bluuebunny/crossref_metadata_2025 huggingface dataset:
Ensembles of classifiers for improved SAR image recognition using pseudo Zernike moments
Authors: Bolourchi Pouya , Moradi Masoud , Demirel Hasan , Uysal Sener
Published: April 2019

In this paper, a new approach for improving the classification of different kinds of ground vehicles from moving stationary target acquisition and recognition images is proposed. Pseudo Zernike moments are used for feature extraction due to its capability of being scale, rotation, and translation invariant. To benefit from the diversities of regions we utilize both target and shadow regions as separate regions of interest for vehicle representation. Region of interests in the form of “area,”“boundary,” and “texture” are used for extraction. Extracted features from target and shadow regions of area, boundary, and texture are fused and fed to different classifiers. Five classifiers with different properties are adopted, including support vector machine, which is a parametric classifier that can control overfitting, in contrast to the decision tree, which is a nonparametric classifier, linear discriminant analysis, and k-nearest neighbor, which have cheaper computational cost, and random forest, which is an appropriate classifier for estimating outlier and missing data. In order to improve the overall performance of target recognition, we proposed a novel approach in which first we define six regions and fuse them to a single vector. Then fused feature vectors are fed to classifiers and the final decision is generated using majority voting. Experimental results justify that by combining decision with majority voting the performance is improved.
The Presence of Female Designers in French Video Game Industry, 1985–1993
Authors: Jankowski Filip
Published: April 2019

Increasingly, more people do notice that female designers wrote their first games in the 1970s and 1980s. However, there was another country where women did also design games decades before the #GamerGate movement. This article examines the selected works of three French designers: Clotilde Marion, Chine Lanzmann, and Muriel Tramis. The analysis of those games took into account the self-representation of those designers—and women in general—within the game content. The conducted research has proven that within their games, Marion, Lanzmann, and Tramis included their everyday experiences as women. Using such techniques as simulated point of view and authorial signature, those women indicated their own role in the development and showed how females in general face male oppression against them. This means that the United States is not the only country with a long tradition of female game developers. Thus, video game history remains an undiscovered research field.
The constraint-stabilized implicit methods on Lie group for differential-algebraic equations of multibody system dynamics
Authors: Ding Jieyu , Pan Zhenkuan , Zhang Wei
Published: April 2019

The implicit methods on Lie group are developed for multibody system dynamics. To avoid the violation of the displacement, velocity and acceleration constraints of the nonlinear differential-algebraic equations, the constraint-stabilized equations on Lie group are formulated. The implicit method for the Euler–Lagrange equations and the symplectic Euler method for the constrained Hamilton equations are presented. These methods can keep the stability of the displacement, velocity and acceleration constraints at the same time during the longer simulation. A three-dimensional single pendulum and a three-dimensional double pendulum are used to verify the accuracy of the constraint-stabilized Euler methods on Lie group and the orthogonality preservation of the rotation matrix.
Assessing nurses’ informatics competency and identifying its related factors
Authors: Khezri Hero , Abdekhoda Mohammadhiwa
Published: April 2019

Background

Due to the increasing use of informatics as an infrastructure in developing the quality of care and patient safety, informatics competency has become a crucial requirement for nurses.

Aim

This study was conducted to assess nursing informatics competency, and identify related factors in registered nurses.

Method

This research is an analytical descriptive study in which the research community included 205 nurses working at Tabriz University of Medical Sciences’ hospitals. The researcher-made questionnaire was developed as a data collection tool (α = 98%). The data was entered into SPSS16 software and correlation analysis and regression were carried out.

Results

The mean score percentage of total nursing informatics competency was 59.92%. The highest mean score was related to informatics skills (62.98), followed by the informatics knowledge subscale (59%). In addition, informatics competency was positively correlated with self-efficacy ( r = 0.27, p = 0.001), evidence-based practice ( r = 0.55, p = 0.001) and time spent on hospital information systems ( r = 0.16, p = 0.01).

Conclusion

Computer skills, self-efficacy, evidence-based practice and time spent on hospital information systems are determinant factors of nurses’ informatics competency. Developing nurses’ basic computer skills and incorporating informatics education programmes into the curriculum can enhance nurses’ informatics competency.
Memory and melancholia in the garden of tropical agronomy
Authors: Tinsley Meghan
Published: April 2019

This article traces the processes of celebrating, forgetting, and reimagining the French Empire at the garden of tropical agronomy in Nogent-sur-Marne. Drawing from archival research, semi-structured interviews with stakeholders, and site observation, I consider why ruination has endured despite ongoing attempts to restore the site, and what is at stake in remembering the garden anew. Drawing from theories of national memory and postcolonial theory, I conceptualize the garden as a site of melancholia. Its ruination continues as a consequence of state bureaucracy, the role of the military, and its physical form. Sites of melancholia, I argue, present contested, multivocal, palimpsestic narratives that challenge national memory in two ways: first, by disrupting the relationship between past and present, and second, by foregrounding the racialized violence of the imperial project that gave rise to the contemporary nation. By unsettling the temporal and spatial idea of the nation, sites of melancholia pose a fundamental challenge to any cohesive narrative of national identity.
Wrist arthroscopy for the treatment of scaphoid delayed or nonunions and judging the need for bone grafting
Authors: Liu Bo , Wu Feiran , Ng Chye Yew
Published: April 2019

