BMC Medicine最新文献

Background: Lennox-Gastaut syndrome (LGS) is a severe encephalopathic disease that leads to a decrease in the quality of life, physical injury, psychosocial impairment, and a significant increase in treatment costs. Cannabidiol (CBD) is approved for the adjunctive treatment of tonic-colonic seizures in LGS. This study aimed to determine the cost-effectiveness of CBD compared to the usual treatment in patients with LGS syndrome.

Methods: We developed a lifetime-horizon Markov model to compare the cost-effectiveness of adjunctive CBD versus usual care. Additionally, we performed a budget impact analysis over a 5-year time horizon. The findings were presented as the incremental cost-effectiveness ratio (ICER) for CEA, with a willingness to pay threshold of $18,261 per QALY gained, and as the difference in the overall budget ($) between the scenarios with and without CBD for budget impact assessment.

Results: In the base case scenario, CBD was cost-effective compared with usual care $6573 per QALY. Sensitivity analyses substantiated these results. From a healthcare perspective, there is a 77% probability that CBD is cost-effective at a willingness to pay of $18,261 per quality-adjusted life-year (QALY). Overall, the market access of CBD was associated to an increased budget of about $3,459,846 (+ 33%) in the next 5 years simulated.

Conclusions: Compared to usual care, CBD seems to be cost-effective in LGS patients and sustainable, with less than 34% overall budget increased in the next 5 years. Future studies need to confirm our results in the real word setting and in other countries.

Background: Comorbidity between depression and cardiometabolic diseases is an emerging health concern, with childhood maltreatment as a major risk factor. These conditions are also linked to unhealthy lifestyle behaviours such as physical inactivity, smoking, and alcohol intake. However, the precise degree to which lifestyle behaviours moderate the risk between childhood maltreatment and comorbid depression and cardiometabolic disease is entirely unknown.

Methods: We analysed clinical and self-reported data from four longitudinal studies (N_pooled = 181,423; mean follow-up period of 5-18 years) to investigate the moderating effects of physical activity, smoking, and alcohol intake, on the association between retrospectively reported childhood maltreatment and i) depression, ii) cardiometabolic disease and iii) their comorbidity in older adults (mean age range of 47-66 years). Estimates of these moderation effects were derived using multinomial logistic regressions and then meta-analysed.

Results: No meaningful moderation effects were detected for any of the lifestyle behaviours on the association between childhood maltreatment and each health outcome. Physical activity was linked to lower odds of depression (OR [95% CI] = 0.94 [0.92; 0.96]), while smoking was a risk factor for all three outcomes (OR [95% CI] = 1.16 [1.04; 1.31] or larger). Alcohol intake was associated with slightly lower odds of comorbidity (OR [95% CI] = 0.69 [0.66; 0.73]), although this association was not stable across all sensitivity analyses.

Conclusions: Lifestyle behaviours did not moderate the risk association between childhood maltreatment and depression, cardiometabolic disease, and their comorbidity in older adults. However, we confirmed that childhood maltreatment was associated with these conditions. Further research should address the limitations of this study to elucidate the most optimal targets for intervention.

Background: Approximately 10-30% of individuals continue to experience symptoms classified as post-acute sequelae of coronavirus disease 2019 (COVID-19 (PASC)). PASC is a multisystem condition primarily characterized by respiratory symptoms, such as reduced diffusing capacity for carbon monoxide (DLco). Although many studies have investigated the pathogenesis of acute COVID-19, the long-term molecular changes in COVID-19 convalescents with PASC remain poorly understood.

Methods: We prospectively recruited 70 individuals who had been diagnosed with COVID-19 from 7 January 2020 to 29 May 2020 (i.e., COVID-19 convalescents); we performed follow-up visits at 6 months, 1 year, 2 years, and 3 years after hospital discharge. Thirty-five healthy controls (CONs), recruited from a physical examination center before the COVID-19 pandemic, served as a comparison group. We explored the proteomic and metabolomic profiles of 174 plasma samples from the 70 COVID-19 convalescents and 35 CONs.

Results: We performed a comprehensive molecular analysis of COVID-19 convalescents to investigate host changes up to 3 years after hospital discharge. Our multi-omics analysis revealed activation of cytoskeletal organization and glycolysis/gluconeogenesis, as well as suppression of gas transport and adaptive immune responses, in COVID-19 convalescents. Additionally, metabolites involved in glutathione metabolism; alanine, aspartate, and glutamate metabolism; and ascorbate and aldarate metabolism were significantly upregulated in COVID-19 convalescents. Pulmonary and molecular abnormalities persisted for 3 years in COVID-19 convalescents; impaired diffusing capacity for carbon monoxide (DLco) was the most prominent feature. We used this multi-omics profile to develop a model involving one protein (heterogeneous nuclear ribonucleoprotein K (HNRNPK)) and two metabolites (arachidonoyl-EA and 1-O-(2r-hydroxy-pentadecyl)-sn-glycerol)) for identification of COVID-19 convalescents with abnormal DLco.

