bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient Ischaemic Attack and Stroke
Authors: Luft Andreas , Lüscher Thomas F.
Published: January 2022

Transient ischaemic attacks (TIAs) are caused by an ischaemic focal neurological deficit lasting less than 24 hours without structural brain injury, as determined by diffusion-weighted MRI. Ischaemic stroke, on the other hand, is associated with a structural brain lesion. Causes are a transient or permanent occlusion of a cerebral artery with regional reduction of tissue perfusion, ischaemia, and transient or permanent neurological dysfunction. Cerebral arteries may occlude due to atherosclerosis of large cerebrovascular arteries, microvascular cerebral disease, haemodynamically induced ischaemia in the presence of severe carotid stenosis, or cardiac or paradoxical embolism. Rarely, aortic or carotid dissection can cause TIA or stroke. Risk factors are age, arterial hypertension, diabetes, smoking, lipid disorders, atrial fibrillation, and aortic valve disease, as well as obstructive sleep apnoea. The diagnosis involves cerebral imaging with computer tomography or MRI, as well as colour-coded duplex sonography of the extracranial cerebral arteries. Treatment may involve intravenous thrombolysis or intra-arterial catheter-based thrombectomy or antihypertensive medication in those with blood pressure values above 220 mmHg systolic. Secondary prevention is similar to that of acute coronary syndromes, but also involves left atrial appendix occlusion in those at high bleeding risk, and a history of TIA or embolic stroke.
Acute Pulmonary Embolism
Authors: Konstantinides Stavros V.
Published: January 2022

Acute pulmonary embolism occurs due to dislodgement of a venous thrombus into the pulmonary circulation with obstruction of a major pulmonary artery leading to dyspnoea and, in severe cases, to haemodynamic instability and acute death. Patient outcome is determined by the presence and severity of acute right ventricular failure. Diagnosis today is mainly performed by computer tomography, echocardiography with measurements of pulmonary artery systolic pressure, and biomarkers, such as BNP or NT-proBNP and troponin. The treatment involves immediate anticoagulation, usually with heparin, or more recently with NOACs. High-risk pulmonary embolism may require systemic thrombolysis, and in experienced centres—surgical embolectomy or percutaneous catheter-directed treatment with low dose thrombolysis assisted with ultrasound. Follow-up should be considered at 3–6 months to determine clinical status, pulmonary pressure, and functional limitation. The duration of anticoagulation and potentially other measures, such as catheter-based pulmonary balloon angioplasty or surgical endarterectomy should be decided based on clinical criteria.
Anticoagulation in Atrial Fibrillation
Authors: Reissmann Bruno , Kirchhof Paulus
Published: January 2022

Atrial fibrillation increases mortality and morbidity and in particular leads to thrombotic events in the left atrium, especially in the left atrial appendix leading to embolic stroke or peripheral embolization. The risk of stroke can be assessed by the CHA2DS2-VASc score, which involves vascular disease, history of stroke or TIA, diabetes, hypertension and heart failure, and female sex. Oral anticoagulation prevents stroke and peripheral embolism and premature death in these patients and is generally recommended with a CHA2DS2-VASc score of >2. For those with a CHA2DS2-VASc score of 1, oral anticoagulation can be considered in males, but not in females. The guidelines recommend NOACs as the first choice in this context and vitamin K antagonists in those with mechanical heart valves. In patients with atrial fibrillation and coronary artery disease, particularly those after stenting, antithrombotic management is difficult and controversial. In general, it is recommended to use triple anticoagulation in the first month and thereafter, a P2Y12 inhibitor plus a NOAC possibly at a lower dose in those with high bleeding risk.
Vertebroplasty and kyphoplasty in spinal metastasis pain
Authors: Das Kumar S.V. , Biswas Shubhabrata
Published: January 2022

Percutaneous vertebroplasty (PV) is a minimally invasive vertebral augmentation procedure used to provide pain relief and stabilization to a vertebra which is partially collapsed or at risk of collapse. This chapter covers the advantages, contraindications, and complications related to PV. Kyphoplasty and vertebroplasty with tumour ablative therapy are also discussed and the chapter includes a list of key learning points.
Endocrinology, Sleep, and Circadian Rhythms
Authors: Brabant Georg , Oster Henrik
Published: January 2022

Hormonal signalling is a central component of the regulation of sleep, behaviour, and multiple other physiological processes aligned with external time cues through endogenous circadian clocks. Endocrine feedback to the circadian clock is exerted via key systems and supports the robustness of endogenous rhythmicity. It is challenged by multiple modern lifestyle factors such as shift work, light pollution, or high-calorie diets which may alter this delicate balance and shift physiological set points. The following chapter summarizes current knowledge on the underlying mechanisms controlling this interregulation of circadian timing, sleep, and the endocrine system, and what disorders may be caused by its imbalance.
Principles of Hormone Replacement
Authors: Ross Richard
Published: January 2022

The aim of hormone replacement is to replace the missing physiological effects of a deficient hormone. The last century identified most of the endocrine hormones, which can now be replaced when deficient; however, the challenge of the twenty-first century is to optimize replacement. The guiding principle in hormone replacement is replicating the natural levels and rhythms of hormones at different ages but this requires a good understanding of physiology. There is a need for better biomarkers of hormone actions and using these to develop new ways to deliver hormone replacement tailored to the individual. This chapter discusses current approaches to this problem.
Craniopharyngiomas
Authors: Karavitaki Niki
Published: January 2022

