Coronary artery disease is common in patients undergoing transcatheter aortic valve implantation (TAVI). We aimed to assess whether deferral of percutaneous coronary intervention (PCI) is non-inferior to routine PCI before TAVI in patients with coronary artery disease.

The long-term clinical outcomes of clopidogrel monotherapy versus aspirin monotherapy after percutaneous coronary intervention (PCI) remain uncertain. We conducted a 10-year follow-up of the HOST-EXAM trial to assess the very long-term effects of clopidogrel versus aspirin monotherapy in this setting.

CONCORD is a global public health programme for long-term surveillance of population-based cancer survival. The first three cycles of this programme focused primarily on adults. In CONCORD-4, for the first time, we also included all cancers in children. The WHO Global Initiative for Childhood Cancer (GICC), published in 2018, set a target for 5-year survival for all childhood cancers combined, worldwide, to reach 60% by 2030. We designed the protocol for CONCORD-4 to assess progress towards this target in as many countries as possible.

Retroperitoneal fibrosis is a rare immune-mediated disease characterised by a periaortoiliac fibro-inflammatory tissue that often encases neighbouring structures (eg, ureters). Idiopathic retroperitoneal fibrosis can be isolated or part of IgG4-related disease, whereas secondary forms recognise different aetiologies, such as histiocytosis, malignancies, and infections. Idiopathic retroperitoneal fibrosis has a multifactorial origin, with genetic, environmental, and lifestyle factors being main contributors. The immunopathogenesis of the disease involves B-lymphocyte and T-lymphocyte crosstalk, macrophage and fibrocyte chemotaxis, and recruitment of eosinophils and mast cells. Idiopathic retroperitoneal fibrosis can cause severe complications, such as acute or chronic kidney injury, caval occlusion, and deep vein thrombosis. Although interventional or surgical procedures can be necessary to manage these complications, medical therapy remains the cornerstone of treatment. Glucocorticoids are effective, and B-cell-targeting therapies are increasingly used. However, relapses are frequent after treatment discontinuation. In this Seminar, we provide a contemporary overview of retroperitoneal fibrosis focusing on pathophysiology, differential diagnosis, and management.

Current therapies for osteoarthritis have limitations. LEVI-04 is a p75 neurotrophin receptor (p75NTR) fusion protein that inhibits neurotrophin-3. We assessed the efficacy and safety of LEVI-04 in individuals with knee osteoarthritis.

The clinical benefits of intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma remain uncertain with respect to treatment-related effects on physical function and quality of life. We aimed to compare late functional, patient-reported, disease control, and survival outcomes between IMPT and IMRT.

Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterised by biliary inflammation and fibrosis. Inflammatory bowel disease co-occurs in 50-80% of individuals with primary sclerosing cholangitis and there is an increased risk for hepatobiliary and colorectal cancers. Primary sclerosing cholangitis presentation is highly variable but there is usually a slowly progressive fibrosis of the bile ducts with strictures, development of liver fibrosis and cirrhosis, and eventually a need for liver transplantation, after which primary sclerosing cholangitis can reoccur. Primary sclerosing cholangitis is diagnosed mostly at the asymptomatic stage but, as the disease advances, people often have itching, fatigue, upper right abdominal pain, recurrent cholangitis, or complications related to portal hypertension. There are few treatment options and its exact cause and pathogenesis remain unclear. It is widely believed that both genetic and environmental factors are important, with the intestinal microbiome increasingly recognised as crucial to disease development, progression, and outcomes. This Seminar explores the clinical features of primary sclerosing cholangitis, summarises the current understanding of its pathogenesis, and gives insights into the challenges and opportunities in managing the disease.

Evidence, including animal, clinical, and real-world studies in individuals with type 2 diabetes and/or obesity, suggests reduced risk of dementia and Alzheimer's disease after GLP-1 receptor agonist exposure. The evoke and evoke+ trials aimed to investigate the efficacy and safety of oral semaglutide in individuals with early Alzheimer's disease.

Video-assisted thoracoscopic surgery (VATS) is currently the most common approach for pulmonary lobectomy in early-stage lung cancer. Reported advantages include less pain, fewer complications, faster recovery, and improved postoperative quality of life. The widespread adoption of VATS lobectomy is principally based on non-oncological benefits. Its oncological equivalence to open surgery remains assumed as no single trial has been powered for survival. To address this important question, we sought to conduct an individual patient data meta-analysis of eligible randomised trials.

Increased fluid intake is universally recommended to decrease the risk of recurrent urinary stones; however, adherence is challenging. The effectiveness of interventions to maintain high fluid intake has not been well studied. We sought to determine whether a multicomponent behavioural intervention programme to promote high fluid intake reduces symptomatic stone recurrence, compared with a control.

For patients undergoing surgical valve procedures with concomitant coronary artery disease, current guidelines recommend that coronary artery bypass grafting (CABG) should be anatomically guided on the basis of stenosis severity, as assessed by coronary angiography. We aimed to test whether a physiologically guided strategy using angiography-derived fractional flow reserve (FFR) could improve clinical outcomes in this population.

Men and partners are important contributors to the health of future generations, yet their own preconception health and wellbeing remain secondary considerations in research, practice, and policy. Siloed research has exacerbated this deficit. Clinical research typically has a narrow focus on proximal behavioural factors related to periconceptional events (eg, paternal dietary influences on the sperm epigenome), with social research focusing largely on postnatal parenting. Here, we update and reappraise the evidence for men's role in preconception health through a transdisciplinary review. Across biological and behavioural research, young men's early life course experiences have been shown to shape their own and their partner's preconception physical, emotional, and behavioural health. Moreover, focusing on men's preconception health offers a corrective for legacies of sexism, which place responsibility for intergenerational health solely on the birthing parent, and of racism and colonialism, which have disproportionately disrupted the familial and societal roles of Black and Brown men. We provide three case studies illustrating these ethical concerns and conclude that greater attention to young men would lead to more equitable and holistic preconception health interventions and policy.

