One in five people are at high risk for atherosclerotic cardiovascular disease and aortic valve stenosis due to high lipoprotein(a). Lipoprotein(a) concentrations are lowest in people from east Asia, Europe, and southeast Asia, intermediate in people from south Asia, the Middle East, and Latin America, and highest in people from Africa. Concentrations are more than 90% genetically determined and 17% higher in post-menopausal women than in men. Individuals at a higher cardiovascular risk should have lipoprotein(a) concentrations measured once in their lifetime to inform those with high concentrations to adhere to a healthy lifestyle and receive medication to lower other cardiovascular risk factors. With no approved drugs to lower lipoprotein(a) concentrations, it is promising that at least five drugs in development lower concentrations by 65-98%, with three currently being tested in large cardiovascular endpoint trials. This Review covers historical perspectives, physiology and pathophysiology, genetic evidence of causality, epidemiology, role in familial hypercholesterolaemia and diabetes, management, screening, diagnosis, measurement, prevention, and future lipoprotein(a)-lowering drugs.

Frequentist and Bayesian statistics represent two differing paradigms for the analysis of data. Frequentism became the dominant mode of statistical thinking in medical practice during the 20th century. The advent of modern computing has made Bayesian analysis increasingly accessible, enabling growing use of Bayesian methods in a range of disciplines, including medical research. Rather than conceiving of probability as the expected frequency of an event (purported to be measurable and objective), Bayesian thinking conceives of probability as a measure of strength of belief (an explicitly subjective concept). Bayesian analysis combines previous information (represented by a mathematical probability distribution, the prior) with information from the study (the likelihood function) to generate an updated probability distribution (the posterior) representing the information available for clinical decision making. Owing to its fundamentally different conception of probability, Bayesian statistics offers an intuitive, flexible, and informative approach that facilitates the design, analysis, and interpretation of clinical trials. In this Review, we provide a brief account of the philosophical and methodological differences between Bayesian and frequentist approaches and survey the use of Bayesian methods for the design and analysis of clinical research.

The search for safe and efficacious products to prevent severe respiratory syncytial virus (RSV) disease in young infants has lasted more than 60 years. In high-income and middle-income countries, two new products have been authorised: an RSV monoclonal antibody for administration to infants (nirsevimab) and an RSV prefusion F maternal vaccine (RSVpreF [Pfizer, Puurs, Belgium]) for administration to pregnant people. These products are not yet available in low-income and lower-middle-income countries, where most RSV deaths occur. Other papers in this Series describe the acute burden of RSV disease in young children, the effects of RSV infection in early childhood on long-term lung health, and the burden of RSV disease and disease prevention products in older adults. In this Series paper, we briefly review the efficacy, effectiveness, and safety of nirsevimab and RSVpreF maternal vaccine for protection of infants. We then explore potential regulatory, policy, and implementation pathways and provide case studies of intervention uptake in Spain and Argentina, and considerations for use in Kenya. We also explore the health economic evidence to inform product introduction decisions. With sufficient political will and affordable pricing, RSV disease prevention in infants can become a global reality.

The global burden of respiratory syncytial virus (RSV) lower respiratory tract infection (LRTI) in young children is high. The RSV prevention strategies approved in 2023 will be essential to lowering the global disease burden. In this Series paper, we describe clinical presentation, burden of disease, hospital management, emerging therapies, and targeted prevention focusing on developments and groundbreaking publications for RSV. We conducted a systematic search for literature published in the past 15 years and used a non-systematic approach to analyse the results, prioritising important papers and the most recent reviews per subtopic. Annually, 33 million episodes of RSV LRTI occur in children younger than 5 years, resulting in 3·6 million hospitalisations and 118 200 deaths. RSV LRTI is a clinical diagnosis but a clinical case definition and universal clinical tool to predict severe disease are non-existent. The advent of molecular point-of-care testing allows rapid and accurate confirmation of RSV infection and could reduce antibiotic use. There is no evidence-based treatment of RSV, only supportive care. Despite widespread use, evidence for high-flow nasal cannula (HFNC) therapy is insufficient and increased paediatric intensive care admissions and intubation indicate the need to remove HFNC therapy from standard care. RSV is now a vaccine-preventable disease in young children with a market-approved long-acting monoclonal antibody and a maternal vaccine targeting the RSV prefusion protein. To have a high impact on life-threatening RSV infection, infants at high risk, especially in low-income and middle-income countries, should be prioritised as an interim strategy towards universal immunisation. The implementation of RSV preventive strategies will clarify the full burden of RSV infection. Vaccine probe studies can address existing knowledge gaps including the effect of RSV prevention on transmission dynamics, antibiotic misuse, the respiratory microbiome composition, and long-term sequalae.

