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.

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.

An understanding of the causes of postpartum haemorrhage is needed to provide appropriate treatment and services. Knowledge of the risk factors for postpartum haemorrhage can help address modifiable risk factors. We did a systematic review and meta-analysis to identify and quantify the various causes and risk factors for postpartum haemorrhage.

Coronary artery disease has long been understood through the paradigm of epicardial coronary artery obstruction, causing myocardial ischaemia (a mismatch between myocardial blood supply and demand). However, this model, which focuses on diagnosing and managing coronary artery disease based on ischaemia and cardiovascular events, is flawed. By the time ischaemia manifests, it is often too late for optimal intervention, limiting the effectiveness of treatment options. Despite decades of medical advances, coronary artery disease continues to be a leading cause of morbidity and mortality globally, highlighting the inadequacy of this traditional ischaemic-centric approach. The central limitation of current approaches is the focus on the temporary solutions of restoring myocardial blood flow after obstruction, rather than tackling the underlying disease. Coronary artery disease, caused by atherosclerosis, often results in myocardial infarction through mechanisms that emerge earlier in the progression of disease. The focus of medical care has predominantly been on the recognition of symptoms and treatment of acute events, missing opportunities for early detection and prevention of disease. Billions of dollars in health-care funding continue to be spent on identifying and managing coronary ischaemia; yet, the dominant mechanisms for myocardial infarction are atherosclerotic plaque rupture or erosion and, to a lesser extent, erupted calcified nodules that can emerge at a much earlier stage of the disease. This Commission advocates for a shift in the conceptual framework of coronary artery disease. We suggest reclassifying the condition as atherosclerotic coronary artery disease (ACAD), moving away from the traditional emphasis on ischaemia and acute cardiac events towards a more systematic understanding of atherosclerosis. This reframing will enable the identification and management of the disease much earlier in its course, potentially saving millions of lives worldwide. Risk of ACAD develops over a lifetime, beginning in utero, progressing through childhood and adolescence, and continuing into older age. The early stages of disease, which involve the formation of atherosclerotic plaques, are often undetected. A major shift is needed from acute event-centred care to strategies focused on early diagnosis, prevention, and management of atherosclerosis. In this new framework, ACAD should be recognised across all stages, from the earliest signs of atheroma formation to the advanced stages of disease. Our goals should not just to be to manage symptoms and events but to prevent the disease from developing in the first place and, where possible, reverse its course.

Hidradenitis suppurativa is a chronic inflammatory disease characterised by painful, deep-seated nodules, abscesses, and draining tunnels in the skin of axillary, inguinal, genitoanal, or inframammary areas. In recent years, the body of knowledge in hidradenitis suppurativa has advanced greatly. This disorder typically starts in the second or third decade of life. The average worldwide prevalence is 1% but varies geographically. Hidradenitis suppurativa has a profound negative effect on patients' quality of life and on the gross value added to society. Comorbidities (eg, metabolic syndrome, inflammatory arthritis, and inflammatory bowel disease) frequently accompany skin alterations, because of systemic inflammation. Pathogenesis of hidradenitis suppurativa is complex and includes innate immune mechanisms (eg, macrophages, neutrophils, IL-1β, tumour necrosis factor [TNF], and granulocyte colony-stimulating factor), T-cell mechanisms (eg, IL-17 and IFN-γ), and B-cell mechanisms (eg, associated with dermal tertiary lymphatic structures and autoantibodies). Chronic inflammation leads to irreversible skin damage with tunnel formation and morbid scarring. Current treatment includes drug therapy (for the initial, purely inflammatory phase), combined drug and surgical therapy (for the destructive phase), or surgery alone (for the burnout phase). The first systemic therapies approved for hidradenitis suppurativa targeting TNF (adalimumab) and IL-17 (secukinumab and bimekizumab) have expanded drug therapy options for moderate-to-severe disease, which were previously mainly restricted to oral antibiotics. Moreover, there is a robust pipeline of immunomodulatory drugs in various stages of development for hidradenitis suppurativa. Aims of management should include early intervention to prevent irreversible skin damage, adequate control of symptoms including pain, and mitigation of extra-cutaneous comorbidities, all requiring early diagnosis and an interdisciplinary, holistic and personalised approach.

