Background The USA struggled in responding to the COVID-19 pandemic, but not all states struggled equally. Identifying the factors associated with cross-state variation in infection and mortality rates could help to improve responses to this and future pandemics. We sought to answer five key policy-relevant questions regarding the following: 1) what roles social, economic, and racial inequities had

Background Since May 1, 2018, every alcoholic drink sold in Scotland has had minimum unit pricing (MUP) of £0·50 per unit. Previous studies have indicated that the introduction of this policy reduced alcohol sales by 3%. We aimed to assess whether this has led to reductions in alcohol-attributable deaths and hospitalisations. Methods Study outcomes, wholly attributable to alcohol consumption, were

Background Lassa fever is a substantial health burden in west Africa. We evaluated the safety, tolerability, and immunogenicity of a recombinant, live-attenuated, measles-vectored Lassa fever vaccine candidate (MV-LASV). Methods This first-in-human phase 1 trial—consisting of an open-label dose-escalation stage and an observer-blinded, randomised, placebo-controlled treatment stage—was conducted at

Background Neurokinin 3 receptor antagonists are potential non-hormonal therapies for the treatment of vasomotor symptoms in menopausal women as options are scarce for those who cannot or do not want to take hormone therapy. Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause. This study investigated

Background Lower respiratory tract infections (LRTIs) in early childhood are known to influence lung development and lifelong lung health, but their link to premature adult death from respiratory disease is unclear. We aimed to estimate the association between early childhood LRTI and the risk and burden of premature adult mortality from respiratory disease. Methods This longitudinal observational

Background Bordetella pertussis epidemics persist as transmission remains unabated despite high acellular pertussis vaccination rates. BPZE1, a live attenuated intranasal pertussis vaccine, was designed to prevent B pertussis infection and disease. We aimed to assess the immunogenicity and safety of BPZE1 compared with the tetanus–diphtheria–acellular pertussis vaccine (Tdap). Methods In this double-blind

Background Intermittent preventive treatment in pregnancy (IPTp) with dihydroartemisinin–piperaquine is more effective than IPTp with sulfadoxine–pyrimethamine at reducing malaria infection during pregnancy in areas with high-grade resistance to sulfadoxine–pyrimethamine by Plasmodium falciparum in east Africa. We aimed to assess whether IPTp with dihydroartemisinin–piperaquine, alone or combined with

Background Inflammation and hyperlipidaemia jointly contribute to atherothrombotic disease. However, when people are treated with intensive statin therapy, the relative contributions of inflammation and hyperlipidaemia to the risk of future cardiovascular events might change, which has implications for the choice of adjunctive cardiovascular therapeutics. We aimed to evaluate the relative importance

Background Influenza vaccination rates remain suboptimal despite effectiveness in preventing influenza infection and related complications. We investigated whether behavioural nudges, delivered via a governmental electronic letter system, would increase influenza vaccination uptake among older adults in Denmark. Methods We did a nationwide, pragmatic, registry-based, cluster-randomised implementation

Background In patients with acute coronary syndrome and multivessel coronary disease, complete revascularisation by percutaneous coronary intervention (PCI) is associated with improved clinical outcomes. We aimed to investigate whether PCI for non-culprit lesions should be attempted during the index procedure or staged. Methods This prospective, open-label, non-inferiority, randomised trial was done

Background Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately

Background Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein–kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly

Background Effectiveness of a non-physician community health-care provider-led intensive blood pressure intervention on cardiovascular disease has not been established. We aimed to test the effectiveness of such an intervention compared with usual care on risk of cardiovascular disease and all-cause death among individuals with hypertension. Methods In this open-label, blinded-endpoint, cluster-randomised

Background Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. The objective of this trial was to evaluate the efficacy and safety

Background Baricitinib is an oral selective inhibitor of Janus kinase 1 and 2 approved for the treatment of rheumatoid arthritis, atopic dermatitis, and alopecia areata. In a 24-week phase 2 study in patients with systemic lupus erythematosus (SLE), baricitinib 4 mg significantly improved SLE disease activity compared with placebo. In this Article, we report the evaluation of efficacy and safety of

Background Reirradiation in standard fractionation for locally advanced recurrent nasopharyngeal carcinoma after a previous course of high-dose radiotherapy is often associated with substantial late toxicity, negating its overall benefit. We therefore aimed to investigate the efficacy and safety of hyperfractionation compared with standard fractionation in intensity-modulated radiotherapy. Methods

