Immune thrombocytopenia (ITP) is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury. ITP has complicated immunopathological mechanisms that need further elucidation. It is well known that the costimulatory molecules OX40 ligand (OX40L) and OX40 play essential roles in the immunological mechanisms of autoimmune diseases. Previously, we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells (PBMCs) of ITP patients. In our present study, OX40L-induced follicular helper T (Tfh) cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator (ICOS), programmed cell death protein-1 (PD-1), and cluster of differentiation 40 ligand (CD40L) in vitro. Moreover, aberrant OX40L‒OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo, inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model, which might accelerate the progression of ITP. Additionally, signal transduction through the OX40L‒OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor (TRAF)‒nuclear factor-κB (NF-κB) and Janus kinase (JAK)‒signal transducer and activator of transcription (STAT) signaling pathways. Overall, OX40L‒OX40 signaling is proposed as a potential novel therapeutic target for ITP.
Animals ; OX40 Ligand/physiology* ; Purpura, Thrombocytopenic, Idiopathic/immunology* ; Cell Differentiation ; Mice ; T-Lymphocytes, Helper-Inducer/cytology* ; T Follicular Helper Cells/cytology* ; Signal Transduction ; Receptors, OX40 ; Mice, Inbred C57BL ; Humans ; Female

The p21-activated kinase 4 (PAK4), a key regulator of malignancy, is negatively correlated with immune infiltration and has become an emergent drug target of cancer therapy. Given the lack of high efficacy PAK4 inhibitors, we herein reported the identification of a novel inhibitor 13 bearing a tetrahydrobenzofuro[2,3-c]pyridine tricyclic core and possessing high potency against MIA PaCa-2 and Pan02 cell lines with IC₅₀ values of 0.38 and 0.50 μmol/L, respectively. This compound directly binds to PAK4 in a non-ATP competitive manner. In the mouse Pan02 model, compound 13 exhibited significant tumor growth inhibition at a dose of 100 mg/kg, accompanied by reduced levels of PAK4 and its phosphorylation together with immune infiltration in mice tumor tissue. Overall, compound 13 is a novel allosteric PAK4 inhibitor with a unique tricyclic structural feature and high potency both in vitro and in vivo, thus making it worthy of further exploration.

OBJECTIVE: To analyze the rules of moxibustion for low back pain by ZHOU Meisheng by using data mining and knowledge graph technology. METHODS: Taking the medical cases of moxibustion for low back pain from ZHOU Meisheng's legacy manuscripts and existing works as the research objects, information on disease types, symptoms, tongue manifestations, pulse conditions, syndrome patterns, moxibustion methods and acupoints were collected. Frequency statistics and community analysis were conducted by the ancient and modern medical record cloud platform V 2.3.7, cluster analysis of high-frequency acupoints was performed by SPSS26.0, association rule analysis of high-frequency acupoints was performed by SPSS Modeler 18.0, and the generated linked data were imported into Cytoscape 3.9.1 for complex network analysis. Knowledge graph of moxibustion for low back pain by ZHOU Meisheng was constructed based on the results of data mining. The data storage and display of knowledge graph were realized through the Neo4j 3.5.25 graph database, and the Cypher query language was used for knowledge graph retrieval and discovery. RESULTS: A total of 219 medical cases were collected, involving 14 disease types, 85 related clinical symptoms, 5 related TCM syndrome types, and 6 moxibustion methods. The acupoints were mostly attributed to the governor vessel, the bladder meridian of foot-taiyang, non-meridian and non-acupoint areas. The core prescription of acupoints derived from complex network analysis included tender points, Shenshu (BL23), Jinsuo (GV8), Yinjiao (CV7), Yaoyangguan (GV3), Yanglingquan (GB34), which were largely coincides with high-frequency acupoints. Cluster analysis obtained 4 cluster combinations. Community analysis yielded 6 communities, each corresponding to different acupoints.The constructed knowledge graph contained 187 nodes and 696 relationships, by retrieving clinical elements related to low back pain, the disease-moxibustion association graph, disease-acupoint association graph, accompanying symptom-acupoint association graph and syndrome type-matching point association graph were obtained. CONCLUSION When treating low back pain with moxibustion, ZHOU Meisheng adopts the principle of promoting circulation, distinguishing diseases to determine the treatment, selecting acupoints according to the diseases, and matching points according to the symptoms.And taking tender points, Shenshu (BL23), Jinsuo (GV8), Yinjiao (CV7), Yaoyangguan (GV3), Yanglingquan (GB34) as core acupoints, combined with tenderness point selection, acupoint selection based on meridian and zangfu syndrome differentiation, "sunshine area" acupoint selection, yin-yang acupoint matching. Additionally, he skillfully employs special points, such as Zhongzhu (KI15) and ear tips, pays attention to the reform of moxibustion tools, and innovates the moxibustion techniques, using distinctive moxibustion tools and methods to treat low back pain.
Moxibustion/methods* ; Humans ; Data Mining ; Low Back Pain/history* ; Acupuncture Points ; History, Ancient ; Female ; China ; Male ; Adult ; Middle Aged

