BMC Medicine最新文献

Background: Bile acids (BAs) have emerged as important mediators in neuroinflammation and neurodegeneration, important features of multiple sclerosis (MS). This study aimed to examine serum BA levels in newly diagnosed people with MS (pwMS) and explore their association with disability worsening.

Methods: The study included 907 pwMS and 907 matched controls from the Swedish population-based EIMS cohort, with clinical follow-up data from the Swedish MS Registry. Serum BA levels were analyzed using liquid chromatography-high-resolution mass spectrometry. Differential expression analysis was used to study differences in BAs between pwMS and controls. Cox proportional-hazard models were used to assess associations between BA concentrations and confirmed disability worsening (CDW) and the risk of reaching EDSS milestones 4.0 and 6.0.

Results: PwMS had lower concentrations of the primary conjugated BA, glycochenodeoxycholic acid (GCDCA, log₂ FC - 0.29, p = 0.009) compared to controls. In relapsing-remitting MS compared to controls, lower concentrations of primary conjugated BAs (log2 FC - 0.30, p = 8.40E - 5), secondary conjugated BAs (log2 FC - 0.18, p = 0.007), and total BAs (log2 FC - 0.22, p = 2.99E - 4) were found. Sex-specific differences were also found, with male pwMS showing more substantial BA alterations. Elevated total BA levels were associated with increased risk for CDW (HR 1.22, 95% CI 1.08-1.39), driven mainly by primary conjugated (HR 1.19, 95% CI 1.06-1.33) and secondary conjugated BAs (HR 1.21, 95% CI 1.08-1.39).

Conclusions: This study identified alterations in serum BA profiles in pwMS compared to controls, with strong associations between conjugated BAs and the risk of disability worsening. These findings underscore the potential role of BAs in MS pathogenesis and disability worsening, suggesting they may be promising targets for future therapeutic interventions. Further research is warranted to clarify the underlying mechanisms of these associations.

Background: Primary biliary cholangitis (PBC) is a liver-specific autoimmune disease. Treatment of PBC with ursodeoxycholic acid (UDCA) is not sufficient to prevent disease progression. Our previous study revealed that the number of hepatic double-negative T cells (DNT), which are unique regulatory T cells, was reduced in PBC patients. However, whether replenishment of DNT can prevent the progression of PBC remains unclear.

Methods: DnTGFβRII (Tg) mice and 2OA-BSA-immunized mice received DNT alone or in combination with oral UDCA. After 6-12 weeks of treatment, these mice were assessed for serological changes, liver pathological manifestations and intrahepatic immune responses.

Results: Adoptive transfer of DNT alone significantly decreased serum levels of alanine transaminase (ALT), aspartate transaminase (AST), antimitochondrial antibody M2 (AMA-M2) and immunoglobulin M (IgM) in both Tg and 2OA-BSA-immunized PBC mouse models. In addition, DNT exhibited a strong killing effect on liver T cells and strong inhibition of their proliferation, but did not significantly improve the histology of PBC liver. However, combination therapy with DNT and oral UDCA predominantly ameliorated liver inflammation and significantly inhibited hepatic T and B cells. In vitro further study revealed that UDCA up-regulated the proliferation of DNT, increased the expression of the functional molecule perforin, and reduced the expression of NKG2A and endothelial cell protein C receptor (EPCR) through the farnesoid X receptor (FXR)/JNK signaling pathway in both mice and human DNT.

Conclusions: A single transfer of DNT ameliorated PBC in mice, while combination therapy of DNT with oral UDCA displayed a better efficacy, with stronger inhibition of hepatic T and B cells. This study highlights the potential application of DNT-based combination therapy for PBC, especially for UDCA non-responders.

Background: Intra-articular corticosteroid injection (IACI) is an established treatment option for uncontrolled pain in osteoarthritis. There is a lack of longer-term follow-up in most studies of the effects of IACI, meaning there is scarcity of data on the impact of IACI on the subsequent need for joint replacement. Our aim was to assess the effect of IACI for knee osteoarthritis on the subsequent incidence of knee replacement surgery and on associated post-operative outcomes.

Methods: We conducted a cohort study of knee osteoarthritis patients registered in the Clinical Practice Research Datalink (CPRD) GOLD database with an incident diagnosis between 2005 and 2019. Exposure was single or repeated IACI use, analysed separately. The primary outcome was knee replacement during 1-year and 5-year follow-ups. Secondary outcomes included post-operative patient-reported outcome measures and adverse events. Primary analyses used general practitioner practice preference for IACI as an instrumental variable given this methodology can account for strong and unmeasured confounding. Secondary analyses used propensity score matching, accounting for measured covariates only.