Background People living with HIV have accounted for 38–50% of those affected in the 2022 multicountry mpox outbreak. Most reported cases were in people who had high CD4 cell counts and similar outcomes to those without HIV. Emerging data suggest worse clinical outcomes and higher mortality in people with more advanced HIV. We describe the clinical characteristics and outcomes of mpox in a cohort of

Background Understanding the level and characteristics of protection from past SARS-CoV-2 infection against subsequent re-infection, symptomatic COVID-19 disease, and severe disease is essential for predicting future potential disease burden, for designing policies that restrict travel or access to venues where there is a high risk of transmission, and for informing choices about when to receive vaccine

Background There is increasing interest in replacing alteplase with tenecteplase as the preferred thrombolytic treatment for patients with acute ischaemic stroke. We aimed to establish the non-inferiority of tenecteplase to alteplase for these patients. Methods In this multicentre, prospective, open-label, blinded-endpoint, randomised controlled, non-inferiority trial, adults with an acute ischaemic

Background Effective adjuvant therapy for patients with resected localised renal cell carcinoma represents an unmet need, with surveillance being the standard of care. We report results from part A of a phase 3, randomised trial that aimed to assess the efficacy and safety of adjuvant nivolumab plus ipilimumab versus placebo. Methods The double-blind, randomised, phase 3 CheckMate 914 trial enrolled

Background Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. Methods In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from

Background Due to the national dynamic zero-COVID strategy in China, there were no persistent local transmissions of SARS-CoV-2 in Beijing before December, 2022. However, imported cases have been frequently detected over the past 3 years. With soaring growth in the number of COVID-19 cases in China recently, there are concerns that there might be an emergence of novel SARS-CoV-2 variants. Routine surveillance

Background Sotorasib is a specific, irreversible inhibitor of the GTPase protein, KRASG12C. We compared the efficacy and safety of sotorasib with a standard-of-care treatment in patients with non-small-cell lung cancer (NSCLC) with the KRASG12C mutation who had been previously treated with other anticancer drugs. Methods We conducted a randomised, open-label phase 3 trial at 148 centres in 22 countries

Background Few therapeutic options are available for patients with moderate-to-severe hidradenitis suppurativa. We aimed to assess the efficacy of secukinumab in patients with moderate-to-severe hidradenitis suppurativa in two randomised trials. Methods SUNSHINE and SUNRISE were identical, multicentre, randomised, placebo-controlled, double-blind phase 3 trials done in 219 primary sites in 40 countries

Background One in four pregnancies end in a pregnancy loss. Although the effect on couples is well documented, evidence-based treatments and prediction models are absent. Fetal aneuploidy is associated with a higher chance of a next successful pregnancy compared with euploid pregnancy loss in which underlying maternal conditions might be causal. Ploidy diagnostics are therefore advantageous but challenging

Background The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene

Background Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus

Background High ambient temperatures are associated with many health effects, including premature mortality. The combination of global warming due to climate change and the expansion of the global built environment mean that the intensification of urban heat islands (UHIs) is expected, accompanied by adverse effects on population health. Urban green infrastructure can reduce local temperatures. We

Background Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator

Background WHO has identified Marburg virus as an emerging virus requiring urgent vaccine research and development, particularly due to its recent emergence in Ghana. We report results from a first-in-human clinical trial evaluating a replication-deficient recombinant chimpanzee adenovirus type 3 (cAd3)-vectored vaccine encoding a wild-type Marburg virus Angola glycoprotein (cAd3-Marburg) in healthy

Background On the basis of low-quality evidence, international critical care nutrition guidelines recommend a wide range of protein doses. The effect of delivering high-dose protein during critical illness is unknown. We aimed to test the hypothesis that a higher dose of protein provided to critically ill patients would improve their clinical outcomes. Methods This international, investigator-initiated

Background Metabolic acidosis is common in kidney transplant recipients and is associated with declining graft function. Sodium bicarbonate treatment effectively corrects metabolic acidosis, but no prospective studies have examined its effect on graft function. Therefore, we aimed to test whether sodium bicarbonate treatment would preserve graft function and slow the progression of estimated glomerular

