bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of simple knee sleeves on pain and knee adduction moment in early unilateral knee osteoarthritis
Authors: Mohd Sharif Nahdatul Aishah , Usman Juliana , Wan Safwani Wan Kamarul Zaman , Siew Li Goh , Abdul Karim Samihah , Mohamed Nur Anisah , Khan Soobia Saad , Khan Saad Jawaid
Published: October 2019

Knee sleeves are often prescribed to alleviate pain in people with early knee osteoarthritis. However, the biomechanics underlying their pain-relieving effect are still not well understood. This pre–post study aims at evaluating and comparing the effects of two different types of knee sleeves on knee adduction moment. Patients with clinically diagnosed knee osteoarthritis were recruited from the University of Malaya Medical Centre and were randomly assigned to two test groups using (1) a simple knee sleeve and (2) a simple sleeve with patella cutout. Knee adduction moment was collected using the Vicon motion capture system with two Kistler force plates. Pain, stiffness and physical functions were recorded using the Western Ontario and McMaster Universities Osteoarthritis Index. All measurements were taken before, immediately after and at the completion of 6 weeks of application (primary time point). In total, 17 participants with early unilateral knee osteoarthritis (47.7 (9.7) years) completed the study. Overall results show significant reduction in pain, early stance and late stance knee adduction moment and increased walking speed after 6 weeks of both knee sleeves application. This study results suggest that knee sleeves can reduce knee adduction moments in early unilateral knee osteoarthritis by 14.0% and 12.1% using the simple sleeve and the sleeve with patella cutout, respectively, and can potentially delay disease progression. In addition, knee sleeve with patella cutout does not provide additional benefits when compared to the simple knee sleeve.
Helical milling response of glass fiber-reinforced polymer composite with carbon nanotube buckypaper interlayer
Authors: Wang Xinrui , Melly Stephen Kirwa , Li Nan , Wang Gong-Dong , Peng Tian , Li Yingchi , Zhao Qi Di
Published: October 2019

Fiber-reinforced polymer composites are increasingly utilized in applications where both the weight and the strength of the components are critical as in the aerospace industry. However, the full utilization of these materials could be hindered by the weak out-of-plane properties which precipitate delamination. Carbon nanotubes (CNTs) have recently gained massive interests due to its superior mechanical properties, which are excellent for improving the fiber/matrix interface. The current study considered two specimens of glass fiber-reinforced polymer composites (with and without CNT buckypaper) and subjected them to two tests, namely interlaminar shear strength and helical milling tests. Results show that the CNTs increase the interlaminar strength of the laminates by about 25% and the images of the machined parts reveal a separation of layers (delamination) on the specimens without CNT while on the other hand uncovering a relatively good quality surface and a good fiber/matrix/CNT interface for the specimens with CNT.
Collective Action and Tragedy of Tank Water
Authors: Sarkar Sukumar , Ray Biswajit
Published: October 2019

Tank irrigation is important in agriculture-dependent developing economies such as India. Since tank water is a common pool resource, managing tanks cost-effectively through collective action (CA) is a challenge. This notion raises the following principal questions on the tank commons: What is the relationship between transaction costs (that is, cost of cooperation) and CA? And what drive the use of tank water for irrigation? For satisfactory answers, we carried out field studies on 127 farmers of seven tank villages in the districts of Bardhaman and West Midnapore in West Bengal, India between September 2015 and May 2017. Interesting findings have emerged from our study. We notice that CAs are inversely correlated with transaction costs in the study sites. Regarding the factors influencing tank water use (WU) we find based on Logit models that CA matters in WU significantly and positively. This impact of CA on WU is also robust irrespective of the model specifications. However, low income households participate more by offering labour than money but unfortunately they seem to have no primary motives for tank reconstruction. Moreover, in communities where tanks are large, local people’s participation more in terms of labour and such participation in reconstruction of the tanks is their primary motive, and also where the institutional arrangements are both formal and informal, people tend to use tank water more. The practical implication is that the absence of Water User Association and hence proper collaborative management coupled with weak nestedness between the village people and the State is one of the major causes of inadequate tank WU, leading to the decline of the tank commons.

JEL: Q01, Q25
Integrating Ethics Education and Training Into Palliative Medicine Fellowships: A Response to Vig and Merel
Authors: Potter Jordan , Gordon Pamela , Lesandrini Jason
Published: October 2019

In a recent American Journal of Hospice and Palliative Medicine article entitled “Ethics Education During Palliative Medicine Fellowship,” Dr Elizabeth Vig and Dr Susan Merel detail the ethics curriculum of the University of Washington School of Medicine’s Palliative Medicine Fellowship, including their efforts in the past several years to increase and bolster the fellowship’s ethics curriculum. This letter builds upon this topic and discusses some other strategies and methods for ethics education and training that fellowship programs may consider adopting to bolster their ethics curriculum.
Stock Market Reactions to New Product Launches in International Markets: The Moderating Role of Culture
Authors: Talay M. Berk , Akdeniz M. Billur , Obal Michael , Townsend Janell D.
Published: October 2019

