BMC Medicine最新文献

{"title":"Assessment of Trophoblast cell surface antigen 2 (Trop-2) expression and its clinical significance in breast cancer: a multi-level analysis of protein and gene expression.","authors":"Maria Angeliki Toli, Michail Sarafidis, Panagiotis Filis, Evangelos Tzoras, Nikolaos Tsiknakis, Emmanouil Sifakis, Efstathia Liatsou, Georgios Rassidakis, Jonas Bergh, Alexios Matikas, Ioannis Zerdes, Theodoros Foukakis","doi":"10.1186/s12916-026-05093-3","DOIUrl":"10.1186/s12916-026-05093-3","url":null,"abstract":"<p><strong>Background: </strong>Trophoblast cell surface antigen 2 (Trop-2) is a targetable transmembrane glycoprotein commonly overexpressed in breast cancer (BC). This study combines a systematic review and meta-analysis with a retrospective analysis of an independent early BC patient cohort, aiming to investigate the expression patterns of Trop-2 and their clinical significance in BC.</p><p><strong>Methods: </strong>A systematic literature search was conducted up to October 2025 to identify studies evaluating Trop-2 protein expression levels and clinical outcomes in patients with BC receiving Trop-2-directed antibody-drug conjugates (ADCs) or chemotherapy. Random-effects meta-analyses were performed to estimate pooled Trop-2 positivity rates and to assess progression-free (PFS) and overall survival (OS) across Trop-2 expression levels. Additionally, an association analysis between Trop-2 protein and gene expression was performed in an early BC patient cohort (n = 564) using immunohistochemistry and gene expression data. Trop-2 protein expression was assessed using both conventional observer-based methods and digital quantitative image analysis.</p><p><strong>Results: </strong>A total of 41 studies fulfilled the inclusion criteria. The overall pooled Trop-2 protein positivity rate was 72% [95% Confidence Interval (CI), 67-77%; 41 studies, n = 9170]. Trop-2-directed ADCs improved PFS versus chemotherapy across different H-score groups, with the greatest benefit in tumours with high H-score [3 studies; n = 575; Hazard Ratio (HR) = 0.33, 95% CI 0.20-0.56, p < 0.0001]. For OS, the benefit was observed in the low H-score group (2 studies; n = 272; HR = 0.75, 95% CI 0.57-0.98, p = 0.034). In the study cohort, Trop-2 protein by observer-read assessment was detected in 396/454 patients (87.22%). Digital pathology identified 54 (11.90%) tumours with low, 326 (71.80%) with medium, and 74 (16.30%) with high H-scores. Observer-read and digital assessments were significantly associated (Pearson's chi-square test, p < 0.001). Higher Trop-2 protein and gene expression were associated with worse distant recurrence-free interval (HR_adj = 1.45, 95% CI 1.01-2.08, p = 0.04 and HR_adj = 1.33, 95% CI 1.05-1.68, p = 0.02, respectively), particularly in Luminal B subtype.</p><p><strong>Conclusions: </strong>Trop-2 was detectable across all BC subtypes, exhibiting a wide range of expression levels. Our study suggests that Trop-2 may have a potential prognostic significance in early BC.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13445770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148677135","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trends, disparities, and pregnancy outcomes of gestational diabetes mellitus in North West London: A nine-year population-based cohort study.","authors":"Sara Sousi, Sevasti Panagiota Glynou, Sabrina Hyman, Natasha Singh, Simon Dryden, Ara Darzi, Ana Luisa Neves","doi":"10.1186/s12916-026-05103-4","DOIUrl":"https://doi.org/10.1186/s12916-026-05103-4","url":null,"abstract":"<p><strong>Background: </strong>Gestational diabetes mellitus (GDM) affects approximately 1 in 20 pregnancies in England. North West London (NWL) serves a diverse population of 2.4 million with substantial ethnic and socioeconomic variation. However, population-level epidemiological evidence from NWL remains limited. This study aims to characterise GDM incidence, temporal trends, risk determinants, and associated pregnancy outcomes.</p><p><strong>Methods: </strong>A retrospective population-based cohort study using routinely collected data from the Whole Systems Integrated Care database included all birth episodes from 2017 to 2025, categorised as GDM or non-GDM. Incidence per 1,000 births was calculated and temporal trends were analysed. Multivariable generalised estimating equation (GEE) logistic regression models were used to examine maternal risk determinants for GDM and pregnancy outcomes associated with GDM, while controlling for confounders and accounting for within-woman clustering across pregnancies.