is immediately reflected in higher molecular remission rates; they have also shown that high-dose consolidation might not be able to compensate for less intensive induction regimens. Persistence or reappearance of MRD in clinical remission proved to be highly predictive for imminent clinical relapse associated with shorter overall survival. Therefore, the investigation of novel MRD-guided treatment strategies aimed at early eradication of MRD and pre-emptive treatment of molecular relapse seems warranted. Furthermore, the integration of MRD assessment into clinical response criteria could result in a more specific and potentially earlier end point for treatment efficacy. New technical developments such as high-throughput sequencing will further enhance the wide applicability of MRD detection in MCL.
Myeloma: management of the newly diagnosed high-risk patient
Authors: Dispenzieri Angela
Published: December 2016

Although there have been many definitions for high-risk (HR) myeloma, most recent consensus for classifying risk in patients with newly diagnosed multiple myeloma (NMM) comes from the International Myeloma Working Group. This recently published revised International Staging System includes del(17p) or t(4;14) by fluorescence in situ hybridization, β-2 microglobulin, albumin, and lactate dehydrogenase. These elements should be captured in all NMM patients. The optimal treatments for HR myeloma have not been fully worked out; therefore, these patients should be considered for clinical trials. Outside of the trial setting for those patients who are not eligible for autologous stem cell transplantation (ASCT), a regimen with bortezomib, but not thalidomide, should be considered, with a duration of therapy of at least 1 year. The regimen with the best results to date is bortezomib, melphalan, and predisone. A nonthalidomide maintenance could also be considered. In patients who are eligible for ASCT, an induction regimen with bortezomib and an immunomodulatory drug should be administered for 3 to 6 months followed by 2 ASCTs. Finally, a consolidation/maintenance regimen containing at least 1 year of bortezomib should be administered followed by maintenance thereafter. For patient convenience, an oral agent that is not thalidomide could be prescribed as maintenance. Finally, in patients with HR myeloma, allogeneic SCT may be associated with reasonable outcomes, but this too will require further research.
Pure red cell aplasia
Authors: Means Robert T.
Published: December 2016

Pure red cell aplasia (PRCA) is a syndrome defined by a normocytic normochromic anemia with severe reticulocytopenia and marked reduction or absence of erythroid precursors from the bone marrow. Diamond-Blackfan anemia is a congenital form of PRCA. Acquired PRCA may be either a primary disorder or secondary to some other disorder or agent. Primary acquired PRCA is an autoimmune disorder that is frequently antibody-mediated. Myelodysplastic syndromes may also present with the morphologic appearance of PRCA. Secondary acquired PRCA may be associated with collagen vascular/autoimmune disorders such as systemic lupus erythematosus; lymphoproliferative disorders such as chronic lymphocytic leukemia or large granular lymphocyte leukemia; infections, particularly B19 parvovirus; thymoma and other solid tumors; or a variety of other disorders, drugs, or toxic agents. The therapeutic approach to PRCA typically involves immunosuppression, but specific pathogenic subtypes are associated with specific therapeutic approaches. Cyclosporine A, with or without concurrent corticosteroids, appears to be the single most effective immunosuppressive agent.
Cellular and vaccine immunotherapy for multiple myeloma
Authors: Garfall Alfred L. , Stadtmauer Edward A.
Published: December 2016

Allogeneic hematopoietic cell transplantation and donor lymphocyte infusion for multiple myeloma (MM) can induce graft-versus-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented its widespread use. Cellular immunotherapies and vaccines seek to induce more specific, reliable, and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Advances in molecular biology, and basic and applied immunology, have led to promising approaches such as genetically engineered T cells with chimeric antigen receptors and T-cell receptors targeting myeloma-specific epitopes, vaccine primed ex vivo expanded autologous T cells, expanded marrow-infiltrating lymphocytes, and plasma cell/dendritic cell fusion vaccines. The addition of these emerging therapies to immunomodulatory drugs and inhibitors of programmed death-1 T-cell regulatory pathways are poised to improve outcome for our patients with myeloma.
Update from the latest WHO classification of MPNs: a user’s manual
Authors: Passamonti Francesco , Maffioli Margherita
Published: December 2016

