Metastatic castration-resistant prostate cancer remains incurable and is particularly aggressive in patients with alterations in DNA damage repair genes involved directly or indirectly in homologous recombination repair (HRR). In the primary analysis of TALAPRO-2, talazoparib plus enzalutamide significantly improved radiographic progression-free survival (rPFS) versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer harbouring HRR gene alterations. At primary analysis, overall survival was immature. Here we report final prespecified overall survival analysis, updated rPFS, safety, and patient-reported outcomes in the HRR-deficient cohort of TALAPRO-2.

Development assistance for health (DAH) rose to its highest levels during the COVID-19 pandemic but has since reduced amid rising global economic uncertainty and competing fiscal demands. In early 2025, major donors including the USA and the UK announced substantial reductions in aid, prompting concerns about the future of health financing in middle-income and low-income countries. To date, no comprehensive assessment has quantified the effects of these announced cuts on overall DAH levels or its future trajectories.

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 Sustainable Development Goals (SDGs) include ending the epidemics of HIV, tuberculosis, and malaria by 2030. With 5 years remaining to meet this goal, and with the Global Fund to Fight AIDS, Tuberculosis and Malaria seeking funding for programmes in 2027-29, establishing what can be achieved through continued investment in combatting these diseases is crucial. We aimed to estimate the potential for impact by analysing the funding landscape and epidemiological situations of these three diseases, the costs of key programmes, and the extent of possible future progress in the countries eligible for Global Fund support.

Clade I monkeypox virus is endemic in DR Congo. We aim to describe the epidemiological trends of the cocirculating subclades Ia and Ib mpox outbreaks in Kinshasa, DR Congo.

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 US Agency for International Development (USAID) is the largest funding agency for humanitarian and development aid worldwide. The aim of this study is to comprehensively evaluate the effect of all USAID funding on adult and child mortality over the past two decades and forecast the future effect of its defunding.

For the Spanish, French, Arabic, Russian and Chinese translations of the abstract see Supplementary Materials section.

Since its inception in 1974, the Essential Programme on Immunization (EPI) has achieved remarkable success, averting the deaths of an estimated 154 million children worldwide through routine childhood vaccination. However, more recent decades have seen persistent coverage inequities and stagnating progress, which have been further amplified by the COVID-19 pandemic. In 2019, WHO set ambitious goals for improving vaccine coverage globally through the Immunization Agenda 2030 (IA2030). Now halfway through the decade, understanding past and recent coverage trends can help inform and reorient strategies for approaching these aims in the next 5 years.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin disease caused by mutations in the COL7A1 gene encoding type VII collagen. Individuals with RDEB have fragile skin and most develop large, chronic wounds. The aim of the VIITAL study was to evaluate the efficacy and safety of a one-time surgical application of prademagene zamikeracel in wound healing.

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.

Endoscopic surveillance is the clinical standard for Barrett's oesophagus, but its effectiveness is inconsistent. We have developed a test comprising a pan-oesophageal cell collection device coupled with biomarkers to stratify patients into three risk groups. We aimed to prospectively evaluate the prespecified risk stratification tool to establish whether it can identify those at highest risk of dysplasia or cancer to prioritise the timing of endoscopy; and safely be used to follow up the low-risk group, thus sparing patients from unnecessary endoscopies.

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.

Insulin efsitora alfa (efsitora), a once-weekly basal insulin, has the potential to reduce the treatment burden of people with type 2 diabetes who require insulin. We aimed to assess the efficacy and safety of once-weekly efsitora compared with insulin glargine U100 in adults with type 2 diabetes treated with basal and prandial insulin.