Craniopharyngiomas are rare tumours with an incidence of around 0.13 cases per 100 000 person-years. There are two histological subtypes with distinct pathological features: adamantinomatous and papillary. Their pathogenesis remains to be elucidated and recent data suggest the implication of Wnt signalling pathway (for adamantinomatous) and activating mutations in BRAF (V600E) (for papillary). They may present with a variety of clinical manifestations attributed to pressure effects on vital structures of the brain (visual pathways, brain parenchyma, ventricular system, major blood vessels, and hypothalamo-pituitary system). Main management approach is surgery combined or not with adjuvant radiotherapy and, in cases of hypothalamic involvement, conservative surgery is advocated. Patients with craniopharyngioma suffer from significant long-term morbidities (mainly endocrine, visual, hypothalamic, neurobehavioural, and cognitive) attributed to the damage of critical neuronal structures by the primary or recurrent tumour and/or to the adverse effects of the therapeutic interventions and requiring lifelong care. The recent data on the pathogenesis of craniopharyngiomas are promising for the development of targeted therapies.
Causes and Laboratory Investigations of Thyrotoxicosis
Authors: Latrofa Francesco , Vitti Paolo
Published: January 2022

The term thyrotoxicosis identifies the clinical syndrome caused by elevated circulating thyroid hormones of all sources, while hyperthyroidism includes only the disorders due to an increased secretion of hormones by the thyroid gland. Hyperthyroidism is the most frequent cause of thyrotoxicosis. Unregulated discharge of preformed thyroid hormones due to destructive processes of the gland (destructive thyrotoxicosis) and exogenous ingestion or extrathyroidal production of thyroid hormones (thyrotoxicosis of non-thyroidal origin) are less common causes of thyrotoxicosis. Although careful history taking and physical examination often direct towards the diagnosis of thyrotoxicosis, laboratory confirmation by measurement of thyroid-stimulating hormone (TSH) and thyroid hormones is always needed. Once thyrotoxicosis is confirmed, laboratory testing and thyroid imaging are required to identify the cause of thyrotoxicosis.
Antithyroid Drugs for Thyrotoxicosis
Authors: Bartalena Luigi
Published: January 2022

Antithyroid drugs (ATDs) effectively and conservatively control Graves’ hyperthyroidism, being a valid alternative to the definitive treatments, radioiodine or thyroidectomy, which cause lifelong hypothyroidism. However, ATD withdrawal is followed by a relapse of hyperthyroidism in 30–70% of patients. Relapsing hyperthyroidism should in most cases be managed by a definitive treatment. ATD adverse events are usually minor, but major and even life-threatening adverse events may rarely occur, including agranulocytosis, severe hepatotoxicity, and vasculitis. Major adverse events are more frequent (and dose-unrelated) with propylthiouracil (PTU) than with methimazole (MMI). Accordingly, MMI is the first-choice ATD. PTU maintains a role in the first trimester of pregnancy because of the potential (although rare) ‘methimazole embryopathy’. ATDs represent the treatment of choice in pregnant and lactating women, and the first-line treatment in children and adolescents.
Management of Thyrotoxicosis Without Hyperthyroidism
Authors: Wiersinga Wilmar M.
Published: January 2022

Thyrotoxicosis without hyperthyroidism is due to destructive thyroiditis (a self-limiting condition caused by release of preformed T4 and T3 stored in the colloid space, like in subacute thyroiditis of De Quervain and in amiodarone-induced thyrotoxicosis type 2), thyrotoxicosis factitia (excess of exogenous thyroid hormone, recognized by undetectable serum thyroglobulin), or struma ovarii. Characteristics are low to absent thyroidal radioiodine uptake, and low to absent thyroid vascularity on ultrasonography. Cytokine-, iodine-, and amiodarone-induced thyrotoxicosis manifest themselves either as thyrotoxicosis without hyperthyroidism, or as thyrotoxicosis with hyperthyroidism in which thyroidal radioiodine uptake is preserved. Both types are discussed in this chapter, along with techniques for their management.
Management of the Single Thyroid Nodule
Authors: Hegedüs Laszlo , Bennedbæk Finn N.
Published: January 2022

The main concern of patients and physicians alike, when dealing with the solitary thyroid nodule, is to diagnose the few cancers (approximately 5%) as rapidly and cost-effectively as possible and to reduce superfluous thyroid surgery. Very little is known regarding the natural history of thyroid nodules, since data are highly selected and generally concern patients with small nodules without suspicion of malignancy and not causing pressure symptoms or cosmetic complaints. With these restrictions, most nodules appear not to change appreciably over time. The nodules that increase in size are predominantly solid and carry a higher risk of harbouring thyroid carcinoma than those predominantly cystic, being more prone to decrease in size or even disappear. This chapter focuses on the palpably discrete swelling within an otherwise normal gland in the clinically and biochemically euthyroid patient. The toxic nodule is dealt with in Chapter 3.3.11, and thyroid malignancy in Chapters 3.5.4–3.5.7.
Genetics of Adrenal Insufficiency
Authors: Chan Li F. , Ramachandrappa Shwetha
Published: January 2022

