BMC Medicine最新文献

Background: Pain-anxiety comorbidity represents a prevalent clinical concern. This study aims to investigate the molecular mechanisms underlying the comorbidities via focusing on the activity of dorsal raphe nucleus (DRN) glutamatergic neurons and the functional role of their 5-hydroxytryptamine 2C (5-HT2C) receptors in relation to gut microbiota.

Methods: We established a Complete Freund's Adjuvant (CFA)-induced pain-anxiety comorbidity model in mice and systematically investigated the role of the brain-gut axis in the comorbidity using behavioral phenotyping, molecular biology, pharmacological/chemogenetic modulation, and gut microbiota profiling.

Results: Heightened activity in the glutamatergic neurons of the DRN was found in mice with comorbidity. Chemogenetic activation of DRN glutamatergic neurons replicated the comorbid phenotype in naïve mice, while the selective inhibition of DRN glutamatergic neurons effectively reversed the behavioral and physiological impairments induced by CFA. Notably, a significant upregulation in the protein levels of 5-HT2C receptors in the DRN was detected in the comorbid state. Bidirectional manipulation of 5-HT2C receptors in the DRN glutamatergic neurons bidirectionally regulates neuronal excitability and comorbid phenotypes: agonism or overexpression exacerbates comorbidity, while antagonism or knockdown attenuates CFA-induced deficits.

Conclusions: These findings uncover the role of 5-HT2C receptors in DRN glutamatergic neurons in pain-anxiety comorbidity, thereby presenting novel targets for potential therapeutic interventions.

Background: Helicobacter pylori (H. pylori) infection is associated with enhanced efficacy of immunotherapy in gastric cancer (GC). However, the mechanisms underlying this enhancement are not fully understood.

Methods: We recruited 218 GC patients, 134 esophageal squamous cell carcinoma (ESCC) patients, and 86 dMMR/MSI-H colorectal cancer (CC) patients and collected their stool and tumor samples to analyze the gut and intratumoral microbiome. We assessed microbial diversity and composition and correlated these findings with clinical outcomes to evaluate the relationship between H. pylori status, microbiome alterations, and immunotherapy efficacy.

Results: H. pylori-positive patients showed higher alpha diversity and unique microbial signatures, which were associated with increased immune-related progression-free survival (irPFS) and overall survival (irOS). In addition, we found that the abundance of 45 gut microbiome species was significantly different between the two groups. The gut microbiome of the H. pylori-positive GC group was enriched with species such as Clostridium leptum, Oscillibacter sp. ER4, and Ruminococcus bromii, which were associated with improved treatment response. However, they predicted poor prognosis in patients with esophageal squamous cell carcinoma and colorectal cancer patients with dMMR/MSI-H. Microbial co-occurrence network revealed significantly distinct interaction patterns among the groups. In addition, we found enhanced L-arginine biosynthesis in the gut microbiome of H. pylori-positive GC. In terms of intratumoral bacteria, we identified two genera, Streptococcus and Granulicatella, that were mutually exclusive with H. pylori infection in GC. Enhanced L-lysine fermentation to acetate and butanoate was observed among intratumoral bacteria, suggesting potential metabolic shifts in the tumor microenvironment. Incorporating H. pylori infection status into the microbiome-based prediction model further improved the accuracy of predicting immunotherapy outcomes in GC.

Conclusion: These findings suggest that H. pylori had significant effects on the structure and functional activity of gut and intratumoral microbiome, some of which may affect the efficacy of immunotherapy. The clinical value of H. pylori infection status should be considered when establishing a prediction model for immunotherapy efficacy based on gut microbiome.

Background: Current evidence is limited concerning the temporal impact of atrial fibrillation (AF) ablation timings on post-ablation outcomes.

Methods: Patients who experienced ablation in the CABANA trial were enrolled in our analysis. Diagnosis to ablation time (DAT) was calculated from the date when the initial AF episode was documented. The primary endpoint was a composite of death, disabling stroke, serious bleeding or cardiac arrest. Secondary end points included AF recurrence, all-cause mortality, and all-cause mortality or cardiovascular hospitalisation. Associations between DAT and post-ablation outcomes were evaluated by restricted cubic spline (RCS) curves based on Cox models.

Results: Out of 1145 patients (median age 67.0 years, interquartile range (IQR) 61.0-72.0; 36.7% female) included, 538 (47.0%) underwent early ablation (DAT ≤ 1 year), including 242 (45.0%) who received very early ablation (DAT ≤ 90 days). The overall median DAT was 423 days (IQR 118-1473). The L-shaped association was observed between DAT and the primary outcome (P for non-linear = 0.034). The lowest point was located at a DAT of approximately 1 to 3 years. For AF recurrences, the RCS curve rose progressively with increasing DAT (P for non-linear = 0.062), showing a reduced risk when DAT was less than 1 year. Effects of early ablation on the primary outcome favoured patients with initial AAD use (HR 0.86, 95% confidence interval (CI) 0.43-1.73 vs. HR 2.20, 95% CI p-interaction = 0.045).