Objective To explore the differences in the use of hypoglycemic drugs and glycated hemoglobin(HbA1c)levels among elderly patients with type 2 diabetes mellitus(T2DM)of different age groups,and to provide some references for individualized blood glucose control in elderly T2DM patients.Methods A retrospective study was conducted.A total of 187 elderly(≥70 years old)T2DM patients admitted to Guangdong Provincial People's Hospital from October 2022 to August 2024 were selected as the research subjects.The patients were divided into three groups according to age:70-79(93 cases),80-89(52 cases),and≥90(42 cases)years old.The differences in glucose metabolism,lipid metabolism,renal function and the use of hypoglycemic drugs among the groups were compared.Results With increasing age,the hospital stays for the 70-79,80-89,and≥90 years old groups significantly increased(days:7.78±2.84,10.17±7.97,15.45±11.21,P<0.05),diastolic blood pressure gradually decreased[mmHg(1 mmHg≈ 0.133 kPa):75.60±9.15,73.77±10.79,67.45±9.50],estimated glomerular filtration rate(eGFR)and HbA1c both significantly decreased[eGFR(mL·min-1·1.73 m-2):65.55±23.01,49.68±20.19,46.39±16.41;HbA1c(9.02±1.99)%,(8.75±2.21)%,(7.80±1.43)%,all P<0.05].In terms of hypoglycemic treatment,the average number of hypoglycemic drugs used by the≥90 years old group was significantly less than that of the 80-89 years old group and the 70-79 years old group(types:1.86±0.78 vs.2.67±1.12,2.88±0.93,both P<0.01).With increasing age,the usage rates of sodium-glucose cotransporter 2 inhibitors(SGLT-2i)and metformin(MET)in the 70-79,80-89,and≥90 years old groups gradually decreased[SGLT-2i:50.54%(47/93),42.31%(22/52),26.19%(11/42),MET:46.24%(43/93),30.77%(16/52),7.14%(3/42),all P<0.05].Conclusions Medical workers have fully considered factors such as renal function,diabetic cardiovascular complications,health status,and life expectancy in the use of hypoglycemic drugs for elderly T2DM patients and have implemented individualized blood glucose management.However,in the≥90 years old group,the HbA1c level is too strict,and the risk of hypoglycemia should be carefully prevented.

The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease(CKD), cardiovascular disease(CVD), diabetes, osteoarthritis(OA), and gastrointestinal disorders. This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO(population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation(GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus. The guideline presents 26 evidence-based recommendations addressing 7 clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage≥3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra-articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti-inflammatory treatments for patients with CKD, gastrointestinal diseases and OA are recommended. The guideline also introduces emerging therapies, such as interleukin-1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases. The update offers a comprehensive, patient-centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.

Objective:To analyze the epidemiological and clinical characteristics of leptospirosis in Wenzhou City, and to provide a scientific basis for formulating prevention and control strategies of leptospirosis in Wenzhou City.Methods:Information on leptospirosis case from 2019 to 2023 was collected from the China Information System for Disease Control and Prevention. Descriptive epidemiological methods were used to analyze the three-dimensional distribution and clinical manifestations of leptospirosis.Results:From 2019 to 2023, the annual average incidence rate of leptospirosis in Wenzhou City was 0.43/100 000, and the annual average mortality was 0.01/100 000. The incidence rate was the highest in 2021 (0.74/100 000), and there was a statistically significant difference in the incidence rate over the five years ( χ2 = 35.48, P < 0.001). Cases were reported in all regions in Wenzhou City except for Dongtou District and Longgang City, with Yongjia County had the highest number of cases (114 cases). The impact rate of streets/townships was 35.14% (65/185), among them Yongjia County had the highest impact rate of steets/townships (86.36%, 19/22). The onset season was from August to October (88.83%, 159/179), with a male to female ratio of 4.97 ∶ 1.00 (149/30). The age group of 61 - 70 years old was the most affected (39.66%, 71/179), and farmers were the main occupation (70.95%, 127/179). Twenty-six point eighty-two per cent (48/179) of the cases had a clear history of animal contact within one month before onset, and 68.16% (122/179) had a history of contact with contaminated water. The main clinical type was influenza-typhoid type (23.46%, 42/179), with the main clinical manifestations being fever (84.92%, 152/179), chills (55.87%, 100/179), and fatigue (62.57%, 112/179). Twelve point twenty-nine per cent 12.29% (22/179), 8.38% (15/179), and 22.91% (41/179) of cases showed conjunctival congestion, lymph node enlargement, and gastrocnemius muscle tenderness, respectively. Clinical outcomes showed that 73.74% (132/179) of the cases recovered or improved, and 3 cases died. Conclusions:From 2019 to 2023, the overall prevalence of leptospirosis in Wenzhou City is at a low level, but there are deaths that need to be taken seriously. In order to control the disease, continuous monitoring should be carried out, health education for relevant populations should be strengthened, and the risk of leptospirosis should be reduced.

