医学最新文献

Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most prevalent chronic liver disease in the United States, yet therapeutic options remain limited. Emerging evidence implicates the gut‒liver axis and intestinal permeability in disease pathogenesis. Previous studies in animal models and human cell culture indicated that bile salt hydrolases (BSHs), which are gut bacterial enzymes that deconjugate host-derived bile acids, damage intestinal barrier integrity and cause liver damage through the generation of unconjugated bile acids (UBAs). However, the relevance of these findings to MASLD patients is unknown. Here, we demonstrate that BSH activity is elevated in fecal samples from MASLD patients with advanced liver fibrosis and correlates with reduced fecal bile acid levels, which is consistent with a proposed model of increased intestinal permeability during MASLD progression. Through anaerobic culturing and activity-guided screening, we identify diverse BSH-active bacteria from patient fecal samples, suggesting broad microbial contributions to bile acid deconjugation in MASLD patients. Importantly, small-molecule BSH inhibitors suppressed BSH activity in both fecal communities and monocultures from MASLD patients without affecting bacterial viability. These findings indicate that BSH activity is a microbial function associated with MASLD progression and suggest that BSH inhibitors could be developed as a microbiome-targeted strategy for MASLD treatment.

The recurrence following the discontinuation of medication is a formidable challenge in managing psoriasis. Changes in the microbiome accompany the onset of psoriasis relapse, highlighting a potential therapeutic modality. To evaluate the superiority of the topical administration of aptamer-functionalized curcumin mesoporous silica (Apt-GA+Cur@μmS) plus blue light (BL) in restoring dysbiosis and intervening in recurrence in a murine model, a psoriasis relapse murine model with double imiquimod induction was established. With a BL-responsive shell, Apt-GA+Cur@μmS released curcumin (Cur) to assist BL to improve the preventative and therapeutic effects in the psoriasis relapse murine model, as evidenced by the psoriasis area and severity index, histology, splenic index, and dorsal IL-17A level. We also observed a negative correlation between splenic nitric oxide (NO) levels and the splenic index, indicating a possible mechanism by which Apt-GA+Cur@μmS&BL may function in the treatment of splenomegaly. Treatment with Apt-GA+Cur@μmS&BL exhibited a higher alpha diversity than the model group, with levels similar to those of healthy mice, indicating that this combination could adjust the composition of the dorsal microbiome to a healthier state. A reduction in the combined relative abundance of Staphylococcus, Streptococcus, and Corynebacterium as well as restoration of dysbiosis was also verified through 16S rDNA gene sequencing in vivo. Collectively, BL and Apt-GA+Cur@μmS cotherapy alleviates psoriasiform lesions in a double imiquimod-induced murine model by inhibiting IL-17A and increasing splenic NO. Additionally, this cotherapy restores the eubiosis of the dorsal lesions. Thus, it is a promising and innovative therapeutic modality for psoriasis inflammation alleviation and recurrence intervention.

Purpose: This study aimed to qualitatively examine the daily lives of motorcycle-based food delivery workers, focusing on how they experience, perceive, and interpret their health-related issues.

Methods: Semi-structured in-depth interviews were conducted with nine MFDWs in South Korea between July and September 2024 to explore their perceptions of health. Participants were recruited through purposive and snowball sampling, and data were analyzed using thematic analysis.

Results: Thematic analysis revealed the following key findings: MFDWs' challenging working conditions posed physical and emotional stressors, which contributed to negligent driving and unhealthy habits. Although they recognized traffic accidents as the most critical health risk, they exhibited a tendency toward risky driving behaviors. Unhealthy lifestyles were linked to further health deterioration. While the majority showed a passive attitude toward health management, a few adopted individual strategies to maintain their health.

Conclusions: The findings suggest the need for policy-level attention to mitigate traffic accident risk factors among MFDWs. Larger and more diverse studies are required to confirm these findings and to provide a stronger evidence base for policy recommendations. In addition, delivery applications could be further refined to help reduce occupational risks, and the development of tailored health promotion interventions may support their health and well-being.

