Beijing Friendship Hospital

Subcortical vascular cognitive impairment (SVCI) is a heterogeneous cognitive impairment caused by small vessel disease. Diagnosis of SVCI remains challenging when neuropsychological assessment is impractical. This study proposes a diffusion tensor imaging (DTI)-based DenseNet to identify SVCI from subcortical ischemic vascular disease (SIVD) and to profile multidomain cognitive risks. We collected neuropsychological scales and DTI from 134 SVCI and 171 SIVD patients in our internal dataset for model development. An external target-domain dataset of 90 SVCI and 103 SIVD patients was used for unsupervised domain adaptation (UDA). Within this dataset, 45 SVCI and 53 SIVD patients were used for unlabeled UDA fitting; the remaining 45 SVCI and 50 SIVD patients were held out as a target-domain test set. Model-generated salient maps identified white matter (WM) regions associated with SVCI. Mutual information (MI) maps between DTI and 6 neuropsychological scales were computed to identify structural correlates of cognitive domains for cognitive profiling. We computed structural similarity index measure (SSIM) between individual-level salient maps derived from DenseNet and the MI maps for unsupervised clustering to stratify domain-specific cognitive impairment risk in SVCI. The DenseNet achieves high accuracy (0.902 internal, 0.926 target-domain) with AUCs of 0.951 and 0.942, respectively. SVCI probabilities reflect cognitive severity, and salient maps are associated with neuropsychological performance. Regarding cognitive profiling, each cognitive domain is divided into low, moderate, and high subgroups, with significantly different SSIM. Our DTI-based study demonstrates accurate SVCI identification and individualized multi-domain cognitive profiling. This offers a complementary framework to support diagnosis and personalized intervention.

BackgroundPatients with acute pancreatitis (AP) commonly present with thyroid dysfunction in clinic. The present study aimed to characterize thyroid dysfunction in AP patients, identify the risk factors, assess its dynamics during AP resolution and evaluate its value for predicting AP severity.MethodsA total of 182 AP patients and 61 age- and gender-matched patients with chronic pancreatitis (CP) were enrolled. Demographic characteristics, biochemical parameters and thyroid function were collected.ResultsAP patients had an average age of 53.3±16.7 years and 61.5% were males; CP patients had an average age of 52.7±11.9 years and 59.0% were males. Compared with CP group, the level of T3, T4, FT3 and TSH was significantly lower in AP group. A high prevalence of thyroid dysfunction (87.4%), manifested as decreased thyroid hormones and TSH, was observed in AP patients. The extent of hormone reduction was progressively exacerbated with increasing the disease severity. Albumin (Alb) was independently positive correlation, and hs-CRP and lactate (Lac) were independently negatively correlated with thyroid function. The levels of thyroid hormones and TSH increased during AP resolution. TSH demonstrated superior predictive value for moderate-to-severe AP compared to traditional markers (hs-CRP, Alb, Ca) and established severity scores (APACHE II, BISAP). The cut-off value of TSH was 0.42 µIU/mL with the highest AUC (0.772 (0.693–0.851)) and the highest Youden’s index (0.478).ConclusionThyroid dysfunction was common in AP patients, characterized by a reduction in thyroid hormones and TSH. Lower Alb and higher hs-CRP and Lac were independent risk factors of thyroid dysfunction. During AP resolution, thyroid dysfunction could spontaneously recover. Furthermore, a low level of TSH at admission showed promising predictive value for moderate to severe AP in the early stage.

