Chronic suppurative otitis media (CSOM) is a leading global cause of potentially preventable hearing loss in children and adults, associated with socioeconomic deprivation. There is an absence of consensus on the definition of CSOM, which complicates efforts for prevention, treatment, and monitoring. CSOM occurs when perforation of the tympanic membrane is associated with severe or persistent inflammation in the middle ear, leading to hearing loss and recurrent or persistent ear discharge (otorrhoea). Cholesteatoma, caused by the inward growth of the squamous epithelium of the tympanic membrane into the middle ear, can also occur. The optimal treatment of discharge in CSOM is topical antibiotics. In resource-limited settings where topical antibiotics might not be available, topical antiseptics are an alternative. For persistent disease, surgery to repair the tympanic membrane or remove cholesteatoma might offer long-term resolution of otorrhoea and potential improvement to hearing. Recent developments in self-fitted air-conduction and bone-conduction hearing aids offer promise as new options for rehabilitation.

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

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

Pharmacotherapy provides an option for adults with overweight and obesity to reduce their bodyweight if lifestyle modifications fail. We summarised the latest evidence for the benefits and harms of weight-lowering drugs.

The historical and contemporary alignment of medical and health journals with colonial practices needs elucidation. Colonialism, which sought to exploit colonised people and places, was justified by the prejudice that colonised people's ways of knowing and being are inferior to those of the colonisers. Institutions for knowledge production and dissemination, including academic journals, were therefore central to sustaining colonialism and its legacies today. This invited Viewpoint focuses on The Lancet, following its 200th anniversary, and is especially important given the extent of The Lancet's global influence. We illuminate links between The Lancet and colonialism, with examples from the past and present, showing how the journal legitimised and continues to promote specific types of knowers, knowledge, perspectives, and interpretations in health and medicine. The Lancet's role in colonialism is not unique; other institutions and publications across the British empire cooperated with empire-building through colonisation. We therefore propose investigations and raise questions to encourage broader contestation on the practices, audience, positionality, and ownership of journals claiming leadership in global knowledge production.

Valvular heart disease is common and its prevalence is rapidly increasing worldwide. Effective medical therapies are insufficient and treatment was historically limited to the surgical techniques of valve repair or replacement, resulting in systematic underprovision of care to older patients and those with substantial comorbidities, frailty, or left ventricular dysfunction. Advances in imaging and surgical techniques over the past 20 years have transformed the management of valvular heart disease. Better understanding of the mechanisms and causes of disease and an increasingly extensive and robust evidence base provide a platform for the delivery of individualised treatment by multidisciplinary heart teams working within networks of diagnostic facilities and specialist heart valve centres. In this Series paper, we aim to provide an overview of the current and future management of valvular heart disease and propose treatment approaches based on an understanding of the underlying pathophysiology and the application of multidisciplinary treatment strategies to individual patients.

Valvular heart disease (VHD) is becoming more prevalent in an ageing population, leading to challenges in diagnosis and management. This two-part Series offers a comprehensive review of changing concepts in VHD, covering diagnosis, intervention timing, novel management strategies, and the current state of research. The first paper highlights the remarkable progress made in imaging and transcatheter techniques, effectively addressing the treatment paradox wherein populations at the highest risk of VHD often receive the least treatment. These advances have attracted the attention of clinicians, researchers, engineers, device manufacturers, and investors, leading to the exploration and proposal of treatment approaches grounded in pathophysiology and multidisciplinary strategies for VHD management. This Series paper focuses on innovations involving computational, pharmacological, and bioengineering approaches that are transforming the diagnosis and management of patients with VHD. Artificial intelligence and digital methods are enhancing screening, diagnosis, and planning procedures, and the integration of imaging and clinical data is improving the classification of VHD severity. The emergence of artificial intelligence techniques, including so-called digital twins-eg, computer-generated replicas of the heart-is aiding the development of new strategies for enhanced risk stratification, prognostication, and individualised therapeutic targeting. Various new molecular targets and novel pharmacological strategies are being developed, including multiomics-ie, analytical methods used to integrate complex biological big data to find novel pathways to halt the progression of VHD. In addition, efforts have been undertaken to engineer heart valve tissue and provide a living valve conduit capable of growth and biological integration. Overall, these advances emphasise the importance of early detection, personalised management, and cutting-edge interventions to optimise outcomes amid the evolving landscape of VHD. Although several challenges must be overcome, these breakthroughs represent opportunities to advance patient-centred investigations.

