Diabetic foot (DF) is one of the most serious chronic complications of diabetes. The incidence rate among global diabetes patients is as high as 15% to 25%, and about 50% of patients will develop contralateral foot ulcers within 5 years after the first unilateral ulcer. As a non-invasive prevention and control solution, the application progress of functional insoles is mainly reflected in the following aspects:(1) Material innovation. The application of new composite materials and smart materials has significantly enhanced the pressure reduction effect and comfort. (2) Structural optimization. The development of multi-layer design and local pressure reduction structure has achieved more precise pressure distribution regulation. (3) Manufacturing process. 3D printing and parametric design have enabled the personalized customization of functional insoles. (4) Intelligent monitoring. It integrates functions such as pressure sensing and temperature monitoring, achieving real-time monitoring and early warning of foot conditions. Clinical research has confirmed that personalized functional insoles could reduce the incidence of foot ulcers and shorten the healing time of ulcers. At present, the research hotspots mainly focus on the development of smart materials, the construction of multi-functional integration and remote monitoring systems. However, in-depth research is still needed in the aspects of biomechanical mechanisms, standardized evaluation systems and long-term efficacy assessment. The development of future functional insoles should focus on the coordinated advancement of "personalization-intelligence-standardization", with the aim of providing more effective solutions for the prevention and treatment of DF.
Humans ; Diabetic Foot/therapy* ; Foot Orthoses

OBJECTIVE: To investigate the therapeutic potential of pseudolaric acid B (PAB) on non-alcoholic fatty liver disease (NAFLD) and its underlying molecular mechanism in vitro and in vivo. METHODS: Eight-week-old male C57BL/6J mice (n=32) were fed either a normal chow diet (NCD) or a high-fat diet (HFD) for 8 weeks. The HFD mice were divided into 3 groups according to a simple random method, including HFD, PAB low-dose [10 mg/(kg·d), PAB-L], and PAB high-dose [20 mg/(kg·d), PAB-H] groups. After 8 weeks of treatment, glucose metabolism and insulin resistance were assessed by oral glucose tolerance test (OGTT) and insulin tolerance test (ITT). Biochemical assays were used to measure the serum and cellular levels of total cholesterol (TC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). White adipose tissue (WAT), brown adipose tissue (BAT) and liver tissue were subjected to hematoxylin and eosin (H&E) staining or Oil Red O staining to observe the alterations in adipose tissue and liver injury. PharmMapper and DisGeNet were used to predict the NAFLD-related PAB targets. Peroxisome proliferator-activated receptor alpha (PPARα) pathway involvement was suggested by Kyoto Encyclopedia of Genes and Genomes (KEGG) and search tool Retrieval of Interacting Genes (STRING) analyses. Luciferase reporter assay, cellular thermal shift assay (CETSA), and drug affinity responsive target stability assay (DARTS) were conducted to confirm direct binding of PAB with PPARα. Molecular dynamics simulations were applied to further validate target engagement. RT-qPCR and Western blot were performed to assess the downstream genes and proteins expression, and validated by PPARα inhibitor MK886. RESULTS: PAB significantly reduced serum TC, TG, LDL-C, AST, and ALT levels, and increased HDL-C level in HFD mice (P<0.01). Target prediction analysis indicated a significant correlation between PAB and PPARα pathway. PAB direct target binding with PPARα was confirmed through luciferase reporter assay, CETSA, and DARTS (P<0.05 or P<0.01). The target engagement between PAB and PPARα protein was further confirmed by molecular dynamics simulations and the top 3 amino acid residues, LEU321, MET355, and PHE273 showed the most significant changes in mutational energy. Subsequently, PAB upregulated the genes expressions involved in lipid metabolism and mitochondrial biogenesis downstream of PPARα (P<0.05 or P<0.01). Significantly, the PPARα inhibitor MK886 effectively reversed the lipid-lowering and PPARα activation properties of PAB (P<0.05 or P<0.01). CONCLUSION PAB mitigates lipid accumulation, ameliorates liver damage, and improves mitochondrial biogenesis by binding with PPARα, thus presenting a potential candidate for pharmaceutical development in the treatment of NAFLD.
Animals ; PPAR alpha/metabolism* ; Non-alcoholic Fatty Liver Disease/pathology* ; Male ; Mice, Inbred C57BL ; Lipid Metabolism/drug effects* ; Diterpenes/therapeutic use* ; Organelle Biogenesis ; Diet, High-Fat ; Humans ; Mice ; Liver/metabolism* ; Insulin Resistance ; Mitochondria/metabolism* ; Molecular Docking Simulation

