The 2 × 2 PEACE-1 study showed that combining androgen-deprivation therapy with docetaxel and abiraterone improved overall and radiographic progression-free survival in patients with de novo metastatic castration-sensitive prostate cancer. We aimed to examine the efficacy and safety of adding radiotherapy in this population.

The effectiveness of using a balloon guide catheter during endovascular thrombectomy in patients with acute ischaemic stroke due to large vessel occlusion of the anterior circulation remains uncertain. We aimed to assess the effectiveness and safety of using a balloon guide catheter during endovascular thrombectomy, compared with using a conventional guide catheter, in this patient population.

Since the discovery of statins and the Scandinavian Simvastatin Survival Study (4S) results three decades ago, remarkable advances have been made in the treatment of dyslipidaemia, a major risk factor for atherosclerotic cardiovascular disease. Safe and effective statins remain the cornerstone of therapeutic approach for this indication, including for children with genetic dyslipidaemia, and are one of the most widely prescribed drugs in the world. However, despite the affordability of generic statins, they remain underutilised worldwide. The use of ezetimibe to further decrease plasma LDL cholesterol and the targeting of other atherogenic lipoproteins, such as triglyceride-rich lipoproteins and lipoprotein(a), are likely to be required to further reduce atherosclerotic cardiovascular disease events. Drugs directed at these lipoproteins, including gene silencing and editing methods that durably suppress the production of proteins, such as PCSK9 and ANGPTL3, open novel therapeutic options to further reduce the development of atherosclerotic cardiovascular disease.

Building on the evidence from the first paper in this Series highlighting the fundamental importance of healthy and nurturing environments for children's growth and development in the next 1000 days (ages 2-5 years), this paper summarises the benefits and costs of key strategies to support children's development in this age range. The next 1000 days build on the family-based and health-sector based interventions provided in the first 1000 days and require broader multisectoral programming. Interventions that have been shown to be particularly effective in this age range are the provision of early childhood care and education (ECCE), parenting interventions, and cash transfers. We show that a minimum package of 1 year of ECCE for all children would cost on average less than 0·15% of low-income and middle-income countries' current gross domestic product. The societal cost of not implementing this package at a national and global level (ie, the cost of inaction) is large, with an estimated forgone benefit of 8-19 times the cost of investing in ECCE. We discuss implications of the overall evidence presented in this Series for policy and practice, highlighting the potential of ECCE programming in the next 1000 days as an intervention itself, as well as a platform to deliver developmental screening, growth monitoring, and additional locally required interventions. Providing nurturing care during this period is crucial for maintaining and further boosting children's progress in the first 1000 days, and to allow children to reach optimal developmental trajectories from a socioecological life-course perspective.

Following the first 1000 days of life that span from conception to two years of age, the next 1000 days of a child's life from 2-5 years of age offer a window of opportunity to promote nurturing and caring environments, establish healthy behaviours, and build on early gains to sustain or improve trajectories of healthy development. This Series paper, the first of a two-paper Series on early childhood development and the next 1000 days, focuses on the transition to the next 1000 days of the life course, describes why this developmental period matters, identifies the environments of care, risks, and protective factors that shape children's development, estimates the number of children who receive adequate nurturing care, and examines whether current interventions are meeting children's needs. Paper 2 focuses on the cost of inaction and the implications of not investing in the next 1000 days. In low-income and middle-income countries (LMICs), only 62 million children aged 3 and 4 years (25·4%) currently receive adequate nurturing care during the next 1000 days, leaving 181·9 million children exposed to risks that jeopardise their healthy development. Inputs across nurturing care dimensions of health, nutrition, protection, responsive care, and learning vary substantially across countries. In LMICs, although 86·2% of children have a healthy weight in this period, less than one in three children have access to developmental stimulation or are protected from physical punishment, and only 38·8% have access to early childhood care and education services. Intervention research in LMICs in the next 1000 days is scarce. The continuity of developmentally appropriate nurturing care, coordination across health, education, and protection sectors, and the implementation of interventions to support caregivers and improve the quality of education and care remain top priorities in this period. These sectors play key roles in promoting quality early care and education for this age group, which will help maximise developmental potential and opportunities of children globally and help progress towards the achievement of the Sustainable Development Goals.