As efforts to support pregnancy planning and improve preconception health are increasing at scale, appropriate systems to monitor progress are required. Despite developments in a few countries, no surveillance systems currently in operation are using a comprehensive set of indicators for monitoring preconception health. This Review describes relevant indicators, reflecting both system-level and individual-level factors, that can be drawn from routine data sources to form the basis for developing new surveillance systems. We present a new framework for national and international surveillance that incorporates, for the first time, community perspectives on the factors that matter most before pregnancy and parenthood. Finally, we describe an international collaboration working towards a core set of indicators that can be compared across low-income, middle-income, and high-income countries, and discuss future directions to enhance and expand international monitoring of pregnancy planning and preconception health.

Hereditary haemolytic anaemias represent the most prevalent group of genetic disorders worldwide and have a substantial impact on global health. Current treatments are few and primarily supportive. Recent studies suggest a crucial and overlapping role of metabolic impairment of red blood cells in these diseases, extending beyond the primary genetic defect. Pyruvate kinase activators enhance glycolysis, thereby targeting this shared metabolic impairment by increasing ATP production and improving cellular homeostasis. The first pyruvate kinase activator has been approved for the treatment of pyruvate kinase deficiency. Clinical trials evaluating pyruvate kinase activators in other haemolytic disorders, including thalassaemia, sickle cell disease, and red blood cell membrane disorders have provided evidence of clinical efficacy by ameliorating haemolytic anaemia and improving other disease-related outcomes, while maintaining a generally favourable safety profile. Ongoing preclinical and translational research continues to provide further insights into other potential indications for pyruvate kinase activators.

Sickle cell disease is a genetic red blood cell disorder, affecting millions of people globally. This Seminar provides a comprehensive update on the disease, emphasising its complex pathophysiology involving sickle haemoglobin polymerisation, vaso-occlusion, haemolysis, and inflammation that lead to acute, life-threatening complications and progressive organ damage. We review the spectrum of the most frequent acute manifestations-vaso-occlusive crises, acute chest syndrome, stroke, and infections-alongside chronic complications affecting virtually all organ systems. Recent advances include expanded implementation of hydroxyurea in low-resource settings and the optimisation of hydroxyurea protocols, refined transfusion therapy, improved haematopoietic stem cell transplantation outcomes with alternative donor strategies, and gene therapies now approved for clinical use. Additionally, new drugs are being evaluated in clinical trials globally. We examine successful implementation strategies in low-income and middle-income countries using point-of-care diagnostics and integrated care models. Controversies and challenges include the management of sickle haemoglobin-C and haemoglobin S/β+ variants, cerebrovascular complication prevention, hydroxyurea use in pregnancy, and the transition from paediatric to adult care.

In sub-Saharan Africa, the burden of diabetes and hypertension is high, alongside a high prevalence of HIV. Whether these conditions can be managed in an integrated way in the community is unknown. We aim to compare integrated community-based care with integrated facility-based care for people with HIV, diabetes, and hypertension in Tanzania and Uganda.

Tenosynovial giant cell tumour (TGCT) is a rare, locally aggressive neoplasm that affects otherwise healthy adults. There are few systemic treatment options, highlighting an unmet need. We report the results of part 1 of the MANEUVER trial, which aimed to evaluate the efficacy and safety of pimicotinib, a highly selective, potent, colony-stimulating factor-1 receptor inhibitor, in patients with TGCT.

Aldosterone dysregulation is an important contributor in the pathogenesis of hard-to-control hypertension. We aimed to assess the effect of baxdrostat, a selective aldosterone synthase inhibitor, on ambulatory blood pressure in patients with resistant hypertension.

Hypofractionated radiotherapy is standard for whole-breast radiotherapy, but 50 Gy in 25 fractions (5-week radiotherapy) is still standard in many countries when nodal radiotherapy is needed for morbidity concerns. The UNICANCER HypoG-01 trial aimed to assess morbidity and efficacy of hypofractionated locoregional radiotherapy delivering 40 Gy in 15 fractions (3-week radiotherapy) versus 5-week radiotherapy.

Atrial fibrillation affects approximately 37·6 million people worldwide, with the prevalence predicted to double over the next 35 years. The ubiquitous use of wearable devices and other technologies with inbuilt diagnostic algorithms allows greater detection of atrial fibrillation among the general public than previously. Atrial fibrillation increases the risk of stroke and thromboembolism, heart failure, and death, and is associated with reductions in quality of life. Patients with atrial fibrillation frequently have comorbidities, and the accumulation of risk factors, including lifestyle factors associated with poorer health outcomes, and increasing age, often adds to the complexity of managing such patients. All major clinical guidelines advocate that stroke prevention, symptom relief, identification of risk factors, and optimisation of risk factor management, incorporated into an integrated care approach, with multidisciplinary input as required, are essential elements of atrial fibrillation management. Avoidance of stroke with oral anticoagulation remains the default for most patients with atrial fibrillation and, more recently, catheter ablation has been reconsidered as an initial treatment option for symptom relief. The dynamic nature of risk factors requires early identification and appropriate management of new and existing risk factors to optimise atrial fibrillation care. Patient-centred care and better health literacy can empower patients to take a more active role in their atrial fibrillation management.