BMC Medicine最新文献

Background: Pregnant women are significantly underrepresented in clinical trials, yet most of them take medication during pregnancy despite the limited safety data. The objective of this study was to characterize medication use during pregnancy and apply propensity score matching method at scale on patient records to accelerate and prioritize the drug effect signal detection associated with the risk of preterm birth and other adverse pregnancy outcomes.

Methods: This was a retrospective study on continuously enrolled women who delivered live births between 2013/01/01 and 2022/12/31 (n = 365,075) at Providence St. Joseph Health. Our exposures of interest were all outpatient medications prescribed during pregnancy. We limited our analyses to medication that met the minimal sample size (n = 600). The primary outcome of interest was preterm birth. Secondary outcomes of interest were small for gestational age and low birth weight. We used propensity score matching at scale to evaluate the risk of these adverse pregnancy outcomes associated with drug exposure after adjusting for demographics, pregnancy characteristics, and comorbidities.

Results: The total medication prescription rate increased from 58.5 to 75.3% (P < 0.0001) from 2013 to 2022. The prevalence rate of preterm birth was 7.7%. One hundred seventy-five out of 1329 prenatally prescribed outpatient medications met the minimum sample size. We identified 58 medications statistically significantly associated with the risk of preterm birth (P ≤ 0.1; decreased: 12, increased: 46).

Conclusions: Most pregnant women are prescribed medication during pregnancy. This highlights the need to utilize existing real-world data to enhance our knowledge of the safety of medications in pregnancy. We narrowed down from 1329 to 58 medications that showed statistically significant association with the risk of preterm birth even after addressing numerous covariates through propensity score matching. This data-driven approach demonstrated that multiple testable hypotheses in pregnancy pharmacology can be prioritized at scale and lays the foundation for application in other pregnancy outcomes.

Background: The aims of this study were to assess the presence of inverse publication bias (IPB) in adverse events, evaluate the performance of visual examination, and explore the impact of considering effect direction in statistical tests for such assessments.

Methods: We conducted a cross-sectional study using the SMART Safety, the largest dataset for evidence synthesis of adverse events. The visual assessment was performed using contour-enhanced funnel plots, trim-and-fill funnel plots, and sample-size-based funnel plots. Two authors conducted visual assessments of these plots independently, and their agreements were quantified by the kappa statistics. Additionally, IPB was quantitatively assessed using both the one- and two-sided Egger's and Peters' tests.

Results: In the SMART Safety dataset, we identified 277 main meta-analyses of safety outcomes with at least 10 individual estimates after dropping missing data. We found that about 13.7-16.2% of meta-analyses exhibited IPB according to the one-sided test results. The kappa statistics for the visual assessments roughly ranged from 0.3 to 0.5, indicating fair to moderate agreement. Using the one-sided Egger's test, 57 out of 72 (79.2%) meta-analyses that initially showed significant IPB in the two-sided test changed to non-significant, while the remaining 15 (20.8%) meta-analyses changed from non-significant to significant.

Conclusions: Our findings provide supporting evidence of IPB in the SMART Safety dataset of adverse events. They also suggest the importance of researchers carefully accounting for the direction of statistical tests for IPB, as well as the challenges of assessing IPB using statistical methods, especially considering that the number of studies is typically small. Qualitative assessments may be a necessary supplement to gain a more comprehensive understanding of IPB.

Background: To determine the optimal fluid resuscitation volume in septic patients with acutely decompensated heart failure (ADHF).

Methods: Septic patients with ADHF were identified from a tertiary urban medical center. The generalized additive models were used to explore the association between fluid resuscitation volume and endpoints, and the initial 3 h fluid resuscitation volume was divided into four groups according to this model: < 10 mL/kg group, ≥ 10 to ≤ 15 mL/kg group, > 15 to ≤ 20 mL/kg group, and > 20 mL/kg group. Logistic and Cox regression models were employed to explore the association between resuscitation volume and primary endpoint, in-hospital mortality, as well as secondary endpoints including 30-day mortality, 1-year mortality, invasive ventilation, and ICU admission.