</p><p><strong>Results: </strong>Among 172,332 births from 134,991 women, 18,892 (10.9%) were GDM-affected. Overall incidence was 109.6 per 1,000 births (95% CI: 108.2-111.1), rising from 80.5 per 1,000 births in 2017 to 138 per 1,000 births in 2025. Incidence increased with maternal age and deprivation (119 vs. 85.4 in most vs. least deprived quintiles). Asian women had the highest risk (aOR 2.27, 95% CI: 2.15-2.40) relative to White. GDM was associated with higher rates of labour induction (51% vs. 41%), caesarean delivery (47% vs. 36%), preterm birth (7.3% vs. 5.2%), greater maternity care costs (£4,674 vs. £3,971) and longer maternal length of stay (3 vs. 2 days).</p><p><strong>Conclusion: </strong>The incidence of GDM in NWL substantially exceeds national estimates and has nearly doubled over nine years, with pronounced ethnic and socioeconomic disparities. Targeted culturally appropriate prevention strategies and equity-focused service planning are needed in this population.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reduced neural sensitivity to emotional faces and voices in preterm five-year-olds: a comparative study.","authors":"Rowena Van den Broeck, Lisa Gistelinck, Silke Vos, Bieke Bollen, Els Ortibus, Gunnar Naulaers, Stephanie Van der Donck, Bart Boets","doi":"10.1186/s12916-026-05097-z","DOIUrl":"10.1186/s12916-026-05097-z","url":null,"abstract":"<p><strong>Background: </strong>Accurate emotion processing is crucial for social development. Preterm birth is associated with neurodevelopmental alterations and increased vulnerability to subtle socio-emotional difficulties, often described within the preterm behavioral phenotype. Previous studies have reported impaired emotion recognition in preterm populations, but have largely relied on behavioral tasks and primarily focused on facial expressions. Because explicit emotion recognition is still developing in early childhood, objective neural markers of implicit emotion discrimination may be particularly informative for early detection.</p><p><strong>Methods: </strong>We administered a series of frequency-tagging electroencephalography (EEG) paradigms to investigate neural sensitivity to brief changes in emotional expressions in a cohort of five-year-old preterm children (N = 66), and age-matched full-term peers (N = 32). Frequency-tagging EEG utilizes fast periodic stimulation to elicit synchronized brain responses measurable in the frequency domain. Neural sensitivity to changes in emotional expressions was examined in both the visual and auditory modality, using oddball paradigms with neutral faces or voices presented at base frequency and emotional expressions (either fearful or happy) presented as periodic oddballs. Linear mixed models were used to investigate the effects of group, emotion, and prematurity severity.</p><p><strong>Results: </strong>All children showed implicit neural discrimination between neutral and emotional expressions. Compared to full-term peers, children born before 32 weeks of gestation, but not those born between 33 and 36 weeks of gestation, showed reduced neural sensitivity to facial emotional expression changes. In contrast, all preterm children (< 37 weeks of gestation) showed reduced neural sensitivity to vocal emotional expression changes. Across modalities, reduced neural sensitivity to happy emotional expressions was associated with higher parent-reported social difficulties.</p><p><strong>Conclusions: </strong>Five-year-old children born preterm show reduced neural sensitivity to brief changes in facial and vocal emotional expressions compared with full-term peers. Strikingly, the impact of prematurity severity differed between the visual and auditory modalities, indicating differential maturation of higher-level visual and auditory processing following preterm birth. These findings contribute to a more detailed understanding of socio-emotional development after preterm birth and highlight the importance of early, modality-sensitive monitoring of socio-emotional development across the entire preterm population.