Mineralocorticoid receptor antagonists can prevent cardiovascular events in patients with heart failure and non-severe chronic kidney disease, but their effects in patients with kidney failure requiring dialysis are uncertain. We aimed to assess the efficacy and safety of mineralocorticoid receptor antagonists in this patient population.

Advancements over the past decade in understanding vesicular monoamine transporter 2 (VMAT2) inhibitors highlight their key role in the treatment of movement and neuropsychiatric disorders. VMAT2 is crucial for packaging neurotransmitters such as serotonin, dopamine, and norepinephrine into synaptic vesicles, facilitating their release and reuptake in synaptic transmission. VMAT2 inhibitors, such as tetrabenazine, deutetrabenazine, and valbenazine, show therapeutic efficacy in managing hyperkinetic movement disorders, including Huntington's disease, tardive dyskinesia, and Tourette's syndrome. These inhibitors modulate excessive synaptic activity by reducing neurotransmitter storage and release. Genetic variations, particularly in the cytochrome P450 enzyme family, influence VMAT2 inhibitor metabolism, necessitating personalised dosing to optimise efficacy and minimise adverse events. Recent studies have provided further structural insights into VMAT2 inhibition mechanisms, paving the way for the development of inhibitors with enhanced potency and selectivity. Leveraging pharmacogenetics for precision medicine and exploring VMAT2 inhibition in broader therapeutic contexts could revolutionise treatment frameworks for neurological and psychiatric conditions.

Plastics are a grave, growing, and under-recognised danger to human and planetary health. Plastics cause disease and death from infancy to old age and are responsible for health-related economic losses exceeding US$1·5 trillion annually. These impacts fall disproportionately upon low-income and at-risk populations. The principal driver of this crisis is accelerating growth in plastic production-from 2 megatonnes (Mt) in 1950, to 475 Mt in 2022 that is projected to be 1200 Mt by 2060. Plastic pollution has also worsened, and 8000 Mt of plastic waste now pollute the planet. Less than 10% of plastic is recycled. Yet, continued worsening of plastics' harms is not inevitable. Similar to air pollution and lead, plastics' harms can be mitigated cost-effectively by evidence-based, transparently tracked, effectively implemented, and adequately financed laws and policies. To address plastics' harms globally, UN member states unanimously resolved in 2022 to develop a comprehensive, legally binding instrument on plastic pollution, namely the Global Plastics Treaty covering the full lifecycle of plastic. Coincident with the expected finalisation of this treaty, we are launching an independent, indicator-based global monitoring system: the Lancet Countdown on health and plastics. This Countdown will identify, track, and regularly report on a suite of geographically and temporally representative indicators that monitor progress toward reducing plastic exposures and mitigating plastics' harms to human and planetary health.

Acute lymphocytic leukaemia (ALL) is a haematological malignancy of the lymphoid progenitor cells. Enhanced genetic analyses have led to the identification of over 23 subtypes of B-cell and 17 subtypes of T-cell ALL. In parallel, the development of highly sensitive measurable residual disease assays have refined disease monitoring and risk stratification. Breakthroughs in molecular therapeutics and immunotherapies have improved treatment efficacy while reducing toxicity, challenging the traditional notion of 2·5-3 years of intensive chemotherapy. Notable progress includes the use of more potent BCR::ABL1 tyrosine-kinase inhibitors, and antibodies targeting CD19 and CD22 leukaemia surface antigens, which have delivered unprecedented outcomes in BCR::ABL1-positive ALL. Historically, adults have had poorer outcomes than paediatric cases, largely due to the higher prevalence of adverse genetic subtypes and less favourable genetic subtypes. However, development of new therapies has improved overall survival in B-cell ALL to approximately 80-90%, even in adult and infant populations. Chimeric antigen receptor T-cell therapies have also transformed outcomes for children with refractory or relapsed ALL and are now being incorporated into the front-line treatment of adult ALL. These innovations hold the promise of increasing the cure rates while reducing reliance on intensive chemotherapy and allogeneic stem-cell transplantation.

The hallmark of bipolar disorder is hypomania or mania, and the predominant phase of illness is depression. Affecting approximately 40 million individuals worldwide, bipolar disorder is associated with a substantial psychosocial, medical, and financial burden and increased mortality from suicide and other causes. Diagnosis can be challenging due to symptom overlap with attention-deficit hyperactivity disorder, major depressive disorder, psychotic spectrum disorders, and personality disorders, which often leads to a delay in diagnosis. Recent advancements in understanding disease risk and pathophysiology have identified multigene risk and possible infectious and mitochondrial causes. Treatment approaches include pharmacotherapy, psychotherapy, and lifestyle modifications, which should always be patient-centred and aligned with individual goals and priorities. Future directions for bipolar disorder care include increasing the availability of psychosocial interventions aimed at self-management, addressing treatment-resistant bipolar depression, deepening the understanding of pathophysiology, and exploring novel interventions, such as ketamine, esketamine, other rapid-acting antidepressants, and various neuromodulation approaches.

Epilepsies that present during childhood pose unique challenges and include developmental and epileptic encephalopathies, specific distinctive constellations, and epilepsies with seizure subtypes, such as epileptic spasms, myoclonic-atonic seizures, and myoclonic absences. Self-limited focal epilepsies and genetic generalised epilepsy phenotypes are also evident during childhood. However, determining the cause-whether structural, genetic, metabolic, infectious, or autoimmune-is increasingly relevant. Although history and clinical examination form the fundamental basis of diagnosis, exclusion of epilepsy mimics in childhood can prove challenging, requiring specialist input and supportive electrophysiology. With crucial evidence-based medicine emerging on the treatment of infantile epileptic spasm syndrome, Dravet syndrome, and Lennox-Gastaut syndrome, with a focus on improving outcomes, early identification of surgically remediable epilepsies is crucial for neurodevelopmental outcomes. Practical questions remain regarding pathophysiology, the effects of causative factors and interictal epileptiform activity on cognition, and the efficacy of precision medicine-based approaches based on insights from epilepsy genetics.

