Antidepressants induce physiological alterations; however, the degree to which these occur in treatment with various antidepressants is unclear. We aimed to compare and rank antidepressants based on physiological side-effects by synthesising data from randomised controlled trials (RCTs).

For the first time, reductions in cerebral β-amyloid pathology load and rate of cognitive and functional decline have been achieved in Alzheimer's disease, through pharmacological intervention in randomised controlled trials. However, the results from phase 3 randomised controlled trials of anti-β amyloid monoclonal antibodies are interpreted in different ways, with some experts supporting a clinically meaningful disease-modifying effect, and others judging insufficient benefit-to-risk ratio and opposing market authorisation. In the final paper of this Series, we discuss these contrasting views, all of which wish to contribute to improvements in the quality of life of people with, or at risk of, Alzheimer's disease. We contrast the efficacy, societal costs, and generalisability of monoclonal antibodies for Alzheimer's disease to biologics for other conditions (eg, cancer, multiple sclerosis, and rheumatoid arthritis) and set this debate in the larger context of modern personalised medicine. We discuss current practice implications, future developments directed to β-amyloid and non-amyloid targets that might have more clinical efficacy and less adverse effects for those with the disease, and large-scale prevention interventions for those at risk.

Over the last three decades, the evidence on how to best treat the cognitive and non-cognitive symptoms of patients with Alzheimer's disease has increased. Although these pharmacological and non-pharmacological strategies have significantly improved health outcomes for patients with Alzheimer's disease, many lack stringent evidence of efficacy. In this second paper of the Series, we provide practical and realistic advice on how to prioritise pharmacological and non-pharmacological strategies to ameliorate cognitive impairment and behavioural and psychological symptoms of dementia. In this clinical environment, dementia specialists are faced with the challenge of holistically integrating the much anticipated and, in some respects, controversial anti-β amyloid monoclonal antibodies. Here, we present the current approval scenario of monoclonal antibodies, our view on how they might further contribute to improve patients' quality of life, and how they could be seamlessly integrated with existing best care options.

Alzheimer's disease involves a drastic departure from the cognitive, functional, and behavioural trajectory of normal ageing, and is both a dreaded and highly prevalent cause of disability to individuals, and a leading source of health and social care expenditure for society. Before the advent of biomarkers, post-mortem examination was the only method available to establish a definitive diagnosis. In this first paper of the Series, we review state-of-the-art diagnostic practices and the typical patient journey in specialist settings, where clinicians engage in a differential diagnosis to establish whether Alzheimer's pathology (cerebral deposition of β-amyloid and hyperphosphorylated tau) is a contributor to cognitive impairment. Biomarkers indicating dysregulation of β-amyloid and tau homeostasis, measured with PET and cerebrospinal fluid analysis, allow a molecular-level diagnosis-a mandatory step in defining eligibility for the recently approved anti-amyloid treatments. We anticipate that easily accessible blood biomarkers, already available in some countries, will lead to a new diagnostic revolution and bring about major changes in health-care systems worldwide.

The treatment of type 1 diabetes is entering a transformative era. Teplizumab, the first immunotherapy treatment to delay the onset of clinical type 1 diabetes, has been approved by the US Food and Drug Administration. Other immune-based therapies show promise in preserving β-cell function. Public health screening using islet autoantibodies is expanding, enabling earlier diagnosis, reducing diabetic ketoacidosis, and allowing timely introduction of disease-modifying treatments before the need for insulin therapy. β-cell replacement is shifting from traditional transplantation of organ donor islets and the pancreas to stem cell-derived β cells. Bioengineering methods, such as encapsulation, and gene editing to create hypoimmune cells could reduce the need for immunosuppression that has hampered β-cell replacement, and patient-derived stem cells open doors to personalised therapies. Although these innovations have been made available to a small number of patients, scaling them to widespread use remains a challenge. Meanwhile, glucose regulation is improving through the use of automated insulin delivery systems that combine glucose monitoring with insulin pumps. New-generation insulins (those that are ultrarapid, ultralong, and glucose-responsive) improve outcomes by minimising blood sugar fluctuations. Together, these breakthroughs offer renewed hope for improving long-term management and quality of life for people living with type 1 diabetes.

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 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.

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.

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.

Frequentist and Bayesian statistics represent two differing paradigms for the analysis of data. Frequentism became the dominant mode of statistical thinking in medical practice during the 20th century. The advent of modern computing has made Bayesian analysis increasingly accessible, enabling growing use of Bayesian methods in a range of disciplines, including medical research. Rather than conceiving of probability as the expected frequency of an event (purported to be measurable and objective), Bayesian thinking conceives of probability as a measure of strength of belief (an explicitly subjective concept). Bayesian analysis combines previous information (represented by a mathematical probability distribution, the prior) with information from the study (the likelihood function) to generate an updated probability distribution (the posterior) representing the information available for clinical decision making. Owing to its fundamentally different conception of probability, Bayesian statistics offers an intuitive, flexible, and informative approach that facilitates the design, analysis, and interpretation of clinical trials. In this Review, we provide a brief account of the philosophical and methodological differences between Bayesian and frequentist approaches and survey the use of Bayesian methods for the design and analysis of clinical research.

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.