WHO has determined a public health emergency of international concern (PHEIC) seven times, and beyond this nomenclature declared COVID-19 to be a pandemic. Under the International Health Regulations (IHR), and through their operationalisation in the joint external evaluation (JEE), governments are urged to create suitable legislation to be able to enact a response to a public health emergency. Whether the pandemic declaration had a greater effect than a PHEIC in encouraging goverments to act, however, remains conjecture, as there is no systemic analysis of what each term means in practice and whether either has meaningful legal implications at the national level. We undertook a legal scoping review to assess the utilisation of PHEIC and pandemic language within national legislation in 28 WHO member states. Data were collected from national websites, JEE reviews, COVID Analysis and Mapping of Policies Tool, Natlex, and Oxford Compendium of National Legal Responses to COVID-19. We found that only 16% of countries have any reference to the PHEIC in national legislation and 37·5% of countries reference the term pandemic. This finding paints a weakened picture of the IHR and PHEIC mechanisms. Having such legalese enshrined in legislation might enhance the interaction between WHO determining a PHEIC or declaring a pandemic and resulting action to mitigate transnational spread of disease and enhance health security. Given the ongoing negotiations at WHO in relation to the amendments to the IHR and creation of the pandemic accord, both of which deal with this declaratory power of the PHEIC and pandemic language, negotiators should understand the possible implications of any changes to these proclamations at the national level and for global health security.

Lung development starts in utero and continues during childhood through to adolescence, reaching its peak in early adulthood. This growth is followed by gradual decline due to physiological lung ageing. Lung-function development can be altered by several host and environmental factors during the life course. As a result, a range of lung-function trajectories exist in the population. Below average trajectories are associated with respiratory, cardiovascular, metabolic, and mental health comorbidities, as well as with premature death. This Review presents progressive research into lung-function trajectories and assists the implementation of this knowledge in clinical practice as an innovative approach to detect poor lung health early, monitor respiratory disease progression, and promote lung health. Specifically, we propose that, similar to paediatric height and weight charts used globally to monitor children's growth, lung-function charts could be used for both children and adults to monitor lung health status across the life course. To achieve this proposal, we introduce our free online Lung Function Tracker tool. Finally, we discuss challenges and opportunities for effective implementation of the trajectory concept at population level and outline an agenda for crucial research needed to support such implementation.

Recent advances in mRNA technology and its delivery have enabled mRNA-based therapeutics to enter a new era in medicine. The rapid, potent, and transient nature of mRNA-encoded proteins, without the need to enter the nucleus or the risk of genomic integration, makes them desirable tools for treatment of a range of diseases, from infectious diseases to cancer and monogenic disorders. The rapid pace and ease of mass-scale manufacturability of mRNA-based therapeutics supported the global response to the COVID-19 pandemic. Nonetheless, challenges remain with regards to mRNA stability, duration of expression, delivery efficiency, and targetability, to broaden the applicability of mRNA therapeutics beyond COVID-19 vaccines. By learning from the rapidly expanding preclinical and clinical studies, we can optimise the mRNA platform to meet the clinical needs of each disease. Here, we will summarise the recent advances in mRNA technology; its use in vaccines, immunotherapeutics, protein replacement therapy, and genomic editing; and its delivery to desired specific cell types and organs for development of a new generation of targeted mRNA-based therapeutics.

