EClinicalMedicine最新文献

Background: Drug overdose is an escalating public health crisis in the United States (U.S.). This study evaluated the temporal trend of drug overdose-related deaths in the U.S., with an emphasis on identifying disparities across subpopulations and the contributing drugs.

Methods: Using the nationwide death dataset from the National Vital Statistics System (NVSS), we estimated the drug overdose-related age-standardized mortality rate (ASMR) and temporal trends for individuals aged 12 and older from 2012 to 2022. Excess mortality during the Coronavirus disease 2019 (COVID-19) pandemic was evaluated based on the pre-pandemic trends using predictive modeling analysis.

Findings: Among 809,967 overdose-related deaths during 2012-2022, ASMR increased by 8.9% [95% confidence interval (CI): 6.0%-11.9%] per year from 2012 to 2019 and increased to 12.9% (95% CI: 2.1%-24.8%) from 2019 to 2022, with the excess ASMR of 16.9% in 2020, increased to 26.4% in 2021 and then decreased to 19.3% in 2022. Significant age, sex, racial/ethnic and geographic disparities were demonstrated, with adolescents (annual percentage change [APC]:21.6%) and males (APC:13.6%) having the most pronounced increase during the pandemic. Ethnic minorities especially the non-Hispanic American Indian/Alaska Native experienced the highest excess ASMR (33.1% in 2020). Illicit fentanyl and synthetics starting with the lowest ASMR in 2012 (1.0 per 100,000), marked the most dramatic increase and became the leading cause of overdose-related death since 2016 (7.5 per 100,000), leading to the highest ASMR by 2022 (27.4 per 100,000). All drug types except heroin experienced varying degrees of excess ASMRs, with prescription opioid pain relievers (23.5%-55.1%), benzodiazepines (27.4%-40.9%) and antidepressants (10.4%-17.8%) exhibiting consistent increases from 2020 to 2022, while the excess ASMRs for illicit fentanyl and synthetics (25.3%-10.0%), psychostimulants (32.8%-14.6%) and methadone (35.0%-33.3%) decreased between 2021 and 2022.

Interpretation: Overdose-related mortality is increasing at an alarming rate, and the stark differences point to the need for targeted interventions to reduce the burden of drug overdose deaths.

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Background: Countries are recommended to immunise adolescent girls routinely with one or two doses of human papillomavirus (HPV) vaccines to eliminate cervical cancer as a public health problem. With most existing vaccine doses absorbed by countries (mostly high-income) with existing HPV vaccination programmes, limited supply has been left for new country introductions until 2022; many of those, low- and middle-income countries with higher mortality. Several vaccination strategies were considered by the Strategic Advisory Group of Experts on Immunization to allow more countries to introduce vaccination despite constrained supplies.

Methods: We examined the impact of nine strategies for allocating limited vaccine doses to 100 pre-introduction countries from 2020 to 2030. Two algorithms were used to optimise the total number of cancer deaths that can be averted worldwide by a limited number of doses (knapsack and decreasing order of country-specific mortality rates), and an unoptimised algorithm (decreasing order of Human Development Index) were used.

Findings: Routinely vaccinating 14-year-old girls with either one or two doses and switching to a routine 9-year-old programme when supply is no longer constrained could prevent the most cervical cancer deaths, regardless of allocation algorithm. The unoptimised allocation averts fewer deaths because it allocates first to higher-income countries, usually with lower cervical cancer mortality.

Interpretation: To optimise the deaths averted through vaccination when supply is limited, it is important to prioritise high-burden countries and vaccinating older girls first.

Funding: WHO, Bill & Melinda Gates Foundation.

Background: The Gender-Equity Model for liver Allocation corrected by serum sodium (GEMA-Na) and the Model for End-stage Liver Disease 3.0 (MELD 3.0) could amend sex disparities for accessing liver transplantation (LT). We aimed to assess these inequities in Spain and to compare the performance of GEMA-Na and MELD 3.0.

Methods: Nationwide cohort study including adult patients listed for a first elective LT (January 2016-December 2021). The primary outcome was mortality or delisting for sickness within the first 90 days. Independent predictors of the primary outcome were evaluated using multivariate Cox's regression with adjusted relative risks (RR) and 95% confidence intervals (95% CI). The discrimination of GEMA-Na and MELD 3.0was assessed using Harrell c-statistics (Hc).