Conclusions: The benefits of earlier ablation in reducing AF recurrence might not equate to improvements in post-ablation cardiovascular prognosis. Timely treatment combining AADs and ablation may provide additional cardiovascular benefits.

Trial registration: ClinicalTrials.gov Identifier: NCT00911508.

Background: Sodium-glucose cotransporter-2 (SGLT-2) inhibitors with pleiotropic effects beyond glycemic control potentially improve clinical outcomes in cirrhosis; however, large-scale human evidence remains limited. We aimed to compare liver outcomes and mortality risk in adults with type 2 diabetes and compensated cirrhosis, who initiated either SGLT-2 inhibitors or dipeptidyl peptidase-4 (DPP-4) inhibitors.

Methods: Using the TriNetX Global Collaborative Network and a target trial emulation framework, we identified adults with compensated cirrhosis and type 2 diabetes initiating an SGLT-2- or DPP-4 inhibitor between 2016 and 2024. Baseline demographics, laboratory information, comorbidities and concomitant medications were matched by propensity scores. The primary outcome was a composite of incident hepatic decompensation, hepatocellular carcinoma and all-cause mortality. We used Cox proportional hazards models to estimate the hazard ratios (HR) with 95% confidence intervals (CI).

Results: We included 5,398 patients (mean [SD] age: 63.9 [10.3] years), receiving SGLT-2 inhibitors, matched to 5,398 DPP-4 inhibitor users, with an overall mean follow-up of 49.8 months. Compared to DPP-4 inhibitors, SGLT-2 inhibitors were associated with a lower risk of the primary composite outcome (HR: 0.85, 95% CI: 0.79-0.91), with similar results for all-cause mortality (HR: 0.77, 95% CI: 0.69-0.85) and incident hepatic decompensation (HR: 0.89, 95% CI: 0.82-0.96), but not for hepatocellular carcinoma (HR: 0.96, 95% CI: 0.82-1.14).

Conclusions: Among adults with compensated cirrhosis and type 2 diabetes, SGLT-2 inhibitors were associated with lower risk of all-cause mortality and incident hepatic decompensation, compared to DPP-4 inhibitors. Future clinical trials are warranted to confirm this observation.

Background: Embryo implantation failure and early pregnancy loss remain significant challenges in assisted reproductive technology (ART). Lipid peroxidation is known to be involved in reproductive physiology. However, its role during the implantation window and its effects on post-embryo transfer outcomes remain incompletely understood.

Methods: This translational study combined clinical and animal model research. Clinically, serum samples (n = 2040) and uterine fluid samples (n = 487) from patients undergoing in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles were analyzed using propensity score matching (PSM), univariate and multivariate logistic regression analysis, restricted cubic spline (RCS) analysis, and subgroup analysis. A murine model of lipid peroxidation was established by administering erastin during the implantation window to investigate its effects on endometrial receptivity and decidualization.

Results: Elevated serum levels of malondialdehyde (MDA) and non-heme iron were independently associated with recurrent implantation failure (RIF). Among patients without RIF, elevated pre-transfer serum levels of MDA, non-heme iron, 12-hydroxyeicosatetraenoic acid (12-HETE), and 15-HETE were associated with implantation failure and early pregnancy loss. Consistent with this, intrauterine MDA levels were significantly higher in patients with these pregnancy failures compared to those with ongoing pregnancy. Complementary murine studies supported these clinical observations, showing that elevated lipid peroxidation during the maternal implantation window was associated with impaired endometrial receptivity and decidualization.

Conclusions: Elevated maternal lipid peroxidation is independently associated with RIF. In patients without RIF, it is similarly associated with implantation failure and early pregnancy loss. The endometrium appears particularly sensitive to this peroxidation, which may impair receptivity and decidualization. These support further investigation of redox-modulating strategies in ART.

Background: Necrotising soft tissue infections (NSTI) are life-threatening conditions caused by diverse bacteria. Treatment strategies have remained largely universal and unchanged, and only modest improvements in patient outcomes have been observed. Emerging insights into NSTI pathogenesis may enable more targeted approaches. Because microbial aetiology is central to guiding appropriate therapy, we aimed to develop and externally validate machine learning models capable of predicting microbial aetiology using only data available at an early stage. In parallel, we explored whether similar models could predict selected clinical endpoints related to surgical management, patient handling, and organ support.