Conclusions: These data provide insights concerning molecular sequelae among COVID-19 convalescents up to 3 years after hospital discharge, clarify mechanisms driving respiratory sequelae, and support the development of a novel model to predict reduced DLco. This longitudinal multi-omics analysis may illuminate the trajectory of altered lung function in COVID-19 convalescents.

Background: The primary challenges in CD19-specific chimeric antigen receptor T-cell (CD19 CAR T) therapy for patients with refractory/relapsed B-cell acute lymphoblastic leukemia (r/r B-ALL) are non-response and relapse; it is urgent to reveal these mechanisms. Neutrophils play a critical role in the immunosuppressive tumor microenvironment (TME), which can hinder CAR T efficacy. Our previous research identified a subset of immunosuppressive neutrophils with a special phenotype (CD14^-CD10^-CD45^-HLA-DR^-SSC⁺⁺, termed CD10^- neuts), which suppress T cell function. Therefore, we speculate that CD10^- neuts may also influence CAR T efficacy, and this study aims to clinically validate this hypothesis.

Methods: We enrolled 44 patients with r/r B-ALL undergoing CD19 CAR T therapy and 47 healthy controls (HCs). Peripheral blood samples were obtained prior to CAR T infusion to detect CD10^- neuts levels by flow cytometry. Key parameters included the percentage of CD10^- neuts in neutrophils (CD10^- neuts/neutrophils), in all nucleated cells (CD10^- neuts/nucleated cells), and the absolute count of CD10^- neuts. We analyzed the correlations between these indicators and therapeutic response, relapse-free survival (RFS), overall survival (OS), and CAR T cell persistence time.

Results: CD10^- neuts levels were significantly elevated in patients with r/r B-ALL compared to HCs. Additionally, non-responding patients exhibited higher CD10^- neuts levels than those in remission. Specifically, CD10^- neuts/neutrophils, CD10^- neuts/nucleated cells, and absolute CD10^- neuts count were 64.44% vs. 25.43% (p = 0.004), 28.61% vs. 9.81% (p = 0.018), and 766.1/μL vs. 152.9/μL (p = 0.04), respectively. Among these indices, only CD10^- neuts/neutrophils emerged as an independent risk factor for CAR T response (OR = 19.8, p = 0.013), relapse (HR = 4.704, p = 0.004), and survival (HR = 6.417, p = 0.001). Patients with CD10^- neuts/neutrophils ≥ 21.57% demonstrated significantly shorter RFS and OS compared to those with lower levels (p = 0.001; p = 0.0002). Furthermore, CD10^- neuts/neutrophils were negatively correlated with the persistence time of CAR T cells.

Conclusions: As one of the key factors in the TME, abnormally elevated CD10^- neuts correlate with CAR T therapy resistance. Targeting these neutrophils could enhance the effectiveness of CAR T treatment.

Background: In general, traditional antidepressants often have limited efficacy in patients with major depressive disorder (MDD). Agomelatine, as an antidepressant with a different mechanism of action, might have adjunctive effects on traditional antidepressants. This study aimed to investigate the augmentation effect of agomelatine versus placebo in treating MDD patients who failed to respond to selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs).

Methods: This is an 8-week, multi-centred, double-blinded, randomized, and placebo-controlled trial. Participants diagnosed with MDD and demonstrated inadequate response to SSRI or SNRI lasting at least 2 weeks were randomly allocated to receive either agomelatine or placebo in conjunction with SSRIs or SNRIs. The 17 items of the Hamilton Depression Scale (HAMD-17) were employed to assess depression severity. The primary outcome is the total score of HAMD-17 at week 8. Secondary outcomes included HAMD-17 scores at weeks 2 and 4 and clinical remission and response over 8 weeks. Adverse events (AEs) reported in both groups were recorded. A linear mixed model was established for both primary and secondary outcomes.

Results: A total of 123 eligible participants were included, among which 60 were randomized into the agomelatine group, and 63 were randomized into the placebo group. The between-group difference in HAMD-17 score reduction from baseline to week 8 was not significant (difference = - 0.12, 95% CI = - 3.94 to 3.70, P = 0.90; Cohen's d = 0.022). In addition, we did not observe significant differences between the two treatment groups for secondary outcomes, including response remission, and AEs.

