Abstract The issue of multimorbidity in children and adolescents is becoming increasingly prominent, but there is no consensus on the definition of multimorbidity. As research deepens, issues related to the comparability and standardization of relevant findings are gradually emerging. As a solution, a systematic review of both domestic and international research on multimorbidity is conducted, and a classification system for defining the concept of multimorbidity is proposed, offering more convenient conditions for the advancement of future research and cross study exchange.

ObjectiveTo investigate the modifiable areal unit problem （MAUP） in the spatial pattern of Pseudostellaria heterophylla production regions and reveal the impact of statistical scales on the spatial distribution characteristics of this medicinal plant species. MethodsUsing multi-source data （literature records， field surveys， and statistical data）， we systematically analyzed the spatial patterns across three administrative levels （provincial， prefectural， and county scales）. Spatial autocorrelation （Moran's I） analysis， high-low clustering （Getis-Ord General G）， and hot/cold spot analysis （Getis-Ord Gi*） were employed. ResultsThe literature-based analysis showed that the production regions of P. heterophylla presented random distribution on the provincial scale and significant aggregation on the prefectural scale. The field survey data showed that the production regions displayed random distribution on the provincial scale but significant aggregation on both prefectural and county scales. The statistical data revealed that the production regions lacked spatial autocorrelation on the provincial scale but demonstrated significant aggregation on prefectural and county scales. ConclusionMAUP effects have substantive implications for understanding and decision-making in the arrangement of medicinal plant production regions. The county scale proves to be the most sensitive and explanatory level for analyzing the spatial pattern of P. heterophylla production regions， providing a critical foundation for habitat modeling， suitability evaluation， and ecological cultivation planning of medicinal plants.

Objective To explore the efficacy of progressive exercise training based on the modified Medical Research Council dyspnea scale (mMRC) grading in respiratory rehabilitation for patients with chronic obstructive pulmonary disease (COPD) at a primary healthcare setting. Methods A total of 106 patients with COPD admitted to Zhuanqiao Community Health Service Center in Shanghai from Aug.1, 2022 to Jul. 30, 2024 were selected as research subjects. They were randomly divided into a study group and a control group in a 1∶1 ratio, with 53 patients in each group. The control group received conventional treatment, while the study group received conventional treatment combined with progressive exercise training. After 4 weeks of continuous treatment, the changes in the 6-minute walk test (6MWT), COPD assessment test (CAT) score, mMRC grading, Global Initiative for Chronic Obstructive Lung Disease (GOLD) grading and pulmonary function were compared between the two groups. Results Patients in both groups showed improvements in 6MWT distance, CAT score, mMRC grading, GOLD grading, and pulmonary function compared to baseline (P＜0.05). Moreover, the study group had better improvements in 6MWT distance, CAT score, mMRC grading, GOLD grading, and pulmonary function than the control group (P＜0.05). Conclusions Conventional treatment combined with progressive exercise training based on mMRC grading can enhance the effect of respiratory rehabilitation in patients with COPD, particularly in improving pulmonary function and exercise tolerance.