Results: A total of 598 septic patients with a well-documented history of HF were enrolled in the study; 405 patients (68.8%) had sepsis-induced hypoperfusion. Patients with NYHA functional class III and IV were 494 (83.9%) and 22 (3.74%), respectively. Resuscitation volumes above 20 mL/kg (OR 3.19, 95% CI 1.31-8.15) or below 10 mL/kg (OR 2.33, 95% CI 1.14-5.20) significantly increased the risk of in-hospital mortality in septic patients, while resuscitation volumes between 15 and 20 mL/kg were not associated with the risk of in-hospital death in septic patients (OR 1.79, 95% CI 0.68-4.81). In the multivariable Cox models, the effect of resuscitation volume on 30-day and 1-year mortality in septic patients was similar to the effect on in-hospital mortality. Resuscitation volume exceeds 15 mL/kg significantly increased the risk of tracheal intubation, while fluid resuscitation volume was not associated with ICU admission in the septic patients. In septic patients with hypoperfusion, these fluid resuscitation volumes have similar effects on patient outcomes. This association was consistent across the three subgroups with worsened cardiac function, as well as in sensitivity analyses.

Conclusions: Our study observed that an initial fluid resuscitation volume of 10-15 mL/kg in the first 3 h was optimal for early resuscitation in septic patients with ADHF, particularly those with worsened cardiac function. These results need to be confirmed in randomized controlled trials with larger sample sizes.

Background: Biomedical and lifestyle factors in Western populations have significantly shifted in recent decades, influencing public health and contributing to the increasing prevalence of non-communicable diseases (NCDs) that share inflammation as common pathology.

Methods: We investigated the relationship between these factors and 11 NCDs in the cross-sectional FoCus cohort (n = 1220), using logistic regression models. Associations with age-at-disease-onset were specifically analyzed for type 2 diabetes (T2D, low-grade chronic inflammation) and inflammatory bowel disease (IBD, high-grade chronic inflammation) in disease-specific cohorts (FoCus-T2D, n = 514; IBD-KC, n = 1110). Important factors for disease risk were identified using Cox-PH-regression models and time-to-event analysis. We further explored the interaction between identified risk factors and gut microbiome composition using linear models.

Results: Lifestyle factors were clearly linked to disease phenotypes, particularly in T2D and IBD. Still, some factors affected only the age-at-onset, but not disease prevalence. High-quality nutrition significantly delayed onset for both IBD and T2D (IBD: HR = 0.81 [0.66; 0.98]; T2D: HR = 0.45 [0.28; 0.72]). Smoking accelerated T2D onset (HR = 1.82 [1.25; 2.65]) but delayed onset in ulcerative colitis (UC: HR = 0.47 [0.28; 0.79]). Higher microbiota diversity delayed IBD onset (Shannon: HR = 0.58 [0.49; 0.71]) but had no effect on T2D. The abundance of specific microbial genera was strongly associated with various biomedical and lifestyle factors in T2D and IBD. In unaffected controls, these effects were smaller or reversed, potentially indicating a greater susceptibility of the gut microbiome to negative influences in T2D and IBD.

Conclusions: The dual insights into age-at-disease-onset and gut microbiota composition in disease emphasize the role of certain biomedical and lifestyle factors, e.g., nutrition quality, in disease prevention and management. Understanding these relationships provides a foundation for developing targeted strategies to mitigate the impact of metabolic and inflammatory diseases through lifestyle modifications and gut health management.

Background: Cigarette smoking is incredibly harmful, even for people who do not smoke every day. This study aimed to estimate trends in non-daily smoking in England between 2006 and 2024, how these differed across population subgroups, and to explore changes in the profile of non-daily smokers in terms of their sociodemographic and smoking characteristics and vaping and alcohol consumption.

Methods: Data were collected monthly between November 2006 and April 2024 as part of a nationally representative, repeat cross-sectional survey of adults (≥ 18 years; n = 353,711). We used logistic regression to estimate associations between survey wave and non-daily smoking and used descriptive statistics to characterise the profile of non-daily smokers across 3-year periods.

Results: The proportion who smoked non-daily was relatively stable between November 2006 and November 2013, at an average of 10.5% [10.1-10.9%] of cigarette smokers, then increased to 27.2% [26.0-28.4%] of cigarette smokers (4.0% [3.7-4.2%] of adults) by April 2024. This increase was particularly pronounced among younger adults (e.g. reaching 52.8%, 20.4%, and 14.4% of 18-, 45-, and 65-year-old cigarette smokers by April 2024) and those who vape (reaching 34.2% among vapers vs. 23.1% among non-vapers). Over time, there were reductions in non-daily smokers' mean weekly cigarette consumption (from 34.3 in 2006-2009 to 21.1 in 2021-2024), urges to smoke (e.g. the proportion reporting no urges increased from 29.2 to 38.0%), and motivation to stop smoking (e.g. the proportion highly motivated to quit within the next 3 months decreased from 30.8 to 21.0%).