Results: During 1-year follow-up, 1628/33,357 (4.9%) knee osteoarthritis patients underwent knee replacement, for which single IACI was associated with lower risk, which persisted to 5-year follow-up (incidence rate ratio: 0.52 [0.36, 0.77]). Conversely, in secondary propensity score analyses no association was found between IACI use and knee replacement rate at 1-year follow-up, and an estimated increased rate of knee replacement at 5-year follow-up. Use of IACI pre-joint replacement was not associated with any adverse post-operative outcomes, for example, 1-year complication rates (per 100 person-years) following knee replacement were 4.6 (3.8, 5.8), 4.0 (2.7, 6.0) and 5.0 (3.1, 8.1) among patients with no, single and repeat pre-joint replacement IACI use, respectively.

Conclusions: Findings from our main analysis suggest that short-term pain reduction following IACI for knee osteoarthritis may translate to lower rates of knee replacement over 5 years follow-up, although contradictory associations were observed in secondary analyses which likely reflected residual confounding by indication. Reassuringly, IACI use before knee replacement was not associated with post-operative adverse outcomes.

Background: Graft-versus-host disease (GVHD) and relapse are major complications following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Metabolites play crucial roles in immune regulation, but their causal relationships with GVHD and relapse remain unclear.

Methods: We utilized genetic variants from genome-wide association studies (GWAS) of 309 known metabolites as instrumental variables to evaluate their causal effects on acute GVHD (aGVHD), gut GVHD, chronic GVHD (cGVHD), and relapse in different populations. Multiple causal inference methods, heterogeneity assessments, and pleiotropy tests were conducted to ensure result robustness. Multivariable MR analysis was performed to adjust for potential confounders, and validation MR analysis further confirmed key findings. Mediation MR analysis was employed to explore indirect causal pathways.

Results: After correction for multiple testing, we identified elevated pyridoxate and proline levels as protective factors against grade 3-4 aGVHD (aGVHD₃) and relapse, respectively. Conversely, glycochenodeoxycholate increased the risk of aGVHD₃, whereas 1-stearoylglycerophosphoethanolamine had a protective effect. The robustness and stability of these findings were confirmed by multiple causal inference approaches, heterogeneity, and horizontal pleiotropy analyses. Multivariable MR analysis further excluded potential confounding pleiotropic effects. Validation MR analyses supported the causal roles of pyridoxate and 1-stearoylglycerophosphoethanolamine, while mediation MR revealed that pyridoxate influences GVHD directly and indirectly via CD39⁺ Tregs. Pathway analyses highlighted critical biochemical alterations, including disruptions in bile acid metabolism and the regulatory roles of vitamin B6 derivatives. Finally, clinical metabolic analyses, including direct fecal metabolite measurements, confirmed the protective role of pyridoxate against aGVHD.

Conclusions: Our findings provide novel insights into the metabolic mechanisms underlying GVHD and relapse after allo-HSCT. Identified metabolites, particularly pyridoxate, may serve as potential therapeutic targets for GVHD prevention and management.

Background: Malformations of cortical development (MCD) are a group of congenital brain malformation disorders commonly associated with pharmacoresistant epilepsy (PRE). While studies often focus on surgery outcomes, the pharmacological treatment is still imperative and the odyssey to PRE remains underexplored. We aim to investigate the influence of anti-seizure medications (ASMs) on the development of PRE in this specific patient population.

Methods: We retrospectively included a cohort of epilepsy patients with MRI-confirmed MCD due to abnormal cell proliferation and apoptosis (group I, mainly FCD II), and abnormal neuronal migration (group II, mainly heterotopia, lissencephaly, and polymicrogyria) from March 2013 to June 2023. The clinical features of group I and group II were compared. Factors associated with PRE were analyzed. The time to development of PRE with different ASMs was assessed using Kaplan-Meier survival analysis.