The optimum number of units of blood and the associated number of blood donors required to meet a given population's needs remain undetermined globally. Typically, a whole blood donation rate of ten donations per 1000 population, at a minimum, is necessary to meet a country's blood needs. This rate is attributed to a WHO recommendation that 1% of a given country's population should donate blood to ensure a blood supply that is sufficient to meet clinical needs. This often cited metric was first referenced in a 1971 WHO report, yet neither supporting data or references were provided, suggesting that it was flawed at its founding. Regardless, this metric does not provide an accurate or contemporary determination of blood needs, which has ramifications for health service provision and planning, particularly in low-income and lower-middle-income countries. Modelling studies that account for geographical variability in disease burden, health-care infrastructure, and transfusion practices are needed to accurately estimate blood needs. A paucity of data to inform modelling remains a major obstacle in this regard. We discuss the history of the global blood donation index and highlight some factors that should be considered to better understand contemporary blood needs.

Dual antiplatelet therapy (DAPT) for 12 months is the standard of care after coronary stenting in patients with acute coronary syndrome (ACS). The aim of this individual patient-level meta-analysis was to summarise the evidence comparing DAPT de-escalation to ticagrelor monotherapy versus continuing DAPT for 12 months after coronary drug-eluting stent implantation.

Primary biliary cholangitis is a chronic, autoimmune, cholestatic disease that mainly affects women aged 40-70 years. Recent epidemiological studies have shown an increasing incidence worldwide despite geographical heterogeneity and a decrease in the female-to-male ratio of those the disease affects. Similar to other autoimmune diseases, primary biliary cholangitis occurs in genetically predisposed individuals upon exposure to environmental triggers, specifically xenobiotics, smoking, and the gut microbiome. Notably, the diversity of the intestinal microbiome is diminished in individuals with primary biliary cholangitis. The intricate interplay among immune cells, cytokines, chemokines, and biliary epithelial cells is postulated as the underlying pathogenic mechanism involved in the development and progression of primary biliary cholangitis, and extensive research has been dedicated to comprehending these complex interactions. Following the official approval of obeticholic acid as second-line treatment for patients with an incomplete response or intolerance to ursodeoxycholic acid, clinical trials have indicated that peroxisome proliferator activator receptor agonists are promising additional second-line drugs. Future dual or triple drug regimens might reach a new treatment goal of normalisation of alkaline phosphatase levels, rather than a decrease to less than 1·67 times the upper limit of normal levels, and potentially improve long-term outcomes. Improvement of health-related quality of life with better recognition and care of subjective symptoms, such as pruritus and fatigue, is also an important treatment goal. Promising clinical investigations are underway to alleviate these symptoms. Efforts to facilitate better access to medical care and dissemination of current knowledge should enable diagnosis at an earlier stage of primary biliary cholangitis and ensure access to treatments based on risk stratification for all patients.

Antiviral post-exposure prophylaxis with neuraminidase inhibitors can reduce the incidence of influenza and the risk of symptomatic influenza, but the efficacy of the other classes of antiviral remains unclear. To support an update of WHO influenza guidelines, this systematic review and network meta-analysis evaluated antiviral drugs for post-exposure prophylaxis of influenza.

The optimal antiviral drug for treatment of severe influenza remains unclear. To support updated WHO influenza clinical guidelines, this systematic review and network meta-analysis evaluated antivirals for treatment of patients with severe influenza.

