bluuebunny/crossref_metadata_2025_split huggingface dataset:
Urinary tract infection
Authors: Tomson Charles , Sheerin Neil 
Published: February 2020

Abstract
Urinary tract infection (UTI) is a common condition, accounting for 1 to 3% of all primary care consultations in the United Kingdom. It affects patients of both sexes and all ages. The commonest organism causing uncomplicated community-acquired bacterial UTI is Escherichia coli. The occurrence and course of a UTI is influenced by the integrity of the host defence and by bacterial virulence factors. Disruption of the highly specialized transitional cell epithelium which lines the urinary tract, incomplete bladder emptying, anatomical abnormalities, and the presence of a foreign body, such as a urinary catheter, can all contribute to disruption of the host defence and increase the likelihood of infection. Sexual intercourse and use of spermicides increase the risk, and genetic factors influence the susceptibility of some people. Diagnosis—acute uncomplicated UTI can often be diagnosed on symptoms alone, with urinalysis increasing diagnostic accuracy. Submission of a sample for microbiological testing is unnecessary in most cases. Differential diagnoses (‘culture-negative syndromes’) include chlamydial infection, urethral syndrome, and painful bladder syndrome (interstitial cystitis). Investigation—beyond microbiological testing, further investigation of women with uncomplicated UTI is seldom justified. In men, and those women with features indicating complicated infection, investigation for an underlying cause should be considered. Management: antibiotics—trimethoprim and nitrofurantoin remain the first choice for community-acquired UTI in the United Kingdom. Complicated UTI is caused by a wider spectrum of organisms, and recommendations for treatment differ. This chapter discusses the prevention of recurrent uncomplicated UTI and management of complicated UTIs due to urethral catheterization, urinary tract stones, anatomically abnormal kidneys, and pregnancy, and other causes such as fungal infections, tuberculosis, and schistosomiasis.
Urinary tract obstruction
Authors: Yaqoob Muhammad M. , McCafferty Kieran 
Published: February 2020

Abstract
Obstructive nephropathy can manifest as either a sudden or an insidious decline in renal function, which can be halted or even reversed by relief of obstruction. Obstruction can be due to anatomical or functional abnormalities of the urethra, bladder, ureter, or renal pelvis, which may be congenital or acquired, and it can also occur as a consequence of diseases extrinsic to the urinary tract. Although dilatation of the outflow system proximal to the site of obstruction is a characteristic finding, widening of the ureter and/or pelvicalyceal system does not necessarily indicate the presence of obstruction, and flow may be obstructed without such dilatation. Aetiology—calculi and pelviureteric junctional obstruction are common causes of unilateral obstruction, while prostatic enlargement, stone disease, and bladder and pelvic tumours account for about 75% of cases of bilateral obstruction in developed countries. To the clinician, the first and most important question is whether urinary tract obstruction is of recent onset (acute obstruction) or long-standing (chronic obstruction). The pathophysiological changes, clinical features, approach to investigation, and management differ in important respects in these two circumstances, which are discussed separately in this chapter under the headings of acute upper urinary tract obstruction, acute lower urinary tract obstruction, chronic upper urinary tract obstruction, and chronic lower urinary tract obstruction. Retroperitoneal fibrosis, a rare condition, is also discussed.
Introduction to haematology
Authors: Hatton Chris 
Published: February 2020

Abstract
Haematology is the study of the composition, function, and diseases of the blood. The approach to a patient suspected of having a haematological disorder begins with taking a history (particularly noting fatigue, weight loss, fever, and history of bleeding) and performing a clinical examination (looking for signs of anaemia, infection, bleeding, and signs of cellular infiltration causing splenomegaly and/or lymphadenopathy). Key investigations include a full blood count, a blood film, and (in selected cases) examination of the bone marrow. Further diagnostic tests now routinely performed on blood and marrow samples include immunophenotyping and cytogenetic and molecular analysis. Mutational signatures may be diagnostically useful and potentially define treatment, keeping haematology in the vanguard of advances in modern medicine.
Myelodysplastic syndromes
Authors: Brierley Charlotte K. , Steensma David P. 
Published: February 2020