Over the past several decades, the overweight and obesity epidemic in the USA has resulted in a significant health and economic burden. Understanding current trends and future trajectories at both national and state levels is crucial for assessing the success of existing interventions and informing future health policy changes. We estimated the prevalence of overweight and obesity from 1990 to 2021 with forecasts to 2050 for children and adolescents (aged 5-24 years) and adults (aged ≥25 years) at the national level. Additionally, we derived state-specific estimates and projections for older adolescents (aged 15-24 years) and adults for all 50 states and Washington, DC.

Cardiogenic shock is a complex syndrome defined by systemic hypoperfusion and inadequate cardiac output arising from a wide array of underlying causes. Although the understanding of cardiogenic shock epidemiology, specific subphenotypes, haemodynamics, and cardiogenic shock severity staging has evolved, few therapeutic interventions have shown survival benefit. Results from seminal randomised controlled trials support early revascularisation of the culprit vessel in infarct-related cardiogenic shock and provide evidence of improved survival with the use of temporary circulatory support in selected patients. However, numerous questions remain unanswered, including optimal pharmacotherapy regimens, the role of mechanical circulatory support devices, management of secondary organ dysfunction, and best supportive care. This Review summarises current definitions, pathophysiological principles, and management approaches in cardiogenic shock, and highlights key knowledge gaps to advance individualised shock therapy and the evidence-based ethical use of modern technology and resources in cardiogenic shock.

Oesophageal cancer is the seventh leading cause of cancer mortality worldwide. Two major pathological subtypes exist: oesophageal squamous cell carcinoma and oesophageal adenocarcinoma. Epidemiological studies in the last decade have shown a gradual increase in the incidence of oesophageal adenocarcinoma worldwide. The prognosis of oesophageal cancer has greatly improved due to breakthroughs in screening, surgical procedures, and novel treatment modalities. The success achieved with combined modality therapies, including surgery, chemotherapy, and radiotherapy, to treat locally advanced oesophageal cancer is particularly notable. Immunotherapy has become a crucial treatment for oesophageal cancer, with immune checkpoint inhibitor-based therapies now established as the standard of care in adjuvant and metastatic first-line settings. This Seminar provides an overview of advances in the screening, diagnosis, and treatment of oesophageal squamous cell carcinoma and oesophageal adenocarcinoma, with a particular focus on neoadjuvant therapies for locally advanced oesophageal cancer and immune checkpoint inhibitor-based therapies.

Glofitamab monotherapy induces durable remission in patients with relapsed or refractory diffuse large B-cell lymphoma after two or more previous therapies, but has not previously been assessed as a second-line therapy. We investigated the efficacy and safety of glofitamab plus gemcitabine-oxaliplatin (Glofit-GemOx) versus rituximab (R)-GemOx in patients with relapsed or refractory diffuse large B-cell lymphoma.

Diabetes can be detected at the primary health-care level, and effective treatments lower the risk of complications. There are insufficient data on the coverage of treatment for diabetes and how it has changed. We estimated trends from 1990 to 2022 in diabetes prevalence and treatment for 200 countries and territories.

With the advent of the first disease-modifying, anti-amyloid β-directed passive immunotherapy for Alzheimer's disease, questions arise who, when, and how to treat. This paper describes shortly the pathogenic basis of and preclinical data, which have, more than two decades ago, initiated the development of this vaccination therapy. We discuss clinical trial results of aducanumab, lecanemab, and donanemab. We also review appropriate use recommendations of these novel treatments on patient selection and safety monitoring. Furthermore, estimations of numbers of patient who will qualify for treatment regarding inclusion and exclusion criteria and estimations on readiness of health-care systems for identifying the right patients and for providing the treatment are reported. In our view, we are experiencing a fundamental shift from syndrome-based Alzheimer's dementia care to early, biomarker-guided treatment of Alzheimer's disease. This shift requires substantial adjustments of infrastructure and resources, but also holds promise of eventually achieving substantial slowing of disease progression and delaying dementia.