Conclusions: This study did not obtain significant findings in favour of the augmentation effect of agomelation for MDD patients. However, agomelatine was generally well tolerated and demonstrated a favourable safety profile when used in combination with SSRIs and SNRIs.

Trial registration: This trial is registered at ClinicalTrials.gov ( https://clinicaltrials.gov ), the registration number is NCT04589143.

Background: Confounder adjustment is critical for accurate causal inference in observational studies. However, the appropriateness of methods for confounder adjustment in studies investigating multiple risk factors, where the factors are not simply mutually confounded, is often overlooked. This study aims to summarise the methods for confounder adjustment and the related issues in studies investigating multiple risk factors.

Methods: A methodological study was performed. We searched PubMed from January 2018 to March 2023 to identify cohort and case-control studies investigating multiple risk factors for three chronic diseases (cardiovascular disease, diabetes and dementia). Study selection and data extraction were conducted independently by two reviewers. The study objectives were grouped into two categories: widely exploring potential risk factors and examining specific risk factors. The methods for confounder adjustment were classified based on a summarisation of the included studies, identifying six categories: (1) each risk factor was adjusted for potential confounders separately (the recommended method); (2) all risk factors were mutually adjusted (i.e. including all factors in a multivariable model); (3) all risk factors were adjusted for the same confounders separately; (4) all risk factors were adjusted for the same confounders with some factors being mutually adjusted; (5) all risk factors were adjusted for the same confounders with mutual adjustment among them being unclear; and (6) unable to judge. All data were descriptively analysed.

Results: A total of 162 studies were included, with 88 (54.3%) exploring potential risk factors and 74 (45.7%) examining specific risk factors. The current status of confounder adjustment was unsatisfactory: only ten studies (6.2%) used the recommended method, all of which aimed at examining several specific risk factors; in contrast, mutual adjustment was adopted in over 70% of the studies. The remaining studies either adjusted for the same confounders across all risk factors, or unable to judge.

Conclusions: There is substantial variation in the methods for confounder adjustment among studies investigating multiple risk factors. Mutual adjustment was the most commonly adopted method, which might lead to overadjustment bias and misleading effect estimates. Future research should avoid indiscriminately including all risk factors in a multivariable model to prevent inappropriate adjustment.

Background: Indonesia faces challenges in achieving its goal of eliminating malaria by 2030, with cases stagnating between 2015 and 2019. This study analysed regional epidemiological trends and demographic changes in malaria cases from 2010 to 2019, considering differences in surveillance across the country.

Methods: We analysed national and sub-national malaria routine surveillance data using generalised additive and generalised linear models to assess temporal trends in case reporting, test positivity, demographics, and parasite species distribution while accounting for surveillance variations.

Results: After adjusting for increased testing from 2015 onwards, we estimated declining malaria incidence in six of seven Indonesian regions. These regions showed a demographic shift toward older, predominantly male cases, suggesting a transition from household to occupational transmission. In contrast, Papua maintained high transmission with cases concentrated in children. Despite comprising only 2% of Indonesia's population, Papua's contribution to national malaria cases rose from 40 to 90% (2010-2019).

Conclusion: While most Indonesian regions progress toward elimination by addressing mobile and migrant populations and P. vivax transmission, Papua shows different patterns with persistently high transmission among children. Achieving nationwide elimination requires enhanced control measures, improved healthcare access, and strengthened multisectoral collaboration to address these region-specific challenges.

Background: The relationship between coronary artery calcium (CAC) and progression of diastolic dysfunction (DD) during longitudinal follow-up is uncertain. This study aimed to investigate the prevalence and progression of DD according to severity of CAC and understand their synergistic effect on mortality.

Methods: This was a population-based cohort study. All 15,193 adults who underwent a health screening exam with simultaneous echocardiography and CAC scan were enrolled. Definite DD (≥ 3/4 abnormal parameters for DD [e', E/e', tricuspid regurgitation velocity, and left atrial volume index]) and definite or probable DD (≥ 2/4) were defined. All-cause mortality was assessed based on the CAC and DD.

Results: Among the population, 7995 participants (52.6%) had CAC = 0; 4661 (30.7%) had 0 < CAC < 100; and 2537 (16.7%) had CAC ≥ 100. The prevalence ratios for definite (adjusted ratio: 1.72, 95% CI: 1.23-2.22) and definite or probable DD (adjusted ratio: 1.83, 95% CI: 1.31-2.36) were significantly higher in individuals with CAC ≥ 100 than in those with CAC = 0. There was significant linear association of CAC with E/e' (adjusted p for linearity = 0.001). Compared with CAC < 100 without definite DD, the adjusted HRs with 95% CI for mortality of CAC ≥ 100 without definite DD, CAC < 100 with definite DD, and CAC ≥ 100 with definite DD were 2.56 (95% CI: 1.67-3.94), 3.08 (95% CI: 1.28-7.39), and 3.91 (95% CI: 1.68-9.10). Among participants without DD at CAC measurement who had at least two echocardiographic measurements, the presence of significant CAC (≥ 100) was significantly associated with accelerated progression in definite DD over time (adjusted HR: 1.46, 95% CI: 1.13-1.88), with more rapid elevation of E/e' during follow-up (difference: 0.06, 95% CI: 0.02-0.10, p = 0.003).