Abstract
The myelodysplastic syndromes (MDS) are marrow failure syndromes characterized by cytopenias, blood cell dysmorphology, acquired clonal cytogenetic and molecular genetic mutations, and a risk of development of acute myeloid leukaemia. MDS may evolve in patients previously treated with cytotoxic chemotherapy or radiotherapy for a solid tumour, but most commonly arise de novo in patients over 60 years old. Most patients present with features of chronic anaemia or manifestations related to thrombocytopenia or infection. The diagnosis may be suggested by the presence of normocytic or macrocytic anaemia, with the peripheral blood smear showing dysplastic changes in red blood cells or neutrophils. Bone marrow aspirate and biopsy permits detailed cytogenetic study, which is critical for diagnostic classification and prognosis. Increasingly, molecular genetic assays (next-generation sequencing panels) aid in diagnosis and prognosis.
The World Health Organization (WHO) classification recognizes various MDS subtypes based on the morphological appearance of the peripheral blood and bone marrow. These include MDS with excess blasts, MDS with deletion of the long arm of chromosome 5, and MDS with ring sideroblasts.
Treatment is symptomatic in most cases. The only potentially curative treatment is allogeneic bone marrow transplantation, which is often precluded due to patients’ advanced age or comorbidity. Higher-risk patients may experience a survival benefit from treatment with the DNA hypomethylating agent azacitidine, and decitabine delays disease progression to acute myeloid leukaemia. Some patients with lower-risk disease may show a response to immunosuppression with antithymocyte globulin and ciclosporin. Patients with isolated chromosome 5q deletions and lower-risk disease may respond dramatically to lenalidomide, an immunomodulatory drug.
Chronic myeloid leukaemia
Authors: Copland Mhairi , Holyoake Tessa L. 
Published: February 2020

Abstract
Chronic myeloid leukaemia (CML) has a worldwide incidence of 1 to 2 per 100 000 of the population. Most cases are caused by translocation of the distal end of chromosome 9 on to chromosome 22 which leads to the creation of a fusion protein expressed from the fusion gene formed by juxtaposition of parts of the BCR and ABL1 genes. The resulting oncoprotein is a constitutive tyrosine kinase and appears to operate as an initiator for the development of the leukaemia. Clinical features—many patients are asymptomatic at diagnosis, which is made following a routine blood test. Others present with signs and symptoms including fatigue, sweats, fever, weight loss, haemorrhagic manifestations, and abdominal discomfort (due to splenomegaly). Diagnosis—this is typically made by the examination of a peripheral blood film and the demonstration of the Ph chromosome by conventional cytogenetics in a bone marrow aspirate or peripheral blood sample. Polymerase chain reaction analysis of peripheral blood confirms the presence of a BCR-ABL1 transcript and characterizes the BCR-ABL1 junction. Treatment—the original TKI, imatinib, has had a very significant impact on the first-line management of patients with CML. It induces durable complete cytogenetic responses in the majority of patients and prolongs overall survival substantially. Second- and third-generation TKIs show enhanced potency against BCR-ABL1 activity and are licensed within Europe for first-line (dasatinib, nilotinib) or second-line or subsequent (dasatinib, nilotinib, bosutinib, ponatinib) use in CML. Patients with suboptimal responses to first-line treatment can be offered a different second-line TKI; or a third-line TKI, such as ponatinib; or allogeneic stem cell transplantation—for patients less than 65 years of age and with a suitable donor.
The polycythaemias
Authors: Aruch Daniel , Hoffman Ronald 
Published: February 2020

