Symmetries and dynamics in constrained systems

We review in detail the Hamiltonian dynamics for constrained systems. Emphasis is put on the total Hamiltonian system rather than on the extended Hamiltonian system. We provide a systematic analysis of (global and local) symmetries in total Hamiltonian systems. In particular, in analogue to total Hamiltonians, we introduce the notion of total Noether charges. Grassmannian degrees of freedom are also addressed in details.Comment: 1+97 pages, No figure, Expanded version of a lecture note by J.-H. Park at Sogang University, Seoul during 2007-2008. Accepted for publication in the European Physical Journal C as a review article; Reference adde

Challenges in Clinical Metaproteomics Highlighted by the Analysis of Acute Leukemia Patients with Gut Colonization by Multidrug-Resistant Enterobacteriaceae.

The microbiome has a strong impact on human health and disease and is, therefore, increasingly studied in a clinical context. Metaproteomics is also attracting considerable attention, and such data can be efficiently generated today owing to improvements in mass spectrometry-based proteomics. As we will discuss in this study, there are still major challenges notably in data analysis that need to be overcome. Here, we analyzed 212 fecal samples from 56 hospitalized acute leukemia patients with multidrug-resistant Enterobactericeae (MRE) gut colonization using metagenomics and metaproteomics. This is one of the largest clinical metaproteomic studies to date, and the first metaproteomic study addressing the gut microbiome in MRE colonized acute leukemia patients. Based on this substantial data set, we discuss major current limitations in clinical metaproteomic data analysis to provide guidance to researchers in the field. Notably, the results show that public metagenome databases are incomplete and that sample-specific metagenomes improve results. Furthermore, biological variation is tremendous which challenges clinical study designs and argues that longitudinal measurements of individual patients are a valuable future addition to the analysis of patient cohorts

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14�294 geography�year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61·7 years (95 uncertainty interval 61·4�61·9) in 1980 to 71·8 years (71·5�72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7�17·4), to 62·6 years (56·5�70·2). Total deaths increased by 4·1 (2·6�5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0 (15·8�18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1 (12·6�16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1 (11·9�14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1, 39·1�44·6), malaria (43·1, 34·7�51·8), neonatal preterm birth complications (29·8, 24·8�34·9), and maternal disorders (29·1, 19·3�37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146�000 deaths, 118�000�183�000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393�000 deaths, 228�000�532�000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost YLLs) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background Non-fatal outcomes of disease and injury increasingly detract from the ability of the world's population to live in full health, a trend largely attributable to an epidemiological transition in many countries from causes affecting children, to non-communicable diseases (NCDs) more common in adults. For the Global Burden of Diseases, Injuries, and Risk Factors Study 2015 (GBD 2015), we estimated the incidence, prevalence, and years lived with disability for diseases and injuries at the global, regional, and national scale over the period of 1990 to 2015. Methods We estimated incidence and prevalence by age, sex, cause, year, and geography with a wide range of updated and standardised analytical procedures. Improvements from GBD 2013 included the addition of new data sources, updates to literature reviews for 85 causes, and the identification and inclusion of additional studies published up to November, 2015, to expand the database used for estimation of non-fatal outcomes to 60�900 unique data sources. Prevalence