This paper reviews the current situation of massive open online course (MOOC) construction both domestically and internationally, highlighting the similarities, differences, and limitations of MOOC construction across nations. Based on the full-cycle MOOC construction of the "clinical epidemiology" course at Southern Medical University, including course design, resource integration, online deployment, and teaching evaluation, this study explored the significance, implementation path, and challenges of MOOC construction. This paper also reflects on the activation of teaching content, teacher-student interaction, and teaching mode, aiming to provide a reference for the construction and continuous enhancement of MOOC in China.

Objective:To analyze the relationships among sense of coherence, social avoidance and distress, and severity of depressive symptoms in adolescent patients with depression.Methods:A total of 98 adolescent patients with depression hospitalized at the Affiliated Mental Health Center of Zhejiang University School of Medicine (Hangzhou Seventh People's Hospital) from June 2023 to January 2024 were selected by convenience sampling. The Center for Epidemiologic Studies Depression Scale (CES-D), the Sense of Coherence Scale-13 (SOC-13), and the Social Avoidance and Distress Scale (SADS) were used for assessment. Pearson correlation analysis was conducted to examine the correlations among severity of depressive symptoms, sense of coherence, and social avoidance and distress. A structural equation model was established using AMOS 23.0 software, and the mediating effect was verified by the percentile Bootstrap method with the PROCESS macro.Results:The CES-D total score of the 98 patients was (22.36±1.75) ; the SOC-13 total score was (55.02±3.38), with the highest dimension score in manageability (mean 4.38±0.52 per item). The SADS total score was (19.40±1.39), including a score of (10.26±0.98) for social avoidance and (9.14±1.01) for social distress. Pearson correlation analysis indicated that CES-D total score was negatively correlated with SOC-13 total score and positively correlated with SADS total score ( P<0.05). Mediation analysis showed that social avoidance and distress partially mediated the relationship between sense of coherence and severity of depressive symptoms in adolescents with depression, with a mediation effect value of -0.333, accounting for 62.95% of the total effect (-0.333/-0.529) . Conclusions:Adolescent patients with depression had a generally low level of sense of coherence and a high level of social avoidance and distress. Sense of coherence was negatively correlated with social avoidance and distress.

Venous system diseases mainly include varicose veins and venous malformations of lower limbs and the genital system. Most of them are chronic diseases that cause serious clinical symptoms to patients and affect their health and quality of life. Sclerotherapy has become the first-line therapy for venous system diseases. However, there are problems such as incomplete fibrosis and vascular recanalization after sclerotherapy, and improper operation will cause serious adverse consequences. Therefore, exploring a safe and effective sclerotherapy strategy is essential for developing clinically successful sclerotherapy. To solve the above problems, we proposed a new sclerotherapy strategy with a dual mechanism of "vascular damage and plasmin (PLA) system inhibition." We intended to construct a novel cationic surfactant (AEO_x-TA) by reacting tranexamic acid (TA), a parent structure, with fatty alcohol polyoxyethylene ether (AEO_x) by ester bonds. AEO_x-TA could damage vascular endothelium and initiate a coagulation cascade effect to induce thrombus. Furthermore, AEO_x-TA could be degraded by esterase and release the parent drug, TA, which could inhibit the PLA system to inhibit the degradation of thrombus and extracellular matrix and promote the process of vascular fibrosis. In addition, such surfactant-based sclerosants have foam-forming properties, and they can be blended with polyvinyl alcohol (PVA) to prepare a highly stable foam formulation (AEO_x-TA/P), which can achieve a precise drug delivery and prolonged drug retention time, thereby improving drug efficacy and reducing the risk of ectopic embolism. Overall, the novel cationic surfactant AEO_x-TA provides a new avenue to resolve the bottleneck: surfactant sclerosants' efficiency is relatively low in the current sclerotherapy.

Biosensors based on acetylcholinesterase (AChE) are crucial for early diagnosis, less invasive treatment, and drug evaluation of Alzheimer's disease (AD). However, existing technologies often suffer from enzyme conformational changes, leading to altered activity and loss and reduced sensor efficacy. To address this challenge, we developed a novel right-side-out-oriented red blood cell membrane-coated electrochemical biosensors (ROCMCBs) to evaluate AChE inhibitors from traditional Chinese medicines (TCMs) as potential anti-AD agents. The developed right-side-out-oriented coating based on immunoaffinity not only fully exposed the binding sites of AChE on the cell membrane but also ensured its conformation and stability as a peripheral membrane-anchoring protein, which was conducive to maintaining its biological activity and producing optimal interaction with drugs. At the same time, the biosensors exhibited a satisfactory sensitivity (limit of detection = 0.41 pmol/L). Ultimately, six potentially active compounds against AD (baicalin, geniposide, gastrodin, berberine, rhynchophylline, and senkyunolide A) were rapidly identified and evaluated from TCMs. This project provides a promising strategy for developing cell membrane-coated electrochemical biosensors. The application of cell membrane-coated electrochemical biosensors with well-defined cell membrane orientation further expands new perspectives and methods for AChE-targeted anti-AD research.