This study reports outcomes of arthroscopy in the treatment of delayed or nonunions of 25 scaphoids (25 patients). The surgery was performed between 8 and 43 weeks after injury. Intraoperatively, 11 fractures were deemed stable to probing and underwent percutaneous screw fixation only; 14 were unstable and received arthroscopic bone grafting with percutaneous screw fixation. All fractures united. At a mean follow-up of 21 months (range 12–48), the mean Mayo wrist score was 96, and patient-rated wrist evaluation was 4, and the flexion–extension arc was 90% of the contralateral wrist. We conclude that arthroscopy is valuable in the treatment of scaphoid delayed or nonunions and in judging the need for bone grafting. Our data indicate that regardless of cystic formation in the scaphoid, bone grafting is not always necessary. Percutaneous fixation alone is sufficient when scaphoid delayed or nonunions are between 8 weeks and 1 year following injury, without scaphoid nonunion advanced collapse or dorsal intercalated segment instability, and when forceful probing confirms stability of the scaphoid arthroscopically.

Level of evidence: IV
A health utility assessment of trapeziectomy with ligament reconstruction and tendon interposition for thumb trapeziometacarpal osteoarthritis
Authors: Efanov Johnny Ionut , Nguyen David-Dan , Izadpanah Ali , Danino Michel Alain , Harris Patrick
Published: April 2019

Trapeziectomy with ligament reconstruction and tendon interposition (LRTI) for trapeziometacarpal joint osteoarthritis may have both postoperative benefits and complications. This study sought to determine the health state utility outcome measures of trapeziectomy with LRTI. Patients who underwent trapeziectomy with LRTI were invited to complete the brief Michigan Hand Questionnaire and utility questionnaires outcomes using a visual analogue scale , time trade-off and standard gamble. Quality-adjusted life years (QALYs) were derived from these utility measures. For this study 32 patients were recruited, with a mean age of 61. Most patients (27/32) perceived the procedure as successful. Utility measures and QALYs serve the purpose of comparing different surgical procedures in terms of their impact on the quality of life of patients as a function of the benefits and complications of each procedure. In this study, the utility of trapeziectomy with LRTI was less than has been described for open palmar fasciectomy but more than for total wrist arthrodesis.

Level of evidence: IV
Are Big Five Traits and Facets Associated With Anchoring Susceptibility?
Authors: Cheek Nathan N. , Norem Julie K.
Published: April 2019

Anchoring, the assimilation of judgments to previously considered values, is one of the most robust findings in psychology, and researchers have been increasingly interested in finding individual difference moderators of anchoring effects. Several investigations have examined the relation between Big Five traits and anchoring susceptibility, but previous studies have produced a confusing and contradictory pattern of results. We identify limitations of previous work and report a large preregistered study ( N = 945) to test whether Big Five traits and facets relate to anchoring. We find no significant relations between any traits or facets and anchoring susceptibility. We discuss the implications of our results and future directions for research on individual differences in anchoring susceptibility.
Right atrial myxoma presenting as a pulmonary embolism in a 32-year-old female
Authors: Pandey Amitabh C , Carey John J , Thompson Jess L
Published: April 2019

Primary cardiac tumors are typically benign, with myxomas being most common. We present a 32-year-old female with a chief complaint of dyspnea and a constant non-radiating chest pressure along the left sternal border. She was found to have a pulmonary embolism that was ultimately caused by embolization of a right atrial myxoma with remnants of a large, highly mobile mass attached to the right inter-atrial septum prolapsing through the tricuspid valve. The patient underwent a median sternotomy, right atrial mass resection, pulmonary embolectomy, and inter-atrial septum reconstruction using the patient’s pericardium. The importance of finding the etiology of initial diagnoses is stressed with long-term outcomes for patients.
Proposal for a standardized discharge letter after hospital stay for acute myocardial infarction
Authors: Schiele Francois , Lemesle Gilles , Angoulvant Denis , Krempf Michel , Kownator Serge , Cheggour Saida , Belle Loic , Ferrières Jean , Bauters Christophe , Bergerot Cyrille , Beygui Farzin , Boccara Franck , Bonnefoy Eric , Bruckert Eric , Cayla Guillaume , Collet Jean-Philippe , Coste Pierre , Descotes-Genon Vincent , Ducrocq Gregory , Elbaz Meyer , Farnier Michel , Ferrari Emile , Guedj Dominique , Levai Laszlo , Mansourati Jacques , Mansencal Nicolas , Meneveau Nicolas , Meune Christophe , Morel Olivier , Ohlmann Patrick , Paillard Francois , Piot Christophe , Puymirat Etienne , Rioufol Gilles , Roubille François , Sabouret Pierre , Teiger Emmanuel
Published: April 2019