X-linked hypophosphataemia is a genetic disease caused by defects in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene and is characterised by X-linked dominant inheritance. The main consequence of PHEX deficiency is increased production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) in osteoblasts and osteocytes. Chronic exposure to circulating FGF23 is responsible for renal phosphate wasting and decreased synthesis of calcitriol, which decreases intestinal phosphate absorption. These mechanisms result in lifelong hypophosphataemia, impaired growth plate and bone matrix mineralisation, and diverse manifestations in affected children and adults, including some debilitating morbidities and possibly increased mortality. Important progress has been made in disease knowledge and management over the past decade; in particular, targeting FGF23 is a therapeutic approach that has substantially improved outcomes. However, patients affected by this complex disease need lifelong care and innovative treatment strategies, such as gene repair of PHEX, are necessary to further limit the disease burden.

Obesity has increased in prevalence worldwide and WHO has declared it a global epidemic. Population-level preventive interventions have been insufficient to slow down this trajectory. Obesity is a complex, heterogeneous, chronic, and progressive disease, which substantially affects health, quality of life, and mortality. Lifestyle and behavioural interventions are key components of obesity management; however, when used alone, they provide substantial and durable response in a minority of people. Bariatric (metabolic) surgery remains the most effective and durable treatment, with proven benefits beyond weight loss, including for cardiovascular and renal health, and decreased rates of obesity-related cancers and mortality. Considerable progress has been made in the development of pharmacological agents that approach the weight loss efficacy of metabolic surgery, and relevant outcome data related to these agents' use are accumulating. However, all treatment approaches to obesity have been vastly underutilised.

Targeted therapies and immunotherapies have radically improved treatment for advanced non-small-cell lung cancer (NSCLC). Tyrosine kinase inhibitors targeting oncogenic driver mutations continue to evolve over multiple generations to enhance effectiveness and tackle drug resistance. Immune checkpoint inhibitors remain integral for the treatment of NSCLCs that do not have specific actionable genetic mutations. Antibody-drug conjugates and bispecific antibodies are being integrated into treatment guidelines, and emerging therapies include T-cell engagers, cellular therapies, cancer vaccines, and external devices. Despite these advances, challenges remain in identifying predictive biomarkers to individually tailor treatments, abrogate resistance, reduce costs, and ensure optimal cancer treatment accessibility.

Acute liver failure (ALF) is a life-threatening disorder characterised by rapid deterioration of liver function, coagulopathy, and hepatic encephalopathy in the absence of pre-existing liver disease. The cause of ALF varies across the world. Common causes of ALF in adults include drug toxicity, hepatotropic and non-hepatotropic viruses, herbal and dietary supplements, antituberculosis drugs, and autoimmune hepatitis. The cause of liver failure affects the management and prognosis, and therefore extensive investigation for cause is strongly suggested. Sepsis with multiorgan failure and cerebral oedema remain the leading causes of death in patients with ALF and early identification and appropriate management can alter the course of ALF. Liver transplantation is the best current therapy, although the role of artificial liver support systems, particularly therapeutic plasma exchange, can be useful for patients with ALF, especially in non-transplant centres. In this Seminar, we discuss the cause, prognostic models, and management of ALF.

Understanding the proportion of invasive cervical cancer (ICC) caused by different human papillomavirus (HPV) genotypes can inform primary (ie, vaccination) and secondary (ie, screening) prevention efforts that target specific HPV genotypes. However, using the global literature to estimate population attributable fractions (AFs) requires a methodological framework to address HPV genotype-specific causality from aggregated data. We aimed to estimate the proportion of ICC caused by different HPV genotypes at the global, regional, and national level.

Post-COVID-19 condition (also known as long COVID) is generally defined as symptoms persisting for 3 months or more after acute COVID-19. Long COVID can affect multiple organ systems and lead to severe and protracted impairment of function as a result of organ damage. The burden of this disease, both on the individual and on health systems and national economies, is high. In this interdisciplinary Review, with a coauthor with lived experience of severe long COVID, we sought to bring together multiple streams of literature on the epidemiology, pathophysiology (including the hypothesised mechanisms of organ damage), lived experience and clinical manifestations, and clinical investigation and management of long COVID. Although current approaches to long COVID care are largely symptomatic and supportive, recent advances in clinical phenotyping, deep molecular profiling, and biomarker identification might herald a more mechanism-informed and personally tailored approach to clinical care. We also cover the organisation of services for long COVID, approaches to preventing long COVID, and suggestions for future research.