Conclusions: An increasing proportion of adults in England who smoke cigarettes do not smoke every day, particularly younger adults. Although non-daily smokers report smoking fewer cigarettes and weaker urges to smoke than they used to, which may make it easier for them to stop smoking, they appear to be decreasingly motivated to quit.

Background: Systemic corticosteroid has been recommended for the treatment of severe acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Little is known about the use of systemic corticosteroid in patients admitted to intensive care units (ICU) since most of previous trials excluded these critically ill patients.

Methods: We conducted a matched cohort study based on the Medical Information Mart in Intensive Care-IV database. Patients with AECOPD in ICUs were included. Patients in the exposure group should be intravenously administrated with methylprednisolone or treated with oral prednisone within 24 h after ICU admission. The propensity score matching and multivariable analyses were used to adjust for covariates. The primary outcome was 28-day mortality, and secondary outcomes included ICU mortality, in-hospital mortality, the duration of ICU stay, and mechanical ventilation. Subgroup analyses for the primary outcome were performed according to age, sex, type of corticosteroid, type of ICU admission, type of mechanical ventilation, and co-morbidities/complications.

Results: The entire cohort and the matched cohort included 763 and 412 patients, respectively. In the matched cohort, the use of systemic corticosteroid had no impact on 28-day mortality (OR: 1.00, 95% CI: 0.61-1.64, P = 1.000). The results kept consistent in all subgroups. Additionally, systemic corticosteroid showed no benefits on ICU mortality, in-hospital mortality, the length of ICU stay, and the duration of mechanical ventilation.

Conclusions: The results of this study do not support routine use of systemic corticosteroid in patients with AECOPD admitted to ICUs.

Background: The role of plant-based dietary patterns in preventing cardiovascular disease (CVD) among individuals with prediabetes and diabetes remains unclear. We aimed to evaluate the associations of plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) with cardiovascular disease (CVD) risk and explore potential contributing factors among people with prediabetes and diabetes.

Methods: A total of 17,926 participants with prediabetes and 7798 with diabetes were enrolled from the UK Biobank between 2006 and 2010 and followed until the end of 2020. We calculated the PDI, hPDI, and uPDI based on 18 major food groups including plant-based foods and animal-based foods and applied Cox proportional hazard models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for CVD risk related to PDI, hPDI, and uPDI. Decomposition analysis was performed to assess the role of dietary components, and mediation analysis was performed to assess the potential mediating role of serum biomarkers underlying these associations.

Results: A total of 2324 CVD events were documented among individuals with prediabetes, while 1461 events occurred among patients with diabetes. An inverse association was found between hPDI and CVD risk among individuals with prediabetes (HR T3 vs. T1 = 0.88, 95% CI = 0.79-0.98, P_trend = 0.025) but not those with diabetes. A positive association was found between uPDI and CVD risk among individuals with prediabetes (HR T3 vs. T1 = 1.17, 95% CI = 1.05-1.30, P_trend = 0.005) and those with diabetes (HR T3 vs. T1 = 1.14, 95% CI = 1.00-1.29, P_trend = 0.043). High-sugar-sweetened beverages (SSB) intake accounted for 35% of the hPDI-CVD association and 15% of the uPDI-CVD association among individuals with prediabetes, whereas low intake of whole grain accounted for 36% of the association among patients with diabetes. Elevated cystatin C levels explained the largest proportion of the association between uPDI and CVD risk among individuals with prediabetes (15%, 95% CI = 7-30%) and diabetes (44%, 95% CI = 9-86%).

Conclusions: Adherence to an unhealthy plant-based diet is associated with a higher CVD risk in people with prediabetes or diabetes, which may be partially attributed to low consumption of whole grains, high intake of SSB, and high blood cystatin C levels.

Background: Inflammation is characterized by a metabolic switch promoting glycolysis and lactate production. Hexokinases (HK) catalyze the first reaction of glycolysis and inhibition of epithelial HK2 protected from colitis in mice. HK2 expression has been described as elevated in patients with intestinal inflammation; however, there is conflicting data from few cohorts especially with severely inflamed individuals; thus, systematic studies linking disease activity with HK2 levels are needed.

Methods: We examined the relationship between HK2 expression and inflammation severity using bulk transcriptome data derived from the mucosa of thoroughly phenotyped inflammatory bowel disease (IBD) patients of two independent cohorts including both subtypes Crohn's disease (CD) and ulcerative colitis (UC). Publicly available single-cell RNA sequencing data were analyzed, and immunofluorescence staining on colonic biopsies of unrelated patients with intestinal inflammation was performed to confirm the RNA-based findings on cellular and protein level.

