Early-onset type 2 diabetes (defined as type 2 diabetes diagnosed in people aged <40 years) is an increasingly prevalent condition with a more aggressive disease trajectory than late-onset type 2 diabetes. It is associated with accelerated microvascular and macrovascular complications, reduced life expectancy, and adverse pregnancy outcomes. Despite its rising incidence, global management strategies have mostly been extrapolated from studies in older adults with limited evidence specific to younger populations. In this Series paper, we aim to highlight the unique challenges in the management of early-onset type 2 diabetes and why current models of care are inadequate. We emphasise that early-onset type 2 diabetes necessitates proactive and combination treatment strategies to address weight, faster β-cell decline, worse insulin resistance, and rapidly progressing hyperglycaemia compared with late-onset type 2 diabetes. However, there is minimal evidence on how best to address these factors and clinical inertia risks contributing to glycaemic burden. Cardiovascular risk assessment tools underestimate long-term risk, contributing to low use of statin and antihypertensive therapy. Reproductive health remains a key concern, yet preconception and pregnancy care are inadequate, with low adherence to recommended interventions. Health-care systems are not optimised to address the distinct needs of young adults, and gaps in transitional care (from paediatric to adult services) contribute to disengagement and adverse outcomes. Addressing these challenges requires tailored management strategies that consider the unique metabolic and psychosocial factors in this population. In this Series paper, we summarise the evidence base for the management of early-onset type 2 diabetes, key evidence gaps, and discuss the multisectoral and transdisciplinary elements needed to achieve population-level prevention to reverse these concerning trends.

Early-onset type 2 diabetes (defined as type 2 diabetes diagnosed in people aged <40 years) is increasingly prevalent with substantial health and socioeconomic implications. Unlike late-onset type 2 diabetes, early-onset type 2 diabetes is a high-risk and aggressive phenotype, with accelerated pancreatic β-cell decline and greater insulin resistance due to the rising rate of obesity. People with early-onset type 2 diabetes have higher rates of macrovascular and microvascular complications with increased health-care use and premature mortality (due to cardiovascular and non-cardiovascular complications) than do people with late-onset type 2 diabetes. Emerging evidence also suggests that people with early-onset type 2 diabetes face an increased risk of complications in reproductive health (eg, during periconception and postpartum periods), metabolic-associated steatotic liver disease, mental health (eg, diabetes distress, depression, anxiety, and psychotic disorders), and some cancers, creating additional challenges in managing multiple long-term conditions. In this Series paper, we highlight the consequences of early-onset type 2 diabetes and the key driver for these risks-long duration of exposure to hyperglycaemia, with its effects amplified by younger age at type 2 diabetes diagnosis and interactions with other cardiometabolic risk factors. Recognising these adverse risks associated with early-onset type 2 diabetes is crucial for guiding the development and implementation of a more focused and integrated life-course approach to mitigate its long-term effect on individuals, communities, and health-care systems globally. However, substantial research gaps remain that must be addressed, particularly in diverse populations.

The incidence of early-onset type 2 diabetes is increasing, with a growing number of cases now occurring in children, adolescents, and young adults. This transition is primarily driven by the rising prevalence of obesity in younger populations, especially in high-income countries. However, the relationship between obesity and early-onset type 2 diabetes varies across ethnic groups, with some populations exhibiting a higher risk at lower BMI thresholds, possibly due to differences in insulin resistance and β-cell function. Socioeconomic factors further shape disease patterns, with early-onset type 2 diabetes disproportionately affecting lower-income populations in high-income settings, whereas in low-income and middle-income countries, economic development and urbanisation have contributed to increasing incidence among more affluent groups. The consequences of this transition to early-onset type 2 diabetes are severe, with accelerated disease progression, heightened risks of microvascular and macrovascular complications, and considerable societal and health-care burdens compared with later-onset disease. Given the continuing rise in childhood and adolescent obesity, the incidence of early-onset type 2 diabetes is expected to increase further, placing mounting pressure on health-care systems worldwide. In the first of three papers in this Series, we examine global trends in the incidence and prevalence of early-onset type 2 diabetes, identify key drivers of this transition to diagnosis at younger ages, and review the evidence for risk factors both at population and individual level.