and incidence by cause and sequelae were determined with DisMod-MR 2.1, an improved version of the DisMod-MR Bayesian meta-regression tool first developed for GBD 2010 and GBD 2013. For some causes, we used alternative modelling strategies where the complexity of the disease was not suited to DisMod-MR 2.1 or where incidence and prevalence needed to be determined from other data. For GBD 2015 we created a summary indicator that combines measures of income per capita, educational attainment, and fertility (the Socio-demographic Index SDI) and used it to compare observed patterns of health loss to the expected pattern for countries or locations with similar SDI scores. Findings We generated 9·3 billion estimates from the various combinations of prevalence, incidence, and YLDs for causes, sequelae, and impairments by age, sex, geography, and year. In 2015, two causes had acute incidences in excess of 1 billion: upper respiratory infections (17·2 billion, 95% uncertainty interval UI 15·4�19·2 billion) and diarrhoeal diseases (2·39 billion, 2·30�2·50 billion). Eight causes of chronic disease and injury each affected more than 10% of the world's population in 2015: permanent caries, tension-type headache, iron-deficiency anaemia, age-related and other hearing loss, migraine, genital herpes, refraction and accommodation disorders, and ascariasis. The impairment that affected the greatest number of people in 2015 was anaemia, with 2·36 billion (2·35�2·37 billion) individuals affected. The second and third leading impairments by number of individuals affected were hearing loss and vision loss, respectively. Between 2005 and 2015, there was little change in the leading causes of years lived with disability (YLDs) on a global basis. NCDs accounted for 18 of the leading 20 causes of age-standardised YLDs on a global scale. Where rates were decreasing, the rate of decrease for YLDs was slower than that of years of life lost (YLLs) for nearly every cause included in our analysis. For low SDI geographies, Group 1 causes typically accounted for 20�30% of total disability, largely attributable to nutritional deficiencies, malaria, neglected tropical diseases, HIV/AIDS, and tuberculosis. Lower back and neck pain was the leading global cause of disability in 2015 in most countries. The leading cause was sense organ disorders in 22 countries in Asia and Africa and one in central Latin America; diabetes in four countries in Oceania; HIV/AIDS in three southern sub-Saharan African countries; collective violence and legal intervention in two north African and Middle Eastern countries; iron-deficiency anaemia in Somalia and Venezuela; depression in Uganda; onchoceriasis in Liberia; and other neglected tropical diseases in the Democratic Republic of the Congo. Interpretation Ageing of the world's population is increasing the number of people living with sequelae of diseases and injuries. Shifts in the epidemiological profile driven by socioeconomic change also contribute to the continued increase in years lived with disability (YLDs) as well as the rate of increase in YLDs. Despite limitations imposed by gaps in data availability and the variable quality of the data available, the standardised and comprehensive approach of the GBD study provides opportunities to examine broad trends, compare those trends between countries or subnational geographies, benchmark against locations at similar stages of development, and gauge the strength or weakness of the estimates available. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980�2015: a systematic analysis for the Global Burden of Disease Study 2015

