Nature Reviews Disease Primers最新文献

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy and represents a leading cause of morbidity and mortality. HCM is a sarcomeric disease characterized by genetically determined defects in sarcomere proteins, leading to left ventricular hypertrophy, hypercontractility and diastolic dysfunction. The phenotypic spectrum of the disease is heterogeneous, ranging from mild forms that can remain stable and asymptomatic for many years, through to childhood-onset, severe cases that can result in progressive heart failure and ventricular arrhythmias. Multi-imaging techniques including echocardiography and cardiac magnetic resonance are pivotal for diagnostic and prognostic assessment in HCM. For decades, therapeutic approaches were limited to invasive septal reduction therapies and nonspecific pharmacological treatment for heart failure. In the last 10 years, however, an in-depth understanding of the pathological mechanisms of HCM has led to the development of targeted therapies, such as myosin inhibitors, which have proven to be safe and effective in improving functional capacity and reducing symptoms. Innovative therapeutic approaches, such as gene therapies that aim to target the genetic variants underpinning the condition, are currently under investigation.

Mesothelioma is a lethal cancer caused by exposure to asbestos, which arises predominantly in the pleural lining of the thoracic cavity or, less commonly, in the peritoneum, pericardium or tunica vaginalis. The incidence of mesothelioma increased globally during the late twentieth century, correlating with the use of asbestos, and it continues to rise in some regions. Asbestos tumorigenesis involves fibre persistence that leads to DNA damage mediated by chronic inflammation. The genomic landscape of mesothelioma is predominantly characterized by tumour suppressor alterations, most frequently occurring in BAP1, CDKN2A, CDKN2B, MTAP, NF2 and TP53. Patients with mesothelioma commonly present with fatigue, dyspnoea and/or cough caused by pleural effusion, pain and reduced appetite with weight loss. Imaging, cytology, histology and immunohistochemistry are used in diagnosis and support tumour staging. Genetic tests are relevant to reveal disease predispositions. Mesotheliomas are classified on the basis of histology into three distinct subtypes: epithelioid (the most common subtype with the best prognosis), biphasic and sarcomatoid (worst prognosis). Chemotherapy has been the standard of care for the past two decades but immune checkpoint inhibition targeting PD1 and CTLA4 is now considered to be the first-line treatment, showing improvement compared with chemotherapy. Few randomized trials have investigated the role of surgery and radiotherapy and none has found a clear benefit over systemic therapies. Mesothelioma is associated with considerable negative effects on quality of life in physical and emotional domains and also substantially affects patients' families and caregivers.

Differences of sex development (DSD) represent a group of congenital conditions that affect human sex development and maturation owing to discrepancies of chromosomal, gonadal and phenotypic sex. The Chicago consensus classifies DSD as sex chromosome DSD, 46,XY DSD and 46,XX DSD, with subclassifications according to gonadal determination into testes and ovaries and hormone-dependent differentiation of Müllerian and Wolffian embryonic structures into female-typical or male-typical internal and external sex organs. DSD may occur as an isolated condition or as part of a complex syndrome. Diagnosis is based on clinical characteristics, imaging studies, hormonal measurements and genetic investigations. Management includes lifelong psychosocial support, hormonal treatments and surgical interventions that require personalization for each case as DSD encompasses a wide variety of aetiologies and presentations. This personalization must also consider individual values and preferences to ensure that clinical care is tailored to meet the unique needs and circumstances of each person, ideally provided by a care team with diverse specialities. This care involves psycho-educational counselling on the condition and its consequences, considering family and cultural norms. Additional efforts are needed to bridge gaps in knowledge related to diagnosis, management and long-term outcomes. Enhancing our understanding of the distinctions between sex and gender in societies is essential as greater awareness will inform and enrich public debates.

Intrahepatic cholestasis of pregnancy is the most common pregnancy-related liver disease, manifesting typically during the third trimester of pregnancy with pruritus and elevated serum bile acids. This condition is associated with increased fetal morbidity and mortality, and its pathogenesis is still incompletely understood, but is most likely multifactorial, involving ethnicity, genetics, hormones and environmental factors. Available evidence covering the pathophysiology of both maternal and fetal manifestations, and potential new areas of interest such as microbiota and the environment, have been reviewed, as well as available biomarkers that can be used particularly with regard to genetics, multiomics and the possible use of machine learning algorithms to predict intrahepatic cholestasis of pregnancy. Ursodeoxycholic acid is still the mainstay of therapy with limited alternative options; however, a new class of drugs inhibiting intestinal bile acid transport might be on the horizon. Intrahepatic cholestasis of pregnancy is still not completely understood, warranting a critical appraisal of its epidemiology, pathogenesis, diagnosis and management.

Prediabetes or intermediate hyperglycaemia represents a preliminary stage in the development of type 2 diabetes mellitus (T2DM). In addition to an increased likelihood of developing T2DM, individuals with prediabetes have an elevated risk of various vascular and non-vascular complications. No consensus has been achieved on the ideal screening strategy for prediabetes, with fasting plasma glucose concentration, glycated haemoglobin (HbA1c) and the oral glucose tolerance test being the most frequently measured parameters. The two major phenotypes of prediabetes, that is, impaired fasting glucose and impaired glucose tolerance, may represent different pathophysiologies with varying natural history, risk of adverse outcomes and responsiveness to treatment. Most of the evidence for managing prediabetes focuses on lifestyle modification with or without medications in individuals with overweight or obesity and impaired glucose tolerance. Whether these interventions are beneficial in individuals with impaired fasting glucose and those of normal body weight is unclear, as is the cost-effectiveness and sustainability of pharmacotherapy for treating prediabetes. Large-scale national T2DM prevention programmes are currently under way to assess whether the benefits of interventions for prediabetes can be translated to the community setting.