Abstract
Polycythaemia or erythrocytosis is characterized by an abnormal increase in the numbers of red blood cells, leading to an elevation in the haemoglobin concentration and haematocrit (&gt;49% in men and &gt;48% in women). The cause may be either (1) primary—due to an intrinsic defect of haematopoietic stem cells; or (2) secondary—due to extrinsic stimulation of progenitor erythroid cells by circulating growth factors; and the condition needs to be distinguished from (3) pseudopolycythaemia—in which haematocrit is raised because the plasma volume is decreased. Secondary polycythaemias: associated with appropriate erythropoietin secretion—conditions that are ultimately the result of tissue hypoxia and subsequent excessive erythropoietin production include (1) living at high altitude, (2) chronic lung disease, (3) cyanotic congenital heart disease with right-to-left shunting, (4) carbon monoxide intoxication—as occurs in heavy smokers, (5) haemoglobin variants with increased oxygen affinity, and (6) mutations in genes involved in the oxygen sensing pathway. Associated with inappropriate erythropoietin secretion—in the absence of tissue hypoxia, inappropriate erythropoietin production commonly originates from the kidney and many renal disorders are associated with erythrocytosis. Tumour-associated polycythaemia may also result from cerebellar haemangioblastoma, hepatocellular carcinoma, phaeochromocytoma, and other adrenal tumours. Primary polycythaemia: polycythaemia vera—is a clonal, chronic progressive haematological malignancy characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic elements in the bone marrow. Aetiology—up to 95% of cases are caused by somatic mutations in the pluripotent haemopoietic stem cells leading to replacement of a key valine residue by phenylalanine at position 617 of the JAK2 kinase (V617F), which releases it from autoinhibition. Less common mutations have been described recently, primarily JAK2 exon 12 and LNK mutations.
Histiocytosis
Authors: Hatton Chris 
Published: February 2020

Abstract
The histiocytoses are disorders derived from the dendritic cell and monocyte/macrophage lineages, with the classification of this group of disorders relating to the underlying cell of origin. Dendritic cell disorders—there has been much debate about the nature of these conditions, and their status as neoplastic or primary inflammatory diseases; for Langerhans’ cell histiocytosis in particular, there is increasing evidence of their clonal nature, as manifest by recurrent BRAF mutations. Clinical features and diagnosis—these are highly variable and dependent on the sites affected by histiocytic infiltration. Symptoms and signs may include rashes, bony pain, lymphadenopathy, hepatomegaly and splenomegaly, cough and dyspnoea, features of marrow failure, and endocrine presentations (classically diabetes insipidus). Diagnosis typically follows imaging and biopsy, with the demonstration of a histiocytic infiltrate confirmed by immunostaining. Treatment and prognosis—the rarity and heterogeneity of these diseases has made it difficult to achieve a consensus on treatment. For localized disease, curettage, steroid injections, or targeted radiotherapy may be helpful. For more systemic disease, combination chemotherapy is typically used. Treatment schedules differ between adults and children. Prognosis is dependent mainly on the site(s) of involvement. Our expanding appreciation of the molecular basis of these conditions also provides some justification for the use of BRAF inhibitors and other targeted small molecule therapies. Macrophage-related disorders—these include haemophagocytic lymphohistiocytosis, a collection of macrophage-activating syndromes which may be either reactive to underlying inflammatory, infective, or neoplastic disease, or consequent upon a primary genetic lesion affecting cytotoxic T-cell killing function. Rosai–Dorfman disease is a separate macrophage proliferation syndrome, thought to be non-neoplastic, which causes massive cervical lymphadenopathy, usually in children.
Hodgkin lymphoma
Authors: Bhatt Vijaya Raj , Armitage James O. 
Published: February 2020

Abstract
Hodgkin’s lymphoma is derived from a profoundly defective B cell, with the pathobiology, histology, and clinical features being both characteristic and distinct from non-Hodgkin’s lymphomas. Its cause is unknown. Incidence is about 3 per 100 000 per year in Western countries with a bimodal age distribution meaning that it is one of the commoner lymphomas of young people. Most cases are highly responsive to combination chemotherapy, with many patients being cured of their disease. Patients with Hodgkin’s lymphoma may present with lymphadenopathy, a mediastinal (or other) mass, and systemic symptoms including weight loss, fever, and night sweats (B-symptoms). Workup requires staging with positron emission tomography (PET)-CT imaging, and biopsy. Classical Hodgkin’s lymphoma is defined by the presence of the binucleate Reed–Sternberg cell in an appropriate inflammatory histological context. These cells have a characteristic immunohistochemical phenotype, showing CD15 and CD30 positivity, but being immunonegative for classical B-cell markers such as CD20. Additional histological subtypes have been defined, with the most clinically significant being lymphocyte-predominant Hodgkin’s lymphoma. Patients with localized disease may be treated with chemotherapy with or without radiotherapy. Those with more advanced-stage disease require combination chemotherapy, with radiotherapy to sites of initial bulk disease. While relapse is uncommon in patients with early-stage disease, some 20% of patients with advanced-stage disease may need ‘salvage’ chemotherapy regimens for relapsed disease, when the aim is to attain PET negativity before embarking on high-dose therapy with stem cell rescue. Since many patients have a good outcome, it is essential to minimize the long-term sequelae of treatment. Risk stratification is a major focus of clinical trials in this area to determine optimal treatment strategies.
Acquired aplastic anaemia and pure red cell aplasia
Authors: Marsh Judith C.W. , Gandhi Shreyans , Mufti Ghulam J. 
Published: February 2020