Cerebral palsy is a lifelong physical disability affecting movement and posture. The motor impairments of cerebral palsy result from non-degenerative brain injuries, brain malformations, and genetic variations, arising from multiple risk factors and causal pathways during preconception, pregnancy, birth, or within the first 2 years of life. Over the past decade, substantial progress in diagnosing, preventing, and managing the condition has transformed treatment approaches. A key discovery is that up to 30% of individuals with CP have a genetic contribution. In high-income countries, the prevalence has decreased by as much as 40%, from 2·1 per 1000 livebirths to 1·6 per 1000 livebirths. However, the prevalence is higher in low-income and middle-income countries. Advances in early diagnosis make identification of cerebral palsy at as early as age 3 months possible, enabling timely, intensive early intervention that improves child and parent outcomes. Additionally, new medical, regenerative, and rehabilitation therapies have emerged, enhancing function and participation. Growing awareness of the health challenges and physical decline faced by adults underscores the need for a lifelong approach. This Seminar highlights the best available evidence and recent progress to help clinicians address key questions identified by individuals with lived experience.

This Review offers an evaluation of current treatments for symptomatic uterine fibroids, including uterine artery embolisation, MRI-guided high-intensity focused ultrasound, laparoscopic radiofrequency ablation, transcervical radiofrequency ablation, ulipristal acetate, and oral gonadotropin-releasing hormone antagonists with add-back therapy. Placing these therapies within the IDEAL (Idea, Development, Exploration, Assessment, And Long-Term Follow-Up) framework and the clinical phases of drug development framework, we highlight key gaps in the evidence such as the lack of head-to-head comparisons with standard care, scarce long-term data, and inadequate consideration of real-world fibroid and patient characteristics. We provide a clear overview, assess the strength of the available evidence, and propose a practical flowchart to help clinicians navigate treatment decisions, ensuring the best care for women with symptomatic fibroids at various stages of therapy development. Insight into these matters equips both patient and clinician with essential information to support the process of shared and fully informed decision making. Importantly, this Review also identifies knowledge gaps that contribute to the specification of the fibroid research agenda.

Vaccines have had a major impact on the control of infectious disease, most recently by helping to combat the COVID-19 pandemic. Prophylactic cancer vaccines have prevented several malignancies by protecting against cancer-causing pathogens. By contrast, therapeutic vaccines training the immune system to eliminate established tumours are now showing real promise in clinical settings. In the adjuvant setting, vaccines against melanoma and pancreatic cancer appear to be reducing minimal residual disease and relapse. In the macrometastatic setting, in-situ vaccines have induced systemic regressions in advanced-stage lung and breast cancers and lymphomas. More effective cancer vaccines are being developed through having a deeper understanding of crucial cellular factors in tumour immunology, the incorporation of newer vaccine components to effectively mobilise and activate cells, the use of omics and artificial intelligence in vaccine design, and addition of immune checkpoint blockade. In this Viewpoint, we analyse cancer vaccine trials, the strengths and limitations of different vaccine approaches, and we discuss how the next generation of cancer vaccines can help improve patient outcomes and quality of life.

Acute rheumatic fever (ARF) is an autoimmune disorder resulting from Group A Streptococcus (GAS) pharyngitis or impetigo in children and adolescents, which may evolve to rheumatic heart disease (RHD) with persistent cardiac valve damage. RHD causes substantial mortality and morbidity globally, predominantly among socioeconomically disadvantaged populations, with an interplay of social determinants of health and genetic factors determining overall risk. ARF diagnosis is based on a constellation of clinical and laboratory features as defined by the 2015 Jones Criteria, although advances in molecular point-of-care testing and the ongoing search for ARF biomarkers offer the potential to revolutionise diagnostics. There are persistent gaps in ARF pathophysiology with little progress in therapeutics over the last several years. The greater focus towards primordial, primary, and secondary prevention such as advances in GAS vaccine development, innovations in digital health technology, improved antibiotic formulations for secondary prevention, and decentralised programmatic implementation to improve health-care delivery offer feasible solutions towards reducing future ARF burden globally.

Testicular cancer is the most common solid malignancy in people with testicles aged 15-44 years, accounting for 1-2% of all tumours in males of all ages. Approximately 95% of testicular cancers are testicular germ cell tumours. This Seminar focuses on testicular cancer, with an emphasis on testicular germ cell tumours. We delve into the epidemiology, clinical presentation, disease management, controversies, clinical dilemmas, follow-up, and future directions. Furthermore, we explore distinct treatment approaches for seminoma and non-seminoma testicular germ cell tumours across all clinical stages and discuss post-treatment salvage options after relapse. Our Seminar aims to provide a comprehensive review of testicular cancer, to enhance understanding, and inform clinicians and researchers about the latest developments in management.