Adrenal insufficiency is a rare and potentially fatal medical condition. In children, the cause is often genetic. With the increasing availability and reducing cost of next generation sequencing, the number of causative gene mutations that give rise to adrenal insufficiency (isolated or as part of a syndrome) has increased dramatically. Defects in ACTH signalling, steroidogenesis, antioxidant mechanisms, DNA replication/repair, and autoimmunity have all been described to cause primary adrenal insufficiency, while those affecting pituitary development and POMC synthesis, processing, and transcription give rise to secondary forms of adrenal insufficiency. As well as enhancing our understanding of pituitary/adrenal gland biology these discoveries have yield generated important insights into the tissue and temporal specificity of several fundamental cellular processes.
Glucagonoma
Authors: Meeran Karim
Published: January 2022

Glucagonomas are rare neuroendocrine tumours of the alpha cells of the pancreas that present with a rash and diabetes. There are under five new cases in the United Kingdom each year. The necrolytic migratory erythema presents to dermatologists. Glucagonomas can be benign or malignant in approximately equal proportions. Despite metastatic disease, the usually responds to somatostatin analogues such as octreotide and lanreotide. Tachyphylaxis occurs, so the dose is often increased over the course of the first 2 years. Patients with the gene for multiple endocrine neoplasia type 1 have an increased risk of neuroendocrine tumours of the pancreas including glucagonomas. Because these tumours often express somatostatin receptors, imaging with Gallium 68 labelled dotatate with a PET scan. Treatment choices should be discussed at a multidisciplinary meeting. Patients with uptake on Gallium 68 scanning can be treated with radiolabelled lutetium 177 labelled dotatate. The 5-year survival for patients with glucagonomas is 50–70%.
Multiple Endocrine Neoplasia Type 2a and 2b
Authors: Kebebew Electron , Wiseman Douglas , El Lakis Mustapha
Published: January 2022

Multiple endocrine neoplasia (MEN) type 2a (also referred to as type 2) is an inherited cancer syndrome in which an individual has medullary thyroid carcinoma, primary hyperparathyroidism, and/or phaeochromocytoma occurring either synchronously or metachronously. MEN type 2b (also referred to as type 3) comprises early onset medullary thyroid carcinoma and phaeochromocytoma in addition to phenotypical features such as ophthalmologic abnormalities, skeletal malformations, and a generalized ganglioneuromatosis. MEN 2a and 2b (MEN 2 and 3) are caused by germline mutations in the RET proto-oncogene. The proper and timely diagnosis of MEN 2a and MEN 2b will have a direct impact on patients’ quality of life, disease-specific mortality, and overall survival. It will also impact the life of family members at risk of having MEN 2a and 2b. This chapter addresses the epidemiology, genetics, diagnostic approaches, and management of MEN 2a and MEN 2b. In addition, it highlights the importance of genetic counselling for at-risk family members and optimal surveillance strategies in RET germline mutation carriers.
Hormonal Male Contraception
Authors: Page Stephanie T. , Farrant Maritza T.
Published: January 2022

Despite a number of contraceptive choices for women, nearly 40% of global pregnancies are unplanned. Men play a significant role in effective family planning, accounting for nearly one-quarter of all contraceptive use worldwide. The development of novel male contraceptive methods that are efficacious, reliable, safe, and reversible could help address unmet contraceptive needs. Male hormonal contraception (MHC) is based on the reversible suppression of the hypothalamic–pituitary–testicular axis. Exogenous androgens form the basis of MHC, but combinations of testosterone plus progestins and/or gonadotropin-releasing hormone antagonists, as well as novel compounds with androgenic or androgenic–progestogenic properties show promise. In efficacy studies of 12–24 months, male hormonal contraceptives have failure rates of <5%, superior to condoms, and comparable to female hormonal contraceptives in real use. Side effects are mild and include acne, modest weight gain, and reduction of high-density lipoproteins (HDL). Studies indicate MHC has a high level of acceptability among couples, although side effects and impacts on long-term disease risk require larger, longer trials.
Environmental Influences on Male Reproductive Health
Authors: Toppari Jorma
Published: January 2022

Environmental influences on male reproductive health has been well documented in wildlife and experimental animals, in which mechanisms of action have also been revealed. These examples provide robust evidence of adverse effects of endocrine-disrupting chemicals on male reproductive system. Human effects have been more difficult to pinpoint because of limitations in epidemiological observations, and the best evidence of reproductive toxicity in humans comes from occupational settings and environmental accidents. The general population is exposed to a multitude of chemicals simultaneously—thus mixture effects are of special interest. In utero exposures can cause the most harmful and irreversible effects in postnatal/adult life so that developmental and reproductive toxicities are meaningfully studied in tandem.
The Endocrinology of Anorexia Nervosa
Authors: Miller Karen K.
Published: January 2022