OBJECTIVE: To evaluate the dynamic changes of glucocorticoid (GC) dose and the feasibility of GC discontinuation in rheumatoid arthritis (RA) patients under the background of Chinese medicine (CM). METHODS: This multicenter retrospective cohort study included 1,196 RA patients enrolled in the China Rheumatoid Arthritis Registry of Patients with Chinese Medicine (CERTAIN) from September 1, 2019 to December 4, 2023, who initiated GC therapy. Participants were divided into the Western medicine (WM) and integrative medicine (IM, combination of CM and WM) groups based on medication regimen. Follow-up was performed at least every 3 months to assess dynamic changes in GC dose. Changes in GC dose were analyzed by generalized estimator equation, the probability of GC discontinuation was assessed using Kaplan-Meier curve, and predictors of GC discontinuation were analyzed by Cox regression. Patients with <12 months of follow-up were excluded for the sensitivity analysis. RESULTS: Among 1,196 patients (85.4% female; median age 56.4 years), 880 (73.6%) received IM. Over a median 12-month follow-up, 34.3% (410 cases) discontinued GC, with significantly higher rates in the IM group (40.8% vs. 16.1% in WM; P<0.05). GC dose declined progressively, with IM patients demonstrating faster reductions (median 3.75 mg vs. 5.00 mg in WM at 12 months; P<0.05). Multivariate Cox analysis identified age <60 years [P<0.001, hazard ratios (HR)=2.142, 95% confidence interval (CI): 1.523-3.012], IM therapy (P=0.001, HR=2.175, 95% CI: 1.369-3.456), baseline GC dose ⩽7.5 mg (P=0.003, HR=1.637, 95% CI: 1.177-2.275), and absence of non-steroidal anti-inflammatory drugs use (P=0.001, HR=2.546, 95% CI: 1.432-4.527) as significant predictors of GC discontinuation. Sensitivity analysis (545 cases) confirmed these findings. CONCLUSIONS RA patients receiving CM face difficulties in following guideline-recommended GC discontinuation protocols. IM can promote GC discontinuation and is a promising strategy to reduce GC dependency in RA management. (Trial registration: ClinicalTrials.gov, No. NCT05219214).
Adult ; Aged ; Female ; Humans ; Male ; Middle Aged ; Arthritis, Rheumatoid/drug therapy* ; Glucocorticoids/therapeutic use* ; Medicine, Chinese Traditional ; Retrospective Studies

Tailored lipid nanoparticles (LNPs)-mediated small interfering RNA (siRNA) nanomedicines show promise in treating liver disease, such as acute liver injury (ALI) and non-alcoholic steatohepatitis (NASH). However, constructing LNPs that address biosafety concerns, ensure efficient delivery, and target specific hepatic subcellular fractions has been challenging. To evade above obstacles, we develop three novel self-degradable "gemini-like" ionizable lipids (SS-MA, SS-DC, SS-MH) by incorporating disulfide bonds and modifying the length of ester bond and tertiary amino head. Our findings reveal that the disulfide-bond-bridged LNPs exhibit reduction-responsive drug release, improving both biosafety and siRNA delivery efficiency. Furthermore, the distance of ester bond and tertiary amino head significantly influences the LNPs' pK _a, thereby affecting endosomal escape, hemolytic efficiency, absorption capacity of ApoE, uptake efficiency of hepatocytes and liver accumulation. We also develop the modified-mannose LNPs (M-LNP) to target liver macrophages specifically. The optimized M-MH_LNP@TNFα exhibits potential in preventing ALI by decreasing tumor necrosis factor α (TNFα) levels in the macrophages, while MH_LNP@DGAT2 could treat NASH by selectively degrading diacylglycerol O-acyltransferase 2 (DGAT2) in the hepatocytes. Our findings provide new insights into developing novel highly effective and low-toxic "gemini-like" ionizable lipids for constructing LNPs, potentially achieving more effective treatment for hepatic diseases.