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13689080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic prioritization of HSDL2 in suicide and intentional self-harm: multi-omics evidence linking lipid metabolism and neuronal vulnerability.","authors":"Ziyan Zhang, Yutong Wu, Fanxu Meng, Hanbing Ji, Hai Zhong, Shucheng Si, Yun Wei, Yilei Ge, Sijia Wu, Qingxin Luo, Le Wang, Tiemei Liu, Jiawei Xiu, Yiman Guo, Yue Li, Lei Hou, Hao Chen, Xiaoru Sun, Yuanyuan Yu, Qingzhen Hou, Shanshan Gao, Fuzhong Xue, Hongkai Li","doi":"10.1186/s12916-026-05066-6","DOIUrl":"https://doi.org/10.1186/s12916-026-05066-6","url":null,"abstract":"<p><strong>Background: </strong>Suicide or other intentional self-harm (SSH) represents a critical global public health burden, yet biologically informed targets remain poorly defined due to its complex and incompletely understood etiology. This study aimed to prioritize genetically supported candidate targets for SSH and characterize their biological and translational relevance.</p><p><strong>Methods: </strong>We developed a multi-omics evidence framework integrating transcriptomic and proteomic Mendelian randomization, colocalization, and sensitivity diagnostics. The primary SSH outcome was from FinnGen R12 (11,538 cases; 488,810 controls). eQTLGen and GTEx were used for transcriptomic analyses, and UKB-PPP and ARIC for proteomic validation. Downstream analyses included functional enrichment, tissue expression profiling, exploratory metabolomic pathway analysis, brain cell-type-specific eQTL analyses, phenome-wide liability scanning, structural modeling with docking, virtual screening and molecular dynamics simulations, and baseline SSH classification in UKB-PPP individual-level proteomic data.</p><p><strong>Results: </strong>Transcriptome-wide MR identified 1,164 FDR-significant genes, of which 55 were retained as Tier 1-4 prioritized candidates after proteomic validation, colocalization, and sensitivity assessment. HSDL2 was the sole Tier 1 candidate, supported by consistent eQTL and pQTL evidence, adequate instrument strength, and colocalization at the HSDL2 locus (PP.H4 = 0.797). Genetically predicted HSDL2 expression was associated with higher SSH risk in eQTLGen (OR = 1.133, 95% CI: 1.076-1.192) and showed directionally consistent protein-level evidence in UKB-PPP (OR = 1.050, 95% CI: 1.005-1.098). Enrichment and metabolomic analyses implicated lipid-, bile acid-, and organelle-related pathways. Brain cell-type-specific analyses suggested neuronal involvement, with consistent excitatory-neuron associations across discovery and validation datasets and additional support for inhibitory neurons in SingleBrain, while oligodendrocyte signals required cautious interpretation. Structural analyses supported a putative HSDL2 ligand-binding pocket, providing hypothesis-generating structural context for the metabolic findings. Phenome-wide MR analyses identified additional disease associations, providing phenotypic context for future target evaluation. UKB-PPP baseline classification analyses provided complementary individual-level support for the prioritized protein signal.</p><p><strong>Conclusions: </strong>HSDL2 was prioritized as a genetically supported and biologically plausible candidate target for SSH, implicating a potential lipid-metabolic and neuronal vulnerability axis. These findings provide a foundation for future mechanistic validation and translational investigation.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243171","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ionomics powered single-cell mapping reveals targetable iron dysregulation in endometriosis associated macrophages.","authors":"Ming Yuan, Xue Jiao, Le Xu, Shuang Wang, Lei Yan, Zhaoyang Zhong, Qianhui Ren, Xiaoyu Dong, Hongwei Guan, Na Li, Chunyan Li, Jing Zhao, Kun Liu, Xiaoli Meng, Guoyun Wang","doi":"10.1186/s12916-026-05095-1","DOIUrl":"https://doi.org/10.1186/s12916-026-05095-1","url":null,"abstract":"<p><strong>Background: </strong>Endometriosis affects approximately 10% of women of reproductive age worldwide. Although elemental components of refluxed menstrual blood have been implicated in disease progression, comprehensive ionomic profiling of the endometriotic microenvironment remains limited. Characterizing the localized elemental landscape may generate new hypotheses regarding disease mechanisms.