We hypothesise that amylin receptor agonists (eg, pramlintide) and dual amylin and calcitonin-receptor agonists (eg, cagrilintide), which are emerging treatments for obesity and type 2 diabetes, can activate the renin-angiotensin system (RAS) and potentially undermine the cardiorenal benefits of these therapies. Paradoxically, new-generation amylin-based therapies, such as CagriSema, showed substantial blood pressure reductions in phase 3 trials. Beyond amylin's weight loss-mediated effects, we hypothesise that concurrent use of RAS inhibitors (angiotensin-converting enzyme [ACE] inhibitors or angiotensin-receptor blockers) redirects amylin-induced RAS activation towards the protective alternative RAS pathway, which is characterised by vasodilatory, anti-inflammatory, and antiproliferative effects via Mas receptors, potentially explaining part of their therapeutic benefit and cardioprotective and renoprotective potential. To test this, we propose: (1) preclinical studies investigating amylin-RAS interactions with or without RAS blockade; (2) post-hoc analyses of phase 2/3 trials stratified by RAS inhibitor use; (3) biomarker studies monitoring renin, aldosterone, angiotensin-(1-7), and ACE2; and (4) mechanistic human studies prospectively assessing cardiovascular-kidney metabolic effects by RAS inhibitor status. These suggestions aim to determine whether RAS inhibition enhances the overall efficacy of amylin-based therapies, and whether RAS blockers should be strongly recommended in patients receiving them.

Sexual and reproductive health and rights are fundamental to both human and societal wellbeing and sustainable development, and encompass a broad array of sociocultural and clinical issues that affect all people across the life course. In 2018, the Guttmacher-Lancet Commission described sexual and reproductive health as a state of physical, emotional, mental, and social wellbeing in relation to all aspects of sexuality and reproduction, not merely the absence of disease, dysfunction, or infirmity. The Commission advocated for a positive approach to sexuality and reproduction that recognises the role of pleasurable sexual relationships, trust, and communication in promoting self-esteem and overall wellbeing. The Commission also stipulated that people have a right to make decisions governing their bodies and to access services that support that right. In light of recent sociocultural changes, biomedical advances that have impacted sexual and reproductive health and rights, and the key findings of the Guttmacher-Lancet Commission, we bring together themes from this Lancet Series to discuss the new scientific developments and sociopolitical changes that affect the programmatic integration of sexual and reproductive health services. As people who present for one sexual and reproductive health service frequently have other unmet sexual and reproductive health-related needs, there are often benefits to interventions and services that address multiple connected sexual and reproductive health issues during one clinical encounter (eg, family planning visits, including testing for HIV and other sexually transmitted infections), which supports the rationale for an integrated approach. Historically, key components of sexual and reproductive health have been managed separately, partly because of siloed and inadequate funding streams and structural limitations (eg, separate location of service delivery or insufficient staff cross-training). Vertical methods have also evolved from the need for different approaches to reach key populations, who might be reluctant to seek care from primary health care clinics. We build on the findings of the papers in this Series to discuss the rationale for sexual and reproductive health programmatic integration, which has the potential to better engage patients in care by meeting their preferences, simplify the user experience, and save resources when implemented in a thoughtful, culturally tailored manner. However, wide-scale sexual and reproductive health programmatic integration faces multiple challenges, requiring broadly trained health-care providers, a range of clinical and outreach channels, and well-resourced health systems. Programmatic integration might be further constrained by societal norms and regulations (eg, punitive laws, institutional homophobia, legal restrictions on access to safe abortion, and opposition to sexual and reproductive rights). Notably, the Trump Administration's withdrawal of support from various sexual and reproductive health programmes in January, 2025, is a major threat to continued progress. This Series paper provides a call to action based on the key findings from this Series that delineates the steps needed to better integrate programmes to optimise sexual and reproductive health outcomes.