Methods: We used data from the INFECT study, an international multicentre prospective cohort investigating NSTI characteristics and pathogenesis. A total of 409 adults with surgically confirmed NSTI were enrolled between February 2013 and June 2017 from five Scandinavian hospitals. More than 700 clinical variables were collected from hospital admission to intensive care unit entry. Machine learning models were developed to predict the presence of Streptococcus pyogenes (GAS, Group A streptococcus) and five clinical endpoints: risk of amputation, size of skin defect, maximum skin defect size, length of intensive care (ICU) stay, and need for renal replacement therapy. Unsupervised variable selection was implemented, and Shapley Additive explanations were used for model interpretability. External validation employed a retrospective multicentre cohort of 216 NSTI patients treated in 11 Dutch hospitals between January 2013 and December 2017.

Results: Eight presurgical variables (age, diabetes, affected area, prior surgical intervention, and blood creatinine and haemoglobin concentrations) were sufficient for predicting GAS aetiology with high discriminatory power. Performance was good in both the development cohort (ROC-AUC 0.828; 95% CI 0.763-0.883) and the external validation cohort (ROC-AUC 0.758; 95% CI 0.696-0.821). Prediction of clinical endpoints related to surgical management, ICU stay, and organ support was unsuccessful.

Conclusions: We developed and externally validated a model predicting GAS aetiology in NSTI using presurgical data alone. Early identification of GAS may improve clinical handling and support tailored decisions on treatment and infection control, including management of close contacts and reduction of hospital transmission risk.

Background: Whole food plant-based diets exert anti-inflammatory properties and have been associated with clinical improvements in patients with autoimmune disorders. The underlying mechanisms remain poorly understood and functional insights into nutrient-host physiology cross-talks are urgently warranted. The present study investigated the effects of an isocaloric 8-week vegan diet (VD) intervention on whole blood count parameters and lymphoid composition in comparison to a meat-rich diet (MD).

Methods: We conducted a two-arm, monocentric randomized-controlled trial with healthy adults who were randomly allocated to either a MD or a VD for 8 consecutive weeks. Foods of animal origin were not permitted on the VD, whereas participants in the MD group were asked to consume at least 150 g of meat per day.

Results: Fifty-seven participants completed the study. At week 8, significant between-group differences were found for the white blood cell count (median (interquartile range): 5.17 (1.62) *10³/µL in the VD group vs. 5.39 (1.92) *10³/µL in the MD group, p = 0.029) and the lymphocyte count (1.80 ± 0.53 *10³/µL in the VD group vs. 2.06 (0.74) *10³/µL in the MD group, p = 0.049). This difference was driven by an increase in lymphocytes in MD group participants over the course of the study. Median change scores in platelets differed between VD and MD participants (- 21 (- 31) *10³/µL in the VD group vs. - 1.21 ± 28.37 *10³/µL in the MD group, p = 0.035) and so did the neutrophil change scores (- 0.17 (- 0.31) *10³/µL vs. 0.13 (0.50) *10³/µL, p = 0.034). Mixed models for repeated measures with a time-diet interaction as a fixed effect suggested that changes in white blood cells were driven by the diet factor alone (contrast: - 0.50 (95% CI: - 0.99-(- 0.01)), p = 0.046). Immunophenotyping results suggested significant between-group differences in CD3⁺ and CD8⁺ T-cells, and CD19⁺ B-cells after 8 weeks. CD19⁺ B-cells decreased significantly in the vegan group (214.77 ± 96.64 at baseline vs. 171.56 (102.73) cells/µL at week 8).

Conclusions: The present study suggests that a VD, in comparison to a MD, reduces the number of various immune cells even in healthy individuals. A VD may thus exert anti-inflammatory properties.

Trial registration: Registered at Deutsches Register Klinischer Studien: DRKS00031541.

Background: Clinical trials for multiple sclerosis (MS) disease-modifying treatments selectively enroll patients with favorable risk-benefit profiles. However, these therapies are often prescribed more broadly in clinical practice. We aimed to identify which patients are unlikely to benefit and may face substantial harm, and codify this into a data-driven framework for guiding real-world MS treatment decisions.

Methods: Systematic searches of PubMed and ClinicalTrials.gov identified 61 randomized, blinded phase 2b/3 trials with ≥ 100 adults per arm (all pediatric trials were included due to rarity), ≥ 48 weeks of treatment, and Expanded Disability Status Scale-based confirmed disability progression as an outcome. These trials enrolled 46,611 participants and contributed 91,787 patient-years. We extracted 80 baseline variables per trial arm and derived 30 additional features to reduce bias and train multivariable regression models. Model performance was validated using an independent, longitudinal real-world MS cohort. Infection-related mortality risk was estimated from national life tables and adjusted by treatment-specific hazard ratios.

Results: Baseline characteristics predicted both untreated progression and treatment efficacy. Therapeutic benefit increased with higher relapse rates and presence of enhancing lesions and declined with age and disease duration. Relapse rates in placebo arms declined across trial periods, mirrored by waning treatment efficacy on disability progression, which was confirmed in real-world data. In contrast, treatment-related morbidity and mortality increased with age, disability, and comorbidities. These opposing trends were integrated into a web-based personalized risk-benefit estimator.