The endocrine complications of anorexia nervosa are myriad and reflect the effects of chronic starvation on hypothalamic–pituitary axes, adipokines, and satiety pathways. Hypothalamic amenorrhoea is a common, but not universal, complication of the disorder, as are hypercortisolaemia, non-thyroidal illness syndrome, and hyponatraemia. An additional endocrine complication of anorexia nervosa is growth hormone (GH) resistance, characterized by elevated GH and relatively low insulin-like growth factor-1 (IGF-1) levels. Levels of some anorexigenic adipokines and orexigenic gut peptides reflect both a predicted response to chronic starvation and dysregulation. Much—but not all—of the endocrine dysregulation observed in this disorder appears to be adaptive to low weight and is functional and reversible. However, endocrine dysregulation contributes to the very prevalent and severe bone loss observed in adolescent girls and women with anorexia nervosa and may also contribute to the very common neuropsychiatric comorbidities observed in such patients.
Use and Abuse of Performance-Enhancing Hormones in Sport
Authors: Sonksen Peter , Holt Richard I.G.
Published: January 2022

Attempts to make gains in performance through training is part of normal competitive sport but over generations the lure of being a champion has tempted people to explore other performance-enhancing methods outside the ‘fair playing field’ of sport; this includes the misuse of several hormones. Androgenic anabolic steroids (AAS) are the most frequently misused hormones since, when combined with training, they enhance lean body mass, muscle bulk, and strength resulting in improved performance. Growth hormone, insulin, and IGF-I act in synergy with AAS and are frequently misused together in complicated regimes that are often difficult to detect. Erythropoietin by enhancing oxygen delivery to exercising muscles has also been shown to be a powerful performance-enhancing hormone, particularly in aerobic sports. Attempts to control the misuse of substances and methods has had limited success but is a war that is likely to continue with increasingly sophisticated ‘weapons’ on both sides.
Metastatic Disease in Endocrine Organs
Authors: Papathomas Thomas G. , Nosé Vania
Published: January 2022

Endocrine organs are classified into primary and secondary based on whether a hormone-secreting organ synthesizes the relevant hormone(s) as a primary function or not. The prevalence of metastatic malignancy varies in the clinical setting, and recognition of metastatic disease in endocrine organs is important for various reasons. This chapter will focus on metastatic disease in major endocrine organs, including adrenals, pituitary, thyroid and parathyroid glands, from malignancies other than haemato-lymphoid neoplasms. Their presence is best regarded as generalized involvement rather than metastatic spread. Herein, this chapter discusses the prevalence and importance of recognition of metastases in endocrine organs and highlight various aspects of endocrine organ-specific metastatic disease.
Planning Obesity Care Pathways
Authors: Finer Nicholas
Published: January 2022

The development of care pathways aims to provide a continuum of care often across multiple clinical settings with aim of improving quality and outcomes. While most commonly developed for scenarios in which trajectories of care are predictable and occur over short periods of time, they have also been developed for chronic disease management. Care pathways, as opposed to clinical guidelines, have been recommended and patchily developed in England to coordinate the delivery of management across public health, primary care, and specialist settings. However true comprehensive pathways for the individual patient have been poorly implemented by providers and remain rudimentary and often out of step with guidelines.
Genetic Forms of Dyslipidaemia
Authors: Romeo Stefano , Angelin Bo , Parini Paolo
Published: January 2022

While monogenic diseases are typically considered rare, elevated lipoprotein levels due to single sequence variants are fairly common, with, for example, the prevalence of familial hypercholesterolaemia being as high as 1 in 250 in the general population. Identification of such monogenic disorders and formal genetic diagnosis is imperative to tailor treatment and to pre-empt complications in family members carrying pathogenic mutations. Dyslipidaemias may be ‘primary’ and genetic, in which severe dyslipidaemia is the inevitable result of an underlying genetic mutation, and these will be the main focus of this chapter. This chapter also aims to provide an accessible account of known monogenic disorders causing hyperlipidaemia, with a focus on diagnosis and treatment.
Glucose Monitoring and Sensing
Authors: Pickup John , Oliver Nick
Published: January 2022

Glucose monitoring is critical to enable people with diabetes to self-manage effectively, especially those with insulin-treated diabetes. Self-monitoring of capillary blood glucose (SMBG) has been available to people with diabetes for four decades and is now being supplemented and, for some, superseded by continuous glucose monitoring (CGM) provided by subcutaneously implanted sensors. Information such as estimated glucose concentrations, rate of change, alerts for impending glucose extremes and historical patterns can enable more appropriate carbohydrate intake, physical activity, insulin administration, and lifestyle decisions in real-time. Improvements in overall glycaemic control, as measured by HbA1c, time-in-range for glucose readings, hypoglycaemia exposure, and hypoglycaemic events, as well as quality of life, have all been reported with CGM. Flash glucose monitoring (FGM) with retrospective review of previously recorded continuous glucose readings from a subcutaneous glucose sensor is likely to be a replacement for SMBG. Sensor-augmented insulin pump therapy uses CGM data for feedback control of insulin delivery, and pumps with automatic low glucose-activated suspend of the basal insulin infusion are already in widespread clinical use and effective at reducing hypoglycaemia in type 1 diabetes. Hybrid closed-loop systems employing CGM are entering practice and fully closed-loop systems are under development.
Strategies for the Management of Type 2 Diabetes
Authors: Winocour Peter , Zac-Varghese Sagen
Published: January 2022