Aim To investigate the predictive value of the Murray law-based quantitative flow ratio(μQFR)after target vessel pretreatment for vascular-related adverse events in patients with de novo coronary lesions treated with drug-coated balloon.Methods This retrospective study included 223 lesions from 223 patients who underwent drug-coated balloon-only strategy and completed 2-year clinical follow-up.Coronary angiographic images of target vessels pre-procedure,post-balloon and post-procedure were collected,and analyzed using a novel Murray's law-based algorithm.The μQFR analysis of each target vessel included not only the μQFR value of the target vessel,but also the length of the target vessel,the degree of vessel diameter stenosis,the reference lumen diameter,the minimum lumen diameter and blood flow velocity.The primary endpoint was defined as the postoperative vessel-oriented composite endpoint(VOCE).Results During the2-year clinical follow-up period,a total of 25 patients(11.2%)experienced VOCE events.Com-pared with the control group,patients with VOCE events after pretreatment showed a decrease in μQFR(P<0.001).Multivariate Logistic analysis showed that a lower target vessel μQFR after pretreatment(OR=0.931,95%CI:0.894～0.969,P<0.001)was an independent predictor of VOCE events.ROC curve analysis showed that the cut-off value for predicting 2-year VOCE events using preprocessed μQFR was 0.83(95%CI:0.727～0.840),with a sensitivity of 72.7%and a specificity of 84.0%(AUC=0.773,95%CI:0.676～0.870,P<0.001).Survival analysis showed that compared with patients with μQFR>0.83,patients with μQFR≤0.83 had a significantly higher incidence of VOCE events at 1 and 2 years,increasing to 3.909 times(16.9%vs.4.6%,HR=3.909,95%CI:1.539～9.930,P=0.004)and 2.867 times(19.7%vs.7.2%,HR=2.867,95%CI:1.301～6.316,P=0.009).After adjusting for potential con-founds,patients with pretreated μQFR≤0.83 had a 2.567 times in 2-year incidence of VOCE events(HR=2.567,95%CI:1.151～5.727,P=0.021)and a 3.712 times in 1-year incidence of VOCE events(HR=3.712,95%CI:1.478～9.810,P=0.006)compared to patients with good pretreatment.Conclusions For patients with in situ coronary artery disease,a lower μQFR after pretreatment increases the risk of postoperative adverse clinical events.μQFR≤0.83 may be used to evaluate the effectiveness of lesion pretreatment.

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

Aim To investigate the predictive value of the Murray law-based quantitative flow ratio(μQFR)after target vessel pretreatment for vascular-related adverse events in patients with de novo coronary lesions treated with drug-coated balloon.Methods This retrospective study included 223 lesions from 223 patients who underwent drug-coated balloon-only strategy and completed 2-year clinical follow-up.Coronary angiographic images of target vessels pre-procedure,post-balloon and post-procedure were collected,and analyzed using a novel Murray's law-based algorithm.The μQFR analysis of each target vessel included not only the μQFR value of the target vessel,but also the length of the target vessel,the degree of vessel diameter stenosis,the reference lumen diameter,the minimum lumen diameter and blood flow velocity.The primary endpoint was defined as the postoperative vessel-oriented composite endpoint(VOCE).Results During the2-year clinical follow-up period,a total of 25 patients(11.2%)experienced VOCE events.Com-pared with the control group,patients with VOCE events after pretreatment showed a decrease in μQFR(P<0.001).Multivariate Logistic analysis showed that a lower target vessel μQFR after pretreatment(OR=0.931,95%CI:0.894～0.969,P<0.001)was an independent predictor of VOCE events.ROC curve analysis showed that the cut-off value for predicting 2-year VOCE events using preprocessed μQFR was 0.83(95%CI:0.727～0.840),with a sensitivity of 72.7%and a specificity of 84.0%(AUC=0.773,95%CI:0.676～0.870,P<0.001).Survival analysis showed that compared with patients with μQFR>0.83,patients with μQFR≤0.83 had a significantly higher incidence of VOCE events at 1 and 2 years,increasing to 3.909 times(16.9%vs.4.6%,HR=3.909,95%CI:1.539～9.930,P=0.004)and 2.867 times(19.7%vs.7.2%,HR=2.867,95%CI:1.301～6.316,P=0.009).After adjusting for potential con-founds,patients with pretreated μQFR≤0.83 had a 2.567 times in 2-year incidence of VOCE events(HR=2.567,95%CI:1.151～5.727,P=0.021)and a 3.712 times in 1-year incidence of VOCE events(HR=3.712,95%CI:1.478～9.810,P=0.006)compared to patients with good pretreatment.Conclusions For patients with in situ coronary artery disease,a lower μQFR after pretreatment increases the risk of postoperative adverse clinical events.μQFR≤0.83 may be used to evaluate the effectiveness of lesion pretreatment.