Chronic spontaneous urticaria (CSU) poses a significant burden on both patient and caregiver. Currently treatments for CSU are inadequate for some patients. TLL-018, an oral TYK2/JAK1 inhibitor, is under investigation for CSU treatment. To evaluate the efficacy and safety of TLL-018 for treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines. In this multicenter, double-blind, randomized, placebo-controlled, parallel-group pilot study (NCT05373355), patients with CSU who showed an inadequate response to antihistamines received either 10 mg or 30 mg of TLL-018, or placebo orally twice daily. After 4 weeks, patients on placebo were switched to 20 mg of TLL-018, and continuing treatment for an additional 8 weeks. The primary endpoint was safety, while secondary endpoints included efficacy measures, such as weekly Urticaria Activity Score (UAS7) ≤ 6, UAS7 = 0, and a Dermatology Life Quality Index of 0 or 1 at weeks 4 and 12. The study involved of 41 patients. At week 4, the ANCOVA versus change from placebo of UAS7/weekly Itch Severity Score/weekly Hive Severity Score were -11.5/-8.0/-3.8 in the 10-mg groups and -16.0/-9.0/-7.0 in the 30-mg groups. At week 12, the percentages achieving UAS7 ≤ 6 and UAS7 = 0 were 53.8%/38.5%, 71.4%/64.3%, and 61.5%/53.8% in the placebo-to-20 mg, the 10-mg, and the 30-mg TLL-018 groups, respectively. Common treatment-emergent adverse events included elevated serum creatine kinase and blood lipid levels, hyperglycemia, and urinary occult blood. TLL-018 was well-tolerated and effective in treating moderate-to-severe CSU in patients who had an inadequate response to antihistamines.

Myocardial ischemia/reperfusion (I/R) injury is a common and severe clinical complication in patients with ischemic heart disease after reperfusion therapy. Effective therapeutic strategies for myocardial I/R injury remain limited. Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. However, the mechanisms underlying ferroptosis in myocardial I/R injury are not fully understood. Transcriptomic data from patients with heart failure and cardiomyocytes undergoing ferroptosis were analyzed. Based on the screening results, TRIM28 (tripartite motif-containing 28) expression was evaluated in ferroptotic cardiomyocytes. Cardiac I/R injury models in mice and hypoxia/reoxygenation injury models in neonatal rat ventricular myocytes were established. To explore the function of TRIM28, we used adeno-associated virus serotype 9 to achieve cardiomyocyte-specific overexpression and generated tamoxifen-inducible cardiomyocyte-specific TRIM28 knockout mice. RNA sequencing, coimmunoprecipitation coupled with mass spectrometry, and ubiquitinome profiling were applied to elucidate the underlying mechanisms. Human heart samples from patients with ischemic heart disease were used to evaluate the expression of TRIM28 and its related signaling molecules. The Connectivity Map database was used to screen potential activators of TRIM28. We found that TRIM28 expression was downregulated in ferroptosis inducer-treated and hypoxia/reoxygenation-injured cardiomyocytes, as well as in I/R-injured mouse hearts. Cardiomyocyte-specific overexpression of TRIM28 protected the heart against I/R-induced ferroptosis, whereas its deficiency exacerbated myocardial I/R-induced ferroptotic injury. Mechanistically, TRIM28 functioned as an E3 ubiquitin ligase that directly bound to IRP2 (iron regulatory protein 2) and promoted K48-linked ubiquitination at the K877 site, leading to the downregulation of IRP2 and TFR1 (transferrin receptor 1), suppression of intracellular iron uptake, and consequent attenuation of cardiomyocyte ferroptosis. Furthermore, p55γ interacted with and upregulated TRIM28, thereby mitigating I/R-induced myocardial ferroptosis. Consistent with these findings, protein levels of TRIM28 and p55γ were decreased in heart samples from patients with ischemic heart disease, whereas IRP2 and TFR1 were increased. Last, we demonstrated that perhexiline inhibited I/R-induced myocardial ferroptosis by upregulating p55γ and TRIM28. Our study identifies TRIM28 as an essential E3 ubiquitin ligase of IRP2 and delineates that TRIM28-mediated inhibition of myocardial ferroptosis by targeting IRP2-TFR1 signaling protects the heart against I/R injury, indicating that targeting TRIM28 represents a promising therapeutic strategy for suppressing cardiomyocyte ferroptosis and I/R injury.

Mendelian randomization (MR), polygenic risk score (PRS), Geno Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG) are powerful bioinformatic analysis tools. However, the analysis of MR, PRS, GO, and KEGG may pose a challenge for novices. This article intends to introduce a program that adeptly guides beginners in implementing these analysis functions, ensuring that even those new to the field can confidently use them. The MPGK program was developed to run on the command line. It conveniently implements the MR, PRS, GO, and KEGG analysis functions by calling well-written R programs. The results of our analyses were validated using genome-wide association study (GWAS) summary data for diabetes and psoriasis, as well as gene sequencing data for diabetes. Three demo analyses using the MPGK program demonstrate the comprehensive capabilities of the MPGK program in conducting advanced bioinformatics analysis. First, the MPGK program revealed a causal relationship between diabetes and psoriasis. Additionally, the PRS analysis generated polygenic risk scores for diabetes, demonstrating the implementation of PRS analysis within the MPGK framework. Furthermore, the GO and KEGG analyses indicated that psoriasis is associated with infection and T helper 17 cells. These findings are consistent with the previous literature. MPGK can be easily used to perform comprehensive analysis, including MR, PRS, GO, and KEGG analyses, by both beginners and researchers.