</p><p><strong>Methods: </strong>We employed inductively coupled plasma mass spectrometry (ICP-MS) to profile 63 elements in endometriotic cyst fluid. Single-cell RNA sequencing (scRNA-seq) was performed to explore cellular subpopulations potentially associated with elemental dysregulation. Senescent red blood cells (sRBCs) were used to model retrograde menstruation in endometriosis. The effects of iron chelation with deferoxamine (DFO) and ferroptosis inhibition with ferrostatin-1 (Fer-1) were evaluated.</p><p><strong>Results: </strong>ICP-MS identified iron as the most significantly elevated element in patients with endometriosis, supported by flow cytometry and Prussian blue staining. ScRNA-seq revealed a macrophage subcluster enriched in endometriotic lesions, co-expressing M2-associated markers and ferroptosis-related genes. Mechanistically, sRBC phagocytosis activated HIF-1α and HO-1 expression in macrophages, accompanied by intracellular iron accumulation, sublethal ferroptotic stress characterized by elevated lipid peroxidation and reactive oxygen species, M2-like polarization, and impaired phagocytic capacity. These iron-laden macrophages suppressed CD8⁺ T and NK cell effector functions, at least in part through the CXCL12-CXCR4 signaling axis. In the mouse model, treatment with DFO and Fer-1 partly reversed macrophage polarization, restored phagocytic function, alleviated lymphocyte suppression, and reduced ectopic lesion growth.</p><p><strong>Conclusions: </strong>This exploratory study suggests that sRBC-derived iron overload may be associated with a shift of macrophages toward an immunosuppressive phenotype, potentially linked to the HIF-1α/HO-1/GPX4 pathway. These changes may contribute to local immune dysfunction in endometriosis. These findings highlight macrophage iron metabolism as a potential therapeutic target that warrants validation in larger and independent cohorts.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endothelial cell-specific TGM2 deficiency promotes progression of temporal lobe epilepsy by disrupting S1P metabolism and intercellular communication.","authors":"Sijing Ren, Yanli Wang, Haiqing Zhang, Chengyu Pan, Xuehua Shen, Wanxiang Chen, Liuyan Zhou, Xinyu Wang, Qing-Xia Kong","doi":"10.1186/s12916-026-05077-3","DOIUrl":"https://doi.org/10.1186/s12916-026-05077-3","url":null,"abstract":"<p><strong>Background: </strong>Temporal lobe epilepsy (TLE) is a common and medically refractory neurological disorder with a complex pathogenesis. Blood-brain barrier (BBB) dysfunction is a key pathogenic factor. As a multifunctional protein, TGM2 has been shown to participate in vascular homeostasis, metabolic pathway regulation, and immune-inflammatory responses. This study aimed to systematically investigate the expression pattern, core functions, and molecular regulatory mechanisms of TGM2 in TLE, and to clarify its clinical value.</p><p><strong>Methods: </strong>Temporal cortex tissue and plasma samples from drug-resistant TLE patients and control subjects were collected, alongside kainic acid (KA)-induced epileptic mouse models. Single-cell RNA sequencing was adopted to identify TGM2's cell-specific expression pattern, and qPCR, Western blot and ELISA validated its expression levels. With endothelial cell-specific TGM2 conditional knockout mice, in vivo experiments assessed seizure severity and BBB permeability through behavioral observation, intracranial local field potential (LFP) recording and Evans blue (EB) assay. In vitro siRNA-mediated TGM2 knockdown in brain microvascular endothelial cells verified endothelial functional changes. Metabolomics, RNA-seq, nucleocytoplasmic separation, immunofluorescence and molecular docking were used to clarify regulatory mechanisms, and intercellular communication networks were constructed to analyze ligand-receptor interactions.</p><p><strong>Results: </strong>Results indicated that endothelial TGM2 was significantly downregulated in TLE patients and epileptic mice. Endothelial TGM2 deficiency aggravated recurrent seizures, increased BBB permeability, impaired endothelial function, and reduced the expression of tight junction protein CLDN5. Mechanistically, TGM2 positively regulated sphingosine-1-phosphate (S1P) synthesis. Reduced S1P production abolished the inhibition of RelA nuclear translocation, thereby activating downstream inflammatory genes and triggering endothelial inflammation. Molecular docking confirmed the direct binding between S1P and RelA. Furthermore, TGM2 deficiency remodels endothelial-neuron-microglia communication and disrupts neural circuit homeostasis.