Progress towards The Lancet Commission on Global Surgery's 2030 targets has been too slow and too patchy, particularly in low-income and middle-income countries. The unmet need for surgery has continued to grow, reaching at least 160 million operations per year. Ensuring high-quality surgical care remains a crucial global challenge, with 3·5 million adults dying after surgery each year. The COVID-19 pandemic exposed the fragility of surgical services long undermined by chronic underfunding, workforce shortages, and under-resourced infrastructure. However, The Lancet Commission on Global Surgery inspired a new generation of surgeons to engage with policy, and several countries have developed national surgical plans, although most remain unfunded. Advancements in surgical data science have allowed health systems to identify priorities for improvement. Preserving this infrastructure is important, especially during periods of uncertain global health funding. The next decade requires urgent change to prevent economic instability and armed conflict from forcing surgery down the global health agenda. Reframing surgery as an essential service that saves lives, strengthens health systems, and fosters economic productivity could unlock much needed investment. Sustained progress requires integration of funding both within hospital infrastructure and across care pathways. Such holistic approaches would reinforce entire hospital systems, which are essential to national security and wellbeing.

Although a growing body of evidence supports zero risk of sexual HIV transmission from a person with sustained virological suppression, known as U=U (undetectable equals untransmittable), data have been insufficient to determine whether this is also true for vertical HIV transmission. We conducted a systematic review and meta-analysis to quantify vertical transmission risk by maternal HIV viral load (mHVL) and to evaluate the applicability of U=U to perinatal and postnatal HIV transmission.

Since the emergence of the Zika virus epidemic in 2014 and the associated novel sequalae that emerged, much has been learned about the effects of antenatal exposure to Zika virus. Zika virus in pregnancy carries severe teratogenic potential to the fetus, ranging from congenital Zika syndrome to milder neurodevelopmental sequelae. Congenital Zika syndrome is associated with a spectrum of alterations that can affect cognitive, language, and motor development. Among children with congenital Zika syndrome, dysphagia and seizures are common, as are hospitalisations for pneumonia and urinary tract infections; overall, morbidity and mortality are extremely high. Children without congenital Zika syndrome but exposed to Zika virus antenatally are also at risk of developmental disorders. In addition, in utero exposure to Zika virus does not lead to the production of neutralising antibodies. Although the epidemic has subsided, Zika virus remains endemic in many countries and continues to affect families. Maternal associations have been fundamental in advocating for health care for children with congenital Zika syndrome and economic support for families. Gaps in scientific knowledge include the absence of data on long-term outcomes among school-age children. Future research and investments are needed to improve diagnostics, restart the stalled development of Zika virus vaccines, and evaluate antiviral treatments.

The large deficit in donated organs required to provide transplantation to patients with end-stage organ disease is a global health crisis, exacerbated by regional differences in clinical practice and available resources. This deficit highlights the need for better tools to determine organ suitability for transplantation and to enhance the recovery of potential donor organs which are currently not transplanted due to concerns about organ quality. Novel organ assessment approaches, including epidemiological predictive models, advanced functional biometrics, and refined histological analysis, show potential to better identify donated organs suitable for transplantation. In addition, novel machine perfusion platforms have shown remarkable capacities to preserve and potentially modify injured organs, and a series of xenotransplantation experiments suggest a viable pathway to create a new organ supply. Collectively, these technologies will gradually alleviate the organ shortage and expand access to life-saving transplants.

Transplant medicine faces substantial challenges, as patients require lifelong immunosuppression to prevent graft rejection. Immunosuppressive regimens to date, while reasonably effective at preventing acute rejection, cause numerous health complications, compromising quality of life and patient survival. A shift towards personalised immunosuppression is needed to improve allograft health, reduce long-term adverse effects, and optimise post-transplant outcomes. This necessity has driven advancements in post-transplant monitoring and diagnostics. Innovative monitoring biomarkers and novel diagnostic modalities have been developed to advance transplant care, with many showing promise for widespread clinical implementation. With advances in artificial intelligence, algorithms have the potential to integrate multidimensional data on the immune system and allograft health, offering a comprehensive view of transplant status. This Series paper highlights the state of post-transplant immunosuppression, monitoring, and diagnostics, emphasising the transformative role of emerging innovations to personalise both allograft and patient care. Their implications could extend to xenotransplantation, further broadening their potential to redefine transplant medicine.

Advances in solid organ transplantation, such as improved organ preservation technologies and novel approaches to immunosuppression management, have the potential to improve outcomes in transplant recipients. However, despite these developments, there are persistent disparities in access to transplantation across, and within, certain countries. Low-income and middle-income countries have particularly low rates of transplantation, as well as less access to new technologies, mainly due to limited infrastructure and resources. Additionally, marginalised groups, especially racially and ethnically minoritised people and individuals from low socioeconomic backgrounds, might be most susceptible to these inequities worldwide. In this Series paper, we focus on how policies can advance equity in the field of transplantation, both within individual health systems and across different countries. We propose policy solutions to make progress towards equity in access to transplantation and better outcomes for all patients with end-stage organ disease who could benefit from transplantation.

The optimal timing of oral anticoagulation for prevention of early ischaemic stroke recurrence in people with acute ischaemic stroke and atrial fibrillation remains uncertain. We aimed to estimate the effects of starting a direct oral anticoagulant (DOAC) early (≤4 days) versus later (≥5 days) after onset of ischaemic stroke.

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.