Neonatal regulatory T (Treg) cells in secondary lymphoid organs have greater proliferative capacity and more potent suppressive functions than adult Treg cells. However, the phenotypic and functional features of Tregs in neonatal nonlymphoid organs are not well understood. Our prior work demonstrated that thymus-derived Treg cells entering the neonatal mouse liver enhance immune tolerance and periportal liver maturation. Compared to splenic Treg cells, these hepatic Tregs have faster turnover and superior suppression of naïve T-cell proliferation. To further define this population, we conducted single-cell transcriptomic and immunophenotypic analyses of liver- and spleen-derived Tregs from neonatal and adult mice. Our analysis revealed a distinct T-box transcription factor Tbx21 (T-bet)+ effector Treg subset uniquely enriched in the neonatal liver. These cells possess liver-homing properties, clonal expansion of unique T-cell receptor (TCR) repertoires, and heightened suppressive activity. Interleukin-27 (IL-27) and interferon gamma (IFN-γ), cytokines highly expressed in the neonatal liver, play a critical role in promoting T-bet expression and the acquisition of an ectonucleoside triphosphate diphosphohydrolase 1 (CD39)+ C-X-C chemokine receptor type 3 (CXCR3)+ double-positive phenotype in Treg cells. Collectively, our findings characterize a liver-specific neonatal T-bet+ Treg population shaped by the hepatic microenvironment, highlighting its unique tissue-resident signature and immunoregulatory role.

As a rare autosomal recessive disorder, primary hyperoxaluria type 3 (PH3) presents diagnostic challenges. Our comparative analysis of clinical characteristics between patients with PH3 and non-PH patients revealed distinct characteristics that may facilitate the diagnosis of PH3. Clinical data from pediatric patients with urolithiasis who had undergone whole-exome sequencing from 2016-2024 were analyzed. Patients were divided into PH3 group and non-PH group on the basis of genetic testing. Compared with non-PH patients, PH3 patients presented earlier onset (0.9 vs. 2.0years, P = 0.021), higher incidence of nephrocalcinosis (22.22% vs. 3.17%, P = 0.008), higher serum calcium (2.55 vs. 2.49mmol/L, P = 0.007), higher urinary oxalate levels (333.70 vs. 170.84µg/mg, P = 0.008), higher urinary citrate levels (195.22 vs. 123.13µg/mg, P = 0.015), lower urinary uric acid levels (838.44 vs. 1177.42µg/mg, P = 0.040), and lower urinary calcium levels (113.27 vs. 352.21µg/mg, P < 0.001). Subgroup analyses revealed that patients with PH3 had higher urinary oxalate levels (333.70 vs. 170.84µg/mg, P = 0.042) than patients with cystinuria. Compared with patients in the other stone-related gene mutation groups, patients in the PH3 group presented earlier onset (0.9 vs. 2.5years, P = 0.029), higher urinary oxalate levels (333.70 vs. 105.30µg/mg, P = 0.045), higher urinary citrate levels (195.22 vs. 59.36µg/mg, P < 0.001), and lower urinary calcium levels (113.27 vs. 421.24µg/mg, P = 0.003). Patients with PH3 had greater incidence of nephrocalcinosis (22.22% vs. 0, P = 0.007), higher serum calcium levels (2.55 vs. 2.49mmol/L, P = 0.030), higher urinary oxalate levels (333.70 vs. 182.74µg/mg, P = 0.048) and lower urinary calcium levels (113.27 vs. 368.14µg/mg, P = 0.004) than patients with negative molecular diagnoses. Pediatric patients with PH3 are characterized by early onset, nephrocalcinosis, increased urinary oxalate excretion and lower urinary calcium excretion, which could provide guidance for earlier diagnosis of patients with PH3.