Conclusions: Interpretable models offer a unified view of MS evolution and treatment effects. They show that the therapeutic risk-benefit ratio is dynamic, shaped by individual characteristics and predictable over time. The models project that initiating high-efficacy treatments early, followed by strategic de-escalation yields the best long-term outcomes. Critically, they extrapolate, and real-world data confirm that prescribing disease-modifying treatments to patients who would have been excluded from pivotal trials is more likely to cause harm than benefit. By enabling individualized, evidence-based decisions, this estimator can help clinicians deliver safer, more effective MS care worldwide.

Background: Retinal degenerative diseases represent a complex global health problem due to their significant impact on patients' daily lives and their highly heterogeneous pathogenesis, which challenges therapeutic development. Despite this complexity, many diseases, such as retinitis pigmentosa (RP) and age-related macular degeneration (AMD), share common features, including disrupted proteostasis, oxidative stress, and inflammatory responses, eventually leading to photoreceptor (PR) degeneration and vision loss. The inhibition of valosin-containing protein (VCP) has emerged as a promising mutation-independent therapeutic strategy for RP. However, clinical translation requires rigorous validation in models that closely reflect human retinal physiology.

Methods: Organotypic retinal explants from porcine, macaque, and human donors were placed in an in vitro culture setup and treated with ML240, a selective VCP inhibitor, delivered either as a free compound or encapsulated in mPEG_5kDa-cholane. Photoreceptor survival was assessed via TUNEL assay, outer nuclear layer (ONL) row quantification, and immunostaining. Retinal inflammation was evaluated by microglial staining. A dose-response study was performed to determine safety margins across species, and additional retinal markers were used to assess the preservation of non-photoreceptor retinal cell populations.

Results: Porcine retinal explants exhibited progressive photoreceptor degeneration under ex vivo conditions. Treatment with ML240, particularly when formulated with mPEG_5kDa-cholane, significantly reduced photoreceptor cell death and microglial activation. Macaque and human explants exhibited minimal to no signs of degeneration. Treatment did not affect morphological or histological features of the explant, demonstrating the safety of ML240 in the primate retina.

Conclusions: VCP inhibition via ML240 demonstrates an uncompromised safety profile in porcine, macaque, and human retinal explants. In addition, the neuroprotective activity of ML240 was evident in porcine tissue. Formulation with mPEG_5kDa-cholane enhances the overall performance of the compound, supporting its use for future clinical application as a mutation-independent therapeutic approach for retinal degenerative diseases.

Background: Fragmentation of healthcare delivery can disrupt the maternal care continuum and undermine effective coverage. In Mexico's segmented health system, institutional discontinuities may exacerbate inequities in access and quality. We examined the prevalence, determinants, and consequences of fragmented healthcare (FHC) for effective maternal healthcare coverage (EMHC) between 2009 and 2023.

Methods: We conducted a retrospective, repeated cross-sectional analysis using nationally representative data from the 2014, 2018, and 2023 ENADID surveys, including 71,874 women aged 12-54 with a recent live birth. EMHC was defined as a composite indicator encompassing adequate antenatal care (ANC), skilled or institutional delivery, timely postpartum care, and a complication-free puerperium. FHC was defined as receiving ANC and delivery care from different healthcare providers. Pooled multivariable regressions with survey fixed effects assessed the association between FHC and EMHC, adjusting for sociodemographic and contextual characteristics.

Results: Between 2009 and 2023, roughly one in six women experienced FHC, while only one in three achieved EMHC. Fragmentation was more frequent among women covered by publicly subsidized insurance (Seguro Popular or INSABI), Indigenous women, those living in rural areas, and women with higher obstetric risk. Receiving ANC from private providers tripled the odds of FHC compared with women covered by employment-based social security. Women exposed to FHC had a 4.7 percentage point lower probability of achieving EMHC-equivalent to a 20% reduction in the odds of effective coverage (aOR = 0.80; 95% CI: 0.69-0.91). This adverse effect was consistent across survey waves and most pronounced among Ministry of Health users.

Conclusions: Fragmented maternal healthcare trajectories substantially reduce the likelihood of effective coverage, disproportionately affecting socioeconomically and ethnically disadvantaged populations. The observed reduction in EMHC underscores that fragmentation is not merely a clinical or operational issue, but a structural challenge that requires reforms to improve the coordination of care. Strengthening integration across maternal care networks, ensuring interoperability of health information systems, and adopting continuity-based financing models are critical to improving coordination. Addressing FHC could prevent incomplete or unsafe care and accelerate progress toward universal health coverage. These findings offer actionable lessons for Mexico and other middle-income countries confronting health system fragmentation.