Prior research indicates the importance of new product launches across international markets for firm performance. However, little is known about if, and how, new product launches in international markets drive firm financial value. This study examines the drivers of stock market reactions to a new product introduction in a foreign country, along with the moderating impact of cultural context. Using a sample of 1,154 products in 34 product categories launched in 48 countries between 2011 and 2018, the authors investigate how product characteristics such as product innovativeness and product type affect abnormal stock reactions to a new product launch event. Furthermore, the authors assess the role of the national culture by considering the individualism, uncertainty avoidance, and indulgence characteristics of the country where the new product is launched. Results of a mixed-effects estimation model indicate that product launches in international markets with innovativeness and hedonism characteristics positively affect firm value. The effects of culture are complex and multifarious, providing valuable insights regarding the impact of new product introductions in global markets on firm value.
The Role of Dispensing Device and Label Warnings on Dosing for Sunscreen Application: A Randomized Trial
Authors: Harben Alyssa , Robinson Shelby , de la Fuente Javier , Bix Laura
Published: October 2019

Drug manufacturers are expected to provide labeling information needed to yield safe and effective product use. However, it is not clear that consumers dose sunscreen, an over-the-counter drug, appropriately; in fact, existing evidence suggests underdosing as a common phenomenon. The objective of this study was to evaluate the effect of dispensing device and labeling on self-administered doses of sunscreen in young adults. To investigate those effects, a 2 × 2 factorial laboratory experiment crossing dispensing device (two levels) with labeling treatment (two levels) was conducted. Participants applied sunscreen from each of the four treatments; dosing concentration, measured in mg/cm2, served as the response variable. Participants ( n = 94) were recruited on the campuses of Michigan State University (East Lansing, MI) and California Polytechnic State University (San Luis Obispo, CA). Each participant applied sunscreen from each unique treatment to sites on their arms and legs (four applications). Postapplication, a survey was completed to characterize demographics, risk perception, and sunscreen use patterns. Results indicate participants applied approximately 30% less sunscreen from the pump bottles than the squeeze bottles (difference estimate of 0.3059 mg/cm2, standard error = 0.0607, p < .0001); there was no evidence of a difference based on label treatments. Post hoc recognition tests indicated only 55% of participants were able to recognize the two experimental labels they had viewed immediately following sunscreen application. Sunscreen application density was directly related to level of worry regarding skin cancer and frequency of sunscreen use (α = .05). Our results suggest the dispensing device used to deliver sunscreen impacts the dosage amount consumers apply.
What are tourists willing to pay for securing the survival of a flagship species? The case of protection of the Ethiopian wolf
Authors: Estifanos Tafesse , Polyakov Maksym , Pandit Ram , Hailu Atakelty , Burton Michael
Published: October 2019

Ecotourism can be an important tool for protecting biodiversity in developing countries. Tourists have preferences for viewing charismatic species and for their conservation, but our understanding of these preferences remains limited. Using choice experiment surveys, we investigate tourists’ preferences and willingness to pay (WTP) for the protection of the Ethiopian wolf ( Canis simensis) in Ethiopia’s Bale Mountains National Park. Results from a random parameter logit model show that tourists were willing to pay up to US$5.82/day/trip for increasing the wolf population from 200 to a more viable number of 250 but very little for a more substantial increase. Tourists also valued increases in the size of the protected area (PA) and access to the wolf habitat. The WTP is found to be dependent on tourists’ prior experience to Ethiopian PAs and whether they had viewed other unique species in the park. The findings suggest opportunities for ecotourism to support the Ethiopian wolf, which is in a critical state, and that the primary motivation for tourists’ support might be due to the wolf’s existence value.
Effects of random winds and waves on a long-span cross-sea bridge using Bayesian regularized back propagation neural network
Authors: Fang Chen , Tang Haojun , Li Yongle , Wang Zewen
Published: October 2019

Uncertainties from random multiple factors bring great challenges for assessing response of long-span bridges. This study proposes a dynamic analysis framework by integrating the wind–wave–bridge system with Bayesian regularized back propagation neural network, and then investigates stochastic response of a cross-sea cable-stayed bridge under extreme wind and wave parameters. The wind–wave–bridge system involving wind–bridge and wave–bridge interactions is constructed to calculate dynamic response of the bridge by Newmark-β method, considering stationary fluctuating wind fields and multidirectional random wave fields. To reduce the calculation cost, a Bayesian regularized back propagation neural network model is introduced, and the model evaluation is carried out to illustrate its accuracy and efficiency. After performing small-scale finite element analyses, the response statistics are obtained and later used as the known samples for training the neural network. The power spectrum analyses of the deterministic results are performed to investigate the contribution mechanism of the wind and wave. Finally, the correlation between the bridge response and the single wind–wave parameter is given by uncertainty analysis of the Bayesian regularized back propagation neural network model. The results show that the proposed framework is capable of capturing the nonlinear bridge response resulting from nonlinear wind and wave loads, which, however, is significant different from that under wind alone. The bridge response receives significant contribution from wind and waves relative to the vibration characteristic of the bridge at smaller wind and wave loads. The contribution from vibration characteristic of the bridge becomes significant at larger wind and wave loads. The uncertainty analyses illustrate the significant effects of four wind and wave parameters on girder, tower, and submerged structure.
Translating religion and development: Emerging perspectives from critical ethnographies of faith-based organizations
Authors: Bolotta Giuseppe , Scheer Catherine , Feener R. Michael
Published: October 2019