In patients admitted for acute myocardial infarction, the communication and transition from specialists to primary care physicians is often delayed, and the information imparted to subsequent healthcare providers (HCPs) may be sub-optimal. A French group of cardiologists, lipidologists and diabetologists decided to establish a consensus to optimize the discharge letter after hospitalization for acute myocardial infarction. The aim is to improve both the timeframe and the quality of the content transmitted to subsequent HCPs, including information regarding baseline assessment, procedures during hospitalization, residual risk, discharge treatments, therapeutic targets and follow-up recommendations in compliance with European Society of Cardiology guidelines. A consensus was obtained regarding a template discharge letter, to be released within two days after patient’s discharge, and containing the description of the patient’s history, risk factors, acute management, risk assessment, discharge treatments and follow-up pathway. Specifically for post acute MI patients, tailored details are necessary regarding the antithrombotic regimen, lipid-lowering and anti-diabetic treatments, including therapeutic targets. Lastly, the follow-up pathway needs to be precisely mentioned in the discharge letter. Additional information such as technical descriptions, imaging, and quality indicators may be provided separately. A template for a standardized discharge letter based on 8 major headings could be useful for implementation in routine practice and help to improve the quality and timing of information transmission between HCPs after acute MI.
Prevalence of human T-lymphotropic virus 1/2 in Nigeria’s capital territory and meta-analysis of Nigerian studies
Authors: Anyanwu Nneoma Confidence JeanStephanie , Ella Elijah Ekah , Aminu Maryam , Azam Maleeha , Ajmal Muhammad , Kazeem Haruna Makonjuola
Published: April 2019

Objectives:

This study was aimed at determining human T-lymphotropic virus 1/2 prevalence among apparently healthy, immunocompromised and haematologic malignant individuals in Nigeria’s capital, as well as meta-analysis of all Nigerian studies until date.

Methods:

A total of 200 participants were recruited into a cross-sectional study. In total, 1 mL each of sera and plasma were obtained from 5 mL blood of each participant and analysed for antibodies to human T-lymphotropic virus 1/2 using enzyme-linked immunosorbent assay; positive samples confirmed with qualitative real-time polymerase chain reaction, followed by statistical and meta-analysis. Sociodemographic characteristics and possible risk factors were assessed via questionnaires.

Results:

Enzyme-linked immunosorbent assay yielded 1% prevalence which was confirmed to be zero via polymerase chain reaction. A total of 119 (59.5%) of the participants were male, while the mean age was 35.28 ± 13.61 years. Apart from sex and blood reception/donation, there was generally a low rate of exposure to human T-lymphotropic virus–associated risk factors. Meta-analysis revealed pooled prevalence of human T-lymphotropic virus 1 and 2 to be 3% and 0%, respectively, from Nigerian studies.

Conclusion:

This study discovered zero prevalence of human T-lymphotropic virus 1/2 from five major hospitals in Nigeria’s capital, exposing the importance of confirmatory assays after positive antibody detection assay results. Meta-analysis highlighted the existence of very few reliable Nigerian studies compared to the demography of the nation. Large-scale epidemiological studies and routine screening of risk populations are therefore needed since Nigeria lies in the region of endemicity.
Nailfold capillaroscopy in systemic sclerosis – state of the art: The evolving knowledge about capillaroscopic abnormalities in systemic sclerosis
Authors: Lambova Sevdalina Nikolova , Müller-Ladner Ulf
Published: April 2019

Capillaroscopy is a unique method for morphological evaluation of the nailfold capillaries that plays a crucial role for early diagnosis of systemic sclerosis. The first description of the pathological capillaroscopic changes in systemic sclerosis was made by Brown and O’Leary in 1925. Several decades later they have been validated and accepted as a diagnostic criterion in the current 2013 EULAR/ACR classification criteria. This article summarizes the evolving knowledge about the use of nailfold capillaroscopy in systemic sclerosis. Initially, Maricq et al. suggested two major categories of capillaroscopic findings in systemic sclerosis – an ‘active’and ‘slow’ capillaroscopic pattern. Their description and terminology suggested a correlation between capillaroscopic changes and disease activity and progression. In the later classification of Cutolo et al., three phases were defined, i.e. ‘early’, ‘active’ and ‘late’ that reflect the time-related evolution of the capillaroscopic changes suggesting their association with disease duration. Current knowledge about the microvascular changes in systemic sclerosis supports both associations with disease activity and disease duration. The general opinion about the association of capillaroscopic findings with clinical involvement and disease activity in systemic sclerosis is not uniform. This is supposedly because the phase changes of systemic sclerosis–related microangiopathy are almost a universal feature in scleroderma and are not specific for a certain type of an accompaning clinical manifestation. Thus, the speed of progression of microvascular alterations might be a decisive criterion, and in cases of rapid dynamics of capillaroscopic findings, it could be considered as an indicator of disease activity. Interestingly, vascular ‘recovery’ has been observed after treatment with immunosuppressive drugs, haematopoietic stem cell transplantation, and the endothelin receptor antagonist – bosentan. The evolving knowledge about nailfold capillaroscopy in systemic sclerosis will further spread its application from a mainly diagnostic tool to an established, reliable method for evaluation of disease activity, prognosis and therapeutic response.
AL amyloidosis: from molecular mechanisms to targeted therapies
Authors: Merlini Giampaolo
Published: April 2019