The approach to the management of hyperglycaemia in type 2 diabetes has become increasingly complex with a widening armamentarium of available antihyperglycaemic agents. It is well recognized that several agents have additional benefits (outside of glucose control), for example, on weight management and on cardiovascular and renal outcomes. Recent cardiovascular outcome trial data has had an impact on treatment algorithms. This chapter looks at strategies for deploying the various agents. The initiation of therapy, intensification of therapy, and combination of agents is discussed. The choice of agent in particular circumstances, in cardiovascular disease, renal disease, and hepatic impairment is discussed. Successful management requires a patient-centred approach with careful consideration of the risks and benefits of the treatment options.
Psychological and Behavioural Aspects of Type 2 Diabetes Management
Authors: Skinner Timothy C. , Speight Jane
Published: January 2022

Type 2 diabetes is a complex condition requiring attention to blood glucose, blood pressure, cholesterol, and emotional well-being. The overall objective of diabetes self-management is to reduce these risk factors, thereby preventing, delaying, or minimizing risk of long-term complications. Typical strategies include informed dietary choices and physical activity, medication taking and monitoring glucose levels; and, for many, this will also include the challenge of sustaining some weight loss. Substantial advances in medical technologies and treatments in the past 20 years have not been matched with comparable improvements in biomedical outcomes. This chapter highlights five common facets or ‘SHADEs’ of diabetes distress: Scared, Helpless, Alone, Deprived, and Exhausted. As the role of health professionals is not to manage diabetes but rather support people to self-manage their own diabetes, this acronym can be used in clinical practice to identify constructive and creative ways to motivate and sustain effective self-management.
Regenerative Medicine for Diabetes
Authors: White Michael G. , Ellis Cara E. , Kieffer Timothy J.
Published: January 2022

Insulin-dependent diabetes affects millions of people worldwide and results in significant burdens to both patients and healthcare systems. Islet transplantation provides superior glycaemic control compared to the standard therapy of injectable insulin, with decreased risk of hypoglycaemia. However, cadaveric donor islets will never be a sufficient supply of insulin-producing cells to treat all patients, and the need for chronic immunosuppression to protect the grafts limits the pool of candidates for the procedure. Years of research unravelling the complex processes and signalling pathways that lead to the differentiation and maturation of beta cells during development has facilitated the advancement of multiple diverse strategies towards creating potentially unlimited numbers of insulin-producing cells to treat insulin-dependent diabetes. In this chapter, we review some of the recent progress towards generating beta cells from pluripotent stem cells and inducing expansion of endogenous beta cells.
Hyperglycaemic Emergencies
Authors: Dhatariya Ketan
Published: January 2022

Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic syndrome (HHS) are the most commonly occurring metabolic medical emergencies. They are seldom the first presentation of diabetes, but most frequently occur due to infection, or non-concordance with prescribed medications. The diagnosis of DKA should only be made if all three components (the ‘D’, the ‘K’, and the ‘A’) are present—with a history of diabetes or a glucose concentration of ≥11.1 mmol/L; a ketone concentration of ≥3.0 mmol/L; and a pH <7.3 and/or a serum bicarbonate of <15.0 mmol/L. HHS has no formal diagnostic criteria but should have a glucose of >30.0 mmol/L, a calculated serum osmolality of >320 mOsmol/Kg and the absence of ketones. The management of DKA and HHS are different, and national guidelines exist for both. Both conditions require the administration of intravenous fluid with 0.9% sodium chloride solution to treat the dehydration frequently seen. In DKA, aggressive fluid replacement should accompany a weight based, fixed rate intravenous insulin infusion given at 0.1 units/kg/hour, as well as potassium replacement after the first litre of fluid has been administered. In HHS, fluid and electrolyte replacement are the mainstay of initial treatment, with insulin only being added at 0.05 units/kg/hour once the glucose concentration and osmolality has stopped falling. For both conditions, the early involvement of the specialist diabetes inpatient team is strongly recommended to help guide treatment and also to provide ongoing care and support once the DKA or HHS has resolved and the patient is discharged.
Diabetes in Pregnancy
Authors: Murphy Helen R. , Yamamoto Jennifer M.
Published: January 2022

Although there have been many advances in the treatment of diabetes, the goal of the St. Vincent Declaration (1989) that the outcome of diabetic pregnancy approximates that of non-diabetic pregnancy has still not been realized. Women with diabetes still have an increased risk of pregnancy-related complications including preterm delivery, large-for-gestational-age, neonatal hypoglycaemia, congenital anomaly, stillbirth, and neonatal death. The landscape of diabetes in pregnancy has changed dramatically with one in six pregnancies affected by maternal hyperglycaemia. Approximately half of all women with pre-gestational diabetes in pregnancy now have pre-gestational type 2 diabetes (T2D). This represents a 90% increase in the proportion of pregnancies complicated by T2D over 15 years. Likewise, recent data suggest a 44% increase in the number of pregnancies complicated by type 1 diabetes (T1D). While there remains much room for improvement, pregnancy outcomes for most women with diabetes are good. This likely reflects improvements such as obstetric surveillance, tighter glycaemic targets, improved diabetes technologies, and specialized interdisciplinary teams. There is also evidence of recent improvements, with a 2.5-fold reduction in stillbirths in a large contemporary UK cohort of women with pre-gestational diabetes in pregnancy compared to 15 years earlier. The goal now is to further improve pregnancy outcomes in women with diabetes by optimizing pre-pregnancy care, glycaemic control, and obstetric and diabetes-related surveillance using targeted education, technology, specialized teams, and by empowering women with diabetes.
Diabetic Dyslipidaemia
Authors: Vergès Bruno
Published: January 2022

