medRxiv : the preprint server for health sciences最新文献

The standard treatment for stage I lung adenocarcinoma is surgical resection, in most cases without additional systemic adjuvant treatment. A significant proportion of stage I cases recur with a less than 50% 5-year survival rate. There are clinical data suggesting that adjuvant treatment may improve survival in such recurrent cases. However, previously evaluated predictors such as the IASLC grading system from histological sections and transcriptomic profiles have not been sufficiently accurate and consistent for risk stratification and to guide therapeutic interventions. We hypothesized that these previously investigated diverse diagnostic measurements carry complementary information that may provide higher prognostic power when combined. Here we describe a multimodal deep learning method, PATH-ORACLE. This biomarker is built on top of the prospectively validated transcriptomic-based ORACLE score with the addition of routine histological sections processed by pre-trained foundation models. PATH-ORACLE predicts recurrence with an accuracy of over 85% in two independent cohorts. Given further validation this predictor could be used to prioritize stage IB patients for adjuvant chemotherapy in a more consistent fashion. Furthermore, for stage IA cases, PATH-ORACLE, combined with liquid biopsy-based monitoring may help identify high-risk patients suitable for adjuvant targeted therapy.

Background: The 2023 AHA PREVENT (Predicting Risk of Cardiovascular Disease Events) equations were expected to replace the 2013 ACC/AHA Pooled Cohort Equations (PCE) for estimating atherosclerotic cardiovascular disease (ASCVD) risk. The real-world implications of this transition on statin eligibility and disparity are unknown.

Objectives: To evaluate how transitioning from PCE to AHA PREVENT alters statin eligibility across risk thresholds and racial and ethnic subgroups.

Design setting and participants: Retrospective cohort analyses of adults aged 40-75 years without diabetes, LDL-C ≥190 mg/dL, or prior statin use from Sutter Health (2010-2024) and NHANES (2011-2020). Ten-year ASCVD risk was estimated using both equations. Weighted analyses were applied to NHANES data.

Main outcomes and measures: Statin eligibility at PREVENT-ASCVD thresholds (3%, 4%, 5%, 6%, 7.5%) compared with PCE ≥7.5%, and the proportion of individuals reclassified below PREVENT-ASCVD thresholds.

Results: Among 229,839 Sutter Health patients (mean age 53.7 years; 53.8% women), 22.3% had PCE risk ≥7.5%. Among individuals above PREVENT-ASCVD 5% threshold level (18.0% in the cohort) 94.7% also met PCE criteria. However, 6.3% (11,866) would lose eligibility, disproportionately affecting non-Hispanic Black adults (18.7%) compared with non-Hispanic Asian adults (3.3%) among individuals who were below PREVENT-ASCVD 5% threshold. In NHANES (n=3,226; representing 32.7 million adults), 9.4% overall and 21.7% of non-Hispanic Black adults with PCE ≥7.5% lost eligibility at PREVENT-ASCVD 5% threshold level.

Conclusions: Transitioning from PCE to PREVENT recalibrates statin eligibility and may disproportionately affect non-Hispanic Black adults. Disparity-focused monitoring is essential for clinical implementation of this new model.

Background: The SLC25A46 gene encodes a mitochondrial carrier protein previously implicated in neuropathy and optic atrophy. Biallelic variants in SLC25A46 have been described in patients with Parkinson's disease (PD) with optic atrophy, but the evidence supporting a role in PD remains limited.

Objective: To assess whether SLC25A46 variants contribute to PD, REM sleep behavior disorder (RBD), or Dementia with Lewy Bodies (DLB).

Methods: We examined common variants using four representative PD genome-wide association studies (GWAS) and an RBD GWAS and applied Summary-data-based Mendelian Randomization (SMR) to evaluate whether genetically regulated expression of SLC25A46 shows a causal association with the risk of PD or RBD. Rare variant analyses were conducted in four cohorts of European descent: Accelerated Medicines Partnership: Parkinson's Disease (AMP-PD) PD (3,051 PD, 3,667 controls), UK Biobank (3,267 PD, 14,939 proxy, 54,800 controls), RBD (1,376 RBD, 2,580 controls), and AMP-PD DLB (2,605 DLB, 1,894 controls). Optimal Sequence Kernel Association test (SKAT-O) and meta-analysis were used to assess rare variants.