This Series paper provides a summary of what is known about the funding, cost, and cost-effectiveness of sexual and reproductive health and rights interventions, interrogates the likely impacts of increasing or reducing future sexual and reproductive health and rights funding, and provides recommendations for policy and regulatory changes from an economic perspective. Interventions that target HIV and sexually transmitted infections, contraceptive interventions, and abortion care are among the most cost-effective health interventions worldwide, but their funding is under severe duress. In 2023, approximately US$35 billion was spent on these intervention areas across low-income and middle-income countries-only two-thirds of the $52 billion needed per year. HIV treatment and prevention, as well as contraceptive commodities, rely heavily on donor funding, which has decreased since 2017. The discontinuation of the US Agency for International Development funding in early 2025, in particular, requires that the most impacted countries will have to do more with much less going forward.

The interconnectedness of the global HIV and sexually transmitted infection (STI) epidemics necessitates integrated strategies to address both. This Series paper highlights the biological link between HIV and STIs, and describes the successful progress in HIV response versus STI response over the past decades. The concept of undetectable=untransmissible (U=U) in HIV treatment has revolutionised HIV prevention by reducing stigma and promoting early treatment. In line with this approach, we discuss the role of chronic suppressive therapy for herpes simplex virus type 2 and the importance of the accurate diagnosis and treatment of curable STIs to prevent transmission between sexual partners. This Series paper explores the potential of pre-exposure prophylaxis (PrEP) for HIV in different forms (eg, daily oral PrEP, event-driven PrEP, and long-acting injectable PrEP), and highlights the challenges of adherence to daily regimens and the promise of longer-acting agents, such as cabotegravir and lenacapavir. The potential of doxycycline post-exposure prophylaxis for the prevention of bacterial STIs is also discussed, with concerns about antimicrobial resistance. Although vaccine development for HIV and STIs is a key biomedical advance, we discuss the challenges and possibilities of developing effective vaccines, including lessons learnt from previous HIV vaccine trials, the potential of mRNA-based vaccines for herpes simplex virus, ongoing trials for gonorrhoea and chlamydia vaccines, and the impact of existing human papillomavirus and mpox vaccines. Diagnostic innovations emphasise the importance of point-of-care tests for HIV and STIs. This Series paper discusses the benefits, landscape, and pipeline of rapid diagnostic tests (eg, lateral flow tests and molecular assays) and the challenges of implementing these tests in low-resource settings, particularly the need for rapid results to inform clinical decisions, promote convenience, and reduce cost. This Series paper also addresses innovations in service delivery and advocates for integrated and person-centred approaches (eg, differentiated services) that combine HIV and STI services, and highlights the potential of community-based and home-based models to improve access and reduce stigma.

Contraception and family planning are vital aspects of sexual and reproductive health and rights. Despite major advances in modern contraception over the past 60 years many gaps remain, and the rate of unplanned pregnancies and abortions remains high. These issues have given rise to a new era in contraception research with great opportunities and many challenges. These opportunities include new innovations, particularly in the areas of male contraception, non-hormonal female contraception, and multipurpose prevention methods that provide contraception in combination with protection against leading sexually transmitted pathogens; fast tracking new inventions currently in the pipeline by intensifying support from government, non-profit, and industry entities; the provision of new methods, services, and messaging for underserved populations including men, marginalised women, and transgender individuals; and better understanding the needs of diverse populations. Major challenges in contraception research include inertia, especially in industry involvement; a new wave of conservatism and government interventions that threaten to impede contraception development, services, and education; and understanding what people want and how to provide solutions. The best way to improve family planning and promote women's health is to offer better contraception options to those who wish to avoid unplanned pregnancy. This can be done by renewed commitment from scientists, private foundations, and government institutions, and from industry partners who are needed to bring promising developments to market.