Objective:To investigate the long-term prognosis and related factors in children with multiphasic myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).Methods:A bidirectional cohort study was conducted. This study included 41 children with MOGAD who were treated at the Children′s Medical Center of Peking University First Hospital between January 2013 and December 2024, with a disease duration of ≥5 years. Demographic characteristics, clinical episodes, therapy, and prognostic indicators (including the expanded disability status scale (EDSS) and modified Rankin scale (mRS)) were collected. Children were stratified into relapse and non-relapse groups based on the presence or absence of relapse within 5 years of the last follow-up. χ2 test or Mann-Whitney U test was used to analyze factors associated with relapse. The Log-rank test was used to compare relapse-free rates between children with disease onset 0-<5 years and those with onset at 5-10 years. Results:A total of 41 children were enrolled, including 20 boys and 21 girls. The age at onset was 5.3 (3.8, 8.5) years, the age at last follow-up was 16.1 (13.2, 17.5) years, and the disease duration was 9.4 (8.1, 10.9) years. The annualized relapse rate (ARR) during follow-up was 0.34 (0.19, 0.56) times/year. The duration to first relapse was 0.8 (0.4, 1.5) years. At the last follow-up, the EDSS score was 0.0 (0.0, 0.0) score, and the mRS score was 0 (0, 0) score. A total of 40 children (98%) experienced relapses within the first 5 years after onset, while only 1 child (2%) relapsed at 6.7 years. The relapse rate between 5-10 years was lower than that between 0-<5 years ( HR=0.27, 95% CI 0.16-0.47, P<0.001). A total of 25 children (61.0%) exhibited clustered relapses during the disease course. There were 20 children (49%) in non-relapse groups, who were aged 16.6 (14.8, 17.6) years, disease duration 9.8 (9.3, 10.8) years at the last follow-up. Among those 20 children, 15 children (75%) had discontinued corticosteroids and immunosuppressants. The relapse group had higher clinical event rates and ARR compared to the relapse-free group (both P<0.01), the age at last follow-up was yonger ( P<0.05), while no significant differences were observed in age at onset, disease duration, or timing of immunosuppressant use (all P>0.05). Conclusions:Pediatric multiphasic MOGAD generally has a favorable prognosis, about half of patients remain relapse-free for ≥5 years at last follow-up. Relapses predominantly occur early in the disease course (mostly within 5 years of onset) and often exhibit a clustered pattern.

To analyze the standard establishment approach and compilation rationale for metallic pharmaceutical packaging standard development in the 2025 edition of the Pharmacopeia of the People's Republic of China.This article systematically explained the background and process of establishing the guiding principles for metallic materials and containers used in pharmaceutical packaging in the Chinese Pharmacopoeia through basic information,relevant domestic and international standards,the establishment of key quality attributes of metallic pharmaceutical packaging materials,and the construction of metallic pharmaceutical packaging material standards.The newly established guidelines,the Pharmacopeia of the People's Republic of China 9625,prioritized product critical quality attributes(CQAs)and real-world applicability.This dual emphasis on rigidity and adaptability enhances drug safety,meets the regulatory requirements,and promotes the globalization and scientific advancement of China's pharmaceutical packaging industry.

Objectives:To investigate the predictive value of Murray's law-based quantitative flow ratio(μQFR)in side branches for long-term clinical prognosis in patients with non-left main bifurcation lesions who underwent simple main branch stenting,and to provide a potential functional assessment standard for intervention decision-making on coronary bifurcation lesions.Methods:A retrospective analysis was conducted in 408 patients with non-left main bifurcation lesions who underwent simple main branch stenting at Lianyungang First People's Hospital and Nanjing First Hospital between July 2018 and January 2021.The study utilized third-generation QFR software to analyze pre-and post-procedure anatomical and functional parameters of the target lesion's main branch and key branches.The primary endpoint was target vessel failure(TVF)events during the 3-year follow-up.Patients were stratified into TVF and non-TVF groups.Baseline characteristics,procedural data,and pre-/post-procedural parameters of target vessels were compared between groups.Multivariable Cox regression was performed to identify predictors of TVF.Diagnostic efficacy of predictors was evaluated using area under the receiver operating characteristic(ROC)curve(AUC)with DeLong's method for comparison.Patients were dichotomized based on the optimal cutoffof post-procedural side branch μQFR,with TVF incidence rates compared via Cox regression and Kaplan-Meier analysis.Results:During 3-year follow-up,54 patients(13.2%)experienced TVF(TVF group),data were compared with 354 patients(86.76%)without TVF(non-TVF group).The TVF group showed higher post-procedural side branch diameter stenosis([32.93±17.80]%vs.[22.62±11.96]%,P<0.001)and lower μQFR(0.80±0.10 vs.0.89±0.07,P<0.001).Multivariate Cox regression identified higher post-procedural side branch μQFR as an independent protective factor against 3-year TVF(per 0.01 increase:HR=0.903,95%CI:0.850-0.959,P<0.001).ROC curves indicated that post-procedural side branch μQFR had moderate diagnostic efficacy for predicting 3-year TVF(AUC=0.769,95%CI:0.678-0.861,P<0.001),with a significantly higher AUC value than post-operative side branch area stenosis and minimal lumen diameter(both P<0.001),the optimal cutoffvalue was 0.84.Multivariate Cox regression and Kaplan-Meier survival analysis revealed markedly higher 3-year TVF rates in patients with μQFR≤0.84 compared to patients with μQFR>0.84(HR=4.007,95%CI:2.342-6.855,P<0.001;28.3%vs.7.9%,log-rank P<0.001).Conclusions:For patients with bifurcation lesions not involving the left main,the immediate post-procedural side branch μQFR could better predict 3-year TVF than anatomical indices.Maintaining post-stenting side branch μQFR>0.84 may optimize clinical outcomes when using a single-stent strategy.