Inflammatory bowel disease (IBD) affects reproductive planning due to psychological effects and mechanical problems related to surgery. Children of people with IBD have an increased risk of about 10% if one parent has IBD and up to 33% if both parents have IBD. The fertility of people with IBD is similar to the general population, but fertility might be reduced in individuals with active IBD, ileal pouch-anal anastomosis, or perianal Crohn's disease. Flaring disease during pregnancy increases complications, such as preterm birth. Thus, disease management with appropriate medications can optimise outcomes. As most medications have minimal fetal risks, people with IBD should be informed about the risks of stopping medications and the importance of maintaining remission. A period of disease remission is advisable before pregnancy and could reduce the risks for both the pregnant person and the fetus. Flexible endoscopy, intestinal ultrasound, and gadolinium-free magnetic resonance enterography are safe during pregnancy. We provide state-of-the-art knowledge on the basis of the latest evidence to ensure successful pregnancy outcomes in controlled IBD.

Globally, 9 million women are diagnosed with cancer each year. Breast cancer is the most commonly diagnosed cancer worldwide, followed by colorectal cancer in high-income countries and cervical cancer in low-income countries. Survival from cancer is improving and more women are experiencing long-term effects of cancer treatment, such as premature ovarian insufficiency or early menopause. Managing menopausal symptoms after cancer can be challenging, and more severe than at natural menopause. Menopausal symptoms can extend beyond hot flushes and night sweats (vasomotor symptoms). Treatment-induced symptoms might include sexual dysfunction and impairment of sleep, mood, and quality of life. In the long term, premature ovarian insufficiency might increase the risk of chronic conditions such as osteoporosis and cardiovascular disease. Diagnosing menopause after cancer can be challenging as menopausal symptoms can overlap with other common symptoms in patients with cancer, such as fatigue and sexual dysfunction. Menopausal hormone therapy is an effective treatment for vasomotor symptoms and seems to be safe for many patients with cancer. When hormone therapy is contraindicated or avoided, emerging evidence supports the efficacy of non-pharmacological and non-hormonal treatments, although most evidence is based on women older than 50 years with breast cancer. Vaginal oestrogen seems safe for most patients with genitourinary symptoms, but there are few non-hormonal options. Many patients have inadequate centralised care for managing menopausal symptoms after cancer treatment, and more information is needed about cost-effective and patient-focused models of care for this growing population.

The potential risk for mental health conditions over the menopause transition shapes women's expectations and informs putative physiological mechanisms regulating women's mental health. We review evidence from prospective studies reporting on associations between mental health conditions and the menopause transition. Major depressive disorder and the more prevalent subthreshold depressive symptoms are the most common conditions studied. We reviewed 12 prospective studies reporting depressive symptoms, major depressive disorder, or both over the menopause transition and found no compelling evidence for a universal increased risk for either condition. However, specific subgroups of participants, primarily defined by menopause-related risk factors (ie, vasomotor symptoms that are severe or disturb sleep, a long duration of the transition, or reproductive hormone dynamics) and psychosocial risk factors (eg, stressful life events), were vulnerable to depressive symptoms. The increased risk of major depressive disorder over the menopause transition appears predominantly in individuals with previous major depressive disorder. Greater focus on recognising risk factors in primary care is warranted. On the basis of scarce data, we found no compelling evidence that risk of anxiety, bipolar disorder, or psychosis is universally elevated over the menopause transition. Potential misattribution of psychological distress and psychiatric disorders to menopause could harm women by delaying accurate diagnosis and the initiation of effective psychotropic treatments, and by creating negative expectations for people approaching menopause. A paradigm shift is needed. We conclude with recommendations for the detection and treatment of depressive symptoms or major depressive disorder and strategies to promote good mental health over the menopause transition, while responsibly preparing and supporting those at risk.