ObjectiveThrough multimodal research methods including medication rule mining， network pharmacology， molecular docking and dynamics simulation， and in vivo animal experiments， this study aims to speculate and verify the core composition （Ginseng Radix et Rhizoma Rubra-Salviae Miltiorrhizae Radix et Rhizoma-Notoginseng Radix et Rhizoma） and efficacy （Qi-invigorating and blood-activating） of the drug combination in Yitangkang Compound for improving diabetic cardiomyopathy （DCM）， investigate the interaction relationship and binding strength between core active ingredients of the drug combination and key signaling pathway targets， and further explore the mechanism by which the Qi-invigorating and blood-activating drug combination regulates the calcium signaling pathway to improve cardiac function in DCM rats. MethodsThe Ancient and Modern Medical Cases Cloud Platform was used to construct a DCM prescription database， and the "Analysis Method" module of the platform was applied to mine and summarize medication rules， thereby determining the core composition of the Qi-invigorating and blood-activating drug combination in Yitangkang. Drug-active ingredient-signaling pathway-core target-disease analysis and visualization were conducted by combining network pharmacology with the Traditional Chinese Medicine System Pharmacology Platform （TCMSP） database， SwissTargetPrediction platform， GeneCards database， MetaScape database， CytoScape software， etc. Then， molecular docking was performed via the CB-Dock2 platform， and molecular dynamics simulation of the high-binding-strength docking complexes was carried out by Gromacs software. Finally， in vivo animal experiments were carried out. Twenty-eight Sprague Dawley （SD） rats meeting the research criteria were divided into a normal group， a model group， a drug combination group （3.3 g·kg^-1）， and a Yitangkang group （20 g·kg^-1）. A type 2 diabetes mellitus （T2DM） rat model was established by high-fat diet feeding combined with intraperitoneal injection of streptozotocin （STZ）， followed by continuous feeding for eight weeks until the DCM model was successfully established. During this period， the traditional Chinese medicine （TCM） compound and drug combination were administered for prevention and treatment intervention. Meanwhile， changes in blood glucose， body weight， and heart index of each group were monitored. Cardiac function was assessed by echocardiography， and electrophysiological signals were detected by an electrocardiogram. The heart tissue was observed for pathological changes by hematoxylin-eosin （HE） and Masson staining， and the expression of L-type calcium channel （CACNA1C）， calmodulin （CALM1）， calcium/calmodulin-dependent protein kinase Ⅱδ （CAMK2D）， and neuronal nitric oxide synthase （NOS1） proteins in the calcium signaling pathway of myocardial tissue was detected by Western blot. ResultsIn 62 DCM prescriptions， Ginseng Radix et Rhizoma Rubra， Salviae Miltiorrhizae Radix et Rhizoma， and Notoginseng Radix et Rhizoma were used most frequently. Their meridian tropism mainly involved the spleen， heart， and lung， and their sweet and warm properties were prominent. The drugs for tonifying or blood-activating and stasis-resolving ranked top. In association rule analysis， （Ginseng Radix et Rhizoma Rubra， Salviae Miltiorrhizae Radix et Rhizoma）-Notoginseng Radix et Rhizoma had the highest lift. Network pharmacology obtained 75 active ingredients of the drug combination， 714 drug combination action targets， 2 702 disease targets， and 286 intersection targets. Protein-protein interaction （PPI） network predicted nine interaction component-targets （nine active ingredients and four calcium signaling pathway target genes）. Molecular docking showed the four complexes with the lowest binding energy were 2f3z-ginsenoside Re， 1cll-quercetin， 9blh-（6S）-6-（hydroxymethyl）-1，6-dimethyl-8，9-dihydro-7H-naphtho［8，7-g］benzofuran-10，11-dione， and 5vv0-miltionone Ⅱ. Dynamics simulation showed the CALM1-quercetin complex had the strongest binding affinity. The animal experiment results revealed that compared with the normal group， the model group showed significant changes in blood glucose， body weight， myocardial tissue morphology， heart index， cardiac function， electrophysiological indexes， and the expression levels of CACNA1C， CALM1， CAMK2D， and NOS1 proteins （P<0.05， P<0.01）. Compared with the model group， the Yitangkang group had a certain improvement effect on the above indexes （P<0.05， P<0.01）. Compared with the Yitangkang group， the drug combination group showed no significant difference in improving myocardial tissue morphology， heart index， cardiac function， electrophysiological indexes， and the expression of CACNA1C， CALM1， CAMK2D， and NOS1 proteins， except for blood glucose and body weight. ConclusionGinseng Radix et Rhizoma Rubra， Salviae Miltiorrhizae Radix et Rhizoma， and Notoginseng Radix et Rhizoma are the core Qi-invigorating and blood-activating drug combination in Yitangkang Compound. They have a good preventive and therapeutic effect on STZ-induced DCM in rats， and their mechanism of action may be related to the regulation of the calcium signaling pathway.