The 2016 multiparameter World Health Organization (WHO) classification for Philadelphia-negative myeloproliferative neoplasms (MPNs) integrates clinical features, morphology, and genetic data to diagnose polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The main novelties are: (1) the reduction of the hemoglobin (Hb) level threshold to diagnose PV, now established at 16.5 g/dL for men and 16 g/dL for women (based on the identification of MPN patients with PV-consistent bone marrow [BM] features and a Hb level lower than that established in the 2008 WHO classification for PV); (2) the recognition of prefibrotic/early PMF, distinguishable from ET on the basis of BM morphology, an entity having a higher tendency to develop overt myelofibrosis or acute leukemia, and characterized by inferior survival; (3) the central role of BM morphology in the diagnosis of ET, prefibrotic/early PMF, PMF, and PV with borderline Hb values; megakaryocyte number and morphology (typical in ET, atypical in both PMF forms) accompanied by a new distinction of reticulin fibrosis grade in PMF (grade 1 in prefibrotic/early PMF and grade 2-3 in PMF) constitute diagnostic criteria; and (4) the inclusion of all mutually exclusive MPN driver mutations (JAK2, CALR, and MPL) as major diagnostic criteria in ET and PMF; 10% to 15% of these patients are triple negative, and in these cases the search for an additional clonal marker (eg, mutations in ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, and SF3B1) is warranted.
Mutations in MPNs: prognostic implications, window to biology, and impact on treatment decisions
Authors: Shammo Jamile M. , Stein Brady L.
Published: December 2016

The last decade has witnessed tremendous scientific advances, ushered in by the JAK2 V617F discovery, contributing to enhanced diagnostic capability and understanding of the biology of myeloproliferative neoplasms (MPNs). Discovery of the calreticulin mutations filled a diagnostic gap; more recent work sheds light on its contribution to disease pathogenesis, and prognosis. Recent studies have also identified novel JAK2 and MPL mutations in patients with essential thrombocythemia and myelofibrosis (MF). Especially in MF, the driver mutational profile has prognostic implications, with additive contributions from the acquisition of additional somatic mutations. The hope is that sophisticated molecular profiling will not only aid in prognostication, but also guide selection of therapy for patients with MPNs.
Cytokine release syndrome with novel therapeutics for acute lymphoblastic leukemia
Authors: Frey Noelle V. , Porter David L.
Published: December 2016

T-cell–engaging immunotherapies are exciting new approaches to treat patients with acute lymphoblastic leukemia (ALL). These unique agents, which include blinatumomab, a CD3/CD19 bispecific antibody, and chimeric antigen receptor (CAR) modified T cells targeted to CD19 have shown unprecedented remission rates in the relapsed, refractory ALL setting. Cytokine release syndrome (CRS), resulting from the high magnitude of immune activation by these therapies, is the most significant treatment-related toxicity. CRS manifests with fever and malaise and can progress to life-threatening capillary leak with hypoxia and hypotension. The clinical signs of CRS correlate with T-cell activation and high levels of cytokines, including interleukin 6 (IL-6). Tocilizumab, an anti-IL-6 receptor antagonist, is usually effective in the management of severe CRS induced by CAR T cells and has been adopted by most clinical trial programs. With blinatumomab administration, the goal has been to prevent CRS with corticosteroid premedication, disease cytoreduction, and dose adjustments. Collaborative efforts are underway to harmonize the definition and grading system of CRS to allow for better interpretation of toxicities across trials and allow for informed management algorithms.
Myelodysplastic and myeloproliferative disorders of childhood
Authors: Hasle Henrik
Published: December 2016

