Older patients represent the fastest growing patient group in clinical care. They are a heterogeneous group, for whom evidence for making treatment decisions is often scarce. Important domains for advancing the relevance of clinical trials for older patients are selection and inclusion of representative patients, choosing appropriate therapeutic interventions, and studying relevant outcomes. In the last decade, a myriad of publications has recommended multiple solutions that improve the relevance of trials for older people. Although uptake of these recommendations has been slow, there are now some excellent and successful implementation approaches that show that it is possible to design and execute trials that are inclusive of older patients, address relevant outcomes, and allow for real-world comparisons of intervention effectiveness. Observational studies based on different data sources add useful complementary information. This narrative review aims to synthesise best practices and successful strategies to improve the relevance of clinical trials for older patients.

Alternatives to carbapenems for the treatment of third-generation cephalosporin-resistant Enterobacterales (3GCR-E) are urgently needed to reduce the selection pressure posed by these drugs. Temocillin is a neglected narrow-spectrum β-lactam. The aim of the trial was to investigate if temocillin is non-inferior to carbapenems for the targeted treatment of bacteraemia due to 3GCR-E.

Venetoclax-rituximab (VR) following covalent Bruton tyrosine kinase (BTK) inhibitor therapy is the fixed-duration standard of care for patients with chronic lymphocytic leukaemia (including small lymphocytic lymphoma). Pirtobrutinib, a non-covalent BTK inhibitor, is approved for use after treatment with a covalent BTK inhibitor as a continuous therapy option. We aimed to evaluate the addition of pirtobrutinib to VR as a fixed-duration regimen in patients with relapsed or refractory chronic lymphocytic leukaemia.

Currently children's needs, perspectives, and rights are not adequately included in public policies, with negative consequences for the health and wellbeing of children and future generations. The 2020 WHO-UNICEF-Lancet Commission reviewed threats to children's health and concluded that children's needs and voices should be centred in all policies for a sustainable future. Since 2021, Children in All Policies 2030, a global collaboration of policy makers, scientists, and advocates, has implemented the Commission's recommendations by fostering new approaches to participatory, intersectoral policy making across diverse countries. Efforts to implement the Commission's recommendations encountered challenges including flawed assumptions in prevailing policy-making models, failure to fulfil children's right to participate, and an ongoing scarcity of intersectoral policy integration. Eight lessons on what works for improving policy making and implementation emerged: use creative means to involve children, patiently assemble coalitions, prepare to seize political opportunities, harmonise global data to bridge UN partnerships, create national political and technical platforms, use media to change cultural perceptions, use strategic framing to overcome sectoral barriers, and embrace joint learning. Harnessing people's consideration and concern for children and future generations and engaging children's voices represents a powerful political opportunity to reach current development goals and ensure a healthier, more sustainable future.

Once rapidly fatal, neglected, and orphan diseases without approved therapeutic options, systemic amyloidoses are now highly treatable. Basic scientific discoveries regarding the molecular mechanisms of transthyretin misfolding and aggregation have driven the development of drugs for the treatment of transthyretin (ATTR) amyloidosis, with six novel therapies approved since 2018. The combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone was approved for the treatment of light chain (AL) amyloidosis in 2021. Since then, highly effective immunotherapies, such as bispecific T-cell engagers, have been tested in clinical trials in patients with relapsed AL amyloidosis, with unprecedented efficacy. Thus, suspicion of systemic amyloidosis should be raised early in individuals with a suggestive clinical presentation, followed by rapid tissue diagnosis, with appropriate protein typing and prompt commencement of active therapy. These rapid and exciting therapeutic advancements set the stage for this Review on the epidemiology, pathophysiology, and diagnosis of systemic amyloidosis. Through the lens of the molecular mechanisms underlying amyloidosis pathogenesis, we will focus on approved and investigational therapies. We also discuss future directions and challenges concerning a cure for patients with AL or ATTR amyloidosis.

In patients receiving extracorporeal membrane oxygenation (ECMO), standard practice is full-dose intravenous unfractionated heparin (UFH) targeting an activated partial thromboplastin time of 2·0-2·5 times baseline to reduce thrombotic risk. This approach can increase bleeding without further reducing thrombosis compared with low-dose UFH. Robust evidence to guide anticoagulation targets is absent because anticoagulation targets in ECMO have never been assessed in a sufficiently powered randomised trial. We aimed to determine whether low-dose UFH or therapeutic low-molecular-weight heparin (LMWH) is non-inferior to standard-dose UFH in patients receiving ECMO.