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.

Immunotherapy has transformed the treatment of cancer, yet many patients do not have response or lasting benefit. Strategies to overcome resistance remain of crucial importance. Oncolytic viruses offer a promising approach, with the unique ability to selectively replicate within (and to destroy) cancer cells, remodel the immunosuppressive tumour microenvironment, and stimulate antitumour immunity. Interest in the potential of oncolytic viruses has grown steadily over the past two decades, fuelled by advances in cancer immunology and viral engineering. However, clinical translation has not kept pace, and although a plethora of promising new constructs have entered clinical testing, several barriers continue to restrict widespread clinical implementation. This Therapeutics paper highlights key milestones in oncolytic virus clinical development, discusses the challenges that remain, and, through clinical reflection, considers how future research might be streamlined to achieve meaningful benefit for patients.

Osteoporotic fractures are one of the most common and consequential diseases of advanced ageing and many antifracture therapies are widely available but largely underused. This Seminar presents an updated approach to osteoporosis consultation, drawing upon published evidence and collaborative expert opinion to place the data in a pragmatic and useful context for clinicians. New evidence on osteoporosis screening recommendations, fracture-risk assessment, intervention decisions, nutrition-based therapies, and antiresorptive and anabolic therapies are discussed, along with practical approaches to treatment in the oldest old, those with chronic kidney disease, and patients who continue to fracture despite therapy. Patient safety is emphasised by providing an overview of advice on safe discontinuation of denosumab in those who require it.

Childhood obesity is a global public health issue, which has prompted governments to invest in prevention programmes. We aimed to investigate the effectiveness of parent-focused early childhood obesity prevention interventions globally.

Primary large-vessel vasculitis encompasses conditions that, despite sharing many common features, constitute distinct entities that have their own prognostic implications. These conditions include giant cell arteritis and Takayasu arteritis, with isolated aortitis being increasingly recognised in the literature and studied within this disease spectrum. Epidemiological studies have evidenced a worldwide distribution of Takayasu arteritis. In giant cell arteritis, distinct clinical phenotypes with specific outcomes (ie, cranial and large vessel forms) have been recognised. The advancements that have been made in vascular imaging have enabled improvement in diagnosis and classification of these diseases, although their value in follow-up continues to be assessed. Targeted therapies that can induce clinical remission with reduced glucocorticoid exposure are emerging. However, many patients develop vascular damage over time, highlighting the need for further understanding of the pathophysiological link between inflammation, vascular injury, and remodelling.

Shigella is a Gram-negative, facultative intracellular, gastric acid-resistant bacterium of the Enterobacteriaceae family, which includes four serogroups: Shigella dysenteriae, Shigella sonnei, Shigella flexneri, and Shigella boydii. Globally, shigellosis is the most common cause of invasive bloody diarrhoea in children younger than 5 years. Humans are the only natural reservoir and an inoculum of only 10-100 organisms is required for infection. Rising antibiotic resistance rates increasingly reduce the ability to adequately treat severe disease. The prevention of infection with vaccination and sanitation strategies remains a crucial step in reducing worldwide morbidity and mortality.

Enteric fever, caused by the human-restricted bacteria Salmonella enterica serovar Typhi (typhoid) and Salmonella enterica serovar Paratyphi A, B, and C (paratyphoid), affects persons residing in, or travelling from, areas lacking safe water, sanitation, and hygiene infrastructure. Transmission is by the faecal-oral route. A gradual fever onset over 3-7 days with malaise, headache, and myalgia is typical. Symptoms can be altered by previous antimicrobial use. Life-threatening complications can arise in the second week of untreated illness. Differentiation from other febrile illnesses is challenging. Blood or bone marrow culture remain reference standard diagnostic methods, despite the low sensitivity of blood culture. Azithromycin, ciprofloxacin (excepting cases originating in south Asia due to drug resistance), or ceftriaxone are recommended treatment options for both typhoid and paratyphoid; however, choice should be guided by local resistance patterns. Ciprofloxacin-resistant and ceftriaxone-resistant typhoid is common in Pakistan. Three vaccine types are available for prevention of typhoid disease, including the newer, more effective typhoid Vi-conjugate vaccines. Vaccination as well as water, sanitation, and hygiene measures are cornerstones of prevention.

Although intensive blood pressure control is recommended by major guidelines, its overall benefit-harm balance remains uncertain. In particular, it is unclear how net clinical benefit varies by blood pressure target and patient characteristics. We aimed to quantify the benefit-harm trade-offs of intensive blood pressure control versus standard blood pressure control.