Myelodysplastic syndrome (MDS) and myeloproliferative disorders are rare in children; they are divided into low-grade MDS (refractory cytopenia of childhood [RCC]), advanced MDS (refractory anemia with excess blasts in transformation), and juvenile myelomonocytic leukemia (JMML), each with different characteristics and management strategies. Underlying genetic predisposition is recognized in an increasing number of patients. Germ line GATA2 mutation is found in 70% of adolescents with MDS and monosomy 7. It is challenging to distinguish RCC from aplastic anemia, inherited bone marrow failure, and reactive conditions. RCC is often hypoplastic and may respond to immunosuppressive therapy. In case of immunosuppressive therapy failure, hypercellular RCC, or RCC with monosomy 7, hematopoietic stem cell transplantation (HSCT) using reduced-intensity conditioning regimens is indicated. Almost all patients with refractory anemia with excess blasts are candidates for HSCT; children age 12 years or older have a higher risk of treatment-related death, and the conditioning regimens should be adjusted accordingly. Unraveling the genetics of JMML has demonstrated that JMML in patients with germ line PTPN11 and CBL mutations often regresses spontaneously, and therapy is seldom indicated. Conversely, patients with JMML and neurofibromatosis type 1, somatic PTPN11, KRAS, and most of those with NRAS mutations have a rapidly progressive disease, and early HSCT is indicated. The risk of relapse after HSCT is high, and prophylaxis for graft-versus-host disease and monitoring should be adapted to this risk.
Reversal of direct oral anticoagulants: a practical approach
Authors: Shih Andrew W. , Crowther Mark A.
Published: December 2016

Direct oral anticoagulants (DOACs) have at least noninferior efficacy compared with other oral anticoagulants and have ancillary benefits, including overall better safety profiles, lack of the need for routine monitoring, rapid onset of action, and ease of administration. Reversal of these agents may be indicated in certain situations such as severe bleeding and for perioperative management. DOAC-associated bleeding should be risk stratified: patients with moderate or severe bleeding should have the DOAC discontinued and reversal strategies should be considered. Laboratory testing has limited utility in the acute management of bleeding; thrombin time and activated partial thromboplastin time may be useful for excluding clinically relevant levels of dabigatran. Prothrombin time is potentially useful for rivaroxaban and edoxaban, but calibrated anti-Xa assays are optimal for determining clinically relevant levels of factor Xa inhibitors. Because specific reversal agents are not widely available, supportive care and interventions for local hemostasis remain the cornerstones of therapy in the patient with DOAC-associated bleeding. Nonspecific reversal agents should be considered only in the event of severe bleeding because their efficacy is unknown, and they are associated with risk of thrombosis. Recent results from phase 3/4 studies demonstrate efficacy for an antidote to dabigatran (idarucizumab, a monoclonal antibody fragment with specificity for dabigatran) and an antidote to factor Xa inhibitors (andexanet alfa, a recombinant and inactive form of factor Xa that binds inhibitors). A universal reversal agent (ciraparantag) for many anticoagulants, including the DOACs, shows promise in results from phase 1 and 2 studies.
New challenges in evaluating anemia in older persons in the era of molecular testing
Authors: Steensma David P.
Published: December 2016

Anemia is common in older persons, and often remains unexplained despite a thorough clinical history, physical examination, and focused laboratory testing, including marrow aspiration, biopsy, and karyotyping. The advent of molecular genetic testing panels in hematology clinical practice has complicated the evaluation of older patients with unexplained anemia. While the presence of a somatic mutation provides evidence of clonal hematopoiesis and may support a diagnosis of a hematologic neoplasm such as one of the myelodysplastic syndromes (MDS), with rare exceptions, individual mutations are not strongly associated with one specific diagnosis, nor are they by themselves diagnostic of neoplasia. A clonal mutation in a patient with cytopenias and a nondiagnostic bone marrow may indicate a syndrome with a similar natural history to MDS, but at present there are no clear criteria to distinguish cytopenias coincidentally seen in association with an unrelated clonal mutation from cytopenias that are directly caused by that mutation. Ongoing and planned analyses will help define when mutation patterns alone can identify a disorder equivalent to a morphologically defined myeloid neoplasm such as MDS, further clarifying the etiology and natural history of unexplained anemia in the elderly.
Warm antibody autoimmune hemolytic anemia
Authors: Kalfa Theodosia A.
Published: December 2016