Conclusions: In the general population, there was a significant relationship between CAC and prevalence of DD, and both subclinical parameters were associated with increased mortality. Moreover, CAC ≥ 100 significantly affects the progression of DD independently of other clinical factors.

Background: The increasing prevalence of retracted publications in stem cell research presents significant challenges to scientific integrity. Although retraction notices are issued, retracted studies continue to be cited, facilitating the dissemination of unreliable findings. This study aimed to systematically explore the characteristics of retracted stem cell publications and evaluate the impact of retractions on subsequent citations.

Methods: This study was conducted following the PRISMA guidelines. A comprehensive search of Web of Science, Retraction Watch Database, and PubMed was conducted from their inception through July 25, 2024, to identify retracted stem cell publications. Characteristics including publication details, retraction reasons, and citation counts were extracted. To assess the impact of retraction on subsequent citations, we compared citation patterns between a random sample of retracted papers and matched non-retracted controls from identical journals and issues. Further analysis was conducted to determine whether papers citing retracted articles had an elevated risk of subsequent retraction. Descriptive statistics, chi-squared tests, t-tests, and Mann-Kendall tests were used for data analysis.

Results: The systematic search identified 1421 records, with 517 publications meeting inclusion criteria. Temporal analysis revealed two significant trends: an increasing retraction rate that peaked at 0.84% in 2023 and a declining time-to-retraction (median: 30 months, interquartile range: 13-60; Mann-Kendall, tau = - 0.29; P < 0.001). Hospital-affiliated researchers from China contributed to 244 (47.2%) of retractions. Data and image flaws were identified in 360 (69.6%) of retractions. Among 472 Web of Science-indexed retracted publications, 366 (77.5%) accumulated 4884 post-retraction citations, with 114 (24.2%) receiving more citations post-retraction than pre-retraction. Analysis of a random subset of retracted articles (n = 53) demonstrated that only 14 (4.2%) out of 334 post-retraction citations referenced the retraction notice. Compared with 639 non-retracted control publications, retracted articles showed significantly lower post-retraction citation rates (mean rank: 291.32 vs. 351.08; P = 0.01). Moreover, papers citing retracted articles exhibited an 11-fold higher risk of subsequent retraction (odds ratio (OR): 11.09; 95% confidence interval (CI): 7.06-17.43).

Conclusions: This analysis reveals substantial research integrity challenges within stem cell research. These findings suggest the necessity for enhanced surveillance mechanisms and standardized protocols to identify and curtail the dissemination of flawed research.

Background: Intrahepatic cholestasis of pregnancy (ICP) can be a source of significant distress for both pregnant women and the fetus, impairing the quality of life and well-being of pregnant women, leading to psychological disorders among pregnant women with severe or recurrent ICP, and causing life-threatening complications among fetuses. Regrettably, our current understanding of ICP globally is limited, lacking a comprehensive estimation of its incidence. Therefore, in this systematic review and meta-analysis, we aimed to investigate the global and regional incidence of ICP and identify factors that account for its variety across studies.

Methods: A comprehensive search strategy was implemented across PubMed, Scopus, and Web of Science databases. To stabilize the variance, the Freeman-Tukey double arcsine transformation was employed. Subgroup analyses were conducted based on continent, publication type, study design and timing, regional classifications, developmental status, and World Bank income grouping. A multivariate meta-regression analysis was performed to estimate the effects of the continuous moderators on the effect size.

Results: A total of 42,972,872 pregnant women were analyzed from 302 studies. The overall pooled incidence [95% confidence interval] of ICP was 2.9% [2.5, 3.3]. Studies with larger sample sizes tended to provide significantly lower estimates of ICP incidence: 1.6% [1.3, 2] vs 4.7% [3.9, 5.5]. Asia had the highest incidence of ICP among the continents, whereas Oceania had the lowest. Countries that were classified as developed and with higher income had a lower incidence of ICP than those classified as developing and low and middle income.

Conclusions: The findings of this study will provide valuable insights into the current knowledge regarding the association of the quality of public health and socioeconomic variations with the incidence of ICP on a global scale.