Systemic amyloidosis is caused by misfolding and extracellular deposition of circulating proteins as amyloid fibrils, resulting in the dysfunction of vital organs. The most common systemic amyloidosis, light-chain (AL) amyloidosis, is caused by misfolded light chains produced by a small, dangerous B-cell clone. The process of amyloid formation, organ targeting, and damage is multifaceted and, after disease initiation, the complexity of the downstream pathogenic cascade increases, rendering its control a challenge. Because of the progressive nature of the disease, early diagnosis to prevent end-stage organ damage is vital. Improving awareness and systematic use of biomarkers of organ damage in screening populations at risk may improve the still unsatisfactory diagnostic process. Amyloid imaging is now emerging as an important companion of biomarkers in formulating the diagnosis and prognosis and monitoring the effects of therapy. An accurate diagnosis is the basis for appropriate therapy that is risk-adapted and response-tailored. Effective treatments targeting the clone and rapidly and profoundly reducing the amyloid light chains have produced marked improvements in overall survival, making AL amyloidosis the most successful model of all amyloidoses. New therapies targeting the amyloid deposits are now under development, together with novel agents modulating light chain aggregation and proteotoxicity. The future of AL amyloidosis treatment is combination therapy and will require an innovative collaborative model for a rapid translation from bench to bedside with the ultimate aim of achieving a cure for this complex disease.
Novel approaches to therapy in CML
Authors: Bhatia Ravi
Published: April 2019

Treatment with tyrosine kinase inhibitors (TKIs) results in remission and prolongation of survival in most chronic myeloid leukemia (CML) patients but fails to eliminate the leukemia stem cells (LSCs) responsible for disease development and propagation. This accounts for the clinical observation that TKI discontinuation leads to rapid leukemia relapse. Most patients require continued treatment to prevent relapse, with associated risk of relapse, toxicity, teratogenic effects, financial burden, and noncompliance. Understanding LSC resistance to TKI and development of strategies to increase the proportion of CML patients achieving treatment-free remissions is a critical area of investigation in CML. In addition, LSCs are the source of TKI resistance, relapse, or disease progression, which is another major area of need in CML treatment. It is now understood that BCR-ABL kinase-independent mechanisms are responsible for retention of LSC subpopulations. It is likely that both cell-intrinsic and microenvironmental mechanisms contribute to LSC maintenance. Here, we review the current understanding of mechanisms underlying persistence of CML LSCs during TKI treatment, recently described approaches to target these cells and emerging clinical trials, and the challenges impeding more rapid progress in achieving cures for a greater number of CML patients.
When can we stop anticoagulation in patients with cancer-associated thrombosis?
Authors: Lee Agnes Y. Y.
Published: April 2019

The optimal duration of anticoagulant therapy in patients with cancer-associated venous thromboembolism (VTE) is unknown. Without well-designed studies evaluating the efficacy, safety, and cost-effectiveness of continuing anticoagulant therapy beyond the acute treatment period of 3 to 6 months, evidence-based recommendations are lacking. Consensus guidelines generally suggest continuing anticoagulation treatment in patients with active cancer or receiving cancer treatment, with periodic reassessment of the risks and benefits. Unfortunately, with very little published data on the epidemiology of cancer-associated VTE beyond the initial 6 months, it is not possible for clinicians and patients to weigh risks and benefits in a quantitatively informed manner. Further research is needed to provide reliable and contemporary estimates on the risk of recurrent VTE off anticoagulant therapy, risk of bleeding on anticoagulant therapy, case fatality or all-cause mortality, and other important consequences of living with cancer-associated VTE. This chapter provides an overview of the published literature on real-world data on anticoagulant therapy use, the risks and risk factors of recurrent VTE and bleeding, and patient preference and values regarding long-term anticoagulation treatment. It will conclude with a pragmatic, experience-informed approach for tailoring anticoagulant therapy in patients with cancer-associated VTE.
New monogenic disorders identify more pathways to neutropenia: from the clinic to next-generation sequencing
Authors: Corey Seth J. , Oyarbide Usua
Published: April 2019

Neutrophils are the most common type of leukocyte in human circulating blood and constitute one of the chief mediators for innate immunity. Defined as a reduction from a normal distribution of values, neutropenia results from a number of congenital and acquired conditions. Neutropenia may be insignificant, temporary, or associated with a chronic condition with or without a vulnerability to life-threatening infections. As an inherited bone marrow failure syndrome, neutropenia may be associated with transformation to myeloid malignancy. Recognition of an inherited bone marrow failure syndrome may be delayed into adulthood. The list of monogenic neutropenia disorders is growing, heterogeneous, and bewildering. Furthermore, greater knowledge of immune-mediated and drug-related causes makes the diagnosis and management of neutropenia challenging. Recognition of syndromic presentations and especially the introduction of next-generation sequencing are improving the accuracy and expediency of diagnosis as well as their clinical management. Furthermore, identification of monogenic neutropenia disorders is shedding light on the molecular mechanisms of granulopoiesis and myeloid malignancies.
Non–chemotherapy drug–induced neutropenia: key points to manage the challenges
Authors: Curtis Brian R.
Published: April 2019

