Since 2007, single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) has been proposed as an alternative to Roux-en-Y gastric bypass (RYGB) in the treatment of obesity. We conducted a multicentre randomised trial, with the hypothesis that SADI-S could be more effective than RYGB at 2-year follow-up.

Provider shortages and lack of culturally responsive care limit mental health services in reaching multicultural populations worldwide. We examined the effectiveness of a psychoeducational intervention aimed at building community capacity to address depression and anxiety among racial, ethnic, and linguistic minoritised adults.

ION224, a liver-directed antisense inhibitor of diacylglycerol O-acyltransferase 2 (DGAT2), suppresses de novo lipogenesis, an important metabolic pathway associated with lipotoxicity and the underlying inflammation, hepatocellular injury, and fibrosis in metabolic dysfunction-associated steatohepatitis (MASH). This study aimed to prospectively assess the safety and efficacy of ION224 in patients with MASH and fibrosis.

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.

Efruxifermin is a bivalent fibroblast growth factor 21 analogue in development for the treatment of metabolic dysfunction-associated steatohepatitis (MASH). This trial aimed to prospectively assess the safety and efficacy of efruxifermin administration for 96 weeks in individuals with MASH and moderate (stage 2; F2) or severe (stage 3; F3) fibrosis.

No pharmacological therapy has been shown with certainty to improve the cardiovascular prognosis in patients with kidney failure on chronic haemodialysis. We aimed to investigate the effects of the steroidal mineralocorticoid receptor antagonist spironolactone on cardiovascular outcomes in patients on haemodialysis who are at high risk of cardiovascular events.

Patients undergoing maintenance dialysis for kidney failure are at substantial risk of cardiovascular morbidity and mortality. We aimed to establish if spironolactone reduces heart failure and cardiovascular deaths in these patients.

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.

Rabies is almost invariably fatal. A rabies monoclonal antibody (RmAb) was approved in India in 2016 for passive prophylaxis. This post-marketing study aimed to evaluate the long-term safety, immunogenicity, and efficacy of a post-exposure prophylaxis (PEP) regimen containing RmAb.

Adagrasib is a KRASG12C inhibitor that demonstrated promising activity against KRASG12C-mutated advanced non-small-cell lung cancer (NSCLC) in a phase 2 trial. Here we aimed to compare the efficacy and safety of adagrasib versus docetaxel in patients with KRASG12C-mutated advanced NSCLC previously treated with chemotherapy and immunotherapy.

In postmenopausal women with oestrogen receptor-positive early breast cancer, 5 years of adjuvant tamoxifen substantially reduces 15-year recurrence and mortality; aromatase inhibitor treatment (AIT) is even more effective. We assess the effects of further AIT among women recurrence-free after at least 5 years of endocrine therapy.

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.

For women aged 70 years or older with oestrogen receptor-positive HER2-negative invasive breast cancer, hormonotherapy is a standard adjuvant treatment, while the role of chemotherapy is debated. We aimed to assess the effect of adjuvant chemotherapy on overall survival in these older patients with high-risk tumours according to a prognostic genomic signature.

Soil-transmitted helminths are targeted for elimination as a public health problem. This study assessed whether, with high coverage, community-wide mass drug administration (MDA) could lead to transmission interruption.

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.

Despite the availability of biological therapies, suboptimal disease control remains a problem for patients with Crohn's disease. We report the results of the GALAXI-2 and GALAXI-3 studies, which aimed to assess the efficacy and safety of intravenous induction followed by subcutaneous maintenance therapy with guselkumab over 48 weeks in adults with moderately to severely active Crohn's disease.

The primary analysis of this phase 3 trial combining talazoparib with enzalutamide demonstrated significantly improved radiographic progression-free survival (rPFS) versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer unselected for homologous recombination repair (HRR) gene alterations. Overall survival data were immature at that time. Here we report the final prespecified overall survival analysis, an updated descriptive analysis of rPFS, and safety in the cohort unselected for HRR gene alterations.

Metastatic castration-resistant prostate cancer remains incurable and is particularly aggressive in patients with alterations in DNA damage repair genes involved directly or indirectly in homologous recombination repair (HRR). In the primary analysis of TALAPRO-2, talazoparib plus enzalutamide significantly improved radiographic progression-free survival (rPFS) versus enzalutamide plus placebo in patients with metastatic castration-resistant prostate cancer harbouring HRR gene alterations. At primary analysis, overall survival was immature. Here we report final prespecified overall survival analysis, updated rPFS, safety, and patient-reported outcomes in the HRR-deficient cohort of TALAPRO-2.