Results: No associations were observed between SLC25A46 variants and PD, RBD, or DLB. SMR analyses revealed no evidence supporting a causal relationship between SLC25A46 expression and PD or RBD risk. Rare variant burden analyses did not identify significant associations after multiple-testing correction across cohorts or meta-analyses.

Conclusion: SLC25A46 variants showed no evidence of association, suggesting the gene does not play a major role in PD, RBD, or DLB risk.

Background: Disorders affecting the spinal cord (myelopathies) can cause severe disability. Despite diagnostic advances, approximately 12-18% of myelopathy cases continue to elude an etiological diagnosis, hampering effective treatment.

Methods: This retrospective, multicenter, tertiary care cohort study conducted from 2014 to 2025 evaluated archived biofluids from patients with IM, known autoimmune myelitis, or other neurological diseases (ONDs). Proteome-wide phage display was used to discover novel autoantibodies. Targeted immunoassays were used to screen for a candidate autoantibody. Downstream metabolites were measured in the cerebrospinal fluid (CSF).

Results: Autoantibodies targeting the transcobalamin receptor (CD320) responsible for cellular transport of vitamin B12 were identified in 18 out of 32 IM patients (56%) in a discovery cohort. Bioactive B12 concentration was decreased in the CSF of anti-CD320 positive patients compared to OND controls ( P = 0.0273), indicative of autoimmune B12 central deficiency (ABCD). Compared to anti-CD320 negative IM cases, anti-CD320 positive IM cases demonstrated a higher frequency of subacute time course (56% vs 7%, P = 0.008), normal CSF profile (83% vs 50%, P = 0.044), and dorsolateral spinal cord abnormalities on magnetic resonance imaging (MRI) (61% vs 7%, P = 0.003). In two independent validation cohorts comprising 94 and 25 patients with IM, anti-CD320 was detected in 43 (46%) and 12 (48%) patients, respectively. Comorbid anti-CD320 was detected in a smaller proportion of patients with other known autoimmune etiologies of myelopathy. Five anti-CD320 positive IM patients received B12 supplementation with or without concurrent immunosuppression, and four out of five clinically improved.

Conclusions: ABCD is associated with a substantial proportion of IM. Screening for anti-CD320 followed by metabolic confirmation of a CNS-restricted B12 deficiency may be considered in the diagnostic evaluation of myelopathy.

Background: Glioblastoma multiforme (GBM) is an aggressive brain tumor that is notoriously resistant to treatment, with an average survival time of 17 months. While the overall outcome is poor for both males and females, sex differences in GBM incidence and outcome suggest sex-specific biological mechanisms underlie tumorigenesis. In contrast, low-grade glioma (LGG) is a less aggressive brain tumor that tends to have a better prognosis and a longer survival time.

Methods: To understand mechanisms contributing to treatment resistance in GBM in both males and females, we inferred gene regulatory networks (GRNs) for males and females with LGG and GBM using RNA-seq data from The Cancer Genome Atlas (TCGA). We analyzed these to identify both sex-specific and sex-stratified gene regulation in GBM.

Results: We found few sex-specific differences in gene regulation in individuals with LGG, consistent with the lack of evidence for significant clinical endpoints dependent on sex. However, in GBM-we found sex-specific differential targeting of several pathways, including hypoxia and related pathways (carbohydrate metabolism, innate immune processes, and extracellular matrix pathways) known to be dysregulated in hypoxic conditions. In comparing between individuals with GBM, we found that females exhibited a greater degree of co-regulation between hypoxia with the aforementioned downstream pathways than did males.

Conclusions: Our results suggest that dysregulation of hypoxia-related pathways in GBM plays a female-specific role in resistance to treatment and overall outcomes.

Background: Clinical trajectories in functional neurological disorder (FND) are variable, and the mechanisms underlying this heterogeneity remain poorly understood.

Objective: This longitudinal study examined resting-state functional connectivity predictors and mechanisms of symptom change in FND.

Methods: Thirty-two adults with FND (motor and/or seizure phenotypes) completed baseline questionnaires and a functional MRI (fMRI) session, followed by naturalistic treatment for 6.8±0.8 months. All participants completed follow-up questionnaires; 28 individuals completed a follow-up fMRI. At each timepoint, three graph-theory network metrics of functional connectivity were computed: weighted-degree (centrality), integration ( between-network connectivity), and segregation ( within-network connectivity). Analyses adjusted for age, sex, anti-depressants, head motion, time between sessions, and baseline score-of-interest, with cluster-wise correction. Results were contextualized against 50 age-, sex-, and head motion-matched healthy controls (HCs).