Autoimmune hemolytic anemia (AIHA) is a rare and heterogeneous disease that affects 1 to 3/100 000 patients per year. AIHA caused by warm autoantibodies (w-AIHA), ie, antibodies that react with their antigens on the red blood cell optimally at 37°C, is the most common type, comprising ∼70% to 80% of all adult cases and ∼50% of pediatric cases. About half of the w-AIHA cases are called primary because no specific etiology can be found, whereas the rest are secondary to other recognizable underlying disorders. This review will focus on the postulated immunopathogenetic mechanisms in idiopathic and secondary w-AIHA and report on the rare cases of direct antiglobulin test–negative AIHA, which are even more likely to be fatal because of inherent characteristics of the causative antibodies, as well as because of delays in diagnosis and initiation of appropriate treatment. Then, the characteristics of w-AIHA associated with genetically defined immune dysregulation disorders and special considerations on its management will be discussed. Finally, the standard treatment options and newer therapeutic approaches for this chronic autoimmune blood disorder will be reviewed.
Second-line therapies in immune thrombocytopenia
Authors: Grace Rachael F. , Neunert Cindy
Published: December 2016

Immune thrombocytopenia (ITP) is a rare, acquired autoimmune condition characterized by a low platelet count and an increased risk of bleeding. Although many children and adults with ITP will not need therapy beyond historic first-line treatments of observation, steroids, intravenous immunoglobulin (IVIG), and anti-D globulin, others will have an indication for second-line treatment. Selecting a second-line therapy depends on the reason for treatment, which can vary from bleeding to implications for health-related quality of life (HRQoL) to likelihood of remission and patient preference with regard to adverse effects, route of administration, and cost. Published studies of these treatments are limited by lack of comparative trials, in addition to inconsistent outcome measures, definitions, and efficacy endpoints. This article provides an up-to-date comparison of the second-line treatments, highlighting important outcome measures including bleeding, HRQoL, fatigue, and platelet counts, which influence treatment selection in a shared decision-making model.
Aplastic anemia and clonal evolution: germ line and somatic genetics
Authors: Shimamura Akiko
Published: December 2016

Clonal progression to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) remains a dreaded complication for a subset of patients with bone marrow failure (BMF). Recognizing risk factors for the development of MDS or AML would inform individualized treatment decisions and identify patients who may benefit from early or upfront hematopoietic stem cell transplantation. Now that next-generation DNA sequencing is available in the clinical laboratory, research has focused on the implications of germ line and somatic mutations for diagnosing and monitoring patients with BMF. Most germ line genetic BMF disorders are characterized by a high propensity to develop MDS or AML. Many affected patients lack the physical stigmata traditionally associated with the inherited marrow failure syndromes. Although any single inherited marrow failure disorder is rare, multiplexed genetic sequencing that allows simultaneous evaluation of marrow failure genes en masse demonstrated that, as a group, these inherited disorders compose a significant subset (5% to 10%) of patients with BMF. Early diagnosis of a germ line genetic marrow failure disorder allows individualized monitoring and tailored therapy. Recent studies of somatic variants in marrow failure revealed a high frequency of clonal hematopoiesis with the acquisition of mutations in genes associated with MDS or AML. Investigation of somatic mutations in marrow failure revealed important insights into the mechanisms promoting clonal disease but also raised additional questions. This review will focus on the evaluation and implications of germ line and somatic mutations for the development of clonal disorders in patients with BMF. Challenges and limitations of clinical genetic testing will be explored.
Team rivalry and lending on crowdfunding platforms: an empirical analysis
Authors: Ge Ling , Luo Xuechen
Published: December 2016

Background

Prosocial crowdfunding helps the underprivileged obtain non-profit seeking loans from multitudinous lenders. Some platforms introduce team competition to motivate member participation and may thus induce team rivalry.

Methods

We investigate how team rivalry affects lending decisions using data from Kiva.org. We argue that a rivalry relationship may engage teams to compete directly against rivals by lending to the same project or prevent them from doing so because they intend not to cooperate.