Abstract
Aplastic anaemia (AA) is a rare bone marrow failure (BMF) disorder characterized by pancytopenia and a hypocellular bone marrow. AA is commonly acquired, immune mediated, and idiopathic in nature. Activated autoreactive, cytotoxic CD8+ T cells are present but recent work has shown that CD4+ T cells appear to be more important in the pathogenesis of acquired AA. The immune nature of acquired AA provides the rationale for one of the treatment options, namely immunosuppressive therapy. First-line treatment of acquired AA is either immunosuppressive therapy with antithymocyte globulin and ciclosporin or allogeneic haematopoietic stem cell transplantation (HSCT). Both modalities offer excellent survival. Patients treated with immunosuppressive therapy are at later risk of relapse and clonal evolution to myelodysplastic syndrome and acute myeloid leukaemia, so require long-term follow-up. HSCT, if successful, is curative, but risks include graft rejection, infections, and graft-versus-host disease (GVHD); recent changes to the transplant conditioning regimen have reduced the GVHD risk. The inherited forms of AA include Fanconi’s anaemia, a disorder of DNA repair, dyskeratosis congenita, a disorder of telomere maintenance, and Shwachman–Diamond syndrome, one of the so-called ribosomopathies characterized by defective ribosomal biogenesis. Pure red cell aplasia (PRCA) is a form of BMF characterized by severe anaemia with reticulocytopenia and reduced erythroid progenitors in the bone marrow. PRCA most commonly is an acquired disorder and immune mediated, and often occurs in association with a wide range of conditions. Diamond–Blackfan anaemia, an inherited form of PRCA, is another example of a ribosomopathy, and is caused by mutations in one of many ribosomal protein genes, resulting in haploinsufficiency.
Paroxysmal nocturnal haemoglobinuria
Authors: Luzzatto Lucio 
Published: February 2020

Abstract
Paroxysmal nocturnal haemoglobinuria (PNH) is a unique disorder in which many of the patient’s red cells have an abnormal susceptibility to activated complement. This results from the presence of a clone that originates from a haematopoietic stem cell bearing an acquired somatic mutation in the X-linked gene PIGA, required for the biosynthesis of the glycosylphosphatidylinositol molecule which anchors many proteins to the cell membrane, including the complement regulators CD59 and CD55. The ‘classical’ presentation is with ‘passing blood instead of urine’ (haemoglobinuria). Sometimes the patient presents with the full triad of (1) haemolytic anaemia, (2) pancytopenia, and (3) thrombosis—most commonly of intra-abdominal veins. An element of bone marrow failure is always present; and sometimes the disease may be preceded by or may evolve to bone marrow aplasia indistinguishable from acquired aplastic anaemia. Definitive diagnosis is based on demonstrating the presence of a discrete population of ‘PNH red blood cells’ by flow cytometry using anti-CD59. In most cases, especially when the patient is transfusion dependent and/or has severe signs and symptoms, there is an indication for long-term treatment with the complement inhibitor eculizumab.
Iron metabolism and its disorders
Authors: Cox Timothy M. , Porter John B. 
Published: February 2020