</p><p><strong>Conclusions: </strong>This study establishes a link between TGM2 and BBB function, metabolic pathways, and intercellular communication in TLE, providing an experimental basis for developing TLE therapeutic strategies targeting this pathway.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Minocycline for acute basilar artery occlusion stroke undergoing endovascular treatment: a randomized, evaluator-blinded, open-label, pilot trial.","authors":"Zhirong Fan, Jingjing Zhao, Rui Shi, Li Yao, Huiping Zhang, Rong Yin, Weiwang Li, Liping Yu, Xiangjun Yuan, Yi Jia, Bo Song, Baiya Fan, Xingshun Ma, Xue Li, Deshuai Li, Xiao Zhang, Yang Li, Ling Wang, Duolao Wang, Dong Wei, Wen Jiang","doi":"10.1186/s12916-026-05092-4","DOIUrl":"10.1186/s12916-026-05092-4","url":null,"abstract":"<p><strong>Background: </strong>Minocycline is a promising anti-inflammatory agent for reducing futile recanalization, but whether it improves clinical outcomes in basilar-artery stroke patients treated with endovascular therapy (EVT) remains unclear. In this study, we aimed to assess the efficacy and safety of oral minocycline combined with EVT on outcomes in patients who had basilar-artery stroke.</p><p><strong>Methods: </strong>The Minocycline for acute Ischemic Stroke undergoing endovascular Treatment due to Basilar artery occlusion (MIST-B) trial was a multicenter, randomized, evaluator-blinded, open-label, pilot trial in 12 Chinese hospitals. Adults with basilar-artery stroke no more than 24 h after onset were randomized (1:1) to receive oral minocycline (200 mg loading, then 100 mg every 12 h for 5 days) plus EVT or EVT alone. The primary efficacy outcome was the expanded National Institutes of Health Stroke Scale (e-NIHSS) score at day 5; the primary safety outcome was symptomatic intracranial hemorrhage (sICH) within 24 h. Participants were followed up 90 days after randomization. Modified intention-to-treat analysis examined treatment effect for the primary efficacy outcome using linear mixed models, with the baseline measurement of e-NIHSS score as a covariate.</p><p><strong>Results: </strong>From March 4, 2023, to March 4, 2025, 90 patients were randomized, and 89 were analyzed (mean age 61.7 years, 31.5% women). At day 5, median e-NIHSS was 12.0 (IQR 3.5 to 30.0) in the minocycline group and 10.5 (IQR 2.0 to 35.0) in the control group; corresponding mean values were 15.0 (SD 13.5) and 17.2 (SD 16.9), respectively (adjusted mean difference - 2.83 [95% CI -7.86 to 2.20]; P = 0.27). sICH within 24 h occurred in 2/37 (5.4%) of participants in the minocycline group vs. 6/41 (14.6%) in the control group (adjusted risk ratio, 0.70; 95% CI, 0.11 to 4.67). Other secondary efficacy and safety outcomes, including 90-day modified Rankin Scale, mortality, and adverse events, showed no significant differences between groups.</p><p><strong>Conclusions: </strong>Minocycline was well-tolerated in this population; however, these results did not provide evidence to support prescribing minocycline to improve early neurological outcomes. Larger trials of minocycline with extended treatment duration are warranted.</p><p><strong>Registration: </strong>The trial was registered at ClinicalTrials.gov (NCT05512910) on August 23, 2022.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13688725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenicity shapes distinct brain patterns and clinical profiles of bipolar disorder.","authors":"Yu Feng, Xiaonan Guo, Peng Huang, Ningning Jia, Li Wang, Xiaolong Ji, Zeyu Qin, Meng Li, Jianbo Lai, Xiaofeng Qin, Weihua Yue, Sheng Yang, Shaohua Hu","doi":"10.1186/s12916-026-05096-0","DOIUrl":"https://doi.org/10.1186/s12916-026-05096-0","url":null,"abstract":"<p><strong>Background: </strong>Bipolar disorder (BD) manifests both genetic predispositions and brain imaging abnormalities. Genetic analyses provide a powerful approach to disentangling the associations between BD and brain imaging-derived phenotype (IDP). However, in East Asian (EAS) populations, the genetic basis of these neuroimaging changes and their clinical relevance remains underexplored due to limited integrative evidence.