The concept of sexual and reproductive health and rights has evolved in the 21st century from previous narrower conceptualisations. In 2018, the Guttmacher-Lancet Commission proposed a broader and integrated defining framework, together with a package of essential health service elements. Despite this, progress on the sexual and reproductive health agenda has been inconsistent, with progress in some areas and considerable gaps in others. Even in areas that have seen breakthroughs in biomedicine and technology, progress has been partial owing to inadequacies in funding, policy, and implementation. Additionally, initial executive orders of the Trump administration in early 2025 presented a major challenge to sexual and reproductive health and rights in the USA, and orders on US foreign aid threaten devastating impacts on sexual and reproductive health and rights in recipient low-income and middle-income countries. As discussions of sexual and reproductive health and rights are often seen to be sensitive or controversial, even when had at a senior government level, any consideration of time trends in sexual and reproductive health outcomes need to consider the complex interplay between trends in social and cultural factors, politics and legal frameworks, and technology and biomedicine. The perceived sensitivity of sexual and reproductive health means that providing adequate education on sex, sexuality, and relationships is crucial, and this education is often resisted by religion or traditionalist sentiments. Furthermore, technological change means that many young people receive this education online, which has both positive and negative effects. A thorough understanding of the driving factors behind global epidemiological trends in sexual and reproductive health-such as fluidity in gender and sexual identity, biomedical innovations in contraception and the treatment and prevention of HIV and other sexually transmitted infections, gender-based violence, access to safe abortion, fertility needs, and comprehensive sexuality education-is crucial in assessing progress on the sexual and reproductive health and rights agenda. To this end, this Series paper provides an overview of trends in sexual and reproductive health and rights outcomes since 2018.

Peripartum cardiomyopathy is increasingly recognised and diagnosed in clinical practice. Over the past two decades, a substantial amount of new knowledge on this condition has been accrued, including a better understanding of the pathophysiology, genetic predisposition for a proportion of patients, diagnostic tools, management with a disease-specific therapy, and predictors of outcome. Peripartum cardiomyopathy occurs globally in all ethnic groups and should be suspected in any women who are peripartum presenting with symptoms and signs indicative of heart failure towards the end of pregnancy or in the months following delivery. Verification of left ventricular systolic dysfunction (ejection fraction <45%) is crucial for the diagnosis of peripartum cardiomyopathy and the exclusion of other causes of heart failure, such as pre-existing cardiomyopathy, valvular heart disease, or congenital heart disease. Peripartum cardiomyopathy is a disease with considerable maternal and neonatal morbidity and mortality, with only half of women experiencing complete myocardial recovery within 6 months of the onset of symptoms. This Seminar summarises current knowledge of peripartum cardiomyopathy genetics, pathophysiology, diagnostic approaches, medical management, and outcome. Furthermore, we provide guidance on both risk stratification by use of a novel score to predict recovery and on the outcomes of a subsequent pregnancy.

Non-coeliac gluten sensitivity (NCGS) refers to individuals who report intestinal and extraintestinal symptoms related to the ingestion of gluten-based or wheat-based foods, in the absence of coeliac disease or wheat allergy. Gluten is found in multiple cereals, including wheat, rye, and barley, although the precise trigger of symptoms in NCGS remains unclear. Although approximately 10% of adults worldwide self-report gluten or wheat sensitivity, meta-analyses suggest that, during controlled challenge studies, 16-30% of these individuals have symptoms specifically triggered by gluten. However, methodological variability-including the presence of fermentable carbohydrates in challenge preparations-limits interpretation. Current evidence suggests that fermentable carbohydrates and nocebo effects contribute considerably to symptom generation in many cases. The substantial size of the gluten-free market raises questions about commercial and media influences on how NCGS is portrayed, and on the direction of related research. Definitive diagnosis of NCGS remains elusive due to the absence of biomarkers, significant overlap with disorders of gut-brain interaction, and methodological challenges in dietary evaluation. Until causative agents are identified and diagnostic tests developed, NCGS remains a diagnosis of exclusion, requiring careful systematic evaluation. Management approaches should balance dietary modification with recognition of psychological factors while ensuring nutritional adequacy. This Review critically examines current evidence regarding NCGS as a distinct entity, explores potential mechanisms, and provides practical guidance for assessment and management, while acknowledging major uncertainties in the field.