Children are not born equal in their likelihood of survival. The risk of mortality is highest during and shortly after birth. In the immediate postnatal period and beyond, perinatal events, nutrition, infections, family and environmental exposures, and health services largely determine the risk of death. We argue that current public health programmes do not fully acknowledge this spectrum of risk or respond accordingly. As a result, opportunities to improve the care, survival, and development of children in resource-poor settings are overlooked. Children at high risk of mortality are underidentified and commonly treated using guidelines that do not differentiate care according to the magnitude or drivers of those risks. Children at low risk of mortality are often provided with more intensive care than needed, disproportionately using limited health-care resources with minimal or no benefits. Declines in newborn, infant, and child mortality rates globally are slowing, and further reductions are likely to be incrementally more difficult to achieve once simple, high impact interventions have been universally implemented. Currently, 63 countries have rates of neonatal mortality that are off track to meet the Sustainable Development Goal 2030 target of 12 deaths per 1000 livebirths or less, and 54 countries have rates of mortality in children younger than 5 years that are off track to meet the target of 25 deaths per 1000 livebirths or less. If these targets are to be met, a change of approach is needed to address infant and child mortality and for health-care systems to more efficiently address residual mortality.

The last decade has seen remarkable progress in our understanding of disease biology of chronic lymphocytic leukaemia (CLL) and the development of novel targeted therapies. Randomised clinical trials have reported improved progression-free survival and overall survival with targeted therapies compared with chemoimmunotherapy, and thereby the role of chemoimmunotherapy in todays' era for treatment of CLL is limited. Bruton tyrosine kinase (BTK) inhibitors, BCL2 inhibitors, and CD20 monoclonal antibodies have been established as appropriate therapy options for patients with CLL, both as the first-line treatment and in the treatment of relapsed or refractory CLL. Several ongoing phase 3 trials are exploring different combinations of targeted therapies, and the results of these trials might change the treatment framework in first-line treatment of CLL. Non-covalent BTK inhibitors, chimeric antigen receptor T-cell therapy, and other therapeutic strategies are being investigated in relapsed CLL. Some of the therapies used in relapsed CLL, such as non-covalent BTK inhibitors, are now being pursued in earlier lines of therapy, including first-line treatment of CLL.

First described more than 350 years ago, infective endocarditis represents a global health concern characterised by infections affecting the native or prosthetic heart valves, the mural endocardium, a septal defect, or an indwelling cardiac device. Over recent decades, shifts in causation and epidemiology have been observed. Echocardiography remains pivotal in the diagnosis of infective endocarditis, with alternative imaging modalities gaining significance. Multidisciplinary management requiring expertise of cardiologists, cardiovascular surgeons, infectious disease specialists, microbiologists, radiologists and neurologists, is imperative. Current recommendations for clinical management often rely on observational studies, given the limited number of well conducted randomised controlled trials studying infective endocarditis due to the rarity of the disease. In this Seminar, we provide a comprehensive overview of optimal clinical practices in infective endocarditis, highlighting key aspects of pathophysiology, pathogens, diagnosis, management, prevention, and multidisciplinary approaches, providing updates on recent research findings and addressing remaining controversies in diagnostic accuracy, prevention strategies, and optimal treatment.

The landscape of the management of renal cell carcinoma has evolved substantially in the last decade, leading to improved survival in localised and advanced disease. We review the epidemiology, pathology, and diagnosis of renal cell carcinoma and discuss the evidence for current management strategies from localised to metastatic disease. Developments in adjuvant therapies are discussed, including use of pembrolizumab-the first therapy to achieve overall survival benefit in the adjuvant setting. The treatment of advanced disease, including landmark trials that have established immune checkpoint inhibition as a standard of care, are also reviewed. We also discuss the current controversies that exist surrounding the management of metastatic renal cell carcinoma, including the use of risk assessment models for disease stratification and treatment selection for frontline therapy. Management of non-clear cell renal cell carcinoma subtypes is also reviewed. Future directions of research, including a discussion of ongoing clinical trials and the need for reliable biomarkers to guide treatment in kidney cancer, are also highlighted.