Since the turn of the twenty-first century, there has been a remarkable surge of interest among both policy makers and academics on religion and its engagements with development. Within this context, ‘religious non-governmental organizations (RNGOs)’ or ‘faith-based organizations’ (FBOs) have garnered considerable attention. Early attempts to understand FBOs often took the form of typological mapping exercises, the cumulative effect of which has been the construction of a field of ‘RNGOs’ that can be analysed as distinct from—and possibly put into the service of—the work of purportedly secular development actors. However, such typologies imply problematic distinctions between over-determined imaginations of separate spheres of ‘religion’ and ‘development’. In this article, we innovatively extend the potential of ethnographic approaches highlighting aspects of ‘brokerage’ and ‘translation’ to FBOs and identify new, productive tensions of convergent analysis. These, we argue, provide original possibilities of comparison and meta-analysis to explore contemporary entanglements of religion and development.

This article was written as part of a broader research project on Religion and NGOs in Asia. We are grateful to the Henry R. Luce Initiative on Religion in International Affairs at the Henry Luce Foundation for their generous support of this research. We would also like to thank Philip Fountain and other members of the National University of Singapore’s Asia Research Institute for stimulating conversations that have informed our thinking in this article, and the anonymous reviewers for PIDS who have helped us to improve on earlier drafts.
Spectral tuning of luminance cameras: A theoretical model and validation measurements
Authors: Kruisselbrink TW , Dangol R , Rosemann ALP , van Loenen EJ
Published: October 2019

Presently, luminance distribution measurement devices, using High Dynamic Range technology, are increasingly used as they provide a lot of relevant data related to the lit environment at once. However, the accuracy of these devices can be a concern. It is expected that the accuracy would be improved by incorporating the effect of the camera spectral responsivity and the spectral power distribution of the illuminant under which the measurements are conducted. This study introduces two optimization criteria incorporating these aspects to improve the spectral match and the performance of luminance distribution measurement devices. Both criteria are tested in a theoretical model and in practical measurements using two cameras and three illuminants: LED, halogen and fluorescent. Both methodologies support the hypothesis that the conventional method to determine the luminance introduces spectral mismatches that can be limited by optimizing relative to the spectral responsivity of the camera. Additionally, substantial evidence was found, by both the theoretical model and the validation measurements, that the spectral power distribution of the illuminant also has an effect on the performance.
M-folding method–based elliptic curve cryptosystem for industrial cyber-physical system
Authors: Do Taehoon , Park Seungwoo , Lee Jaehwan , Park Sangoh
Published: October 2019

Recently, cyber-physical system is widely used for smart system control in various fields. Various functions of the cyber-physical system must overcome the limited hardware resources constraint of an embedded system. In addition, the data required from the industrial cyber-physical system are critical; therefore, a highly secure encryption technique is required. However, security and computational throughput are incompatible with each other in the cryptographic technique; therefore, the industrial cyber-physical system needs to adopt a highly efficient and secure encryption technique considering the limited available resources. This study applies the m-folding method to the highly secure elliptic curve algorithm to improve efficiency and proposes the cryptosystem optimized for the resource-constrained industrial cyber-physical system. The proposed m-folding method–based elliptic curve encryption showed 50% faster encryption than the existing methods.
Air passenger travel forecasting model based on both dynamical individual behavior and social influence force
Authors: Wang Jialiang , Liu Xiaoqing , Ding Jianli
Published: October 2019

Air passenger travel forecasting is necessary and becomes very valuable for airline company, because accurately obtaining practical requirements of air passenger, which can not only help airline company to improve air passenger satisfaction degree and enhance user experience so as to gain huge revenue, but also can help air passengers discover suitable travel plan quickly. In order to generate the air passenger travel forecasting model, this paper aims to analyze the internal driving force and social affect factor simultaneously, which was based on dynamical personal behaviors and air passenger social relationship exactly. In particular, three aspects in terms of dynamical personal behaviors, effect of fellow air passenger, and influence of similar air passenger are all considered simultaneously, and then the data from these aspects are further trained so as to obtain weight allocation in many different scenarios. Besides, workday and non-workday are separately considered in order to make the forecasting model feasible and effective.
Mean muscle attenuation correlates with severe acute pancreatitis unlike visceral adipose tissue and subcutaneous adipose tissue
Authors: Sternby Hanna , Mahle Mariella , Linder Nicolas , Erichson-Kirst Laureen , Verdonk Robert C , Dimova Alexandra , Ignatavicius Povilas , Ilzarbe Lucas , Koiva Peeter , Penttilä Anne , Regnér Sara , Bollen Thomas L , Brill Richard , Stangl Franz , Wohlgemuth Walter A , Singh Vijay , Busse Harald , Michl Patrick , Beer Sebastian , Rosendahl Jonas
Published: October 2019

Background

Acute pancreatitis (AP) is a frequent disorder with considerable morbidity and mortality. Obesity has previously been reported to influence disease severity.