Results: Based on patient-reported Clinical Global Impression of Improvement, 59.4% improved, 31.3% were unchanged, and 9.3% worsened. Psychometric scores of core FND symptoms and non-core physical symptoms showed variable trajectories, with no group-level changes. Greater improvement in core FND symptoms was associated with higher baseline between-network integrated connectivity and reduced integration longitudinally within salience, frontoparietal, and default mode network regions. Right anterior insula integration emerged as a prognostic marker and mechanistic site of reorganization, with the most improved participants showing elevated baseline integration compared to HCs. Increased baseline within-network segregated connectivity in dorsal attention network regions correlated with non-core physical symptom improvement. Findings remained significant adjusting for FND phenotype.

Conclusions: This study identified large-scale network interactions as potential prognostic and mechanistically-relevant sites of reorganization related to symptom change in FND.

Recent studies showed that expression QTLs, even from trait-related tissues, explained a small fraction of complex trait heritability. A natural strategy to close this gap is to incorporate molecular QTLs (molQTLs) beyond gene expression, across diverse tissue/cellular contexts. Yet, integrating such QTL data presents analytical challenges. Molecular traits often share QTLs or have QTLs in high LD, complicating the attribution of GWAS signals to specific molecular traits. Our simulations showed that commonly used colocalization and TWAS methods have highly inflated false positive rates in such settings. Building on our earlier work, we developed multi-group causal TWAS (M-cTWAS), for integrating QTLs of different modalities and contexts. M-cTWAS is able to estimate the contribution of each group of molQTLs to the trait heritability, and using such information, identifies the causal molecular traits, informing the modalities and contexts through which genetic variations act on the phenotype. M-cTWAS showed improved control of false discoveries than commonly used methods. Using M-cTWAS, we found that QTLs of multiple modalities greatly increased the explained heritability compared to using eQTLs alone, and enabled the discovery of many more risk genes of a range of complex traits. In conclusion, M-cTWAS effectively integrates diverse molecular QTLs with GWAS to enable causal gene discovery.

Introduction: Previous studies have shown that Aquamin ^® , a multi-mineral extract from red marine algae, enhances barrier integrity proteins in the human colon. These findings prompted further investigation into Aquamin ^® 's effects on gastrointestinal barrier function and permeability.

Methods: Subjects with mild or in remission ulcerative colitis (UC) and healthy controls were enrolled in an open-label trial and received Aquamin ^® capsules (800 mg calcium/day) for 90 days. Intestinal permeability was evaluated before and after the 90-day intervention by urinary mannitol excretion after ingestion of a 5 g mannitol solution, with collections across several time intervals (pre-drink, 0-2 h, 2-8 h, and 8-24 h). The primary outcome was the change in mannitol excretion. Serum samples were also collected to assess liver and renal function.

Results: In this pilot study ( NCT04855799 ), which included UC patients and healthy controls (n = 8 per group), baseline urine mannitol levels in the 0-2 h sample were 54% higher in UC patients compared to healthy subjects (p = 0.006). Following 90 days of Aquamin ^® supplementation, urinary mannitol levels in UC patients decreased by 28%, 26%, and 41% at the 0-2 h, 2-8 h, and 8-24 h timepoints, respectively; the reduction at the 0-2 h interval reached statistical significance (p = 0.015). Overall, Aquamin ^® supplementation reduced total post-intervention mannitol excretion by 29% (p = 0.024). Aquamin ^® was well tolerated, with no serious adverse events reported. The serum metabolic panel revealed a modest but statistically significant reduction in alkaline phosphatase levels after 90 days of intervention.

Conclusion: These results provide preliminary evidence that Aquamin ^® supplementation beneficially modulates gut barrier function and supports epithelial integrity in UC patients. These findings support further investigation of Aquamin ^® as a safe and promising adjunct to current UC management strategies, with potential utility as a barrier therapy in UC.

Summary: Aquamin ^® supplementation for 90 days reduced intestinal permeability in ulcerative colitis patients, as measured by urinary mannitol excretion. The intervention was well tolerated, suggesting Aquamin ^® may be a safe, promising adjunct for enhancing gut barrier function in UC management.