Findings: The study included 6071 patients (4697 men and 1374 women). Mortality or delisting for clinical deterioration occurred in 286 patients at 90 days (4.7%). Women had reduced access to LT (83.7% vs. 85.9%; p = 0.037) and increased risk of mortality or delisting for sickness at 90 days (adjusted RR = 1.57 [95% CI 1.09-2.28]; p = 0.017). Female sex remained as an independent risk factor when using MELD or MELD-Na but lost its significance in the presence of GEMA-Na or MELD 3.0. Among patients included for reasons other than tumours (n = 3606; 59.4%), GEMA-Na had Hc = 0.753 (95% CI 0.715-0.792), which was higher than MELD 3.0 (Hc = 0.726 [95% CI 0.686-0.767; p = 0.001), showing both models adequate calibration.

Interpretation: GEMA-Na and MELD 3.0 might correct sex disparities for accessing LT, but GEMA-Na provides more accurate predictions of waiting list outcomes and could be considered the standard of care for waiting list prioritization.

Funding: Instituto de Salud Carlos III, Agencia Estatal de Investigación (Spain), and European Union.

Background: Longitudinal changes in vaccination-induced immune response remain inadequately characterized in adolescents. We present long-term safety, immunogenicity, and COVID-19 incidence following a 2-dose mRNA-1273 100-μg primary series, and immunogenicity following a single dose of mRNA-1273 50 μg in vaccine-naïve adolescents.

Methods: TeenCOVE (NCT04649151) Part 1 randomized adolescents (12-17 years) to 2-dose mRNA-1273 100 μg (n = 2490) or placebo (n = 1243) 28 days apart. Subsequently, placebo recipients (n = 91) could receive open-label mRNA-1273. Primary objectives included prespecified adverse events through 12 months; secondary objectives were COVID-19 incidence and neutralizing and spike-binding antibodies (nAbs/bAbs) against SARS-CoV-2 (ancestral/variants) through 12 months (study period: December 2020-January 2022). In Part 2, vaccine-naïve adolescents (n = 52) received up to 2 doses of mRNA-1273 50 μg; interim analysis included Day 28 (D28) nAbs post-injection 1 in SARS-CoV-2-baseline-positive participants (serologic/virologic evidence of prior infection).

Findings: In SARS-CoV-2-baseline-negative adolescents (N = 369), mRNA-1273 induced robust nAb responses versus baseline (geometric mean concentration [GMC] = 11; 95% CI, 11-12) at D28 (1868 [1759-1985]), 6 months (625 [583-670]) and 12 months (550 [490-618]) post-injection 2. Similar bAb responses were observed to alpha/beta/delta/gamma variants; nAb/bAb responses were similar in SARS-CoV-2-baseline-positive adolescents. The 2-dose mRNA-1273 100-μg primary series was generally well-tolerated; one case of nonserious, moderate, probable acute myocarditis resolved by 8 days from symptom onset. A single dose of mRNA-1273 50 μg in SARS-CoV-2-baseline-positive adolescents induced higher D28 nAb GMCs against ancestral SARS-CoV-2 than 2-dose mRNA-1273 100 μg in young adults (geometric mean ratio = 4.322 [3.274-5.707]).

Interpretation: The overall risk-benefit profile of mRNA-1273 remains favorable in adolescents, with durable 12-month immune responses against SARS-CoV-2 (ancestral/variants). A single mRNA-1273 50-μg injection in vaccine-naïve adolescents elicited robust immune responses against SARS-CoV-2.

Funding: This project has been funded in whole or in part with federal funds by the Department of Health and Human Services, United States; Administration for Strategic Preparedness and Response, United States; Biomedical Advanced Research and Development Authority, United States, under Contract No. 75A50120C00034. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Department of Health and Human Services or its components.

Background: Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated.

Methods: The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout.

Findings: In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment vs 9.3 g/dL at baseline), bilirubin (≤20.0 μmol/L on-treatment vs 35.0 μmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD.

Interpretation: The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs.

Funding: Sanofi.