Diabetic dyslipidaemia plays an important role in the increased cardiovascular risk of type 2 diabetes. It encompasses not only quantitative lipoprotein abnormalities, but also qualitative and kinetic abnormalities that, together, result in a shift toward a more atherogenic lipid profile. The principal quantitative lipoprotein abnormalities are increased triglyceride levels and decreased high-density lipoprotein (HDL) cholesterol levels. Qualitative lipoprotein abnormalities include increases in large, very low-density lipoprotein subfraction 1 (VLDL1) and small, dense low-density lipoproteins (LDLs), increased triglyceride content of LDLs and HDLs, glycation of apolipoproteins, and increased susceptibility of LDLs to oxidation. Moreover, HDLs from diabetic patients are dysfunctional, having severely reduced antiatherogenic properties. Statin use is recommended in most patients with T2DM because of the cardiovascular benefit demonstrated in many trials. Some post-hoc analyses of trials with fenofibrate suggest a potential CVD reduction in diabetic patients with triglycerides ≥2.6 mmol/L and low HDL cholesterol.
Endocrine Evaluation
Authors: Kaufman Jean-Marc
Published: January 2022

Suspected hypogonadism is confirmed if serum testosterone (T) is consistently and unequivocally low, ascertained in fasting morning blood samples on at least two separate occasions. In situations with altered sex-hormone-binding globulin (SHBG) concentrations, serum-free T is more representative of gonadal status than total T. Serum gonadotropin concentrations differentiate primary hypogonadism of testicular origin with elevated gonadotropins from secondary hypogonadism due to hypothalamic-pituitary malfunction with low or inappropriately normal levels. Additional investigations may include chromosome karyotyping in primary hypogonadism, and serum prolactin, pituitary hormonal testing, imaging, and genetic mutation testing in secondary hypogonadism. Serum levels of T precursors and metabolites, insulin-like peptide-3, inhibin B, or anti-Müllerian hormone do not significantly contribute to the work-up of adult men suspected of hypogonadism. In men with subfertility, high serum FSH indicates deficient spermatogenesis; low inhibin B is equally informative without substantially adding information above that from high FSH.
Diagnostic Semen Analysis
Authors: Kirkman-Brown Jackson C. , Conner Sarah J.
Published: January 2022

Semen analysis is a cornerstone of assessing male reproductive function, but to be correctly interpreted, one must understand that: an individual’s sperm production itself may vary widely over a number of months; how the WHO ‘normal’ laboratory reference ranges were derived; the accuracy of the reported laboratory assessments and potential causes for error. Results such as a total absence of sperm (azoospermia) may vary over time and between laboratories, depending upon the quality of laboratory assessment. It is therefore key to work with laboratories accredited specifically for semen analysis. Discussion provided within this chapter should assist with deciphering correct clinical interpretation of results.
Induction of Spermatogenesis by Gonadotrophin Treatment
Authors: Zitzmann Michael
Published: January 2022

Male hypogonadism (inherited or acquired) is often associated with impaired fertility. In patients with hypogonadotropic hypogonadism due to pituitary damage (secondary hypogonadism, lacking secretion of gonadotropins), that is luteinizing hormone (LH) and follicle-stimulating hormone (FSH) or tertiary hypogonadism due to damage of the hypothalamic area (lacking gonadotropin-releasing hormone [GnRH]), treatment with GnRH or LH/FSH can induce, maintain, or augment spermatogenesis. Recombinant FSH and human chorionic gonadotropin (ß-hCG, substituting activity of LH) are the most commonly used preparations for gonadotrophin replacement. Successful induction of spermatogenesis is more likely in men with pituitary disorders than in those lacking hypothalamic GnRH secretion (tertiary disorders) such as Kallmann syndrome.
Shakespeare: Songs & Sonnets
Authors: Duffin Ross W
Published: January 2022

Considering the fame of the poet and the beauty of the poetry, it is intriguing and somewhat baffling that there are no musical settings of Shakespeare’s sonnets from his lifetime, whether from lack of preservation or a disinclination on the part of composers to set them. This was first wondered at by Charles Burney in 1789, but is essentially explained away today as ‘sonnets are pure poetry’. This article explores possible reasons for the avoidance of sonnet settings in the early song repertory, including the language, versification, structure, and subject matter. The few surviving period sonnet settings are analysed, alongside a version of Sonnet 116 by Henry Lawes, the sole surviving Shakespeare sonnet setting from the seventeenth century. Using criteria from that study, a conjectural musical setting of a Shakespeare sonnet is proposed, based on an existing song by John Dowland.
The three hundred project: galaxy cluster mergers and their impact on the stellar component of brightest cluster galaxies
Authors: Contreras-Santos Ana , Knebe Alexander , Pearce Frazer , Haggar Roan , Gray Meghan , Cui Weiguang , Yepes Gustavo , De Petris Marco , De Luca Federico , Power Chris , Mostoghiu Robert , Nuza Sebastián E , Hoeft Matthias
Published: January 2022