Objective

The aim of this study was to investigate the association of adipose and muscle parameters with the severity grade of AP.

Methods

In total 454 patients were recruited. The first contrast‐enhanced computed tomography of each patient was reviewed for adipose and muscle tissue parameters at L3 level. Associations with disease severity were analysed through logistic regression analysis. The predictive capacity of the parameters was investigated using receiver operating characteristic (ROC) curves.

Results

No distinct variation was found between the AP severity groups in either adipose tissue parameters (visceral adipose tissue and subcutaneous adipose tissue) or visceral muscle ratio. However, muscle mass and mean muscle attenuation differed significantly with p‐values of 0.037 and 0.003 respectively. In multivariate analysis, low muscle attenuation was associated with severe AP with an odds ratio of 4.09 (95% confidence intervals: 1.61–10.36, p‐value 0.003). No body parameter presented sufficient predictive capability in ROC‐curve analysis.

Conclusions

Our results demonstrate that a low muscle attenuation level is associated with an increased risk of severe AP. Future prospective studies will help identify the underlying mechanisms and characterise the influence of body composition parameters on AP.
Principles and Considerations for Responsible Sharing of Safety Information Via the Medical Information Channel
Authors: Hristoskova Sashka , Milligan James , De Wit Jan , Pesonen Jukka , Rennick Robyn
Published: October 2019

The approach used by medical information services in answering unsolicited safety-related questions from health care professionals regarding prescription medicines varies widely across the pharmaceutical industry. A significant amount of information is available in the public domain, but this can be difficult to filter and determine what is most appropriate for a given situation. A team representing the medical information group MILE (Medical Information Leaders Europe) and European Federation of Pharmaceutical Industries and Associations Pharmacovigilance Expert Group have partnered to develop principles and considerations on how to answer unsolicited safety questions. Essentially two key principles are important in ensuring success: (1) Effective collaboration between medical information and patient safety teams is important for an optimal outcome providing accurate, useful, and timely information. This article discusses considerations for an effective, efficient collaboration between medical information and patient safety and suggests a way of working. (2) Collaborating teams will need to evaluate and select the most appropriate sources of information to answer the question. Sources of information that may or may not be in the public domain are discussed. Adoption of principles and considerations discussed in this article may be expected to improve current safety information–sharing practices that tend to be conservative and risk averse. In addition, this presents the opportunity to initiate discussions with regulatory authorities to realize the benefits that will come through greater transparency and communication to support safe and effective use of medicines.
The Extra-Institutional Logics of an Emerging Market Field: Values and Practice in the Bitcoin Experience
Authors: Kinney Alexander B.
Published: October 2019

Mature fields of market activity are characterized by clear norms, entrenched meanings, and rigid power hierarchies that stabilize logics of action. However, how do logics of action emerge in a nascent field of market activity that lacks these types of institutions? To answer this question, I draw on theories of institutions and markets to examine the experiences of 23 adopters of the cryptocurrency Bitcoin during 2015 to 2016. Utilizing an iterative combination of correspondence analysis (CA) techniques and narrative analysis, I show how Bitcoin adoption was motivated by competing value frameworks that corresponded to different user types in the system. This resulted in the emergence novel “extra-institutional logics” that supported the growth of Bitcoin as a whole despite being centered on different visions for the future of the system. These logics provide a unique glimpse into how Bitcoin was able to survive during a period of notable instability preceding a historic market bubble. This article provides support for dynamic theories of markets and demonstrates how logics of action are tethered to the characteristics of the fields in which they emerge.
What Should Children Learn? Americans’ Changing Socialization Values, 1986–2018
Authors: Nomaguchi Kei , Milkie Melissa A.
Published: October 2019

Assessing changes in socialization values for children provides a unique window into how Americans perceive the landscape of their society. We examine whether, since the mid-1980s, Americans (1) emphasized survival values, like hard work, for children, as economic precarity rose or (2) prioritized self-expression values, like autonomy and compassion, as expected in postindustrial society. Analysis of 1986 to 2018 General Social Survey (N = 23,109) supports the precarity thesis: Preferences for hard work increased steadily whereas preferences for autonomy, the top-ranked quality throughout the period, declined. There was some indication of enduring self-expression values, as support for compassion increased and its relative importance to hard work stayed stable. Decomposition analyses show valuing hard work would have been even greater without demographic changes like an increase in college graduates. Aligning with earlier research, valuing obedience in children continued to decline. Our results extend theoretical work on complexities of socioeconomic links to parenting values.
New Views of Sickle Cell Disease Pathophysiology and Treatment
Authors: Rosse Wendell F. , Narla Mohandas , Petz Lawrence D. , Steinberg Martin H.
Published: October 2019