Non–chemotherapy idiosyncratic drug–induced neutropenia (IDIN) is a relatively rare but potentially fatal disorder that occurs in susceptible individuals, with an incidence of 2.4 to 15.4 cases per million population. Affected patients typically experience severe neutropenia within several weeks to several months after first exposure to a drug, and mortality is ∼5%. The drugs most frequently associated with IDIN include metamizole, clozapine, sulfasalazine, thiamazole, carbimazole, amoxicillin, cotrimoxazole, ticlopidine, and valganciclovir. The idiosyncratic nature of IDIN, the lack of mouse models and diagnostic testing, and its low overall incidence make rigorous studies to elucidate possible mechanisms exceptionally difficult. An immune mechanism for IDIN involving neutrophil destruction by hapten (drug)-specific antibodies and drug-induced autoantibodies is frequently suggested, but strong supporting evidence is lacking. Although laboratory testing for neutrophil drug-dependent antibodies is rarely performed because of the complexity and low sensitivity of tests currently in use, these assays could possibly be enhanced by using reactive drug metabolites in place of the parent drug. Patients typically experience acute, severe neutropenia, or agranulocytosis (<0.5 × 109 neutrophils/L) and symptoms of fever, chills, sore throat, and muscle and joint pain. Diagnosis can be difficult, but timely recognition is critical because if left untreated, there is an increase in mortality. Expanded studies of the production and mechanistic role of reactive drug metabolites, genetic associations, and improved animal models of IDIN are essential to further our understanding of this important disorder.
Is molecular remission the goal of multiple myeloma therapy?
Authors: Davies Faith E.
Published: April 2019

The increased number of effective therapies and the wider use of combinations that give deeper remissions have resulted in a reassessment of the goals of myeloma therapy. With the advent of new therapeutic strategies and diagnostic tools, achievement of minimal residual disease (MRD)-negative status has become increasingly important, with some even considering it as the primary endpoint for therapy. The level of MRD that is aimed for is a continuous, rather than an absolute variable, with studies in both transplant-eligible and -noneligible patients showing that the level of MRD achieved is predictive of progression-free survival and overall survival, with an improvement in survival of approximately 1 year for each log-depletion in MRD level. The most widely used methods to assess MRD status include flow cytometry and clonality detection, using next-generation sequencing technologies with sensitivity limits of 1:10−3 to 1:10−6. The timing of when to assess MRD depends on the treatment used, as well as the molecular and cytogenetic subgroup of the myeloma itself. It is also becoming clear that the level of MRD negativity, as well as microenvironmental factors, are important prognostically, including the regeneration of normal plasma cells, and the normalization of the immune repertoire. With advances in antibody-based therapy and immunotherapy, the achievement of stable MRD states is now possible for a significant proportion of patients, and is a prerequisite for myeloma cure.
Iron overload in thalassemia: different organs at different rates
Authors: Taher Ali T. , Saliba Antoine N.
Published: April 2019

Thalassemic disorders lie on a phenotypic spectrum of clinical severity that depends on the severity of the globin gene mutation and coinheritance of other genetic determinants. Iron overload is associated with increased morbidity in both patients with transfusion-dependent thalassemia (TDT) and non–transfusion-dependent thalassemia (NTDT). The predominant mechanisms driving the process of iron loading include increased iron burden secondary to transfusion therapy in TDT and enhanced intestinal absorption secondary to ineffective erythropoiesis and hepcidin suppression in NTDT. Different organs are affected differently by iron overload in TDT and NTDT owing to the underlying iron loading mechanism and rate of iron accumulation. Serum ferritin measurement and noninvasive imaging techniques are available to diagnose iron overload, quantify its extent in different organs, and monitor clinical response to therapy. This chapter discusses the general approach to iron chelation therapy based on organ involvement using the available iron chelators: deferoxamine, deferiprone, and deferasirox. Other novel experimental options for treatment and prevention of complications associated with iron overload in thalassemia are briefly discussed.
Impact of bone disease and pain in thalassemia
Authors: Piga Antonio
Published: April 2019