Background Improving survival and extending the longevity of life for all populations requires timely, robust evidence on local mortality levels and trends. The Global Burden of Disease 2015 Study (GBD 2015) provides a comprehensive assessment of all-cause and cause-specific mortality for 249 causes in 195 countries and territories from 1980 to 2015. These results informed an in-depth investigation of observed and expected mortality patterns based on sociodemographic measures. Methods We estimated all-cause mortality by age, sex, geography, and year using an improved analytical approach originally developed for GBD 2013 and GBD 2010. Improvements included refinements to the estimation of child and adult mortality and corresponding uncertainty, parameter selection for under-5 mortality synthesis by spatiotemporal Gaussian process regression, and sibling history data processing. We also expanded the database of vital registration, survey, and census data to 14�294 geography�year datapoints. For GBD 2015, eight causes, including Ebola virus disease, were added to the previous GBD cause list for mortality. We used six modelling approaches to assess cause-specific mortality, with the Cause of Death Ensemble Model (CODEm) generating estimates for most causes. We used a series of novel analyses to systematically quantify the drivers of trends in mortality across geographies. First, we assessed observed and expected levels and trends of cause-specific mortality as they relate to the Socio-demographic Index (SDI), a summary indicator derived from measures of income per capita, educational attainment, and fertility. Second, we examined factors affecting total mortality patterns through a series of counterfactual scenarios, testing the magnitude by which population growth, population age structures, and epidemiological changes contributed to shifts in mortality. Finally, we attributed changes in life expectancy to changes in cause of death. We documented each step of the GBD 2015 estimation processes, as well as data sources, in accordance with Guidelines for Accurate and Transparent Health Estimates Reporting (GATHER). Findings Globally, life expectancy from birth increased from 61·7 years (95 uncertainty interval 61·4�61·9) in 1980 to 71·8 years (71·5�72·2) in 2015. Several countries in sub-Saharan Africa had very large gains in life expectancy from 2005 to 2015, rebounding from an era of exceedingly high loss of life due to HIV/AIDS. At the same time, many geographies saw life expectancy stagnate or decline, particularly for men and in countries with rising mortality from war or interpersonal violence. From 2005 to 2015, male life expectancy in Syria dropped by 11·3 years (3·7�17·4), to 62·6 years (56·5�70·2). Total deaths increased by 4·1 (2·6�5·6) from 2005 to 2015, rising to 55·8 million (54·9 million to 56·6 million) in 2015, but age-standardised death rates fell by 17·0 (15·8�18·1) during this time, underscoring changes in population growth and shifts in global age structures. The result was similar for non-communicable diseases (NCDs), with total deaths from these causes increasing by 14·1 (12·6�16·0) to 39·8 million (39·2 million to 40·5 million) in 2015, whereas age-standardised rates decreased by 13·1 (11·9�14·3). Globally, this mortality pattern emerged for several NCDs, including several types of cancer, ischaemic heart disease, cirrhosis, and Alzheimer's disease and other dementias. By contrast, both total deaths and age-standardised death rates due to communicable, maternal, neonatal, and nutritional conditions significantly declined from 2005 to 2015, gains largely attributable to decreases in mortality rates due to HIV/AIDS (42·1, 39·1�44·6), malaria (43·1, 34·7�51·8), neonatal preterm birth complications (29·8, 24·8�34·9), and maternal disorders (29·1, 19·3�37·1). Progress was slower for several causes, such as lower respiratory infections and nutritional deficiencies, whereas deaths increased for others, including dengue and drug use disorders. Age-standardised death rates due to injuries significantly declined from 2005 to 2015, yet interpersonal violence and war claimed increasingly more lives in some regions, particularly in the Middle East. In 2015, rotaviral enteritis (rotavirus) was the leading cause of under-5 deaths due to diarrhoea (146�000 deaths, 118�000�183�000) and pneumococcal pneumonia was the leading cause of under-5 deaths due to lower respiratory infections (393�000 deaths, 228�000�532�000), although pathogen-specific mortality varied by region. Globally, the effects of population growth, ageing, and changes in age-standardised death rates substantially differed by