Results: Of 259 enrolled patients with epilepsy and MRI-confirmed MCD (group I, n = 121; group II, n = 138), 73.4% met the criteria for PRE. The median duration of follow-up from seizure onset to the last visit or surgery was 103 months (IQR 45-174), with group I showing a significantly higher PRE rate than group II (90.1% vs. 58.7%, p = 0.000). Binomial regression analysis identified the significant predictors of PRE in MCD patients: high pretreatment seizure frequency (OR = 2.506), group II patients (OR = 0.248), and failure of the first ASM (OR = 5.885). Sodium channel blockers (SCBs) were the most prescribed initial ASMs and demonstrated a higher response rate than other ASMs. Kaplan-Meier analysis revealed that using SCBs as the first ASM significantly prolongs the time to PRE, with a median of 72 months for SCB users versus 48 months for non-SCB users.

Conclusions: Our findings indicate a high prevalence of PRE that varies among different subtypes of MCD. Early appropriate selection of ASMs, particularly SCBs, can significantly delay the time to PRE onset, offering a promising strategy for managing this complex patient population. Tailoring pharmacological approaches is crucial for optimizing outcomes, and further research is warranted to optimize treatment strategies.

Background: While randomized clinical trials of stress ulcer prophylaxis (SUP) have generally shown no overall benefit, subgroup analyses suggest the benefit or harm of SUP in specific patients, indicating heterogeneity of treatment effects (HTE). Understanding HTE is crucial for tailoring SUP to individual treatment.

Methods: This cohort study included patients admitted to intensive care unit (ICU) with at least one risk factor for clinically important gastrointestinal bleeding (GIB). The primary exposure was the use of SUP within 48 h after ICU entry; the primary outcome was 28-day mortality. We employed conventional subgroup analysis, risk-based analysis, and effect-based analysis to explore the HTE of SUP.

Results: A total of 25,475 patients were included, of whom 6199 (24.3%) received SUP, with famotidine being the most commonly prescribed (53.7%). Baseline characteristics were well-balanced between treatment groups after weighting. SUP was not associated with the 28-day mortality in the overall population (median value for the posterior distribution of the odds ratio (OR), 1.03; 95% credible interval (CrI), 0.96-1.11). In conventional subgroups, the impact of SUP on 28-day mortality varied substantially between patients with an age of higher than or equal to 77 years in comparison with other age subgroups (posterior probability of difference in OR, 99.3%), between patients with and without chronic liver disease (posterior probability of difference in OR, 99.9%), between patients with and without coagulopathy (posterior probability of difference in OR, 92.1%), and between patients with and without malignant cancer (posterior probability of difference in OR, 100%). In risk-based analysis, patients at high risk of death exhibited the highest propensity for benefit from SUP (posterior probability of an OR > 1, 1.9%). In effect-based analysis, patients with malignant cancer and a higher Charlson comorbidity index identified at high probability of benefit.

Conclusions: Among ICU patients with at least one risk factor for clinically important GIB, those who are younger, have chronic liver disease, coagulopathy, or malignant cancer are more likely to benefit from SUP.

Background: Influenza A virus (IAV) is a major cause of seasonal and global pandemics, posing serious health risks. Repositioning approved drugs offers an efficient antiviral strategy, particularly as calcium (Ca²⁺) is crucial for IAV infection, making Ca²⁺ channel blockers (CCBs) promising candidates for antiviral agents.

Methods: The in vitro antiviral activity of cilnidipine was evaluated using MTT assays, qRT-PCR, plaque assays, and western blotting. Mechanistic studies involved time-of-addition, viral internalization, pseudovirus neutralization, and HA (hemagglutinin) syncytium assays. For in vivo analysis, BALB/c mice were intranasally infected to evaluate the effects of cilnidipine on viral titer, lung index, pulmonary inflammatory mediators, and survival rate.

Results: In vitro, cilnidipine exhibits antiviral activity against IAV during the early stages of infection. It disrupts clathrin- and caveolin-mediated endocytosis to inhibit the internalization of IAV and interacts with the viral HA2 subunit to impede virus membrane fusion. Additionally, cilnidipine suppresses the PI3K-AKT and p38 MAPK pathways activated by IAV infections. In vivo, cilnidipine reduces virus titers and lung index, ameliorates lung pathology, and inhibits pulmonary inflammatory mediator expression, improving survival rates.

Conclusions: These findings highlight the promising anti-IAV properties of cilnidipine both in vitro and in vivo, suggesting its potential as a clinical agent for emergencies against influenza outbreaks.

Background: The COVID-19 pandemic has exacerbated health disparities, with long COVID emerging as a major global public health challenge. Although clinical risk factors for long COVID are well-documented, the cumulative burden of adverse social determinants of health (SDoH) remains underexplored. This study aims to investigate the association between cumulative social disadvantage and long COVID.