This review addresses several areas of concern in the care of patients with sickle cell disease. In Sections I and II, the fundamental pathogenetic mechanisms of sickle cell disease and their clinical consequences are discussed. Dr. Narla presents the evidence for abnormal cell adhesiveness by SS cells and Dr. Rosse examines the role of the increased whole blood viscosity. In Section III, Dr. Petz reviews common and uncommon alloimmune consequences of transfusion in sickle cell disease and discusses the diagnosis and management of sickle cell patients with hyperhemolysis after transfusion. In Section IV, Dr. Steinberg gives an update on the use of hydroxyurea in the treatment of sickle cell disease, including the SC and S-β thalassemia variants.
Status of Cytomegalovirus Prevention and Treatment in 2000
Authors: Zaia John A. , Sissons J.G. Patrick , Riddell Stanley , Diamond Don J. , Wills M.R. , Carmichael A.J. , Weekes M.P. , Gandhi M. , La Rosa C. , Villacres M. , Lacey S. , Markel S. , Sun J.
Published: October 2019

Cytomegalovirus (CMV) infection continues to be a problem in selected populations following hematopoietic stem cell transplantation (SCT). Although there have been no new antiviral agents for management of this infection in recent years, the methods for using the existing agents have improved with newer assays for detection of virus. In addition, our understanding of immunity to CMV has undergone considerable expansion. This paper will address these new aspects relating to CMV infection in the setting of SCT.

In Section I Dr. Zaia reviews the pathogenesis of CMV and the current epidemiology of CMV disease following marrow or blood allo-SCT with emphasis on late-onset disease. The current lab tests available for preemptive management are summarized including the role for conventional shell vial cultures, and a comparison of the CMV antigenemia assay with the new nucleic acid-based assays, including the hybrid capture assay, the NASBA assay, and “real-time” PCR assays. Use of antiviral agents with these tests in the preemptive management of CMV infection is discussed.

Ultimately, what is necessary is restoration of adequate CMV immunity, and that requires understanding the basics of the CMV-specific immune response. In Section II, Dr. Sissons traces the evolution of the CTL response from primary infection into memory and reviews recent advances in the understanding of cytotoxic T cell based immunity to CMV, based on the use of T cell clonotypic analysis and markers of T cell memory and activation, with conventional CTL functional assays.

In Section III Dr. Riddell presents approaches to correction of the problem of CMV pathogenesis, namely direct restoration of the CMV-specific cellular immune deficiency. Attempts at passive therapies will be reviewed with the focus on current problems and approaches to these problems.

In Section IV, Dr. Diamond presents work on the identification of multiple HLA-allele specific cytotoxic T cell epitopes specific for CMV-pp65 and - pp150. Specific epitopes are recognized by CMV-seropositive individuals including healthy donors, SCT recipients, and AIDS patients, indicating their potential usefulness as vaccines. One of these epitopes is recognized by most individuals who express the HLA A*0201 Class I allele. Pre-clinical evaluation in HLA2.1 transgenic mice of vaccine structures utilizing this epitope, and alternative delivery systems are described. Possible methods for vaccination of donor and/or recipient of a SCT as well as their limitations, utilizing synthetic or viral vaccines, are discusseed.
Clinical Consequences of New Insights in the Pathophysiology of Disorders of Iron and Heme Metabolism
Authors: Brittenham Gary M. , Weiss Günter , Brissot Pierre , Lainé Fabrice , Guillygomarc'h Anne , Guyader Dominique , Moirand Romain , Deugnier Yves
Published: October 2019

This review examines the clinical consequences for the practicing hematologist of remarkable new insights into the pathophysiology of disorders of iron and heme metabolism. The familiar proteins of iron transport and storage—transferrin, transferrin receptor, and ferritin—have recently been joined by a host of newly identified proteins that play critical roles in the molecular management of iron homeostasis. These include the iron-regulatory proteins (IRP-1 and -2), HFE (the product of the HFE gene that is mutated in most patients with hereditary hemochromatosis), the divalent metal transporter (DMT1), transferrin receptor 2, ceruloplasmin, hephaestin, the “Stimulator of Fe Transport” (SFT), frataxin, ferroportin 1 and others. The growing appreciation of the roles of these newly identified proteins has fundamental implications for the clinical understanding and laboratory evaluation of iron metabolism and its alterations with iron deficiency, iron overload, infection, and inflammation.

In Section I, Dr. Brittenham summarizes current concepts of body and cellular iron supply and storage and reviews new means of evaluating the full range of body iron stores including genetic testing for mutations in the HFE gene, measurement of serum ferritin iron, transferrin receptor, reticulocyte hemoglobin content and measurement of tissue iron by computed tomography, magnetic resonance imaging and magnetic susceptometry using superconducting quantum interference device (SQUID) instrumentation.