cause. Our analyses on the expected associations between cause-specific mortality and SDI show the regular shifts in cause of death composition and population age structure with rising SDI. Country patterns of premature mortality (measured as years of life lost YLLs) and how they differ from the level expected on the basis of SDI alone revealed distinct but highly heterogeneous patterns by region and country or territory. Ischaemic heart disease, stroke, and diabetes were among the leading causes of YLLs in most regions, but in many cases, intraregional results sharply diverged for ratios of observed and expected YLLs based on SDI. Communicable, maternal, neonatal, and nutritional diseases caused the most YLLs throughout sub-Saharan Africa, with observed YLLs far exceeding expected YLLs for countries in which malaria or HIV/AIDS remained the leading causes of early death. Interpretation At the global scale, age-specific mortality has steadily improved over the past 35 years; this pattern of general progress continued in the past decade. Progress has been faster in most countries than expected on the basis of development measured by the SDI. Against this background of progress, some countries have seen falls in life expectancy, and age-standardised death rates for some causes are increasing. Despite progress in reducing age-standardised death rates, population growth and ageing mean that the number of deaths from most non-communicable causes are increasing in most countries, putting increased demands on health systems. Funding Bill & Melinda Gates Foundation. © 2016 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY licens

Philadelphia-negative Chronic Myeloproliferative Neoplasms

Chronic myeloproliferative diseases without the Philadelphia chromosome marker (Ph-), although first described 60 years ago, only became the subject of interest after the turn of the millennium. In 2001, the World Health Organization (WHO) defined the classification of this group of diseases and in 2008 they were renamed myeloproliferative neoplasms based on morphological, cytogenetic and molecular features. In 2005, the identification of a recurrent molecular abnormality characterized by a gain of function with a mutation in the gene encoding Janus kinase 2 (JAK2) paved the way for greater knowledge of the pathophysiology of myeloproliferative neoplasms. The JAK2 mutation is found in 90-98% of polycythemia vera and in about 50% essential thrombocytosis and primary myelofibrosis. In addition to the JAK2 mutation, other mutations involving TET2 (ten-eleven translocation), LNK (a membrane-bound adaptor protein); IDH1/2 (isocitrate dehydrogenase 1/2 enzyme); ASXL1 (additional sex combs-like 1) genes were found in myeloproliferative neoplasms thus showing the importance of identifying molecular genetic alterations to confirm diagnosis, guide treatment and improve our understanding of the biology of these diseases. Currently, polycythemia vera, essential thrombocytosis, myelofibrosis, chronic neutrophilic leukemia, chronic eosinophilic leukemia and mastocytosis are included in this group of myeloproliferative neoplasms, but are considered different situations with individualized diagnostic methods and treatment. This review updates pathogenic aspects, molecular genetic alterations, the fundamental criteria for diagnosis and the best approach for each of these entities.342140149Tefferi, A., Vainchenker, W., Myeloproliferative neoplasms: Molecular pathophysiology, essential clinical understanding, and treatment strategies (2011) J Clin Oncol., 29 (5), pp. 573-582. , Comment in: J Clin Oncol. 2011;29(18):e564-5Laszlo, J., Myeloproliferative disorders (MPD): Myelofibrosis, myeloscrerosis, extramedullary hematopoiesis, undifferentiated MPD, and hemorrhagic thrombocythemia (1975) Semin Hematol., 12 (4), pp. 409-432Vardiman, J.W., Harris, N.L., Brunning, R., The World Health Organization (WHO) classification of the myeloid neoplasms (2002) Blood., 100 (7), pp. 2292-2302. , Comment in: Blood. 