Hand eczema is a highly prevalent skin disease and one of the most common work-related disorders. In up to two-thirds of individuals affected by hand eczema, the disease becomes chronic and results in substantial personal and occupational disability. Manifestations of chronic hand eczema vary in severity and appearance over time, and people with eczema typically experience itch, pain, and a burning sensation. The pathophysiology of chronic hand eczema is multifactorial. Major risk factors are current or past atopic dermatitis and excessive or prolonged exposure to irritants or allergens. Based on the suspected main causes, chronic hand eczema is commonly classified into irritant, allergic, and atopic hand eczema. Diagnosis and assessment can be complex, and management is often challenging. Strategies include structured education, avoidance of trigger factors, primary to tertiary prevention, topical anti-inflammatory treatment with glucocorticosteroids, calcineurin inhibitors, or januskinase inhibitors, phototherapy, systemic retinoids, and off-label use of immunosuppressive drugs. Topical and systemic immunomodulatory therapies approved for atopic dermatitis could be used in severe atopic hand eczema and some of them are under clinical development for chronic hand eczema. Additional research is needed to better understand chronic hand eczema subtypes and underlying mechanisms, and the comparative effectiveness and safety of therapies. This Review combines established knowledge with ongoing changes in our understanding of the disease and their implications for prevention, management, and future research.

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.

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.

Despite the initial hope inspired by the 2015 Paris Agreement, the world is now dangerously close to breaching its target of limiting global multiyear mean heating to 1·5°C. Annual mean surface temperature reached a record high of 1·45°C above the pre-industrial baseline in 2023, and new temperature highs were recorded throughout 2024. The resulting climatic extremes are increasingly claiming lives and livelihoods worldwide. The Lancet Countdown: tracking progress on health and climate change was established the same year the Paris Agreement entered into force, to monitor the health impacts and opportunities of the world’s response to this landmark agreement. Supported through strategic core funding from Wellcome, the collaboration brings together over 300 multidisciplinary researchers and health professionals from around the world to take stock annually of the evolving links between health and climate change at global, regional, and national levels. The 2024 report of the Lancet Countdown, building on the expertise of 122 leading researchers from UN agencies and academic institutions worldwide, reveals the most concerning findings yet in the collaboration’s 8 years of monitoring.

Tranexamic acid is a recommended treatment for women with a clinical diagnosis of postpartum haemorrhage, but whether it can prevent bleeding is unclear. We conducted a systematic review and individual patient data (IPD) meta-analysis of randomised controlled trials to assess the effects of tranexamic acid in women giving birth.