In Section II, Dr. Weiss discusses the improved understanding of the molecular mechanisms underlying alterations in iron metabolism due to chronic inflammatory disorders. The anemia of chronic disorders remains the most common form of anemia found in hospitalized patients. The network of interactions that link iron metabolism with cellular immune effector functions involving pro- and anti-inflammatory cytokines, acute phase proteins and oxidative stress is described, with an emphasis on the implications for clinical practice.

In Section III, Dr. Brissot and colleagues discuss how the diagnosis and management of hereditary hemochromatosis has changed following the identification of the gene, HFE, that is mutated in most patients with hereditary hemochromatosis, and the subsequent development of a genotypic test. The current understanding of the molecular effects of HFE mutations, the usefulness of genotypic and phenotypic approaches to screening and diagnosis and recommendations for management are summarized.
Hematology Grants Workshop—2000
Authors: Todd Robert F. , Miller Donald M. , Silverstein Roy L.
Published: October 2019

This year the Hematology Grants Workshop, chaired by Dr. Robert Todd, includes a comprehensive listing of available NIH, VA, and non-federal grants applicable to fellows and junior faculty as well as to established investigators.

In Section II, Dr. Donald Miller discusses the essential principles of successful grant writing with a special emphasis on the young investigator. He highlights the best strategies to take and the common mistakes to avoid.

In Section III, Dr. Roy Silverstein outlines the structure of the current NIH Integrated Review Group (IRG) system and the study sections of the most relevance to hematology. He traces the path that a grant takes from review to funding including the way in which grants are reviewed at NIH Study Section Meetings and provides advice in the preparation of revised applications.
A Polycythemia Vera Update: Diagnosis, Pathobiology, and Treatment
Authors: Pearson Thomas C. , Messinezy Maria , Westwood Nigel , Green Anthony R. , Bench Anthony J. , Green Anthony R. , Huntly Brian J.P. , Nacheva Elizabeth P. , Barbui Tiziano , Finazzi Guido
Published: October 2019

This review focuses on polycythemia vera (PV)—its diagnosis, cellular and genetic pathology, and management. In Section I, Dr. Pearson, with Drs. Messinezy and Westwood, reviews the diagnostic challenge of the investigation of patients with a raised hematocrit. The suggested approach divides patients on their red cell mass (RCM) results into those with absolute (raised RCM) and apparent (normal RCM) erythrocytosis. A standardized series of investigations is proposed for those with an absolute erythrocytosis to confirm the presence of a primary (PV) or secondary erythrocytosis, with abnormal and normal erythropoietic compartments respectively, leaving a heterogenous group, idiopathic erythrocytosis, where the cause cannot be established. Since there is no single diagnostic test for PV, its presence is confirmed following the use of updated diagnostic criteria and confirmatory marrow histology.

In Section II, Dr. Green with Drs. Bench, Huntly, and Nacheva reviews the evidence from studies of X chromosome inactivation patterns that support the concept that PV results from clonal expansion of a transformed hemopoietic stem cell. Analyses of the pattern of erythroid and myeloid colony growth have demonstrated abnormal responses to several cytokines, raising the possibility of a defect in a signal transduction pathway shared by several growth factors. A number of cytogenetic and molecular approaches are now focused on defining the molecular lesion(s).

In the last section, Dr. Barbui with Dr. Finazzi addresses the complications of PV, notably thrombosis, myelofibrosis and acute leukemia. Following an evaluation of published data, a management approach is proposed. All patients should undergo phlebotomy to keep the hematocrit (Hct) below 0.45, which may be all that is required in those at low thrombotic risk and with stable disease. In those at high thrombotic risk or with progressive thrombocytosis or splenomegaly, a myelosuppressive agent should be used. Hydroxyurea has a role at all ages, but 32P or busulfan may be used in the elderly. In younger patients, interferon-α or anagrelide should be considered. Low-dose aspirin should be used in those with thrombotic or ischemic complications.
Thrombophilia: What's a Practitioner to Do?
Authors: Macik B. Gail , Rand Jacob H. , Konkle Barbara A.
Published: October 2019

Management of thrombophilia is an ever-changing field as new disorders are described and additional clinical experience accrues. This paper addresses three common management issues in the care of patients with thrombophilia. The first two topics are updates for common but perplexing hypercoagulable states and the last topic introduces a new option for optimal management of oral anticoagulant therapy. Dr. Jacob Rand updates and organizes the approach to patients with antiphospholipid syndrome. This syndrome is a common acquired thrombophilic state, but the diagnosis and treatment of patients remains a challenge. Dr. Rand outlines his diagnostic and treatment strategies based on the current understanding of this complicated syndrome. Dr. Barbara Konkle addresses the special concerns of managing women with thrombophilia. Hematologists are often asked to advise on the risks of hormonal therapy or pregnancy in a woman with a personal or family history of thrombosis or with an abnormal laboratory finding. Dr. Konkle reviews the available data on the risks of hormonal therapy and pregnancy in women with and without known underlying thrombophilic risk factors. In Section III, Dr. Gail Macik will discuss a new approach to warfarin management. Several instruments are now available for home prothrombin time (PT) monitoring. Self-testing and self management of warfarin are slowly emerging as reliable alternatives to traditional provider-based care and Dr. Macik reviews the instruments available and the results of studies that support this new management option.
The Biology of the Germinal Center
Authors: Natkunam Yasodha
Published: October 2019