Therapeutic immunization against tumor neoantigens has the potential to induce potent and highly selective CD8⁺ T-cell-mediated antitumor immunity. Consequently, immunization strategies that generate robust neoantigen-specific T-cell responses are needed. Here, we tested homologous and heterologous DNA- and peptide-based immunization strategies using a neoantigen model. We observed that priming with DNA followed by peptide boost immunization elicited the strongest CD8⁺ T-cell responses, which exhibited effector and memory precursor phenotypes and led to the formation of circulating and skin-resident memory T cells. In prophylactic settings, this immunization regimen delayed the growth of B16F10 melanoma and rejected EL4 lymphoma cells expressing a self-antigen. In a therapeutic setting, a DNA prime-peptide boost eliminated EL4 tumors expressing the neo-epitope model in most mice. Consistently, DNA prime-peptide boost targeting two bona fide neoepitopes of MC38 tumor model elicited neoepitope-specific CD8⁺ T-cell responses and a marked therapeutic effect, which may be enhanced by combining with anti-PD-1 antibody. These results highlight the potential of DNA prime-peptide boost as a promising strategy for therapeutic neoantigen immunization that elicits strong CD8⁺ T-cell responses and potent antitumor effects.

Background: Rates of hypertensive disorders affecting pregnancy are increasing, and bipolar disorder is more common in pregnancy than previously thought.

Objective: The authors investigated differences in the incidence of hypertensive disorders of pregnancy between those with and without bipolar disorder (BPD) and between those receiving and not receiving pharmacotherapy for BPD. Differences in the incidence of hypertensive disorders of pregnancy in those with BPD between those on prophylactic aspirin (ASA) and not, were also examined.

Methods: EPIC COSMOS was used to examine records from 2019 to 2023.

Results: The authors found a meaningful difference in proportions between those with and without BPD when observing development of hypertensive disorders of pregnancy across years. Slightly increased odds of hypertensive disorders were found among those reporting BPD pharmacotherapy compared to those not. Slightly increased odds of hypertensive disorders occurred in those with BPD reporting ASA.

Conclusions: The increased odds among those reporting BPD pharmacotherapy could be due to sequelae of disease, medication used, or comorbidities. These findings further corroborate prior evidence of the increasing prevalence of both maternal health complications and mental health disorders int eh United States.

Cholangiocarcinoma (CCA) has a complex tumor microenvironment that critically influences tumor progression and therapeutic resistance. Glycosylation abnormalities have been linked to cancer growth and progression. This work was designed to develop a prognostic model based on glycosylation-related genes (GRGs) for predicting CCA outcomes and immunotherapy responses. Glycosylation patterns in macrophage subsets of CCA were analyzed via scRNA-seq. Key genes were identified by integrating module genes from WGCNA and DEGs. A risk model for CCA was established utilizing LASSO Cox regression. In vitro tests were conducted to validate the function of PGK1. The immune checkpoint blockade group exhibited elevated M1 signature scores and higher glycosylation levels. A risk model incorporating five genes (ANXA3, PGK1, PLAUR, CREB5, SPP1) for CCA was established. The high macrophage glycosylation-related risk score group had a considerable infiltration of M0 macrophages. In vitro experiments confirmed that PGK1 advanced glycation end products accumulation, drove M2 polarization of macrophages, and increased CCA cell proliferation and migration. This work proposes a glycosylation-based risk model for predicting CCA prognosis and directing therapeutic strategies. PGK1 is highlighted as a potential therapeutic target in CCA.

Background: Assessment plays an important role in teaching and learning medical communication. Formative assessment is increasingly recognised as a crucial tool for improving learning outcomes and supporting competence development. In this study, we developed and evaluated different versions of automated formative and summative feedback in an online situational judgement test of basic medical communication competence.