</p><p><strong>Methods: </strong>We investigated the genetic architecture and clinical relevance of BD and brain IDPs in East Asian populations using individual-level data from the Chinese Bipolar Disorder (CN-BD) cohort (N = 3,920), summary statistics of BD from the Psychiatric Genomics Consortium (PGC) (N = 16,915) and of IDPs from the CHIMGEN Consortium (N = 7,058), and genotype and clinical data from the Chinese Longitudinal and Systematic Study of Bipolar Disorder cohort (CLASS-BD). We employed genetic correlation (GNOVA), multi-trait meta-analysis (MTAG, CPASSOC), and ancestry-specific fine-mapping (MESuSiE) to identify shared genetic loci. Functional annotation, protein association (SMR, BLISS), and spatiotemporal expression trajectory analyses were conducted. Bidirectional Mendelian Randomization (MR) assessed causal relationships, and polygenic risk score (PRS)-PheWAS explored phenome-level associations with clinical traits.</p><p><strong>Results: </strong>Our multi-trait meta-analysis identified 11 pleiotropic single nucleotide variants (SNVs) implicated in BD-IDP pairs, showing convergent enrichment in lipid metabolism and neurotransmitter biosynthesis pathways. Fine-mapping revealed an EAS-specific causal signal (rs7941324 near RPS27P20), which demonstrated high posterior inclusion probability in EAS but not European ancestries, and colocalized with BD and specific brain alterations. MR revealed 27 IDP-to-BD and 35 BD-to-IDP causal relationships, distinguishing structural changes of the parietal and temporal gyri as markers preceding BD onset and the right precuneus area as a state marker that followed BD onset. Clinically, BD-IDP polygenic risk scores were significantly associated with depressive symptoms, anxiety, and suicide risk. Mediation analysis further indicated that depressive and anxiety symptoms statistically mediated the relationship between BD-IDP PRS and suicide risk. Moreover, PRS-PheWAS identified 135 significant associations with metabolic phenotypes, highlighting a psycho-metabolic nexus in BD.</p><p><strong>Conclusions: </strong>Our findings reveal associations between polygenicity and distinct BD brain patterns and clinical profiles. We identified ancestry-specific causal variants and bidirectional BD-IDP relationships. PRS associations with depressive symptoms, anxiety, suicide risk, and metabolic phenotypes highlight precision medicine potential for BD.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149243230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnostic accuracy of point-of-care ultrasound in adult non-traumatic emergency medicine: an umbrella review.","authors":"Claudio Schneider, Nico Frei, Antoine Fernandez, Catherine Frei, Katharina Wahedi, Julius Husarek, Tanya Karrer, Carole Elodie Aubert, Beat Lehmann, Martin Müller","doi":"10.1186/s12916-026-05094-2","DOIUrl":"10.1186/s12916-026-05094-2","url":null,"abstract":"<p><strong>Background: </strong>Point-of-care ultrasound (POCUS) has become an increasingly used diagnostic tool in adult emergency departments (ED). Although numerous diagnostic test accuracy systematic reviews (DTA-SR) evaluating various POCUS applications are available, clinicians often face uncertainty due to ungraded accuracy estimates and inconsistent evidence. We conducted an umbrella review to (i) summarize diagnostic accuracy evidence for POCUS across adult non-traumatic emergency medicine-relevant conditions, (ii) provide GRADE-based ratings of pooled sensitivity and specificity, and (iii) synthesize findings when multiple DTA-SR addressed the same condition.</p><p><strong>Methods: </strong>We systematically searched PubMed and Embase from database inception to April 2026 for DTA-SR with meta-analysis evaluating the diagnostic performance of POCUS in adult ED populations for non-traumatic emergency medicine-relevant conditions. DTA-SR were included if they reported pooled sensitivity and specificity against accepted reference standards. The methodological quality was assessed using a DTA-adapted AMSTAR 2 tool. Sensitivity and specificity estimates were graded using the GRADE approach. Results were synthesized using a predefined hierarchical decision framework to account for overlap between primary studies.