Background New classes of long-lasting insecticidal nets (LLINs) combining mixtures of insecticides with different modes of action could put malaria control back on track after rebounds in transmission across sub-Saharan Africa. We evaluated the relative efficacy of pyriproxyfen-pyrethroid LLINs and chlorfenapyr-pyrethroid LLINs compared with standard LLINs against malaria transmission in an area of

Background People with cancer have an increased risk of cardiovascular disease. Risk prediction equations developed in New Zealand accurately predict 5-year cardiovascular disease risk in a general primary care population in the country. We assessed the performance of these equations for survivors of cancer in New Zealand. Methods For this validation study, patients aged 30–74 years from the PREDICT

Background In 2021, we showed an increased risk associated with COVID-19 in pregnancy. Since then, the SARS-CoV-2 virus has undergone genetic mutations. We aimed to examine the effects on maternal and perinatal outcomes of COVID-19 during pregnancy, and evaluate vaccine effectiveness, when omicron (B.1.1.529) was the variant of concern. Methods INTERCOVID-2022 is a large, prospective, observational

Background The appropriate duration of postoperative antibiotics for complex appendicitis is unclear. The increasing global threat of antimicrobial resistance warrants restrictive antibiotic use, which could also reduce side-effects, length of hospital stay, and costs. Methods In this pragmatic, open-label, non-inferiority trial in 15 hospitals in the Netherlands, patients with complex appendicitis

Background Binary diagnosis of coronary artery disease does not preserve the complexity of disease or quantify its severity or its associated risk with death; hence, a quantitative marker of coronary artery disease is warranted. We evaluated a quantitative marker of coronary artery disease derived from probabilities of a machine learning model. Methods In this cohort study, we developed and validated

Background The safety, effectiveness, and cost-effectiveness of molnupiravir, an oral antiviral medication for SARS-CoV-2, has not been established in vaccinated patients in the community at increased risk of morbidity and mortality from COVID-19. We aimed to establish whether the addition of molnupiravir to usual care reduced hospital admissions and deaths associated with COVID-19 in this population

Background OX40 is crucial for T-cell differentiation and memory induction. The anti-OX40 antibody, rocatinlimab inhibits the OX40 pathway. We evaluated the efficacy and safety of rocatinlimab in adults with moderate-to-severe atopic dermatitis. Methods This multicentre, double-blind, placebo-controlled phase 2b study was done at 65 secondary and tertiary sites in the USA, Canada, Japan, and Germany

Background Existing evidence on the effects of race and ethnicity on pregnancy outcomes is restricted to individual studies done within specific countries and health systems. We aimed to assess the impact of race and ethnicity on perinatal outcomes in high-income and upper-middle-income countries, and to ascertain whether the magnitude of disparities, if any, varied across geographical regions. Methods

Background Indigenous Brazilian peoples have faced an unparalleled increase in the rate of cardiovascular diseases following rapid nutritional transition to more urban diets. We aimed to conduct a systematic review and meta-analysis to evaluate the association between urbanisation (including data from Amazon rainforest deforestation) and cardiometabolic risk factors and outcomes. Methods In this systematic

Background International and population-specific evidence identifies elevated psychological distress prevalence among those experiencing interpersonal discrimination. We aim to quantify the potential whole-of-population contribution of interpersonal discrimination to psychological distress prevalence and Indigenous–non-Indigenous gaps in Australia. Methods We did a cross-sectional analysis of data

Background Type 2 circulating vaccine-derived polioviruses (cVDPV2) from Sabin oral poliovirus vaccines (OPVs) are the leading cause of poliomyelitis. A novel type 2 OPV (nOPV2) has been developed to be more genetically stable with similar tolerability and immunogenicity to that of Sabin type 2 vaccines to mitigate the risk of cVDPV2. We aimed to assess these aspects of nOPV2 in poliovirus vaccine-naive

Background An improvement in progression-free survival was shown with trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer in the progression-free survival interim analysis of the DESTINY-Breast03 trial. The aim of DESTINY-Breast03 was to compare the efficacy and safety of trastuzumab deruxtecan versus trastuzumab emtansine. Methods This open-label