Results: HK2 expression gradually increased from mild to intermediate inflammation, yet strongly declined at high inflammation scores. Expression of epithelial marker genes also declined at high inflammation scores, whereas that of candidate immune marker genes increased, indicating a cellular remodeling of the mucosa during inflammation with an infiltration of HK2-negative immune cells and a loss of terminal differentiated epithelial cells in the apical epithelium-the main site of HK2 expression. Normalizing for the enterocyte loss clearly identified epithelial HK2 expression as gradually increasing with disease activity and remaining elevated at high inflammation scores. HK2 protein expression was mostly restricted to brush border enterocytes, and these cells along with HK2 levels vanished with increasing disease severity.

Conclusions: Our findings clearly define dysregulated epithelial HK2 expression as an indicator of disease activity in intestinal inflammation and suggest targeted HK2-inhibition as a potential therapeutic avenue.

Background: Eliminating hepatitis C virus (HCV) infections is a goal set by the World Health Organization. This has become possible with the introduction of highly effective and safe direct-acting antivirals (DAA) but limitations remain due to undiagnosed HCV infections and loss of patients from the cascade of care at various stages, including those lost to follow-up (LTFU) before the assessment of the effectiveness of the therapy. The aim of our study was to determine the extent of this loss and to establish the characteristics of patients experiencing it.

Methods: Patients with chronic HCV infection from the Polish retrospective multicenter EpiTer-2 database who were treated with DAA therapies between 2015 and 2023 were included in the study.

Results: In the study population of 18,968 patients, 106 had died by the end of the 12-week post-treatment follow-up period, and 509 patients did not report for evaluation of therapy effectiveness while alive and were considered LTFU. Among patients with available assessment of sustained virological response (SVR), the effectiveness of therapy was 97.5%. A significantly higher percentage of men (p<0.0001) and a lower median age (p=0.0001) were documented in LTFU compared to the group with available SVR assessment. In LTFU patients, comorbidities such as alcohol (p<0.0001) and drug addiction (p=0.0005), depression (p=0.0449) or other mental disorders (p<0.0001), and co-infection with human immunodeficiency virus (HIV) (p<0.0001) were significantly more common as compared to those with SVR assessment. They were also significantly more often infected with genotype (GT) 3, less likely to be treatment-experienced and more likely to discontinue DAA therapy.

Conclusions: In a real-world population of nearly 19,000 HCV-infected patients, we documented a 2.7% loss to follow-up rate. Independent predictors of this phenomenon were male gender, GT3 infection, HIV co-infection, alcohol addiction, mental illnesses, lack of prior antiviral treatment and discontinuation of DAA therapy.

Background: Regulatory applications for cell therapy face more objections compared to conventional small molecule or biological drugs, leading to delays in market approval and clinical adoption. Increased regulatory objections frequently relate to issues regarding preclinical evidence, such as experimental design of animal studies, selection of animal models, endpoints, and determination of mechanism of action. Synthesis and clarification of the preclinical evidence necessary to demonstrate treatment efficacy and advance into early-phase clinical trials is needed to help researchers avoid regulatory objections.

Methods: We conducted a scoping review in which we searched repositories of the International Council for Harmonisation and all national member organizations (N = 38) for documents related to preclinical studies of cell therapies. Active guidance documents related to cell therapy were included, with no restrictions based on the year or language of publication. Data extraction was conducted in duplicate with conflicts resolved through consensus discussion.

Results: From 1215 identified documents, a total of 182 were included and analyzed, with 71% originating from ten major regulatory agencies. The most prevalent preclinical item addressed was the mechanism of action (n = 161, 88% of documents), underscoring its importance in bridging preclinical findings to clinical application. Most documents (n = 140, 77%) emphasized the importance of using clinically relevant preclinical models, though specific recommendations on models of disease were less common (n = 81, 45%). Selection of clinically relevant intervention parameters (n = 136, 75%) and outcome measures (n = 121, 66%) were also frequently recommended, but selection of relevant comparator groups appeared less frequently (n = 35, 19%). Furthermore, robust study design elements such as randomization and blinding were less frequently recommended, appearing in 31% of documents (n = 57). Comparison with clinical trial guidance revealed a significant gap in the rigor of study design recommendations for preclinical research.

Conclusions: Regulatory guidance for preclinical efficacy studies often recommends a strong emphasis on the clinical relevance of animal models, intervention parameters, outcomes, and mechanism of action. Incorporating these recommendations into early preclinical studies should improve the acceptability of preclinical evidence for approval by the relevant national regulators and can be used as a guide to ensure that all evidence that regulators say they expect is efficiently assembled into new clinical trial applications.