Despite extraordinary scientific and medical resources, the US health-care system underperforms. In this Review we consider the damage wrought by decades of market-based policies that have stimulated profit-seeking by insurers and health-care providers. Policy makers have subcontracted coverage under the public Medicaid and Medicare programmes for people with low incomes and those older than 64 years to private insurance firms-which now derive most of their revenues from those programmes-raising taxpayers' costs and constricting patients' care. Despite worrisome evidence of misbehaviour, firms obligated to prioritise shareholders' interests-and, more recently, private equity firms with a single-minded focus on short-term profit-have gained control of vital clinical resources. President Biden rescinded some of Donald Trump's most egregious first-term policies, expanded coverage for lower-income Americans, and initiated modest drug price controls. Since regaining office, President Trump has laid siege to science and public health, cut US$990 billion from Medicaid to offset tax reductions for the wealthy, and is accelerating Medicare's privatisation. State governments can tighten regulation of profit-driven abuses, and the medical community should resist Trump's health-harming agenda. But neither restoring the pre-Trump status quo, nor further attempts to reconcile the human rights of patients with the property claims of investors will suffice. Reforms must, instead, decommercialise insurance and care provision.

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).

Community-acquired pneumonia is a major global health challenge that disproportionately affects vulnerable populations, including older people, immunocompromised people, those with chronic conditions, and young children. Once considered solely an acute illness, community-acquired pneumonia is now recognised as a disease with long-term complications, including cardiovascular events, respiratory impairment, and cognitive decline. Advances, such as nucleic acid amplification tests (NAATs) and the broader availability of point-of-care lung ultrasound, allow for rapid pathogen detection and personalised treatment. However, substantial uncertainties remain regarding the role of NAATs, lung ultrasounds, and serum biomarkers in clinical practice. Antibiotics are the cornerstone of community-acquired pneumonia treatment, but the roles of adjunctive therapies, including corticosteroids and immunomodulators, remain incompletely defined. Comprehensive community-acquired pneumonia management emphasises personalised treatment, rehabilitation after the acute episode, routine cardiovascular screening, and strengthening preventive measures, such as vaccination. As precision medicine advances, integrating diagnostics and tailored therapies will improve outcomes and reduce the global burden of community-acquired pneumonia.

Alcohol use disorders consist of conditions characterised by compulsive heavy alcohol use and loss of control over alcohol intake. Alcohol use disorders are some of the most prevalent mental disorders globally, with higher prevalence in high-income countries and lower prevalence in low-income countries. The recent COVID-19 pandemic was associated with an increase in fully alcohol-attributable mortality, in part triggered by alcohol-specific interactions with stress. Despite their high prevalence, alcohol use disorders remain undertreated, even though there are scientifically established and cost-effective psychosocial, community, and pharmacological interventions available. In addition, promising new treatment modalities have been developed and are currently being tested. The two main barriers to better access to evidence-based alcohol use disorder treatment are low availability, due to the absence of government or public funding for such treatment, and stigma. The first barrier could be overcome by increasing alcohol excise taxation, which currently falls considerably short of covering the social costs of alcohol use. In addition to generating revenues, increasing excise taxation could reduce health-care costs by reducing hospitalisations for all alcohol-attributable conditions, including alcohol use disorders. Overall, integrated alcohol control policies could improve the prevention of alcohol use disorders, improve access to treatment, and reduce stigma.

An estimated 3-10% of patients with asthma are unable to reach full control with currently available inhaled therapies. In a large proportion of these patients, asthma can be driven in whole or in part by type 2 (T2) inflammation, which is usually initiated by an immunological response to stimulation at mucosal surfaces. The introduction of monoclonal antibodies, which target T2 inflammatory processes, provides important options for this population. In the past decade, five anticytokine biologics (ACBs) that block specific T2 inflammatory cytokines have been introduced. Three biologics, mepolizumab, reslizumab, and benralizumab, inhibit the IL-5 or IL-5 receptor pathway; dupilumab blocks IL-4 and IL-13 through its activity on the IL-4 receptor-alpha; and tezepelumab prevents activation of the thymic stromal lymphopoietin cytokine production cascade. These drugs reduce exacerbations and improve lung function and patient-reported asthma quality of life in individuals with a history of asthma exacerbations and evidence of T2 inflammation. Some also allow oral corticosteroid reduction or elimination in patients dependent on these therapies for asthma control. The effect of ACBs varies by the degree of T2 inflammation, which is most easily assessed by blood eosinophil counts and exhaled nitric oxide. The use of ACBs guided by these biomarkers and phenotypic characteristics of patients with severe asthma allows a personalised medicine approach that increases the likelihood of improvement.

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.

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.