Result

We find that a team is less likely to lend to a project that has received funding from its rival team, suggesting that rival teams tend to avoid cooperation.

Conclusions

We discuss the implications of our findings for crowdfunding and competition-based motivation mechanisms in general.
Perceived Challenges in Primary Literature in a Master’s Class: Effects of Experience and Instruction
Authors: Lie Richard , Abdullah Christopher , He Wenliang , Tour Ella
Published: December 2016

Primary literature offers rich opportunities to teach students how to “think like a scientist,” but the challenges students face when they attempt to read research articles are not well understood. Here, we present an analysis of what master’s students perceive as the most challenging aspects of engaging with primary literature. We examined 69 pairs of pre- and postcourse responses from students enrolled in a master’s-level course that offered a structured analysis of primary literature. On the basis of these responses, we identified six categories of challenges. Before instruction, “techniques” and “experimental data” were the most frequently identified categories of challenges. The majority of difficulties students perceived in the primary literature corresponded to Bloom’s lower-order cognitive skills. After instruction, “conclusions” were identified as the most difficult aspect of primary literature, and the frequency of challenges that corresponded to higher-order cognitive skills increased significantly among students who reported less experience with primary literature. These changes are consistent with a more competent perception of the primary literature, in which these students increasingly focus on challenges requiring critical thinking. Students’ difficulties identified here can inform the design of instructional approaches aimed to teach students how to critically read scientific papers.
Do We Need to Design Course-Based Undergraduate Research Experiences for Authenticity?
Authors: Rowland Susan , Pedwell Rhianna , Lawrie Gwen , Lovie-Toon Joseph , Hung Yu
Published: December 2016

The recent push for more authentic teaching and learning in science, technology, engineering, and mathematics indicates a shared agreement that undergraduates require greater exposure to professional practices. There is considerable variation, however, in how “authentic” science education is defined. In this paper we present our definition of authenticity as it applies to an “authentic” large-scale undergraduate research experience (ALURE); we also look to the literature and the student voice for alternate perceptions around this concept. A metareview of science education literature confirmed the inconsistency in definitions and application of the notion of authentic science education. An exploration of how authenticity was explained in 604 reflections from ALURE and traditional laboratory students revealed contrasting and surprising notions and experiences of authenticity. We consider the student experience in terms of alignment with 1) the intent of our designed curriculum and 2) the literature definitions of authentic science education. These findings contribute to the conversation surrounding authenticity in science education. They suggest two things: 1) educational experiences can have significant authenticity for the participants, even when there is no purposeful design for authentic practice, and 2) the continuing discussion of and design for authenticity in UREs may be redundant.
Does the Room Matter? Active Learning in Traditional and Enhanced Lecture Spaces
Authors: Stoltzfus Jon R. , Libarkin Julie
Published: December 2016

SCALE-UP–type classrooms, originating with the Student-Centered Active Learning Environment with Upside-down Pedagogies project, are designed to facilitate active learning by maximizing opportunities for interactions between students and embedding technology in the classroom. Positive impacts when active learning replaces lecture are well documented, both in traditional lecture halls and SCALE-UP–type classrooms. However, few studies have carefully analyzed student outcomes when comparable active learning–based instruction takes place in a traditional lecture hall and a SCALE-UP–type classroom. Using a quasi-experimental design, we compared student perceptions and performance between sections of a nonmajors biology course, one taught in a traditional lecture hall and one taught in a SCALE-UP–type classroom. Instruction in both sections followed a flipped model that relied heavily on cooperative learning and was as identical as possible given the infrastructure differences between classrooms. Results showed that students in both sections thought that SCALE-UP infrastructure would enhance performance. However, measures of actual student performance showed no difference between the two sections. We conclude that, while SCALE-UP–type classrooms may facilitate implementation of active learning, it is the active learning and not the SCALE-UP infrastructure that enhances student performance. As a consequence, we suggest that institutions can modify existing classrooms to enhance student engagement without incorporating expensive technology.
Consensus Bundle on Prevention of Surgical Site Infections After Major Gynecologic Surgery
Authors: Pellegrini Joseph E. , Toledo Paloma , Soper David E. , Bradford William C. , Cruz Deborah A. , Levy Barbara S. , Lemieux Lauren A.
Published: December 2016