</p><p><strong>Results: </strong>A total of 197 DTA-SR were included, most focusing on cardiovascular, gastrointestinal, respiratory, or musculoskeletal conditions. About half were conducted in ED; the rest examined emergency medicine-relevant conditions in specialist settings. Methodological quality was mostly low or moderate. Diagnostic utility varied substantially across conditions. Among 91 evaluated conditions, 12 fulfilled predefined criteria for combined rule-in/rule-out supportive applications, 17 for primarily rule-in supportive applications, and 6 for primarily rule-out supportive applications (defined as pooled sensitivity or specificity ≥ 90% with at least moderate certainty of evidence). The remaining conditions were categorized as adjunctive because these thresholds were not met. Overall, certainty of evidence was frequently low or very low.</p><p><strong>Conclusions: </strong>POCUS shows promising diagnostic accuracy across adult non-traumatic emergency medicine-relevant conditions, often with moderate to high sensitivity and very high specificity. However, the overall strength and consistency of the evidence are limited. Therefore, diagnostic performance estimates should be interpreted with caution and within the context of each specific clinical condition, and should not be considered directly comparable or additive across different indications. Further high-quality research is needed to better define its role in emergency care.</p><p><strong>Clinical trial number: </strong>Clinical trial number: CRD42024587695.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13689006/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149236999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrated proteomics and machine learning reveal AHNAK as a discriminative biomarker of atrial fibrillation in heart failure.","authors":"Wengen Zhu, Zhenbang Gu, Yuwen Huang, Min Ye, Ruicong Xue, Yugang Dong, Yuzhong Wu, Chen Liu","doi":"10.1186/s12916-026-05079-1","DOIUrl":"10.1186/s12916-026-05079-1","url":null,"abstract":"<p><strong>Background: </strong>Atrial fibrillation (AF) is a frequent complication of heart failure (HF), markedly increasing morbidity and mortality. Although atrial fibrosis is increasingly recognized as a central mechanistic substrate linking HF to AF, the molecular determinants driving fibrotic remodeling and enabling early AF discrimination in HF remain poorly defined.</p><p><strong>Methods: </strong>We integrated label-free quantitative plasma proteomics with machine learning-based feature selection to analyze samples from 59 age- and sex-matched patients hospitalized with acute decompensated HF. Differentially expressed proteins were subjected to functional and pathway enrichment analyses, and candidate biomarkers were prioritized using an incremental feature selection framework. AHNAK, the top-ranked candidate, was functionally interrogated in vitro using TGF-β1-stimulated primary mouse atrial fibroblasts with siRNA-mediated knockdown and in vivo using a pressure overload-induced HF model in AHNAK heterozygous mice. A two-sample Mendelian randomization analysis was performed to evaluate the association between genetically proxied AHNAK expression and AF risk.</p><p><strong>Results: </strong>Plasma proteomic profiling identified 126 proteins that were significantly dysregulated in HF patients with AF compared with those in sinus rhythm, among which AHNAK was the most upregulated. Machine learning-based feature selection consistently ranked AHNAK as the most discriminative protein, with robust performance for AF discrimination in HF patients (AUC = 0.897, 95% confidence interval: 0.82-0.97). Functionally, AHNAK heterozygous deficiency promoted a profibrotic phenotype, characterized by increased expression of α-smooth muscle actin, fibronectin, and collagen Iα in atrial fibroblasts and exacerbated atrial fibrosis and cardiac dysfunction in pressure-overloaded mice. Mendelian randomization analysis demonstrated a significant protective effect of higher AHNAK expression against AF, with no evidence of horizontal pleiotropy.</p><p><strong>Conclusions: </strong>This study identifies AHNAK as a discriminative plasma biomarker for AF in HF patients and implicates AHNAK deficiency as a contributor to atrial fibrotic remodeling and AF pathogenesis. External validation in larger and prospective HF cohorts will be required to confirm the clinical utility of AHNAK for AF risk stratification and early detection.</p>","PeriodicalId":9188,"journal":{"name":"BMC Medicine","volume":"24 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13685328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149227189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}