The immune system requires the production of high affinity antibodies of different subclasses to accomplish its many effector functions. Specific steps in B-cell ontogeny that occur within germinal centers of secondary lymphoid organs create much of the diversity in the immune system. This process also provides the raw material for the genesis of B-cell lymphomas as misdirection of the molecular machinery that regulate these steps can cause chromosomal translocations, prevent apoptosis and promote proliferation of abnormal clones. Many recent avenues of investigation have elucidated that the germinal center is a dynamic microenvironment where B-cells undergo repeated rounds of mutation and selection. Gene expression studies have further shown that malignancies derived from germinal center B-cells elaborate specific gene expression signatures that derive from neoplastic cells as well as elements of the host response such as T-cells and macrophages. This review will examine the current understanding of B-cell development in the germinal center and the key molecules involved in this process. Interactions between lymphoma cells and their cellular partners and models in the growth and development of follicular lymphoma will be presented.
Asthma and sickle cell disease: two distinct diseases or part of the same process?
Authors: Field Joshua J. , DeBaun Michael R.
Published: October 2019

A physician diagnosis of asthma in children and adults with sickle cell disease (SCD) has been associated with increased rates of pain and acute chest syndrome (ACS) episodes and premature death. Despite the clinical significance of a doctor’s diagnosis of asthma in individuals with SCD, the criteria for a physician diagnosis of asthma are not well defined. Many features of asthma are common in individuals with SCD, including symptoms of wheezing, obstructive lung disease and airway hyper-responsiveness. However, it is not clear if these signs and symptoms of asthma reflect a physician diagnosis of asthma, or if these asthma features are related to SCD. Further complicating the diagnosis of asthma in children with SCD is the significant overlap in clinical manifestations between an asthma exacerbation and an ACS episode. Evidence supporting the concept that asthma and SCD are separate co-morbid conditions includes a similar prevalence of asthma between children with SCD and those in the general population and the observation that asthma is inherited in a familial pattern in the families of children with SCD. In contrast, there is significant evidence that asthma-like features may be associated with SCD without a diagnosis of asthma, including a higher than expected prevalence of airway hyper-responsiveness and obstructive lung disease. Regardless of whether SCD and asthma are distinct or overlapping co-morbid conditions, we recommend a systematic and complete evaluation of asthma when the diagnosis is suspected or when patients have multiple episodes of pain or ACS.
Costs of Care in Hemophilia and Possible Implications of Health Care Reform
Authors: Johnson Kathleen A. , Zhou Zheng-Yi
Published: October 2019

Economic evaluation in health care is increasingly used to assist policy makers in their difficult task of allocating limited resources. The high cost of care, including that for clotting factor concentrates, makes hemophilia a potential target for cost-cutting efforts by health care payers. Although the appropriate management of hemophilia is key to minimizing and preventing long-term morbidity, comparative effectiveness studies regarding the relative benefit of different treatment options are lacking. Cost-of-illness (COI) analysis, which includes direct and indirect costs from a societal perspective, can provide information to be used in cost-effectiveness and other economic analyses. Quality-of-life assessment provides another methodology with which to measure outcomes and benefits of appropriate disease management. Health care reform has implications for individuals with hemophilia and their families through changes in payment, insurance coverage expansion, and health care delivery system changes that reward quality and stimulate cooperative, team-based care. Providers will benefit from the expansion of insurance coverage and some financial benefits in rural areas, and from the expansion of coverage for preventive services. Accountable care organizations will potentially change the way providers are paid and financial incentives under reform will reward high quality of care.
Where do we stand in the treatment of relapsed acute lymphoblastic leukemia?
Authors: Raetz Elizabeth A. , Bhatla Teena
Published: October 2019

Acute lymphoblastic leukemia (ALL) is the most common and one of the most treatable cancers in children. Although the majority of children with ALL are now cured, 10%-20% of patients are predicted to relapse and outcomes with salvage therapy have been disappointing, with approximately only one-third of children surviving long-term after disease recurrence. Several prognostic factors have been identified, with timing of recurrence relative to diagnosis and site of relapse emerging as the most important variables. Despite heterogeneity in the elements of salvage therapy that are delivered in trials conducted internationally, outcomes have been remarkably similar and have remained static. Because most intensive salvage regimens have reached the limit of tolerability, current strategies are focusing on identifying new agents tailored to the unique biology of relapsed disease and identifying methods to develop these agents efficiently for clinical use. Recently, high-resolution genomic analyses of matched pairs of diagnostic and relapse bone marrow samples are emerging as a promising tool for identifying pathways that impart chemoresistance.
Minimal residual disease: optimal methods, timing, and clinical relevance for an individual patient
Authors: Schrappe Martin
Published: October 2019