Global health 2050 (GH2050), a new report from the Lancet Commission on Investing in Health, finds that dramatic improvements in human welfare are achievable by mid-century with focused health investments. By 2050, countries that choose to do so can halve their probability of premature death (PPD)—the probability of dying before age 70—from their pre-pandemic level in 2019. We call this goal “50 by 50”: a 50% reduction in PPD by 2050. The interventions for achieving “50 by 50” will also reduce morbidity and disability at all ages. Historical experience and continued scientific advance indicate that this is a feasible aspiration. Eight of the 30 most populous countries reduced their PPD over the last decade at a rate that would halve PPD before 2050, including countries as diverse as Bangladesh, Iran, Tanzania, and Turkey. These focused gains can be achieved relatively early on the pathway to full universal health coverage (UHC). The path to achieving “50 by 50” runs through control of a remarkably narrow set of just 15 conditions. For currently high mortality countries, eight infectious diseases and maternal conditions are the highest priority. Seven clusters of noncommunicable diseases and injuries are important everywhere and addressing them will prove central to achieving “50 by 50” in most countries with lower initial levels of mortality. Focused attention to health system strengthening (HSS) for primary care and first level hospitals will generate capacity to better tackle the 15 priority conditions and will be a critical step on the way to improving capacity to address all the conditions in a UHC package. Packaging interventions into 19 modules (e.g., a childhood immunization module, a module on cardiovascular disease prevention and low-cost, widely available treatment) will address the 15 priority conditions. Adopting this focused approach also invests in key areas of HSS and addresses major morbidities, such as psychiatric illness, not already covered by mortality-reducing interventions. Value for money can be assessed through a two-step process: technical cost effectiveness to assess how best to achieve module-specific goals (e.g., reduction in child mortality, reduction in cardiovascular mortality) and political evaluation of trade-offs in investing in expanding module coverage. In many countries seeking reform, standard budgetary mechanisms have failed to successfully reorient systems toward priority interventions that improve health. This mechanism of blanket budget transfers from ministries of finance to ministries of health has not been fit to support such reorientation. The Commission concluded that this problem could be addressed by directing a substantial and increasing fraction of budget transfers to making available and affordable the specific drugs, vaccines, diagnostics, and other commodities that are currently available for control of the 15 priority conditions. Drug availability and affordability will typically require four complementary components: (i) redirecting general budget transfers to line item transfers (subsidies) for specific priority drugs; (ii) centralized procurement by government (or perhaps internationally); (iii) procurement in sufficient volumes to ensure availability when needed; and (iv) use and strengthening of existing supply chains, public and private. Of the many intersectoral policies that governments can adopt to help achieve “50 by 50,” tobacco control is by far the most important, given the number of deaths caused by tobacco and the established and improving capacity of governments to implement tobacco policy. A high level of tobacco taxation is essential, and valuable in the short to medium term for public finance, and should be accompanied by a package of other effective tobacco control policies. Background research conducted for the Commission points to exceptionally high ongoing levels of mortality risk from pandemics. Country performance against COVID-19 varied greatly, although eventual vaccine availability attenuated, but far from eliminated, this variability by the end of COVID-19’s emergency phase. National implementation of public health fundamentals—early action, isolation of infected individuals, quarantining of those exposed, and social and financial support for people isolating or quarantining—accounted for much of the success of the best-performing nations, such as Japan. In the next pandemic, these fundamentals will help to avert mortality while waiting for vaccine development and deployment. The conclusions above are primarily aimed at national governments. Our final conclusion is aimed at the development assistance community. We conclude that such assistance should focus on two broad purposes. The first is to provide direct financial and technical support to countries with the least resources—to help develop health systems to better control diseases. The second is to finance global public goods, including strengthening data systems; reducing the development and spread of antimicrobial resistance; preventing and responding to pandemics; fostering global health leadership and advocacy; identifying and spreading best practices; and developing and deploying new health technologies. For both purposes, focusing efforts on the 15 priority conditions would best contribute to “50 by 50.” A decade ago, there were no malaria vaccines and the only available tuberculosis vaccine had low efficacy. Today, two partially successful malaria vaccines have been approved and three promising tuberculosis vaccine candidates are in late stage trials. These successes exemplify the enormous value in funding development of new medicines, vaccines, diagnostics, and operational research against the 15 priority conditions. The prize of “50 by 50,” with an interim milestone of “30 by 2035” (a 30% reduction in PPD by 2035), remains a prize within reach. The most efficient route is to focus resources against a narrow set of conditions and scale up financing to develop and deploy new health technologies. Our economic analyses have shown that the value of achievable mortality declines remains high and indeed is often a substantial fraction of the value of gains in gross domestic product. Today, the case is better than ever for the value of investing in health for reducing mortality and morbidity, alleviating poverty, growing economies, and improving human welfare.

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.

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.

Chronic urticaria is a common and debilitating mast cell-driven skin disease presenting with itchy wheals, angio-oedema, or both. Chronic urticaria is classified as spontaneous (without definite triggers) and inducible (with definite and subtype-specific triggers; eg, cold or pressure). Current management guidelines recommend step-up administration of second-generation H1-antihistamines to four-fold the approved dose, followed by omalizumab and ciclosporin. However, in many patients, chronic urticaria does not respond to this linear approach due to heterogeneous underlying mechanisms. A personalised endotype-based approach is emerging based on the identification of autoantibodies and other drivers of urticaria pathogenesis. Over the past decade, clinical trials have presented promising options for targeted treatment of chronic urticaria with the potential for disease modification, including Bruton's tyrosine kinase inhibitors, anti-cytokine therapies, and mast cell depletion. This Therapeutics article focuses on the evidence for these novel drugs and their role in addressing an unmet need for personalised management of patients with chronic urticaria.

In 2017, we set out-along with a larger group of authors-to assess Germany's contribution and potential leadership role in global health. We considered the ambitions and manifold efforts of Chancellor Angela Merkel's administration to become a trusted leader in global health governance and a reliable supporter of multilateral institutions, especially WHO. Based on the recommendations of our 2017 paper, in this Review we determine whether the country has indeed lived up to its vision and ambitions expressed in the Global Health Strategy adopted by the cabinet in 2020. Also, we outline what challenges Germany is now facing in a more complex global health environment and geopolitical situation, where leadership in the field is being redefined following the impact of the COVID-19 pandemic and amid broader shifts in the international order.