Using the data set of the three hundred project, i.e. a suite of 324 hydrodynamical resimulations of cluster-sized haloes, we study galaxy cluster mergers and their effect on colour and luminosity changes of their brightest cluster galaxies (BCG). We track the main progenitor of each halo at z = 0 and search for merger situations based on its mass accretion history, defining mergers as very rapid increases in the halo mass. Based upon the evolution of the dynamical state of the cluster we define a pre- and post-merger phase. We create a list of all these events and statistically study their mass ratio and time-scales, with the former verifying that all instances are in fact major mergers. By comparing to a control sample of clusters without mergers, we study the effect mergers have on the stellar component of the BCG. Analysing the mass, age, and metallicity of the BCG stellar particles, we find that the stellar content of BCGs grows significantly during mergers and, even though the main growth mechanism is the accretion of older stars, there is even a burst in star formation induced by the merger. In our simulations, BCGs in mergers form in median around 70 per cent more stars than those normally growing, although this depends on the radius considered for defining the BCG. Regarding observable properties, we see an increase in SDSS-u luminosity of 20 per cent during mergers, accompanied by a slightly slower increase of the galaxy g − r colour as compared to the control sample.
YOUNG Star detrending for Transiting Exoplanet Recovery (YOUNGSTER) – II. Using self-organizing maps to explore young star variability in sectors 1–13 of TESS data
Authors: Battley Matthew P , Armstrong David J , Pollacco Don
Published: January 2022

Young exoplanets and their corresponding host stars are fascinating laboratories for constraining the time-scale of planetary evolution and planet–star interactions. However, because young stars are typically much more active than the older population, in order to discover more young exoplanets, greater knowledge of the wide array of young star variability is needed. Here Kohonen self-organizing maps (SOMs) are used to explore young star variability present in the first year of observations from the Transiting Exoplanet Survey Satellite (TESS), with such knowledge valuable to perform targeted detrending of young stars in the future. This technique was found to be particularly effective at separating the signals of young eclipsing binaries and potential transiting objects from stellar variability, a list of which are provided in this paper. The effect of pre-training the SOMs on known variability classes was tested, but found to be challenging without a significant training set from TESS. SOMs were also found to provide an intuitive and informative overview of leftover systematics in the TESS data, providing an important new way to characterize troublesome systematics in photometric data sets. This paper represents the first stage of the wider YOUNGSTER program, which will use a machine-learning-based approach to classification and targeted detrending of young stars in order to improve the recovery of smaller young exoplanets.
Moving nickel along the hydrogenase–urease maturation pathway
Authors: Tsang Ka Lung , Wong Kam-Bo
Published: January 2022

Hydrogenases and ureases play vital metabolic functions in all three domains of life. However, nickel ions are cytotoxic because they can inactivate enzymes that require less competitive ions (e.g. Mg2+) in the Irving–Williams series to function. Life has evolved elegant mechanisms to solve the problem of delivering the toxic metal to the active site of nickel-containing enzymes inside the cells. Here, we review our current understanding of nickel trafficking along the hydrogenase and urease maturation pathways. Metallochaperones and accessory proteins (SlyD, HypA, HypB, UreD, UreE, UreF, and UreG) form specific protein complexes to allow the transfer of nickel from one protein to another without releasing the toxic metal into the cytoplasm. The role of SlyD is not fully understood, but it can interact with and transfer its nickel to HypB. In the hydrogenase maturation pathway, nickel is transferred from HypB to HypA, which can then deliver its nickel to the hydrogenase large subunit precursor. In Helicobacter pylori, the urease maturation pathway receives its nickel from HypA of the hydrogenase maturation pathway via the formation of a HypA/UreE2 complex. Guanosine triphosphate (GTP) binding promotes the formation of a UreE2G2 complex, where UreG receives a nickel from UreE. In the final step of the urease maturation, nickel/GTP-bound UreG forms an activation complex with UreF, UreD, and apo-urease. Upon GTP hydrolysis, nickel is released from UreG to the urease. Finally, some common themes learned from the hydrogenase–urease maturation pathway are discussed.
The first crystal structures of hybrid and parallel four-tetrad intramolecular G-quadruplexes
Authors: Beseiso Dana , Chen Erin V , McCarthy Sawyer E , Martin Kailey N , Gallagher Elizabeth P , Miao Joanne , Yatsunyk Liliya A
Published: January 2022

G-quadruplexes (GQs) are non-canonical DNA structures composed of stacks of stabilized G-tetrads. GQs play an important role in a variety of biological processes and may form at telomeres and oncogene promoters among other genomic locations. Here, we investigate nine variants of telomeric DNA from Tetrahymena thermophila with the repeat (TTGGGG)n. Biophysical data indicate that the sequences fold into stable four-tetrad GQs which adopt multiple conformations according to native PAGE. Excitingly, we solved the crystal structure of two variants, TET25 and TET26. The two variants differ by the presence of a 3′-T yet adopt different GQ conformations. TET25 forms a hybrid [3 + 1] GQ and exhibits a rare 5′-top snapback feature. Consequently, TET25 contains four loops: three lateral (TT, TT, and GTT) and one propeller (TT). TET26 folds into a parallel GQ with three TT propeller loops. To the best of our knowledge, TET25 and TET26 are the first reported hybrid and parallel four-tetrad unimolecular GQ structures. The results presented here expand the repertoire of available GQ structures and provide insight into the intricacy and plasticity of the 3D architecture adopted by telomeric repeats from T. thermophila and GQs in general.
Surgical and oncological score to estimate the survival benefit of resection and chemoradiotherapy in elderly (≥70 years) glioblastoma patients: A preliminary analysis
Authors: Zorman Mark J , Webb Philip , Nixon Mickaela , Sravanam Sanskrithi , Honeyman Susan , Nandhabalan Meera , Apostolopoulos Vasileios , Stacey Richard , Hobbs Claire , Plaha Puneet
Published: January 2022

Background

Elderly patients with glioblastoma are perceived to face a poor prognosis with perceptions surrounding older age and a relative lack of randomized data contributing. This study evaluated survival prognosticators in elderly glioblastoma patients to more accurately guide their treatment.