The typical age at menopause is 50-51 years in high-income countries. However, early menopause is common, with around 8% of women in high-income countries and 12% of women globally experiencing menopause between the ages of 40 years and 44 years. Menopause before age 40 years (premature ovarian insufficiency) affects an additional 2-4% of women. Both early menopause and premature ovarian insufficiency can herald an increased risk of chronic disease, including osteoporosis and cardiovascular disease. People who enter menopause at younger ages might also experience distress and feel less supported than those who reach menopause at the average age. Clinical practice guidelines are available for the diagnosis and management of premature ovarian insufficiency, but there is a gap in clinical guidance for early menopause. We argue that instead of distinct age thresholds being applied, early menopause should be seen on a spectrum between premature ovarian insufficiency and menopause at the average age. This Series paper presents evidence for the short-term and long-term consequences of early menopause. We offer a practical framework for clinicians to guide diagnosis and management of early menopause, which considers the nature and severity of symptoms, age and medical history, and the individual's wishes and priorities to optimise their quality of life and short-term and long-term health. We conclude with recommendations for future research to address key gaps in the current evidence.

Menopause eventually happens to all people with typically functioning ovaries, and almost one billion women worldwide are postmenopausal. Although the biology of typical menopause is ubiquitous, the experience varies substantially. Factors contributing to the experience include not only individual factors, such as the nature and severity of symptoms, but also psychological, social, and contextual considerations, many of which are modifiable. In this first paper in the Lancet Series on menopause, we argue for a new approach that goes beyond the treatment of specific symptoms, to encompass a broad model to support women transitioning this life stage, using the model of empowerment. WHO defines empowerment as an active process of gaining knowledge, confidence, and self-determination to self-manage health and make informed decisions about care. Rather than focusing on menopause as an endocrine deficiency, we propose an empowerment model that recognises factors modifying the experience, in which the patient is an expert in their own condition and the health-care worker supports the patient to become an equal and active partner in managing their own care.

Crohn's disease is a chronic inflammatory disease of the gastrointestinal tract that might lead to progressive bowel damage and disability. The exact cause of Crohn's disease is unknown, but evidence points towards multifactorial events causing dysregulation of the innate immune system in genetically susceptible people. Commonly affecting the terminal ileum and proximal colon, Crohn's disease inflammation is often discontinuous and patchy, segmental, and transmural. Identification of characteristic findings on ileocolonoscopy and histology remains the diagnostic gold standard, but complete assessment involves laboratory abnormalities, including micronutrient deficiencies, cross-sectional imaging to identify transmural disease extent, severity and complications, and a psychosocial assessment. Treatment strategies for patients with Crohn's disease now go beyond achieving clinical remission to include deeper targets of endoscopic healing and consideration of adjunctive histological and transmural targets to alter disease progression potentially further. The use of early effective advanced therapies and development of therapies targeting alternative novel pathways with improved safety profiles have resulted in a new era of healing in Crohn's disease management. Future combination of advanced therapies with diet or other biological drugs and small molecules, together with improvements in tight control monitoring tools and predictive biomarkers might continue to improve outcomes for patients with Crohn's disease.

Behçet's syndrome is a rare, chronic multisystemic inflammatory disorder also known as the Silk Route disease due to its geographical distribution. Behçet's syndrome is a multifactorial disease and infectious, genetic, epigenetic, and immunological factors contribute to its pathogenesis. Its heterogeneous spectrum of clinical features include mucocutaneous, articular, ocular, vascular, neurological, and gastrointestinal manifestations that can present with a relapsing and remitting course. Differential diagnosis is often hampered by the non-specific clinical presentation and the absence of laboratory biomarkers or pathognomonic histological features. The therapeutic approach is tailored on the basis of patient-specific manifestations and relies on glucocorticoids, colchicine, and traditional and biological immunosuppressants. Despite progress in the knowledge and management of the disease, unmet needs in diagnostics, monitoring, prediction, and treatment personalisation challenge clinical practice, making Behçet's syndrome a complex disorder associated with an increased risk of morbidity.

Previous meta-analyses have shown reduced risks of composite adverse events with intravascular imaging-guided percutaneous coronary intervention (PCI) compared with angiography guidance alone. However, these studies have been insufficiently powered to show whether all-cause death or all myocardial infarction are reduced with intravascular imaging guidance, and most previous intravascular imaging studies were done with intravascular ultrasound rather than optical coherence tomography (OCT), a newer imaging modality. We aimed to assess the comparative performance of intravascular imaging-guided PCI and angiography-guided PCI with drug-eluting stents.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.