Background Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17F and IL-17A. This study compared the efficacy and safety of bimekizumab with placebo over 16 weeks in patients with active psoriatic arthritis and previous inadequate response or intolerance to tumour necrosis factor-α (TNFα) inhibitors. Methods BE COMPLETE was a phase 3, multicentre, randomised, double-blind

Background Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits interleukin (IL)-17A and IL-17F. We assessed the efficacy and safety of bimekizumab in patients with active psoriatic arthritis who were naive to biologic disease-modifying antirheumatic drugs (DMARDs). Methods BE OPTIMAL was a 52-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, active reference

Background Malaria in the first trimester of pregnancy is associated with adverse pregnancy outcomes. Artemisinin-based combination therapies (ACTs) are a highly effective, first-line treatment for uncomplicated Plasmodium falciparum malaria, except in the first trimester of pregnancy, when quinine with clindamycin is recommended due to concerns about the potential embryotoxicity of artemisinins. We

Background Rezafungin is a next-generation, once-a-week echinocandin in development for the treatment of candidaemia and invasive candidiasis and for the prevention of invasive fungal disease caused by Candida, Aspergillus, and Pneumocystis spp after blood and marrow transplantation. We aimed to compare the efficacy and safety of intravenous rezafungin versus intravenous caspofungin in patients with

Background Reducing the burden of death due to infection is an urgent global public health priority. Previous studies have estimated the number of deaths associated with drug-resistant infections and sepsis and found that infections remain a leading cause of death globally. Understanding the global burden of common bacterial pathogens (both susceptible and resistant to antimicrobials) is essential

Background Between May and November, 2022, global outbreaks of human monkeypox virus infection have been reported in more than 78 000 people worldwide, predominantly in men who have sex with men. We describe the epidemiological and clinical characteristics of monkeypox virus infection in cisgender (cis) and transgender (trans) women and non-binary individuals assigned female sex at birth to improve

Background Induction of labour is one of the most common obstetric interventions globally. Balloon catheters and vaginal prostaglandins are widely used to ripen the cervix in labour induction. We aimed to compare the effectiveness and safety profiles of these two induction methods. Methods We did an individual participant data meta-analysis comparing balloon catheters and vaginal prostaglandins for

Background Vasomotor symptoms (hot flushes and night sweats) are experienced by more than two-thirds of women with breast cancer taking oral adjuvant endocrine therapy. Safe and effective treatments are lacking. Q-122 is a novel, non-hormonal compound that has shown promise for reducing vasomotor symptoms by modulation of oestrogen-responsive neurons in the hypothalamus. We aimed to assess the efficacy

Background The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. Methods We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries

Background Resistant hypertension is associated with increased cardiovascular risk. The endothelin pathway has been implicated in the pathogenesis of hypertension, but it is currently not targeted therapeutically, thereby leaving this relevant pathophysiological pathway unopposed with currently available drugs. The aim of the study was to assess the blood pressure lowering efficacy of the dual endothelin

Background There is a paucity of evidence for dose and pace of up-titration of guideline-directed medical therapies after admission to hospital for acute heart failure. Methods In this multinational, open-label, randomised, parallel-group trial (STRONG-HF), patients aged 18–85 years admitted to hospital with acute heart failure, not treated with full doses of guideline-directed drug treatment, were

Background Large trials have shown that sodium glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure or chronic kidney disease, or with type 2 diabetes and high risk of atherosclerotic cardiovascular disease. None of the trials recruiting patients with and without diabetes were designed to assess outcomes separately

Background Previous randomised trials of bivalirudin versus heparin in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) have reported conflicting results, in part because of treatment with different pharmacological regimens. We designed a large-scale trial examining bivalirudin with a post-PCI high-dose infusion compared with

Background For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients

Background Peptic ulcers in patients receiving aspirin are associated with Helicobacter pylori infection. We aimed to investigate whether H pylori eradication would protect against aspirin-associated ulcer bleeding. Methods We conducted a randomised, double-blind, placebo-controlled trial (Helicobacter Eradication Aspirin Trial [HEAT]) at 1208 primary care centres in the UK, using routinely collected

Background The 2015 Lancet Commission on global surgery identified surgery and anaesthesia as indispensable parts of holistic health-care systems. However, COVID-19 exposed the fragility of planned surgical services around the world, which have also been neglected in pandemic recovery planning. This study aimed to develop and validate a novel index to support local elective surgical system strengthening