Methods

The records of 169 elderly (≥70 years) patients with a new diagnosis of glioblastoma who had undergone neurosurgical intervention were retrospectively examined for patient sex, age, performance status, comorbidities, MGMT promoter methylation, surgical intervention, and chemoradiation regime. The adjusted survival impact of these factors was determined using Cox proportional hazards model and used to devise a two-stage scoring system to estimate patient survival at the stage of surgical (Elderly Glioblastoma Surgical Score, EGSS) and oncological management (Elderly Glioblastoma Oncological Score, EGOS).

Results

The median overall survival (mOS) of the cohort was 28.8 weeks. Gross-total and subtotal resection were associated with improved survival compared to biopsy alone (respective mOS 65.3 and 28.1 vs 15.7 weeks, P < .001). Hypofractionated radiotherapy (40Gy in 15 fractions) with Temozolomide was noninferior to the Stupp protocol, P = .72. Exploratory subgroup analysis revealed a significant benefit of Temozolomide-based approaches in MGMT-methylated patients as well as a trend towards improved survival in MGMT-unmethylated patients. Our EGSS and EGOS scores successfully estimated survival in this retrospective cohort with 65% and 73% accuracy.

Conclusions

Where appropriate and safe, elderly glioblastoma patients may benefit from surgical resection and combined chemoradiotherapy with Temozolomide. The proposed EGSS and EGOS scores take into account important prognostic factors to help guide which patients should receive such treatment.
Exposure to Low UV-B Dose Induces DNA Double-Strand Breaks Mediated Onset of Endoreduplication in Vigna radiata (L.) R. Wilczek Seedlings
Authors: De Sayanti , Jose Jismon , Pal Amita , Roy Choudhury Swarup , Roy Sujit
Published: January 2022

Multiple lines of evidence indicate that solar UV-B light acts as an important environmental signal in plants, regulating various cellular and metabolic activities, gene expression, growth and development. Here, we show that low levels of UV-B (4.0 kJ m−2) significantly influence plant response during early seedling development in the tropical legume crop Vigna radiata (L.) R. Wilczek. Exposure to low doses of UV-B showed relatively less growth inhibition yet remarkably enhanced lateral root formation in seedlings. Both low and high (8.0 kJ m−2) doses of UV-B treatment induced DNA double-strand breaks and activated the SOG1-related ATM-ATR-mediated DNA damage response pathway. These effects led to G2-M-phase arrest with a compromised expression of the key cell cycle regulators, including CDKB1;1, CDKB2;1 and CYCB1;1, respectively. However, along with these effects, imbibitional exposure of seeds to a low UV-B dose resulted in enhanced accumulation of FZR1/CCS52A, E2Fa and WEE1 kinase and prominent induction of endoreduplication in 7-day-old seedlings. Low dose of UV-B mediated phenotypical responses, while the onset of endoreduplication appeared to be regulated at least in part via UV-B induced reactive oxygen species accumulation. Transcriptome analyses further revealed a network of co-regulated genes associated with DNA repair, cell cycle regulation and oxidative stress response pathways that are activated upon exposure to low doses of UV-B.
Autumn blooms and seasonality of the dinoflagellate Unruhdinium penardii in the Han River (Korea) as tracked by morphological and molecular techniques
Authors: Kim Taehee , Ki Jang-Seu
Published: January 2022

Dinoflagellate blooms mainly occur in marine environments, and also occur in freshwater. This study reported the autumn blooms of the freshwater dinoflagellate Unruhdinium penardii var. robustum from the Paldang Reservoir in the Han River, South Korea. Morphological and molecular methods were used to examine 2 years of water samples collected monthly in 2012 and 2019. Environmental factors such as temperature, dissolved oxygen and nutrients showed similar seasonal patterns in 2-year comparisons. The chlorophyll-a and phytoplankton cell concentrations were higher in 2019 than in 2012. Dinoflagellate cells were abundantly detected in autumn, with a maximum of 5.1 × 106 cells·L−1 in 2012 and 3.1 × 106 cells·L−1 in 2019. Of these, the dinoflagellate U. penardii var. robustum was predominant in October 2019. Quantitative polymerase chain reaction assays targeting 28S rDNA of Unruhdinium detected the highest copy numbers (5.1 × 108 copies·L−1 in November 2012 and 8.6 × 108 copies·L−1 in October 2019) in autumn. These patterns matched well with the microscopic cell counts. Canonical correspondence analysis showed that autumn samples were correlated with 28S rDNA of Unruhdinium. These results suggest autumn blooms and seasonality of the dinoflagellate U. penardii var. robustum in the Paldang Reservoir.