Persistent physical symptoms (synonymous with persistent somatic symptoms) is an umbrella term for distressing somatic complaints that last several months or more, regardless of their cause. These symptoms are associated with substantial disability and represent a major burden for patients, health-care professionals, and society. Persistent physical symptoms can follow infections, injuries, medical diseases, stressful life events, or arise de novo. As symptoms persist, their link to clearly identifiable pathophysiology often weakens, making diagnosis and treatment challenging. Multiple biological and psychosocial risk factors and mechanisms contribute to the persistence of somatic symptoms, including persistent inflammation; epigenetic profiles; immune, metabolic and microbiome dysregulation; early adverse life experiences; depression; illness-related anxiety; dysfunctional symptom expectations; symptom focusing; symptom learning; and avoidance behaviours, with many factors being common across symptoms and diagnoses. Basic care consists of addressing underlying pathophysiology and using person-centred communication techniques with validation, appropriate reassurance, and biopsychosocial explanation. If basic care is insufficient, targeted psychological and pharmacological interventions can be beneficial. A better understanding of the multifactorial persistence of somatic symptoms should lead to more specific, personalised, and mechanism-based treatment, and a reduction in the stigma patients commonly face.

B-cell lymphomas occur with an incidence of 20 new cases per 100 000 people per year in high-income countries. They can affect any organ and are characterised by heterogeneous clinical presentations and courses, varying from asymptomatic, to indolent, to very aggressive cases. Since the topic of B-cell non-Hodgkin lymphomas was last reviewed in The Lancet in 2017, a deeper understanding of the biological background of this heterogeneous group of malignancies, the availability of new diagnostic methods, and the development and implementation of new targeted and immunotherapeutic approaches have improved our ability to treat patients. This Seminar provides an overview of the pathobiology, classification, and prognostication of B-cell non-Hodgkin lymphomas and summarises the current knowledge and standard of care regarding biology and clinical management of the most common subtypes of mature B-cell non-Hodgkin lymphomas. It also highlights new findings in deciphering the molecular background of disease development and the implementation of new therapeutic approaches, particularly those targeting the immune system.

Prostate cancer is the most common cancer in men in 112 countries, and accounts for 15% of cancers. In this Commission, we report projections of prostate cancer cases in 2040 on the basis of data for demographic changes worldwide and rising life expectancy. Our findings suggest that the number of new cases annually will rise from 1·4 million in 2020 to 2·9 million by 2040. This surge in cases cannot be prevented by lifestyle changes or public health interventions alone, and governments need to prepare strategies to deal with it. We have projected trends in the incidence of prostate cancer and related mortality (assuming no changes in treatment) in the next 10–15 years, and make recommendations on how to deal with these issues. For the Commission, we established four working groups, each of which examined a different aspect of prostate cancer: epidemiology and future projected trends in cases, the diagnostic pathway, treatment, and management of advanced disease, the main problem for most men diagnosed with prostate cancer worldwide. Throughout we have separated problems in high-income countries (HICs) from those in low-income and middle-income countries (LMICs), although we acknowledge that this distinction can be an oversimplification (some rich patients in LMICs can access high-quality care, whereas many patients in HICs, especially the USA, cannot because of inadequate insurance coverage). The burden of disease globally is already substantial, but options to improve care are already available at moderate cost. We found that late diagnosis is widespread worldwide, but especially in LMICs, where it is the norm. Early diagnosis improves prognosis and outcomes, and reduces societal and individual costs, and we recommend changes to the diagnostic pathway that can be immediately implemented. For men diagnosed with advanced disease, optimal use of available technologies, adjusted to the resource levels available, could produce improved outcomes. We also found that demographic changes (ie, changing age structures and increasing life expectancy) in LMICs will drive big increases in prostate cancer, and cases are also projected to rise in high-income countries. This projected rise in cases has driven the main thrust of our recommendations throughout. Dealing with this rise in cases will require urgent and radical interventions, particularly in LMICs, including an emphasis on education (both of health professionals and the general population) linked to outreach programmes to increase awareness. If implemented, these interventions would shift the case mix from advanced to earlier-stage disease, which in turn would necessitate different treatment approaches: earlier diagnosis would prompt a shift from palliative to curative therapies based around surgery and radiotherapy. Although age-adjusted mortality from prostate cancer is falling in HICs, it is rising in LMICs. And, despite large, well known differences in disease incidence and mortality by ethnicity (eg, incidence in men of African heritage is roughly double that in men of European heritage), most prostate cancer research has disproportionally focused on men of European heritage. Without urgent action, these trends will cause global deaths from prostate cancer to rise rapidly.