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.

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.

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.

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

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

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

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

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

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