Surgical site infections are the most common complication of surgery in the United States. Of surgeries in women of reproductive age, hysterectomy is one of the most frequently performed, second only to cesarean birth. Therefore, prevention of surgical site infections in women undergoing gynecologic surgery is an ideal topic for a patient safety bundle. The primary purpose of this safety bundle is to provide recommendations that can be implemented into any surgical environment in an effort to reduce the incidence of surgical site infection. This bundle was developed by a multidisciplinary team convened by the Council on Patient Safety in Women’s Health Care. The bundle is organized into four domains: Readiness, Recognition and Prevention, Response, and Reporting and Systems Learning. In addition to recommendations for practice, each of the domains stresses communication and teamwork between all members of the surgical team. Although the bundle components are designed to be adaptable to work in a variety of clinical settings, standardization within institutions is encouraged.
Phosphorylation of filamin A regulates chemokine receptor CCR2 recycling
Authors: Pons Mònica , Izquierdo Ismael , Andreu-Carbó Mireia , Garrido Georgina , Planagumà Jesús , Muriel Olivia , del Pozo Miguel A. , Geli M. Isabel , Aragay Anna M.
Published: December 2016

Proper endosomal trafficking of ligand-activated G-protein-coupled receptors (GPCRs) is essential to spatiotemporally tune their physiological responses. For the monocyte chemoattractant receptor 2 (CCR2B; one of two isoforms encoded by CCR2), endocytic recycling is important to sustain monocyte migration, whereas filamin A (FLNa) is essential for CCL2-induced monocyte migration. Here, we analyze the role of FLNa in the trafficking of CCR2B along the endocytic pathway. In FLNa-knockdown cells, activated CCR2B accumulated in enlarged EEA-1-positive endosomes, which exhibited slow movement and fast fluorescence recovery, suggesting an imbalance between receptor entry and exit rates. Utilizing super-resolution microscopy, we observed that FLNa–GFP, CCR2B and β2-adrenergic receptor (β2AR) were present in actin-enriched endosomal microdomains. Depletion of FLNa decreased CCR2B association with these microdomains and concomitantly delayed CCR2B endosomal traffic, without apparently affecting the number of microdomains. Interestingly, CCR2B and β2AR signaling induced phosphorylation of FLNa at residue S2152, and this phosphorylation event was contributes to sustain receptor recycling. Thus, our data strongly suggest that CCR2B and β2AR signals to FLNa to stimulate its endocytosis and recycling to the plasma membrane.
On Jordan's and Kober's inequality
Authors: Bhayo Barkat Ali , Sándor József
Published: December 2016

We refine some classical inequalities for trigonometric functions, such as Jordan's inequality, Cusa–Huygens's inequality, and Kober's inequality.
Certain Diophantine equations involving balancing and Lucas-balancing numbers
Authors: Ray Prasanta Kumar
Published: December 2016

It is well known that if x is a balancing number, then the positive square root of 8x2 + 1 is a Lucas-balancing number. Thus, the totality of balancing number x and Lucas-balancing number y are seen to be the positive integral solutions of the Diophantine equation 8x2 +1 = y2. In this article, we consider some Diophantine equations involving balancing and Lucas-balancing numbers and study their solutions.
The Tartu-Moscow School of Semiotics: A transnational perspective
Authors: Pilshchikov Igor , Trunin Mikhail
Published: December 2016

This paper seeks to situate the Tartu-Moscow School of Semiotics of the 1960– 1980s within the larger European intellectual-historical context from which it sprang, and in which it played a vital role. Analysing the school members’ engagement with their peers throughout Europe, we outline an “entangled history” (histoire croisée) of multi-directional scientific and philosophical influence. In this perspective, we discuss the most productive concepts and methods of Tartu-Moscow semiotics in the fields of general verse theory, intertextual theory and cultural theory.