Conventional treatment of thalassemia, namely regular blood transfusion and iron chelation, improves perspectives and quality of life; however, successful treatment leads to more time in which long-term complications such as bone disease can develop. Thalassemia bone disease (TBD) is unique: all aspects, from bone anatomy and bone quality to mineral density, may be affected, with important morbidity including osteoporosis, fractures, spinal deformities, nerve compression, and pain. Clinical presentations include growth impairment, rickets-like features, back pain, spinal deformities, any sign of nerve compression, severe osteoporosis, and fragility fractures. Age, history, physical examination, and diagnostic tests support orientation on risk factors. These include bone marrow expansion, toxicity from iron overload and iron chelation, endocrine dysfunctions (hypogonadism, hypohyperparathyroidism, hypothyroidism, growth hormone deficiency, diabetes), and vitamin (D, C, K) and zinc deficiencies. Several of these may coexist in an individual for a long time and at different degrees, making clarification of the relative contribution and selection of the best therapeutic options a challenge. Milestones for prevention of TBD are early and full inhibition of bone marrow hyperplasia and iron toxicity. Empowering patients’ positive resources is key for achieving long-term healthy habits with regard to diet, physical activity, sunlight exposure, and lifestyle. Pain, related or unrelated to bone disease, is frequent in thalassemia. The most important targets for the hematologist include having an expert orientation on disease-related causes of pain, driving differential diagnosis, providing effective pain relief and, where feasible, removing the cause.
New therapeutic targets in transfusion-dependent and -independent thalassemia
Authors: Cappellini M. Domenica , Motta Irene
Published: April 2019

β-Thalassemias are characterized by reduced production of β-globin chain, resulting in α/β-chain unbalance and precipitation of α-globin–heme complexes and determining ineffective erythropoiesis. Ineffective erythropoiesis, chronic hemolytic anemia, and compensatory hematopoietic expansion are the disease hallmarks, and they are related to the severity of the chain unbalance. Several clinical forms of β-thalassemia, including the coinheritance of β-thalassemia with hemoglobin E resulting in hemoglobin E/β-thalassemia, have been described. Clinically, β-thalassemias can be classified as transfusion-dependent thalassemia (TDT) and non–transfusion-dependent thalassemia (NTDT) according to the severity of the phenotype, which is caused by a wide spectrum of mutations in a homozygous or compound heterozygous state. Current treatment of TDT consists of regular transfusions that lead to iron overload, requiring iron chelation to prevent iron-related organ toxicity. NTDT patients do not require transfusions or only occasionally require them; however, they develop iron overload as well because of increased intestinal iron absorption caused by chronic anemia. Hematopoietic stem cell allogenic transplant is the only approved cure for β-thalassemia; however, it is still limited by clinical conditions and the availability of matched donors as well as by potential graft-versus-host disease (GVHD). Gene therapy could avoid the GVHD risk, although hematopoietic stem cells must be genetically modified ex vivo. Epigenetic manipulation and genomic editing are novel experimental approaches. An increased understanding of the pathophysiology that controls the disease process prompted us to explore alternative therapeutic approaches that address the underlying chain unbalance, ineffective erythropoiesis, and iron dysregulation. Molecules, such as JAK2 inhibitors and the activin-receptor ligand trap that target ineffective erythropoiesis, are already in clinical trials with promising results. Other agents aimed to generate iron-restricted erythropoiesis are also under experimental evaluation.
Tailoring front-line therapy in diffuse large B-cell lymphoma: who should we treat differently?
Authors: Davies Andrew
Published: April 2019

Although there have been significant insights into the biology of diffuse large B-cell lymphoma (DLBCL) over recent years, progress in our therapeutic approach has been disappointing over the same timeframe. This is not for want of trying. In 2017, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the “gold standard,” despite all of our insights into cell-of-origin and other subgroups. We have traditionally used clinical risk factors to tailor our therapies and have tested intensification of chemotherapy with little success. We are now in an era of testing therapies according to the molecular phenotype of the individual’s tumor. Many phase 1/2 studies have looked at adding targeted agents to conventional R-CHOP with some promise. The phase 3 data are now starting to emerge. Are we ready yet to modify our standard of care and have we reached an era of precision medicine in DLBCL? The answer to this is “not yet.” The exception is perhaps patients with the newly defined World Health Organization category of high-grade B-cell lymphoma with rearrangements of MYC and BCL2 and/or BCL6, the so-called double- and triple-hit lymphomas. In these tumors there has been a move away from R-CHOP to more intensified regimens, however, has not been based upon rigorous prospective evaluation but review of retrospective datasets. This article will review the molecular subgroups of DLBCL, interventional strategies, and the outcomes of these interventions to date.
Current treatment of double hit and double expressor lymphoma
Authors: Reagan Patrick M. , Davies Andrew
Published: April 2019

A 60-year-old female presented with abdominal pain and distension. Following computed tomography scans of the abdomen and pelvis, she was taken urgently to the operating room, with the belief that she had appendicitis with perforation. At laparotomy, the findings were consistent with an ovarian carcinoma; there was extensive infiltration of the ovary, bowel, and omental deposits. Cytoreductive surgery was performed including total abdominal hysterectomy and bilateral salpingo-oophorectomy. The final pathology, however, revealed infiltration with medium-sized atypical lymphoid cells positive for CD20, CD10, MYC, BLC2, and BCL6 by immunohistochemistry. MYC and BCL2 translocations were identified by fluorescence in situ hybridization consistent with a diagnosis of high-grade B-cell lymphoma with rearrangements of MYC and BCL2. With the current data available, what is the optimal treatment of this patient?
Safety profiles of novel agent therapies in CLL
Authors: Ahn Inhye E. , Davids Matthew S.
Published: April 2019