Hepatocellular carcinoma (HCC) is one of the fastest growing cancers in the world, ranking fourth among the causes of cancer-induced death in the world. At present, the field of HCC treatment is developing rapidly, and immunotherapy has been recognized as a promising treatment method, in which T cells play a key role in HCC immunotherapy. However, in the case of virus infection or in tumor microenvironment (TME), T cells will be continuously stimulated by antigens and then fall into the state of T cell exhaustion (Tex). This state will not only reduce the immunity of patients but also lead to poor efficacy of immunotherapy. Therefore, to deeply analyze the mechanism of Tex and to explore effective strategies to reverse Tex is the key point in the immunotherapy for HCC. This review aims to summarize the mechanism of Tex in HCC patients, and the current situation and shortcomings of drug research and development to reverse Tex at this stage, in order to provide theoretical basis for the optimization of immunotherapy regimen for HCC patients.
Humans ; Carcinoma, Hepatocellular/therapy* ; Liver Neoplasms/therapy* ; Immunotherapy/methods* ; T-Lymphocytes/immunology* ; Tumor Microenvironment/immunology* ; Animals ; T-Cell Exhaustion

The translocator protein (TSPO) positron emission tomography (PET) can noninvasively detect neuroinflammation associated with epileptogenesis and epilepsy. This study explored the role of the TSPO-targeting radioligand [¹⁸F]F-TFQC, an m-trifluoromethyl ER176 analog, in the PET neuroimaging of epileptic rats. Initially, [¹⁸F]F-TFQC was synthesized with a radiochemical yield of 8%-10% (EOS), a radiochemical purity of over 99%, and a specific activity of 38.21 ± 1.73 MBq/nmol (EOS). After determining that [¹⁸F]F-TFQC exhibited good biochemical properties, [¹⁸F]F-TFQC PET neuroimaging was performed in epileptic rats at multiple time points in various stages of disease progression. PET imaging showed specific [¹⁸F]F-TFQC uptake in the right hippocampus (KA-injected site, i.e., epileptogenic zone), which was most pronounced at 1 week (T/NT 1.63 ± 0.21) and 1 month (T/NT 1.66 ± 0.20). The PET results were further validated using autoradiography and pathological analysis. Thus, [¹⁸F]F-TFQC can reflect the TSPO levels and localize the epileptogenic zone, thereby offering the potential for monitoring neuroinflammation and guiding anti-inflammatory treatment in patients with epilepsy.

Metastatic dissemination is the major cause of death from breast-cancer (BC). Fusobacterium nucleatum (F.n) is widely enriched in BC and has recently been identified as one of the high-risk factors for promoting BC metastasis. Here, with an experimental model, we demonstrated that intratumoral F.n induced BC aggressiveness by transcriptionally activating Epithelial-mesenchymal transition-associated genes. Therefore, the F.n may be a potential target to prevent metastasis. Given the fact that cancer-associated fibroblasts (CAFs) are abundant in BC and located near blood vessels, we report an optogenetic system that drives CAF to in situ produce human antibacterial peptide LL37, with the characteristics of biosafety and freely intercellular trafficking, for depleting intratumoral F.n, leading to a 72.1% reduction in lung metastatic nodules number without affecting the balance of the systemic flora. Notably, mild photothermal treatment was found that could normalize CAF, contributing to synergistically inhibiting BC metastasis. In addition, the system can also simultaneously encode a gene of TNF-related apoptosis-inducing ligand to suppress the primary tumor. Together, our study highlights the potential of local elimination of tumor pathogenic bacteria to prevent BC metastasis.

Hypertrophic scar is a fibrous hyperplastic disorder that arises from skin injuries. The current therapeutic modalities are constrained by the dense and rigid scar tissue which impedes effective drug delivery. Additionally, insufficient autophagic activity in fibroblasts hinders their apoptosis, leading to excessive matrix deposition. Here, we developed an active microneedle (MN) system to overcome these challenges by integrating micromotor-driven drug delivery with autophagy regulation to remodel the scar microenvironment. Specifically, sodium bicarbonate and citric acid were introduced into the MNs as a built-in engine to generate CO₂ bubbles, thereby enabling enhanced lateral and vertical drug diffusion into dense scar tissue. The system concurrently encapsulated curcumin (Cur), an autophagy activator, and triamcinolone acetonide (TA), synergistically inducing fibroblast apoptosis by upregulating autophagic activity. In vitro studies demonstrated that active MNs achieved efficient drug penetration within isolated scar tissue. The rabbit hypertrophic scar model revealed that TA-Cur MNs significantly reduced the scar elevation index, suppressed collagen I and transforming growth factor-β1 (TGF-β1) expression, and elevated LC3 protein levels. These findings highlight the potential of the active MN system as an efficacious platform for autonomous augmented drug delivery and autophagy-targeted therapy in fibrotic disorder treatments.