Methods: We developed four versions of task-based (formative) feedback, differing in their enrichment strategies (i.e. reflection prompts or expert explanations) and the timing of the feedback (i.e. immediate feedback or post-test feedback), and one performance-based (summative) version featuring a test-score profile. In a randomised controlled trial with N = 269 medical students, we evaluated the effects of feedback design on participants' (i) motivation and (ii) cognitive factors (i.e. cognitive load), as well as on their (iii) feedback perception (e.g. fairness and usefulness of the feedback) and (iv) perceived benefits of the feedback, all of which influence learning. We tested the hypotheses that task-based feedback would be more effective than performance-based feedback (H₁) and that task-based versions would have differential effects on the outcome variables (H₂).

Results: Planned contrast analysis revealed that task-based feedback was not consistently more effective than performance-based feedback across all outcomes (H₁). In line with H₂, analyses of variance revealed differential effects of feedback enrichment and timing: expert explanations enhanced cognitive understanding and perceived feedback benefits, whereas post-test feedback improved motivational outcomes such as perceived competence and fairness.

Conclusions: The results highlight the complexity of determining an optimal feedback approach, as different implementations can have differential effects on the motivational and cognitive factors that further shape learning processes. The findings suggest that an optimal feedback approach depends on specific learning outcomes and student characteristics, highlighting the importance of careful selection of feedback strategies tailored to specific educational goals and contexts.

Antigen anisotropy, the directional dependence of protein conformation, epitope exposure, and conformational dynamics, is an under-appreciated determinant of vaccine immunogenicity. Preserving this geometric fidelity may influence outcomes such as neutralization breadth, affinity maturation, and B/T-cell response quality. Native antigens engage B-cell receptors, T-cell receptors, and MHC through oriented interactions that rely on spatial and dynamic constraints for effective immune recognition. This framework is increasingly relevant amid widespread use of nucleoside-modified mRNA vaccines, as recent studies suggest platform-specific deviations in antigen geometry and processing. Platform interventions including chemical inactivation (e.g., formaldehyde and β-propiolactone), formulation and storage conditions, and mRNA design choices (e.g., N¹-methylpseudouridine incorporation, codon optimization) can introduce perturbations that influence folding, glycan shielding, epitope presentation, and hydrodynamic behavior. These effects can generate antigen ensembles that diverge from native forms, and may plausibly contribute to differences in response breadth and quality. Prioritizing anisotropy preservation offers a complementary design principle for next generation vaccines, one that seeks to more closely recapitulate the geometric and dynamic features of natural infection and may improve the predictability and durability of protective immunity.

Combined cytotoxic chemotherapy and immune checkpoint inhibition (ICI) improves outcomes in PD-L1-low lung cancer, but transient and broad PD-1 expression across immune cells complicates the understanding of the underlying mechanisms. We generated Pdcd1-CreERT2 fate-mapping mice to trace PD-1-expressing cells via tdTomato during PD-1 blockade. PD-1-fate-mapped lymphocytes downregulated PD-1 in the spleen but largely retained it in tumors, except for NK cells, which lost PD-1 and regained function. Single-cell transcriptional profiling was performed on immune cells in PD-L1-low Lewis lung carcinoma (LLC) treated with cyclophosphamide (CTX) and/or anti-PD-1 antibodies. Anti-PD-1 monotherapy showed limited efficacy, whereas CTX plus anti-PD-1 markedly improved tumor control. Single-cell analysis identified 15 transcriptionally distinct immune clusters with treatment-dependent abundances. Combination therapy expanded cytotoxic CD8 T cells and a dysfunctional Treg cluster, enhancing CTL activity, including PD-1-fate-mapped CD8 T cells expressing Tpex1 markers. Single-cell TCR analysis revealed that clonotypes selectively expanded by combination therapy, mediating potent cytotoxicity against LLC tumors. PD-1 blockade synergizes with cytotoxic chemotherapy to diversify and expand PD-1 lineage-traced CTL clonotypes, driving robust antitumor immunity. Thus, our fate-mapping system is a valuable tool to search for immune cells responsive to ICI therapy.