Aspirin monotherapy is recommended indefinitely for patients with established coronary artery disease (CAD). The aim of this individual patient level meta-analysis was to provide a comprehensive evaluation of the comparative efficacy and safety of clopidogrel versus aspirin monotherapy in patients with established CAD, most of whom had undergone percutaneous coronary intervention or had acute coronary syndrome.

The effects of β-blocker therapy on clinical outcomes in patients with myocardial infarction and mildly reduced (40-49%) left ventricular ejection fraction (LVEF) are largely unknown. Four recently conducted randomised trials tested the efficacy of β blockers after a recent myocardial infarction in patients without reduced LVEF (LVEF ≥40%). However, none were individually powered to assess these effects in the subgroup of patients with mildly reduced LVEF. We aimed to assess the efficacy of β blockers in patients with myocardial infarction and mildly reduced LVEF during the index hospitalisation.

Heart failure remains one of the 21st century's greatest unmet clinical and public health challenges. Heart failure is a highly prevalent chronic condition that affects approximately 55 million people worldwide. Although heart failure can be prevented, the global burden of this condition continues to grow, fuelled by an ageing population, improved survival after myocardial infarction, and increasing prevalence of metabolic and kidney disease. Public health efforts for cardiovascular disease prevention to date have primarily targeted coronary heart disease. Despite overlapping prevention targets for coronary heart disease and heart failure, prevention of the latter requires tailored approaches to target its unique pathophysiology and heterogeneous subtypes. This Lancet Series serves as a call to action for clinicians, health systems, and governments to prioritise the primary prevention of heart failure. Herein, we review the epidemiology, pathophysiology, and risk factors of heart failure and propose a comprehensive framework for prevention of this condition that includes screening to assess risk of this condition (eg, multivariable risk equations) and detection of pre-heart failure (eg, biomarkers). Successfully reducing the burden of heart failure will require concerted efforts to define clinical workflows across the life course, scalable implementation strategies, and increased public awareness of this pressing crisis.

This Series paper highlights the substantial progress made in understanding and preventing heart failure after acute myocardial infarction. Improving global standards of care for management of acute myocardial infarction with timelier reperfusion has led to stepwise reductions in risk of incident heart failure. Landmark clinical trials have established the role of renin-angiotensin-aldosterone system inhibitors, β blockers, and mineralocorticoid receptor antagonists to specifically reduce the risk of incident heart failure after acute myocardial infarction. However, residual risk of heart failure persists in many individuals, even after revascularisation and standard medical therapies. We review recent epidemiological trends from the past four decades, evolving understanding of the pathological mechanisms underlying incident heart failure, and modern risk stratification tools. We then propose a treatment pathway tailored to individual patient risk and discuss potential future strategies to incrementally improve the risk of development of heart failure after acute myocardial infarction.

The substantial and growing prevalence of heart failure, which remains the leading cause of preventable hospitalisation worldwide, has brought heart failure prevention into sharp focus. Although this condition has historically been characterised by impaired cardiac function, mounting evidence has underscored its complex and multisystem pathobiology. Epidemiological studies have indicated that other forms of cardiovascular disease, along with kidney and metabolic dysfunction, frequently and increasingly contribute to heart failure onset. Clinical trials have additionally demonstrated the power of several new pharmacotherapies to simultaneously modify cardiovascular, kidney, and metabolic (CKM) health. This convergence of epidemiology and therapy highlights deeply interconnected mechanisms of disease, identifying CKM diseases-and their pathophysiological and sociostructural antecedents-as important but often under-recognised targets for heart failure prevention. Herein, we illustrate that positioning heart failure prevention within the broader context of CKM health provides an actionable framework for patients, health-care professionals, health systems, communities, and policy makers.

We aimed to quantify the blood pressure-lowering efficacy of antihypertensive drugs and their combinations from the five major drug classes.

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.

No pharmacological therapy has been shown with certainty to improve the cardiovascular prognosis in patients with kidney failure on chronic haemodialysis. We aimed to investigate the effects of the steroidal mineralocorticoid receptor antagonist spironolactone on cardiovascular outcomes in patients on haemodialysis who are at high risk of cardiovascular events.

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.

In postmenopausal women with oestrogen receptor-positive early breast cancer, 5 years of adjuvant tamoxifen substantially reduces 15-year recurrence and mortality; aromatase inhibitor treatment (AIT) is even more effective. We assess the effects of further AIT among women recurrence-free after at least 5 years of endocrine therapy.

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.