A 70-year-old man with relapsed/refractory chronic lymphocytic leukemia has multiple comorbidities including atrial fibrillation (on warfarin for anticoagulation), irritable bowel syndrome, and chronic renal insufficiency. Two years ago, he received bendamustine and rituximab as first-line therapy for chronic lymphocytic leukemia and achieved partial response, but now has relapsed. Fluorescence in situ hybridization cytogenetics reveals deletion 17p. Which novel agent would you recommend for this patient?
Follicular lymphoma: are we ready for a risk-adapted approach?
Authors: Kahl Brad S.
Published: April 2019

Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab after randomized clinical trials demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Yet, the disease is biologically and clinically heterogeneous with wide variations in outcomes for individual patients. The ability to accurately risk-stratify patients and then tailor therapy to the individual is an area of ongoing research. Historically, tumor grade, tumor burden, and the FL international prognostic index (version 1 and version 2) have been used to distinguish low-risk from high-risk patients. Biologic factors such as mutations in key genes can identify patients at high risk for poor outcomes to first-line therapy (mutational status of 7 genes [EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11] with Follicular Lymphoma International Prognostic Index). More recently, the quality of the response to initial therapy, as measured by either PET imaging or by remission duration, has been show to identify individuals at high risk. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation.
Management of newly diagnosed immune thrombocytopenia: can we change outcomes?
Authors: Neunert Cindy E.
Published: April 2019

Immune thrombocytopenia resulting from antibody-mediated platelet destruction combined with impaired platelet production is a common cause of thrombocytopenia. The decision to treat newly diagnosed patients is based on several factors including ceasing hemorrhagic manifestations, increasing the platelet count, prevention of bleeding, and inducing remission. Current standard first-line therapy is a course of corticosteroids. Although this treatment paradigm increases the platelet count in the majority of patients, a high percentage relapse after discontinuation of corticosteroid therapy. For this reason, intensification of first-line therapy that results in superior long-term remission rates would be desirable. This manuscript focuses primarily on adults with idiopathic thrombocytopenic purpura (ITP), highlighting pediatric data and practice when applicable. The primary aim is to outline upfront strategies for treatment-naive patients with ITP to enhance remission rates, taking into account assessment of the risks and benefits of these approaches.
Improving Emergency Department-Based Care of Sickle Cell Pain
Authors: Glassberg Jeffrey A.
Published: April 2019

Pain is the leading cause of emergency department (ED) visits for individuals living with sickle cell disease (SCD). The care that is delivered in the ED is often cited by patients with SCD as the area of health care in greatest need of improvement. In 2014, the National Heart, Lung, and Blood Institute released guidelines for the care of SCD, including recommendations for the management of acute sickle cell pain in the ED. These guidelines provide a framework to understand the elements of ideal emergency sickle cell pain care; however, they do not provide guidance on barriers and facilitators to achieving these ideals in the complex system of the ED. Presented in this article are 4 tenets of implementing guideline-adherent emergency sickle cell care gleaned from the available literature and continuous quality improvement efforts at our institution. These include: (1) strategies to reduce negative provider attitudes toward patients with SCD; (2) strategies to reduce time-to-first-dose of analgesic medication; (3) strategies to improve ED pain care beyond the first dose of medication; and (4) strategies to improve ED patient safety. Application of the principles discussed within can improve patient and provider satisfaction, quality, and safety.
What is the role of screening for pulmonary hypertension in adults and children with sickle cell disease?
Authors: Willen Shaina M. , Gladwin Mark T.
Published: April 2019

Patient case: An 18-year-old male patient with homozygous hemoglobin SS disease was evaluated for progressive dyspnea and elevated tricuspid regurgitant jet velocity (TRV) on echocardiography. The patient’s case is described in detail in Lancet.1 He had been treated with regular transfusions since childhood for stroke, had rare episodes of vaso-occlusive pain episodes, and did not take narcotic pain medications. He presented with progressive severe dyspnea on exertion and lower extremity edema. His laboratory tests were notable for a total hemoglobin level of 11.8 g/dL and hemoglobin S levels <30% but with 18% reticulocytes and elevated markers of hemolysis, such as high plasma levels of lactate dehydrogenase, aspartate amino transferase, and indirect bilirubin. The computed tomography scan of his chest in Figure 1A-B shows a large pulmonary artery, which has a greater diameter than his aorta, and a mosaic perfusion pattern, typical for severe pulmonary arterial hypertension. His Doppler echocardiographic study (Figure 1C) showed an unusually high TRV of 5.93 m/s, consistent with a calculated pulmonary artery systolic pressure of >140 mm Hg (4 times the TRV squared = 4V2). Additional images in Figure 1D show a dilated right ventricle and right atrium with a compressed left ventricle. The patient’s right heart catheterization revealed a pulmonary artery systolic pressure of 147 mm Hg and diastolic pressure of 49 mm Hg; note that the normal values are ∼25/10 mm Hg.
Incorporating novel approaches in the management of MDS beyond conventional hypomethylating agents
Authors: Odenike Olatoyosi
Published: April 2019