After approximately 20 years of development and after several prospective clinical trials, the detection of minimal residual disease (MRD) has emerged as part of state-of-the-art diagnostics to guide the majority of contemporary treatment programs both in pediatric and adult acute lymphoblastic leukemia (ALL). For ALL, several methods of MRD analysis are available, but 2 are widely applicable. One is based on the detection of aberrant expression of leukemia specific antigens by flow cytometry and the other one uses the specific rearrangements of the TCR or Ig genes, which can be detected by quantitative PCR in the DNA of leukemic cells. In some cases with known fusion genes such as BCR/ABL, RT-PCR can be used as a third method of identifying leukemic cells by analyzing RNA in patient samples. Clinical application of such sophisticated tools in the stratification and treatment of ALL requires reliable, reproducible, and quality-assured methods to ensure patient safety.
Matched and mismatched unrelated donor transplantation: is the outcome the same as for matched sibling donor transplantation?
Authors: Bacigalupo Andrea
Published: October 2019

The outcome of allogeneic stem cell transplantation has improved over the past decades due to a significant reduction of nonrelapse mortality, whereas our ability to control underlying malignant diseases has remained unchanged. Reduction of nonrelapse mortality has been achieved in matched sibling donor transplantation, but perhaps more so with unrelated donor transplantation, in part due to the advances in HLA matching between donor and recipient, but also as a result of improved supportive care, better GVHD prophylaxis, and tailored conditioning regimens. Therefore, over the past decade, results of matched sibling donor and unrelated donor grafts have grown more similar, and the difference in 1-year survival for patients with leukemia has gone from 21% in 1988 in favor of MSD to 9% in 2008. However, due to the significant and combined effect of patient, transplantation, and donor variables, comparisons are made here in the context of defined subsets of patients and specific diseases and in some circumstances also looking at separate studies in children and adults.
Health-related quality of life in patients with hemoglobinopathies
Authors: Panepinto Julie A.
Published: October 2019

The use of patient-reported outcomes to measure the health and well-being of patients from their perspective has become an acceptable method to determine the impact of a disease and its treatment on patients. In patients with hemoglobinopathies, prior work has demonstrated that patients experience significant impairment in health-related quality of life (HRQL, a type of patient-reported outcome). This work has provided a better understanding of the burden that these patients experience and the factors that are associated with worse HRQL. The recent development of disease-specific HRQL instruments in sickle cell disease heralds new opportunities to explore the impact of the disease and its treatment on patients. The standards necessary to incorporate the measurement of HRQL into clinical trials are now well outlined by regulatory agencies. Measuring HRQL within a clinical practice setting and outside of the healthcare setting while the patient is at home are now possible and present new opportunities to understand the health and well-being of patients with hemoglobinopathies.
What is the evidence that hydroxyurea improves health-related quality of life in patients with sickle cell disease?
Authors: Darbari Deepika S. , Panepinto Julie A.
Published: October 2019

A 10-year-old male patient with homozygous sickle cell disease presents for a follow-up clinic visit after a recent hospitalization for a painful vasoocclusive event. His parents mention that in the past year he has had 4 hospitalizations for vasoocclusive events, 2 of which were complicated by the development of acute chest syndrome that resulted in transfer to the intensive care unit. He has missed many school days and may be retained a grade this year. He feels particularly sad about missing the school field trip that occurred during his last hospitalization. He also reports that he is not able to keep up with his friends when participating in physical activities at school. The child's parents are worried that he may be depressed. You as the provider discuss the option of hydroxyurea therapy. His parents ask if hydroxyurea would improve his overall well-being and functioning.
How does PET/CT help in selecting therapy for patients with Hodgkin lymphoma?
Authors: Hutchings Martin
Published: October 2019

Positron emission tomography/computed tomography (PET/CT) has emerged as the most accurate tool for staging, treatment monitoring, and response evaluation in Hodgkin lymphoma (HL). Accurate staging and restaging are very important for the optimal management of HL, but we are only beginning to understand how to use PET/CT to improve treatment outcome. More precise determination of disease extent may result in more precise pretreatment risk stratification, and is also essential for the minimal and highly individualized radiotherapy volumes of the present era. Several trials are currently investigating the use of PET/CT for early response-adapted therapy, with therapeutic stratification based on interim PET/CT results. Posttreatment PET/CT is a cornerstone of the revised response criteria and enables the selection of advanced-stage patients without the need for consolidation radiotherapy. Once remission is achieved after first-line therapy, PET/CT seems to have little or no role in the routine surveillance of HL patients. PET/CT looks promising for the selection of therapy in relapsed and refractory disease, but its role in this setting is still unclear.