Abstract
Iron deficiency and iron storage disease—the latter principally due to inherited and acquired anaemias such as thalassemia—are disorders of massive clinical significance across the globe. Iron deficiency is the commonest cause of anaemia, affecting about 1 billion people, and about 0.75 million people have thalassaemia. Largely neglected by health services in rich and resource-poor countries alike, disorders of iron metabolism, whether inherited, nutritional, or otherwise, represent a long-standing public health challenge. Improved screening methods for detection, diagnosis, and appropriate supplementation—as well as genetic counselling—can offer a great deal to relieve the burden in stricken communities. Advances in chelation therapy have improved the survival of patients with iron-loading anaemias and transfusion-related haemochromatosis, and better understanding of the molecular pathophysiology of iron homeostasis now offers the prospect of definitive therapies to control pathological erythropoiesis and the inappropriate drive to acquire lethal quantities of toxic iron.
Disorders of the synthesis or function of haemoglobin
Authors: Hay Deborah , Weatherall David J. 
Published: February 2020

Abstract
The inherited disorders of haemoglobin are the commonest single-gene disorders in the world. Disorders of haemoglobin can be genetic or acquired and due to disordered production of one or more globin chains or structural change in the globin chain. The most important disorders are the genetic conditions thalassaemia and sickle cell disease. Thalassaemia—a heterogeneous group of genetic disorders, all resulting from a reduced rate of production of one or more of the globin chains of haemoglobin and inherited in a simple Mendelian fashion. They are clinically classified according to their severity into major (a severe transfusion-dependent disorder), intermediate (characterized by anaemia and splenomegaly), and minor (a symptomless carrier state) forms. The β thalassaemias are the most important types of thalassaemia because they are very common and produce severe anaemia in their homozygous and compound heterozygous states. Most countries in which the disease is common are putting a major effort into programmes for its prevention (population screening and prenatal diagnosis). Symptomatic management of severe disease requires regular blood transfusion, judicious use of splenectomy if hypersplenism develops, and chelating agents to reduce iron overload. Sickle cell disease—haemoglobin S differs from haemoglobin A by the substitution of valine for glutamic acid at position 6 in the β globin chain, and homozygosity for haemoglobin S produces the state of sickle cell disease. This occurs very frequently in African populations and, sporadically, throughout the Mediterranean region and the Middle East, with extensive pockets in India. Management of both acute and chronic complications remains largely supportive, with hydroxycarbamide being the only clinically proven effective treatment to date.
Acquired haemolytic anaemia
Authors: Powers Amy , Silberstein Leslie 
Published: February 2020

Abstract
Premature destruction of red cells occurs through two primary mechanisms: (1) decreased erythrocyte deformability that leads to red cell sequestration and extravascular haemolysis in the spleen and other components of the reticuloendothelial system—may be caused by membrane defects, metabolic abnormalities, exogenous oxidizing agents, or pathological antibodies; and (2) red cell membrane damage and intravascular haemolysis—may be caused by exposure to pathological antibodies, activated complement, mechanical forces, chemicals, and infectious agents. Congenital haemolytic anaemias—congenital disorders resulting in a haemolytic anaemia include (1) disorders of the red cell membrane such as hereditary spherocytosis and hereditary elliptocytosis; (2) disorders of red cell enzymes such as glucose-6-phosphate dehydrogenase deficiency and pyruvate kinase deficiency; and (3) disorders of globin structure. Acquired immune haemolytic anaemias—immune haemolysis may occur when IgG, IgM, or IgA antibodies and/or complement bind to the erythrocyte surface. Autoimmune haemolytic anaemias—these are best classified according to the temperature at which the antibody optimally binds to the erythrocyte: warm autoimmune haemolytic anaemia, cold agglutinin-mediated autoimmune haemolytic anaemia, paroxysmal cold haemoglobinuria, and mixed type autoimmune haemolytic anaemia. Drug-induced haemolytic anaemia—haemolysis can be caused by drugs that induce a positive DAT. Drug-induced antibodies may be drug dependent or drug independent depending on whether the presence of the drug is required for their detection. Alloimmune haemolytic anaemias—these include acute haemolytic transfusion reactions and other conditions such as delayed haemolytic transfusion reactions, passenger lymphocyte haemolysis, and haemolytic disease of the newborn. Acquired nonimmune haemolytic anaemias and microangiopathic haemolytic anaemia are also discussed in this chapter.