Glioma represents the most prevalent malignant tumor of the central nervous system, with chemotherapy serving as an essential adjunctive treatment. However, most chemotherapeutic agents exhibit limited ability to penetrate the blood-brain barrier (BBB). This study introduced a novel dual-targeting strategy for glioma therapy by modulating the formation of nanobody-driven protein coronas to enhance the brain and tumor-targeting efficiency of hydrophobic cisplatin prodrug-loaded lipid nanoparticles (C8Pt-Ls). Specifically, nanobodies (Nbs) with fibrinogen-binding capabilities were conjugated to the surface of C8Pt-Ls, resulting in the generation of Nb-C8Pt-Ls. Within the bloodstream, Nb-C8Pt-Ls could bound more fibrinogen, forming the protein corona that specifically interacted with LRP-1, a receptor highly expressed on the BBB. This interaction enabled a "Hitchhiking Effect" mechanism, facilitating efficient trans-BBB transport and promoting effective brain targeting. Additionally, the protein corona interacted with LRP-1, which is also overexpressed in glioma cells, achieving precise tumor targeting. Computational simulations and SPR detection clarified the molecular interaction mechanism of the Nb-fibrinogen-(LRP-1) complex, confirming its binding specificity and stability. Our results demonstrated that this strategy significantly enhanced C8Pt accumulation in brain tissues and tumors, induced apoptosis in glioma cells, and improved therapeutic efficacy. This study provides a novel framework for glioma therapy and underscores the potential of protein corona modulation-based dual-targeting strategies in advancing treatments for brain tumors.

OBJECTIVES: To develop an early atrial fibrillation (AF) risk prediction model based on large-scale electrocardiogram (ECG) data from the Chinese population. METHODS: The data of multiple ECG records of 30 383 patients admitted in the Chinese PLA General Hospital between 2009 and 2023 were randomly divided into the training set and the internal testing set in a 7:3 ratio. The predictive factors were selected based on the training set using univariate analysis, LASSO regression, and the Boruta algorithm. Cox proportional hazards regression was used to establish the ECG model and the composite model incorporating age, gender, and ECG model score. The discrimination power, calibration, and clinical net benefits of the models were evaluated using the area under the receiver operating characteristic curve (AUROC), calibration curves, and decision curves. RESULTS: The cohort included 51.1% male patients with a median age of the patients of 51 (36, 62) years and an AF incidence of 4.5% (1370/30 383). In the ECG model, the parameters related to the P wave and QRS complex were identified as significant predictors. In the testing set, the AUROC of the ECG model for predicting 5-year AF risk was 0.77 (95% CI: 0.74-0.80), which was increased to 0.81 (95% CI: 0.78-0.83) after incorporating age and gender, with a net reclassification improvement of 0.123 and an integrated discrimination improvement of 0.04 (P<0.05). The calibration curve of the model was close to the diagonal line. Decision curve analysis showed that the clinical net benefit of the composite model was higher than that of the ECG model across the majority of threshold probability. CONCLUSIONS The composite model incorporating quantitative ECG features during sinus rhythm, along with age and gender, can effectively predict AF risk in the Chinese population, thus providing a low-cost screening tool for early AF risk assessment and management.
Humans ; Atrial Fibrillation/epidemiology* ; Electrocardiography ; Middle Aged ; Male ; Female ; China/epidemiology* ; Proportional Hazards Models ; Adult ; Risk Factors ; Risk Assessment ; East Asian People