Trachoma, the leading infectious cause of blindness worldwide, is one of several neglected tropical diseases targeted by WHO for elimination by 2030. The disease starts in childhood with repeated episodes of conjunctival Chlamydia trachomatis infection. This infection is associated with recurrent conjunctivitis (active trachoma), which, if left untreated, leads to cicatricial trachoma characterised by scarring of the conjunctiva, and potentially in-turned eyelashes (trachomatous trichiasis) in later life. Trachoma mainly affects the poorest and most rural communities; these populations typically have limited access to water and hygiene facilities. Blinding complications are most common in women who, in many cultures, act as caregivers from a young age for infected children. To eliminate trachoma as a public health problem, programmes implement a package of interventions known as SAFE; namely, surgery to treat trachomatous trichiasis, antibiotic mass drug administration to treat infection, facial cleanliness, and environmental improvement to limit transmission. The SAFE strategy has brought considerable success in the last two decades. As of December, 2024, 21 countries have eliminated the disease, and several others are on track to eliminate it soon. However, persistent and recrudescent active trachoma in some populations might challenge the success of the 2030 global elimination target. In such settings, novel, or more intensive, approaches must be promptly developed, tested, and scaled up to accelerate elimination.

The Lancet Commission on diagnostics made recommendations for ten topics: national strategy (including national essential diagnostics lists), access in primary care, workforce, regulatory framework, national financing, affordability, appropriate use of technology, needs in conflict or fragile situations, advocacy, and an international alliance with oversight capabilities. Since 2021, progress in these areas has benefitted greatly from the adoption of a World Health Assembly resolution on diagnostics and the work of a broad coalition, as assessed by literature surveys by subject matter experts, quantitative findings (where feasible), and an anonymous survey of knowledgeable and engaged individuals. Greater progress was observed where there was political will and the production of diagnostics coincided with industrial policy goals, also in areas where changing the legal and health policy frameworks was involved. Progress was slower on recommendations with substantial resource implications (eg, labour force, affordability, and diagnostics for conflict situations). It is expected that the Global Diagnostics Coalition will consolidate and accelerate progress.

One in five of the population lives with chronic pain. Psychological interventions for pain reveal core principles that can be used to create opportunities for chronic pain self-management in primary practice, across health-care settings, and at home. We highlight the different types of chronic pain and illustrate the psychoneurobiological mechanisms involved. We review core principles for psychological pain management, evaluate the evidence, and illustrate the underlying neurobiology involved. We provide practical advice for how to facilitate pain self-management in clinical practice. Finally, we discuss scientific caveats and practical obstacles to improvement, suggesting possible pathways to implementation.

Improved hypertension control can save millions of lives, but mass hypertension screening, a commonly used approach, is a barrier to progress. Although politically appealing, mass screening diverts resources from improving services in primary health care. Hypertension treatment requires ongoing, long-term care. Mass screening is inefficient: many people with hypertension are not screened or not screened accurately; most people referred do not follow up; many who do follow up are found not to have hypertension; and among those who have hypertension, few initiate and adhere to treatment. Universal measurement of blood pressure among all adults attending health facilities is much more effective and facilitates treatment and ongoing care. Universal facility-based screening can improve diagnosis and control substantially, including among underserved populations. Implementing this approach requires that facilities have validated blood pressure monitors, routinely screen at least all patients aged 30 years and older, and increase the number and proportion of patients being treated for hypertension whose blood pressure is at target (eg, <140/90 mm Hg). The only way to control hypertension is to strengthen facility-based detection and treatment. To prevent heart attacks, strokes, death, and other complications of untreated and inadequately treated hypertension, countries should track and steadily increase the outcome that matters: the number of patients on treatment whose blood pressure is controlled.

Gastric cancer remains a major health challenge worldwide, with nearly 1 million new cases annually contributing to more than 650 000 deaths. Epidemiologically, gastric cancer shows substantial geographical variation in incidence, with higher rates in Asia, South America, and eastern Europe, and a rapid increase in early-onset cases among people younger than 50 years. Key risk factors for gastric cancer include Helicobacter pylori infection, diet, obesity, smoking, and genetic predisposition. Early detection through comprehensive diagnostic procedures is crucial for optimising treatment outcomes. Standard treatment approaches for locally advanced gastric cancer include surgical resection, particularly D2 lymphadenectomy, complemented by chemotherapy and radiotherapy. There is increasing implementation of minimally invasive surgical techniques for operable disease and integration of immune checkpoint inhibitors and targeted therapies for advanced stages. Emerging therapies, such as novel targeted treatments and next-generation immunotherapies, show promise in improving survival and quality of life. Future directions in the management of gastric cancer focus on precision medicine, continued advancement in immunotherapy, novel early detection methods, and a multidisciplinary approach to care. These strategies aim to enhance the overall effectiveness of treatment and prognosis worldwide.

