Ibrutinib, a Bruton tyrosine kinase inhibitor, prolongs progression-free survival when added to immunochemotherapy as first line treatment. The ENRICH trial compared the chemotherapy-free combination of ibrutinib and the anti-CD20 antibody rituximab (ibrutinib-rituximab) with standard immunochemotherapy (R-CHOP [rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisolone] or bendamustine-rituximab) in patients 60 years and older with untreated mantle-cell lymphoma.

Despite the success of immune modulation in the treatment of relapsing multiple sclerosis, disability progression is a major problem driven by multiple mechanisms. Comorbidities (eg, vascular risk) and ageing are thought to augment these neurodegenerative pathologies. In the phase 2b MS-STAT trial of simvastatin (80 mg) versus placebo in secondary progressive multiple sclerosis (SPMS), the adjusted difference in brain atrophy rate between groups was -0·254% per year: a 43% reduction. In this phase 3 MS-STAT2 trial, we aimed to assess the efficacy of simvastatin versus placebo in slowing the progression of disability in SPMS.

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.

Combination inhaled corticosteroid-formoterol reliever monotherapy reduces the rate of asthma attacks compared to short-acting β2-agonist (SABA) reliever monotherapy in adults. Its comparative efficacy in children has not been established.

Antimicrobial resistance is a global health threat. Many children with acute illness in ambulatory care are unnecessarily prescribed antibiotics. We assessed the clinical effectiveness of a clinical decision tool for these children, including a validated decision tree, guided point-of-care C-reactive protein testing (POCT of CRP), and safety-netting advice.

C3 glomerulopathy is an ultra-rare, severe form of glomerulonephritis caused by overactivation of the alternative complement pathway. We aimed to assess efficacy and safety of iptacopan (LNP023), an oral, proximal complement inhibitor that targets factor B to selectively inhibit the alternative pathway of the complement cascade.

Cancer is a leading cause of death globally. Accurate cancer burden information is crucial for policy planning, but many countries do not have up-to-date cancer surveillance data. To inform global cancer-control efforts, we used the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework to generate and analyse estimates of cancer burden for 47 cancer types or groupings by age, sex, and 204 countries and territories from 1990 to 2023, cancer burden attributable to selected risk factors from 1990 to 2023, and forecasted cancer burden up to 2050.

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.

Monoclonal antibodies targeting interleukin-23 and interleukin-12 are efficacious in treating plaque psoriasis but must be delivered via intravenous or subcutaneous injection. Here, we aimed to evaluate the efficacy and safety of icotrokinra (JNJ-77242113), a targeted oral peptide that selectively binds the interleukin-23 receptor, compared with both placebo and deucravacitinib in adults with moderate-to-severe plaque psoriasis.

Type 1 diabetes remains an important health-care problem, with no disease-modifying therapies available in people with recent-onset, clinical type 1 diabetes. Adaptive trial designs, allowing faster evaluation of treatment modalities, remain underexplored in this stage of the disease. We aimed to identify the minimum effective dose of antithymocyte globulin (ATG) in people aged 5-25 years with recent-onset, clinical 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.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality. Generalised-particularly nocturnal-convulsive seizures, longstanding epilepsy, and solitary living have been identified retrospectively as risk factors. No definitive electroclinical biomarkers have been prospectively ascertained. This study aimed to identify SUDEP risk markers using multimodality data with long-term follow-up.

Current treatment options for youth-onset type 2 diabetes are limited and have demonstrated lower glycaemic efficacy than those for adult-onset type 2 diabetes. We aimed to assess the safety and efficacy of tirzepatide, a glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, compared with placebo in youth-onset type 2 diabetes.

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.

Non-communicable diseases (NCDs) have received substantial policy attention globally and in most countries. Our aim was to quantify how much NCD mortality changed from 2010 to 2019 in different countries, especially compared with the preceding decade and with the best-performing country in each region, and the specific NCD causes of death that contributed to change.

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.