2003;101(7):2895-6Tefferi, A., Vardiman, J.W., Classification and diagnosis of myeloproliferative neoplasms: The 2008 World Health Organization criteria and point-of-care diagnostic algorithms (2008) Leukemia., 22 (1), pp. 14-22. , Comment in: Leukemia. 2008;22(11):2118-9Vardiman, J.W., Thiele, J., Arber, D.A., Brunning, R.D., Borowitz, M.J., Porwit, A., The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes (2009) Blood, 114 (5), pp. 937-951. , Comment in: Blood. 2010;115(3):748-9author reply 749-50Thiele, J., Kvasnicka, H.M., Facchetti, F., Franco, V., van der Walt, J., Orazi, A., European consensus on grading bone marrow fibrosis and assessment of cellularity (2005) Haematologica., 90 (8), pp. 1128-1132Thiele, J., Kvasnicka, H.M., Diehl, V., Standardization of bone marrow features-does it work in hematopathology for histological discrimination of different disease patterns? (2005) Histol Histopathol., 20 (2), pp. 633-644Thiele, J., Kvasnicka, H.M., The 2008 WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis (2009) Curr Hematol Malig Rep., 4 (1), pp. 33-40Ahmed, A., Chang, C.C., Chronic idiopathic myelofibrosis: Clinicopathologic features, pathogenesis and prognosis (2006) Arch Pathol Lab Med., 130 (8), pp. 1133-1143Chauffaille, M.L., Neoplasias mieloproliferativas: Revisão dos critérios diagnósticos e dos aspectos clínicos (2010) Rev Bras Hematol Hemoter., 32 (4), pp. 308-316Maciel, J.F., de Lourdes Chauffaille, M., Inaoka, R.J., Colleoni, G.W., Yamamoto, M., Essential Thrombocythemia after treatment of non-Hodgkin's Lymphoma (2007) Leuk Res., 31 (11), pp. 1593-1595Gangat, N., Tefferi, A., Thanarajasingam, G., Patnaik, M., Schwager, S., Ketterling, R., Cytogenetic abnormalities in essential thrombocythemia: Prevalence and prognostic significance (2009) Eur J Haematol., 83 (1), pp. 17-21Baxter, E.J., Scott, L.M., Campbell, P.J., East, C., Fourouclas, N., Swanton, S., Vassiliou, G.S., Green, A.R., Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders (2005) Lancet., 365 (9464), pp. 1054-1061. , Cancer Genome Project. Erratum in: Lancet. 2005;366(9480):122Levine, R.L., Pardanani, A., Tefferi, A., Gilliland, D.G., Role of JAK2 in the pathogenesis and therapy of myeloproliferative disorders (2007) Nat Rev Cancer., 7 (9), pp. 673-683Barosi, G., Bergamaschi, G., Marchetti, M., Vannucchi, A.M., Guglielmelli, P., Antonioli, E., Massa, M., Barbui, T., JAK2 V617F mutational status predicts progression to large splenomegaly and leukemic transformation in primary myelofibrosis (2007) Blood., 110 (12), pp. 4030-4036. , Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA) Italian Registry of MyelofibrosisKantarjian, H., Schiffer, C., Jones, D., Cortes, J., Monitoring the response and course of chronic myeloid leukemia in the modern era of BCR-ABL tyrosine kinase inhibitors: Practical advice on use and interpretation of monitoring methods (2008) Blood, 111 (4), pp. 1774-1780Guglielmelli, P., Barosi, G., Specchia, G., Rambaldi, A., Lo Coco, F., Antonioli, E., Identification of patients with poorer survival in primary myelofibrosis based on the burden of JAK2V617F mutated allele (2009) Blood, 114 (8), pp. 1477-1483Tefferi, A., Lasho, T.L., Huang, J., Finke, C., Hanson, C.A., Mesa, R.A., Low JAK2V617F allele burden in primary myelofibrosis, compared to either a higher allele burden or unmutated status, is associated with inferior overall and leukemia-free survival (2008) Leukemia., 22 (4), pp. 756-761Tefferi, A., Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1 (2010) Leukemia., 24 (6), pp. 1128-1138Tefferi, A., Thiele, J., Orazi, A., Kvasnicka, H.M., Barbui, T., Hanson, C.A., Proposals and rationale for revision of the World Health Organization diagnostic criteria for polycythemia vera, essential thrombocythemia, and primary myelofibrosis: Recommendations from an ad hoc international expert panel (2007) Blood., 110 (4), pp. 1092-1097. , Comment in: Blood. 