Prolonged grief disorder is a mental health disorder recently included in diagnostic manuals worldwide. This Review presents published research evidence in strong support for the current conceptualisation of prolonged grief disorder: a diagnosable mental health condition with core symptoms of yearning, preoccupation, or both, which is associated with symptoms of emotional pain, identity disturbances, loss of meaning and purpose, and functional impairment. The public and academic discourse surrounding prolonged grief disorder has catalysed researchers to produce methodologically rigorous research evidence in support of this much-needed diagnosis. A coherent syndrome of prolonged grief disorder has a typical onset of 6 to 12 months after the death of a close person. Prolonged grief disorder is associated with various poor outcomes, including negative health outcomes (eg, high blood pressure), increased rates of suicidality, low life satisfaction, and increased service use. Psychotherapy is the main treatment for prolonged grief disorder. Theoretical models of the cause and maintenance of prolonged grief disorder are presently being refined through the rapidly increasing empirical literature. Awareness of prolonged grief disorder by general health practitioners, as well as mental health specialists, is key to appropriate early intervention.

Well designed and properly executed randomised trials are considered the most reliable evidence on the benefits of healthcare interventions. However, there is overwhelming evidence that the quality of reporting is not optimal. The CONSORT (Consolidated Standards of Reporting Trials) statement was designed to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996, then updated in 2001 and 2010. Here, we present the updated CONSORT 2025 statement, which aims to account for recent methodological advancements and feedback from end users. We conducted a scoping review of the literature and developed a project-specific database of empirical and theoretical evidence related to CONSORT, to generate a list of potential changes to the checklist. The list was enriched with recommendations provided by the lead authors of existing CONSORT extensions (Harms, Outcomes, Non-pharmacological Treatment), other related reporting guidelines (TIDieR) and recommendations from other sources (eg, personal communications). The list of potential changes to the checklist was assessed in a large, international, online, three-round Delphi survey involving 317 participants and discussed at a two-day online expert consensus meeting of 30 invited international experts. We have made substantive changes to the CONSORT checklist. We added seven new checklist items, revised three items, deleted one item, and integrated several items from key CONSORT extensions. We also restructured the CONSORT checklist, with a new section on open science. The CONSORT 2025 statement consists of a 30-item checklist of essential items that should be included when reporting the results of a randomised trial and a diagram for documenting the flow of participants through the trial. To facilitate implementation of CONSORT 2025, we have also developed an expanded version of the CONSORT 2025 checklist, with bullet points eliciting critical elements of each item. Authors, editors, reviewers, and other potential users should use CONSORT 2025 when writing and evaluating manuscripts of randomised trials to ensure that trial reports are clear and transparent.

PEPFAR (President's Emergency Plan for AIDS Relief), a landmark US foreign health policy, is recognised for saving 26 million lives from HIV. PEPFAR investments have also had life-saving impacts for children across sub-Saharan Africa through childhood HIV prevention, care, and treatment, ensuring 7·8 million babies were born HIV-free, supporting 13 million orphaned and vulnerable children, and protecting 10·3 million girls from sexual abuse. In this Health Policy, we review data from UNAIDS, UNICEF, World Bank, Violence Against Children Surveys, SPECTRUM model data, and Population-based HIV Impact Assessments; synthesise PEPFAR reports; conduct in-depth interviews; search PubMed for programme effectiveness evidence; and review economic reports. PEPFAR support is associated with substantial collateral benefits for the USA and Africa, including a four-fold increase in export of US goods to Africa, and US$71·6 billion in total goods trade between the USA and Africa in 2024. PEPFAR-supported countries in Africa are committed to ownership of HIV responses by 2030-overall, PEPFAR-supported countries in sub-Saharan Africa have progressively increased their co-financing of their health systems through domestic government and private expenditure from $13·7 billion per year in 2004 to $42·6 billion per year in 2021. The feasibility of a 5-year transition to country-led sustainability is supported by evidence of innovative cost-saving models of delivery, including through faith-based and community-based organisations, and high return-on-investment for PEPFAR programmes. There are also collateral benefits of PEPFAR for US and Africa national security and health security, for example, reducing forced migration and increasing capacity to control emerging transborder infectious disease threats. Risks in sub-Saharan Africa remain acute: one in five girls (younger than 18 years) experience rape or sexual assault; one in ten children (younger than 18 years) are orphaned; and a child (younger than 15 years) is estimated to die from AIDS every 7 min. Without continued PEPFAR programmes, models predict that by 2030, an additional 1 million children will become infected with HIV, 0·5 million additional children will die of AIDS, and 2·8 million children will additionally become orphaned by AIDS. There is now an opportunity for a transformational partnership between the USA and Africa, to accelerate domestic government co-financing, private-sector investments, and charitable foundations. A 5-year progressive runway of transition can occur through continued authorisation of PEPFAR programmes, which can lead to the end of AIDS for children and families, an historic achievement.