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.

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.

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.

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.

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.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic cause of chronic kidney disease, resulting in substantial morbidity and mortality globally. Advances in molecular genetics and deep-phenotype imaging techniques have refined existing diagnostic and prognostic tools. The strong evidence-base for tolvaptan as a disease-modifying treatment supports its early use in groups at high risk of kidney failure. Screening and management of potentially serious complications including cyst infection, intracranial aneurysms, and polycystic liver disease are important components of a comprehensive care plan. This Review focuses on current approaches to diagnosis, risk assessment, treatment, and specific aspects of clinical management in ADPKD. An updated understanding of the genetic basis of disease, pathobiology with respect to potential therapeutic targets, and promising therapies now in clinical trials are summarised. We propose a holistic patient-centred care pathway that emphasises shared decision-making with a multidisciplinary clinical team to address the individual needs of patients throughout their lifelong journey.

Sepsis is defined as a dysregulated host response to infection that leads to life-threatening organ dysfunction. The infectious insult triggers a dysregulated immune response that variably activates and suppresses multiple body system functions. Susceptibility to either developing or succumbing to sepsis is influenced by pathogen load and virulence; site of infection; host factors, including genetics, biological variability, comorbidities, immunosuppression, and extremes of age; and a wide range of external influences, such as social deprivation and local environment. Increasing appreciation of the underlying pathobiology has identified differing biological signatures with variable temporal evolution. This variability highlights the requirement to individualise treatment with targeted interventions guided by rapidly accessible biomarkers. Although improved outcomes have been obtained with better prevention, early recognition, and treatment, sepsis is a major cause of global mortality and morbidity. All populations having the benefits currently enjoyed by a privileged few is imperative. This Seminar aims to unravel the complexity of the condition, describing epidemiology and pathophysiology, evolving fundamental shifts, patient management, current challenges, and future developments.

Adding hormone therapy to definitive radiotherapy in localised prostate cancer improves overall survival, but whether it similarly improves overall survival in the context of postoperative radiotherapy (PORT) after radical prostatectomy is unclear. Herein, we report an individual patient data (IPD) meta-analysis of randomised trials aimed at quantifying the benefit of adding hormonal therapy to PORT.

Antipsychotic drugs are the established treatment for acute schizophrenia but differ in receptor-binding profiles. In 2024, a new-in-class muscarinic receptor agonist (xanomeline-trospium) was licenced, acting upstream of antidopaminergic agents, and providing hope to decrease the adverse effects burden of antipsychotics. We aimed to compare the efficacy and tolerability of antipsychotics by performing network meta-analysis of randomised controlled trials (RCTs).

Total hip replacement is a successful operation that aims to restore function and quality of life to millions of people globally. Knowing how long a total hip replacement might last is important for patients, surgeons, and health-care institutions for planning and resource allocation. Over the past 20 years, the use of contemporary bearing surfaces for total hip replacement has substantially altered implant wear and, possibly, longevity. To date, there has been no large-scale study that examines survivorship of these modern implants. We aimed to determine the survivorship of contemporary total hip replacements and bearing materials.

With the introduction of adaptive deep brain stimulation (aDBS) for Parkinson's disease, new questions emerge regarding who, why, and how to treat. This paper outlines the pathophysiological rationale for aDBS, which provides real-time modulation of the stimulation amplitude based on subthalamic beta (range 13-30 Hz) activity and related physiomarkers. We review clinical evidence comparing aDBS with conventional DBS in terms of motor improvement, side-effect reduction, energy efficiency, and technical developments, including sensing-enabled device characteristics, stimulation algorithms, and potential clinical indications. We also discuss limitations, such as physiomarker variability, signal artifacts, and the absence of standardised programming protocols. Finally, we explore the readiness for clinical implementation and future directions, and estimate the scope of eligible patients. In our view, aDBS marks a fundamental change in approach from fixed stimulation towards physiomarker-guided neuromodulation. This evolution necessitates new infrastructure, clinician training, and real-world studies, but holds promise for more personalised and responsive treatment.

Despite the availability of effective antihypertensive therapies, global blood pressure control rates remain unacceptably low. Contributing factors, such as low treatment adherence, therapeutic inertia, and rising multimorbidity, underscore the need for innovative approaches to improve hypertension care. New antihypertensive drug therapies that act on physiological pathways beyond those targeted by conventional drug classes are emerging. These therapies include small interfering RNA agents that inhibit angiotensinogen synthesis as a novel approach to inhibit the renin-angiotensin system, and new strategies to more selectively modulate aldosterone, such as aldosterone synthase inhibitors and non-steroidal mineralocorticoid receptor antagonists. There is also growing interest in therapies to enhance the action of the natriuretic peptide system. Although these innovations present valuable therapeutic opportunities, their benefits must be carefully balanced against considerations of safety, cost, clinical outcomes, and equitable access-all of which are crucial to reducing the residual burden of cardiovascular and chronic kidney disease.

Statin product labels (eg, Summaries of Product Characteristics [SmPCs]) list certain adverse outcomes as potential treatment-related effects based mainly on non-randomised and non-blinded studies, which might be subject to bias. We aimed to assess the evidence for such undesirable effects more reliably through a meta-analysis of individual participant data from large double-blind trials of statin therapy.

Health systems worldwide face two fundamental and connected challenges: pervasive misinformation and disinformation and eroding public trust. This erosion reveals a paradox at the heart of contemporary science-society relations: the more science succeeds in solving complex problems through rigour and institutional coordination, the more it alienates a public that values immediacy, authenticity, emotional resonance, and personal connection. Consequently, those most committed to scientific rigour-scientists, health-care institutions, professional societies, and public health agencies-are increasingly distrusted, whereas those least accountable-untrained influencers, unqualified individuals with financial motives or political agendas, and artificial intelligence bots-are deemed credible. This so-called trust paradox is amplified by engagement-driven social media environments that reward disinformation, immediacy, group identity, and authenticity over factual truth. The consequences are harmful health outcomes and misguided policy decisions. Addressing this paradox requires not only technical accuracy but also co-production from the outset, overarching horizontal communication, infrastructures for transparency and emotional resonance, and regulatory reforms for algorithms and digital environments.