Methods: Using data from the 2022 and 2023 National Health Interview Survey cycles (n = 16,446 U.S.adults), cumulative social disadvantage was quantified through 18 SDoH indicators and categorized into quartiles. The highest quartile represents the most disadvantaged individuals. Long COVID was defined as self-reported symptoms persisting for three months or longer. Weighted logistic regression models were used to examine the association, adjusting for demographic and clinical variables.

Results: Adults in the highest quartile of cumulative social disadvantage exhibited an increased odds of experiencing long COVID compared to those in the lowest quartile (AOR = 2.52, 95% Cl: 2.13, 2.98). This association persisted across demographic subgroups, with particularly pronounced effects among women and non-Hispanic Blacks. Hispanics and non-Hispanic Whites showed weaker, but still statistically significant. Key contributors included mental health difficulties, economic instability, and healthcare access barriers. Furthermore, cumulative social disadvantage was linked to fair or poor general health status among individuals with long COVID.

Conclusions: This study highlights the positive association between cumulative social disadvantage and long COVID. Addressing systemic inequities through integrated public health strategies is essential to mitigate the burden of long COVID and reduce social disparities in health.

Background: To better inform retail food environment policies in the global south, it is necessary to further understand the healthfulness of food and beverages purchased by type of food outlet over time.

Methods: Using repeated cross-sectional data from the National Income and Expenditure Survey (ENIGH) in Mexico (2006 to 2022), we estimate the percentage of food and beverage purchases by processing level for each food outlet for the overall population and stratify by education (proxy of socioeconomic status) and urbanicity levels.

Results: In 2006, the food outlets with the largest proportions of ultra-processed foods purchases were chain convenience stores (49%), small neighborhood stores (37%), and supermarkets (35%). In contrast, the outlets with the highest proportions of minimally processed food purchases were street markets (83%), public markets (81%), and specialty stores (75%). Over time, households increased the proportion of expenditure in minimally processed foods in supermarkets and slightly in small neighborhood stores (49 to 54% and 46 to 47%, respectively). Conversely, the proportion of expenditures in minimally processed foods decreased from 70 to 62% in street vendors. Households without formal education and residing in rural areas increased their minimally processed food purchases in specialty stores, but decreased in street vendors, acquaintances, and public markets. Households with higher education and residing in more urbanized areas increased their purchases of minimally processed foods in supermarkets and small neighborhood stores and decreased in street vendors. These households also increased their purchases in ultra-processed foods in chain convenience stores.

Conclusions: There is a wide range of food outlets in Mexico, each with varying levels of healthfulness. While purchases in supermarkets have become healthier, particularly among higher socioeconomic households and in larger cities, small neighborhood stores have also shown improvements, especially in lower-income households and smaller cities. Since no outlet exclusively sells healthy or unhealthy foods, policies should focus on where people make the majority of their purchases and address healthfulness variations based on education level education and urbanization.

Background: Ethnic minority groups are particularly vulnerable to healthcare inequities, with catastrophic medical expenditures often pushing them into poverty. However, empirical research on the impact of healthcare reforms on these populations remains limited. This study aims to address this gap by exploring the effects of healthcare payment reforms on healthcare outcomes and financial protection during serious illnesses among ethnic minority populations.

Methods: A cross-sectional study was conducted using data from three major ethnic minority groups in China: the Zhuang, Hui, and Manchu. The analysis is based on hospitalization data from 59,622 ethnic minority cancer patients spanning from 2013 to 2024. Ordinary least squares (OLS) linear regression was employed to assess the effects of healthcare payment reforms on healthcare expenses and cost-sharing.

Results: The findings indicate that, compared to traditional payment methods, the implementation of diagnosis-related group (DRG) payment reforms led to reductions in hospitalization, drug, and treatment expenses for ethnic minority patients. However, a closer examination of the cost structure reveals that while DRG payment systems have reduced expenditures for public health insurance fund, they have simultaneously increased out-of-pocket costs for minority patients.

Conclusions: Given that many ethnic minority patients belong to economically disadvantaged groups with limited financial resources, the rise in out-of-pocket costs exacerbates their economic burden, making them more vulnerable to catastrophic medical expenditures. This situation poses a severe challenge to minority patients already in precarious financial circumstances. This study offers insights and lessons from China that may guide governments worldwide in mitigating healthcare inequities faced by vulnerable populations.