In the last decade, the treatment of higher-risk myelodysplastic syndromes (MDS) has revolved around the azanucleosides, azacitidine and decitabine, which at lower doses are postulated to work predominantly via their effects on inhibition of DNA methyltransferases and consequent DNA hypomethylation. For patients who relapse after, or do not respond to, hypomethylating agent therapy, the outcome is dismal, and new agents and approaches that have the potential to alter the natural history of these diseases are desperately needed. Allogeneic stem cell transplant is the only known potentially curative approach in MDS, but its applicability has been limited by the advanced age of patients and attendant comorbidities. There is now an increasing array of new agents under clinical investigation in MDS that aim to exploit our expanding understanding of molecular pathways that are important in the pathogenesis of MDS. This review focuses on a critical appraisal of novel agents being evaluated in higher-risk MDS that go beyond the conventional hypomethylating agent therapies approved by the US Food and Drug Administration.
Pain-measurement tools in sickle cell disease: where are we now?
Authors: Darbari Deepika S. , Brandow Amanda M.
Published: April 2019

Pain is a complex multidimensional experience and the most common morbidity in patients with sickle cell disease (SCD). Tools to assess pain can be of use not only to guide pain treatment but also to provide insight into underlying pain neurobiology. Mechanisms of pain in SCD are multifactorial and are not completely elucidated. Although vaso-occlusion of microcirculation by sickled red cells is believed to be the underlying mechanism of acute vaso-occlusive pain, mechanisms for chronic pain and the transition from acute to chronic pain are under investigation. A number of modalities can be used in clinical practice and/or research to capture various dimensions of pain. Selection of a pain-assessment tool should be directed by the purpose of the assessment. Pain-assessment tools, many of which are currently in the early stages of validation, are discussed here. Development and validation of these multimodal tools is crucial for developing improved understanding of SCD pain and its management.
Targeting novel mechanisms of pain in sickle cell disease
Authors: Tran Huy , Gupta Mihir , Gupta Kalpna
Published: April 2019

Patients with sickle cell disease (SCD) suffer from intense pain that can start during infancy and increase in severity throughout life, leading to hospitalization and poor quality of life. A unique feature of SCD is vaso-occlusive crises (VOCs) characterized by episodic, recurrent, and unpredictable episodes of acute pain. Microvascular obstruction during a VOC leads to impaired oxygen supply to the periphery and ischemia reperfusion injury, inflammation, oxidative stress, and endothelial dysfunction, all of which may perpetuate a noxious microenvironment leading to pain. In addition to episodic acute pain, patients with SCD also report chronic pain. Current treatment of moderate to severe pain in SCD is mostly reliant upon opioids; however, long-term use of opioids is associated with multiple side effects. This review presents up-to-date developments in our understanding of the pathobiology of pain in SCD. To help focus future research efforts, major gaps in knowledge are identified regarding how sickle pathobiology evokes pain, pathways specific to chronic and acute sickle pain, perception-based targets of “top-down” mechanisms originating from the brain and neuromodulation, and how pain affects the sickle microenvironment and pathophysiology. This review also describes mechanism-based targets that may help develop novel therapeutic and/or preventive strategies to ameliorate pain in SCD.
Therapy of primary CNS lymphoma: role of intensity, radiation, and novel agents
Authors: Ferreri Andrés José María
Published: April 2019

Primary central nervous system (CNS) lymphomas represent a subgroup of malignancies with specific characteristics, an aggressive course, and unsatisfactory outcome in contrast with other lymphomas comparable for tumor burden and histological type. Despite the high sensitivity to conventional chemotherapy and radiotherapy, remissions are frequently short lasting. Treatment efficacy is limited by several factors, including the biology and microenvironment of this malignancy and the “protective” effect of the blood-brain barrier, which limits the access of most drugs to the CNS. Patients who survive are at high risk of developing treatment-related toxicity, mainly disabling neurotoxicity, raising the question of how to balance therapy intensification with the control of side effects. Recent therapeutic progress and effective international cooperation have resulted in a significantly improved outcome over the past 2 decades, with a higher proportion of patients receiving treatment with curative intent. Actual front-line therapy consists of high-dose methotrexate-based polychemotherapy. Evidence supporting the addition of an alkylating agent and rituximab is growing, and a recent randomized trial demonstrated that the combination of methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) is associated with a significantly better overall survival. Whole-brain irradiation and high-dose chemotherapy supported by autologous stem cell transplantation are 2 effective consolidation strategies in patients with a disease responsive to induction chemotherapy. Different strategies such as alkylating maintenance, conservative radiotherapy, and nonmyeloablative consolidation are being addressed in large randomized trials and a more accurate knowledge of the molecular and biological characteristics of this malignancy are leading to the development of target therapies in refractory/relapsing patients, with the overall aim to incorporate new active agents as part of first-line treatment. The pros and cons of these approaches together with the best candidates for each therapy are outlined in this article.