2008;111(3): 1741author reply 1742Johansson, P., Epidemiology of the myeloproliferative disorders polycythemia vera and essential thrombocythemia (2006) Semin Thromb Hematost, 32 (3), pp. 171-173Giuglielmelli, P., Tefferi, A., Advances in understanding and management of myeloproliferative neoplasms (2009) CA Cancer J Clin., 59 (3), pp. 171-191Girodon, F., Bonicelli, G., Schaffer, C., Mounier, M., Carillo, S., Lafon, I., Significant increase in the apparent incidence of essential thrombocythemia related to new WHO diagnostic criteria: A population-based study (2009) Haematologica., 94 (6), pp. 865-869Harrison, C.N., Bareford, D., Butt, N., Campbel, P., Conneally, E., Drummond, M., Erber, W., Everington, T., Guideline for investigation and management of adults and children presenting with a thrombocytosis (2010) Br J Haematol., pp. 352-375Lussana, F., Caberlon, S., Pagani, C., Kamphuisen, P.W., Buller, H.R., Cattaneo, M., Association of V617F Jak2 mutation with the risk of thrombosis among patients with essential thrombocythaemia or idiopathic myelofibrosis: A systematic review (2009) Thromb Res., 124 (4), pp. 409-417Biergegard, G., Long-term management of thombocytosis in essential thrombocythaemia (2009) Ann Hematol., 88 (1), pp. 1-10Landolfi, R., Gennaro, L., Prevention of thrombosis in polycythemia vera and essential thrombocythemia (2008) Haematologica., 93 (3), pp. 331-335. , Comment on: Haematologica. 2008;93(3):372-80Finazzi, G., Ruggeri, M., Rodeghiero, F., Barbui, T., Efficacy and safety of long-term use of hydroxyurea in young patients with essential thrombocythemia and a high risk of thrombosis (2003) Blood., 101 (9), p. 3749. , Comment on: Blood. 2001;97(4):863-6Beer, P., Erber, W., Campbell, P., Green, A., How I treat essential thrombocythemia (2011) Blood., 117 (5), pp. 1472-1482. , Comment in: Blood. 2011;118(4):1179-80author reply 1180-1Kerbauy, D.M., Gooley, T.A., Sale, G.E., Flowers, M.E., Doney, K.C., Georges, G.E., Hematopoietic cell transplantation as curative therapy for idiopathic myelofibrosis, advanced polycythemia vera, and essential thrombocythemia. (2007) Biol Blood Marrow Transplant., 13 (3), pp. 355-365Spivak, J., Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation (2010) Ann Intern Med., 152 (5), pp. 300-306Swerdlow, S.H., (2008) WHO classification of tumours of haematopoietic and lymphoid tissues, , International Agency for Research on Cancer., World Health Organization., Louis A. Duhring Fund. 4th ed. Lyon, France: International Agency for Research on CancerTefferi, A., Vaidya, R., Caramazza, D., Finke, C., Lasho, T., Pardanani, A., Circulating interleukin (IL)-8, IL-2R, IL-12, and IL-15 levels are independently prognostic in primary myelofibrosis: A comprehensive cytokine profiling study (2011) J Clin Oncol., 29 (10), pp. 1356-1363Barosi, G., Mesa, R.A., Thiele, J., Cervantes, F., Campbell, P.J., Verstovsek, S., Dupriez, B., Tefferi, A., Proposed criteria for the diagnosis of post-polycythemia vera and post-essential thrombocythemia myelofibrosis: A consensus statement from the International Working Group for Myelofibrosis Research and Treatment (2008) Leukemia., 22 (2), pp. 437-438. , International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)Cervantes, F., Dupriez, B., Pereira, A., Passamonti, F., Reilly, J.T., Morra, E., Vannucchi, A.M., New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for 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Leukemia., 25 (1), pp. 82-88Mesa, R.A., Nagorney, D.S., Schwager, S., Allred, J., Tefferi, A., Palliative goals, patient selection, and perioperative platelet management: Outcomes and lessons from 3 decades of splenectomy for myelofibrosis with myeloid metaplasia at the Mayo Clinic (2006) Cancer., 107 (2), pp. 361-370Elliott, M.A., Tefferi, A., Splenic irradiation in myelofibrosis with myeloid metaplasia: A review (1999) Blood Rev., 13 (3), pp. 163-170Ballen, K.K., Shrestha, S., Sobocinski, K.A., Zhang, M.J., Bashey, A., Bolwell, B.J., Outcome of transplantation for myelofibrosis (2010) Biol Blood Marrow Transplant., 16 (3), pp. 358-367Verstovsek, S., Kantarjian, H., Mesa, R.A., Pardanani, A.D., Cortes-Franco, J., Thomas, D.A., Safety and efficacy of INCB018424, a JAK1 and JAK2 inhibitor, in myelofibrosis (2010) N Engl J Med., 363 (12), pp. 1117-1127. , Comment in: N Engl J Med. 2010363(12): 1180-2N Engl J Med. 2010;363(25):2464author reply 2464-5discussion 2465Pardanani, A., Gotlib, 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