Approximately half of patients with localised, high-risk soft tissue sarcoma of the extremity develop metastases. We aimed to assess whether the addition of pembrolizumab to preoperative radiotherapy and surgery would improve disease-free survival.

There are few proven treatments for acute spontaneous intracerebral haemorrhage, and they all target reducing expansion of the haematoma. The traditional Chinese medicine FYTF-919 (Zhongfeng Xingnao) in an oral solution is comprised of several Chinese herbs that are widely used to treat patients with intracerebral haemorrhage in China on the understanding that they enhance resorption of the haematoma and reduce neuroinflammation. We aimed to provide a reliable assessment of the safety and efficacy of FYTF-919 in patients with moderate to severe acute intracerebral haemorrhage.

Transfusion-dependent β-thalassaemia (TDT) is a severe disease, resulting in lifelong blood transfusions, iron overload, and associated complications. Betibeglogene autotemcel (beti-cel) gene therapy uses autologous haematopoietic stem and progenitor cells (HSPCs) transduced with BB305 lentiviral vector to enable transfusion independence.

The loss of corneal epithelial stem cells from the limbus at the edge of the cornea has severe consequences for vision, with the pathological manifestations of a limbal stem-cell deficiency (LSCD) difficult to treat. Here, to the best of our knowledge, we report the world's first use of corneal epithelial cell sheets derived from human induced pluripotent stem cells (iPSCs) to treat LSCD.

The Human Development Index (HDI)-a composite metric encompassing a population's life expectancy, education, and income-is used widely for assessing and comparing human development and wellbeing at the country level, but does not account for within-country inequality. In this study of the USA, we aimed to adapt the HDI framework to measure the HDI at an individual level to examine disparities in the distribution of wellbeing by race and ethnicity, sex, age, and geographical location.

Stillbirth is a devastating and often avoidable adverse pregnancy outcome. Monitoring stillbirth levels and trends-in a comprehensive manner that leaves no one uncounted-is imperative for continuing progress in pregnancy loss reduction. This analysis, completed as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021, methodically accounted for different stillbirth definitions with the aim of comprehensively estimating all stillbirths at 20 weeks or longer for 204 countries and territories from 1990 to 2021.

The optimal timing of anticoagulation for patients with acute ischaemic stoke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation.

High-dose haemodiafiltration has been shown, in a randomised clinical trial, to result in a 23% lower risk of mortality for patients with kidney failure when compared with conventional high-flux haemodialysis. Nevertheless, whether treatment effects differ across subgroups, whether a dose-response relationship with convection volume exists, and the effects on cause-specific mortality remain unclear. The aim of this individual patient data meta-analysis was to compare the effects of haemodiafiltration and standard haemodialysis on all-cause and cause-specific mortality.

Most individuals use medication during pregnancy. However, decision making on antenatal pharmacotherapy presents considerable ethical and scientific challenges. Amid a sociocultural paradigm prioritising the elimination of fetal risks, available evidence and guidance are limited, and current decision making on antenatal drugs mostly proceeds in an ad-hoc and, often, biased manner. This approach might undermine the health of both mother and child. The need for a systematic approach towards antenatal drug decisions is becoming even more pressing with the growing knowledge of pregnancy-induced changes in drug disposition and effects. With this new complexity, pregnancy-specific doses might be necessary, potentially altering the balance between maternal and fetal benefits and risks. In this Viewpoint, we argue that ethical principles and a pregnant individual's values must be integrated alongside existing evidence when making decisions on antenatal drug use and dosing. We use the example of sertraline to outline practical strategies for achieving this goal. This approach is urgently needed to foster better-informed and balanced decisions on antenatal pharmacotherapy.