BACKGROUND:Gradient artificial bone repair scaffolds can mimic unique anatomical features in musculoskeletal tissues,showing great potential for repairing injured musculoskeletal tissues. OBJECTIVE:To review the latest research advances in gradient artificial bone repair scaffolds for tissue engineering in the musculoskeletal system and describe their advantages and fabrication strategies. METHODS:The first author of the article searched the Web of Science and PubMed databases for articles published from 2000 to 2023 with search terms"gradient,bone regeneration,scaffold".Finally,76 papers were analyzed and summarized after the screening. RESULTS AND CONCLUSION:(1)As an important means of efficient and high-quality repair of skeletal system tissues,gradient artificial bone repair scaffolds are currently designed bionically for the natural gradient characteristics of bone tissue,bone-cartilage,and tendon-bone tissue.These scaffolds can mimic the extracellular matrix of native tissues to a certain extent in terms of structure and composition,thus promoting cell adhesion,migration,proliferation,differentiation,and regenerative recovery of damaged tissues to their native state.(2)Advanced manufacturing technology provides more possibilities for gradient artificial bone repair scaffold preparation:Gradient electrospun fiber scaffolds constructed by spatially differentiated fiber arrangement and loading of biologically active substances have been developed;gradient 3D printed scaffolds fabricated by layered stacking,graded porosity,and bio-3D printing technology;gradient hydrogel scaffolds fabricated by in-situ layered injections,simple layer-by-layer stacking,and freeze-drying method;and in addition,there are also scaffolds made by other modalities or multi-method coupling.These scaffolds have demonstrated good biocompatibility in vitro experiments,were able to accelerate tissue regeneration in small animal tests,and were observed to have significantly improved histological structure.(3)The currently developed gradient artificial bone repair scaffolds have problems such as mismatch of gradient scales,unclear material-tissue interactions,and side effects caused by degradation products,which need to be further optimized by combining the strengths of related disciplines and clinical needs in the future.

Granulation tissue hyperplasia after tracheotomy is a common clinical complication. Endoscopic treatment can temporarily relieve airway obstruction， however， it is associated with a high recurrence rate and poor long-term prognosis. Based on the traditional Chinese medicine （TCM） Kenang （窠囊） theory and combined with modern pathological mechanisms， this paper explores its correlation with the pathogenesis of post-tracheotomy granulation tissue hyperplasia. Drawing from clinical experience in applying the Kenang theory for treatment， this paper proposes that the fundamental pathogenesis of this condition lies in qi deficiency and organ dysfunction， while phlegm and blood stasis interlocking serve as the symptomatic manifestations. The treatment focuses on resolving phlegm and promoting blood circulation， dispersing nodules and eliminating stagnation， regulating qi flow， and reinforcing the body's vital energy while expelling pathogenic factors. This approach aims to dissolve phlegm and blood stasis， dissipate the Kenang， and ultimately prevent and treat granulation tissue hyperplasia.

Objective To investigate the metabolic characteristics of patients with early-onset type 2 diabetes mellitus(T2DM)and to develop a risk prediction model for microvascular complications.Methods A retrospective study was conducted on 980 T2DM patients admitted for treatment between April 2020 and April 2024.Based on age at diagnosis,the patients were divided into two groups,an early-onset T2DM group(age at diagnosis<40 years,n=265)and a late-onset T2DM group(age at diagnosis≥40 years,n=715).Differences in metabolic indicators between the two groups were compared.Patients in the early-onset group were further divided into a complication subgroup(n=142)and a non-complication subgroup(n=123)based on the presence or absence of microvascular complications.Data on baseline characteristics,metabolic parameters,and laboratory indicators were collected and compared between the two groups.Multivariate logistic regression analysis was used to identify independent risk factors for microvascular complications,and a nomogram prediction model was constructed.The model's discriminative performance was assessed using receiver operating characteristic(ROC)curves,and its calibration was evaluated using calibration curves and the Hosmer-Lemeshow test.Decision curve analysis(DCA)was also performed to assess the model's clinical utility.Results Compared with the late-onset group,patients in the early-onset group exhibited more pronounced metabolic abnormalities,including higher body mass index(BMI),proportion of family history of diabetes mellitus,glycated hemoglobin(HbA1c)levels,total cholesterol(TC),triglycerides(TG),low-density lipoprotein cholesterol(LDL-C),triglyceride-glucose index(TyG),and lactate dehydrogenase(LDH)levels(all P<0.05),along with a shorter disease duration and lower levels of high-density lipoprotein cholesterol(HDL-C)(P<0.05).According to a multivariate analysis,systolic blood pressure(SBP),total bilirubin(TBIL),HDL-C,LDL-C,TyG,and LDH were identified as independent risk factors for microvascular complications in patients with early-onset T2DM.A predictive model based on these factors was established as the follows,Log(P)=-19.915+0.017×SBP-0.136×TBIL-1.241×HDL-C+0.684×LDL-C+0.769×TyG+0.050×LDH.The area under the ROC curve(AUC)was 0.864(95%CI,0.820-0.907),and the Hosmer-Lemeshow test indicated good model fit(χ2=10.286,P=0.246).The slope of the DCA curve was also close to 1.Conclusion The nomogram prediction model based on SBP,TBIL,HDL-C,LDL-C,TyG,and LDH demonstrates good predictive performance for microvascular complications and can provide a reference for clinical risk stratification and individualized intervention.

Background::Although overnight fasting is recommended prior to endoscopic retrograde cholangiopancreatography (ERCP), the benefits and safety of high-carbohydrate fluid diet (CFD) intake 2 h before ERCP remain unclear. This study aimed to analyze whether high-CFD intake 2 h before ERCP can be safe and accelerate patients’ recovery.Methods::This prospective, multicenter, randomized controlled trial involved 15 tertiary ERCP centers. A total of 1330 patients were randomized into CFD group ( n = 665) and fasting group ( n = 665). The CFD group received 400 mL of maltodextrin orally 2 h before ERCP, while the control group abstained from food/water overnight (>6 h) before ERCP. All ERCP procedures were performed using deep sedation with intravenous propofol. The investigators were blinded but not the patients. The primary outcomes included postoperative fatigue and abdominal pain score, and the secondary outcomes included complications and changes in metabolic indicators. The outcomes were analyzed according to a modified intention-to-treat principle. Results::The post-ERCP fatigue scores were significantly lower at 4 h (4.1 ± 2.6 vs. 4.8 ± 2.8, t = 4.23, P <0.001) and 20 h (2.4 ± 2.1 vs. 3.4 ± 2.4, t= 7.94, P <0.001) in the CFD group, with least-squares mean differences of 0.48 (95% confidence interval [CI]: 0.26–0.71, P <0.001) and 0.76 (95% CI: 0.57–0.95, P <0.001), respectively. The 4-h pain scores (2.1 ± 1.7 vs. 2.2 ± 1.7, t = 2.60, P = 0.009, with a least-squares mean difference of 0.21 [95% CI: 0.05–0.37]) and positive urine ketone levels (7.7% [39/509] vs. 15.4% [82/533], χ2 = 15.13, P <0.001) were lower in the CFD group. The CFD group had significantly less cholangitis (2.1% [13/634] vs. 4.0% [26/658], χ2 = 3.99, P = 0.046) but not pancreatitis (5.5% [35/634] vs. 6.5% [43/658], χ2 = 0.59, P = 0.444). Subgroup analysis revealed that CFD reduced the incidence of complications in patients with native papilla (odds ratio [OR]: 0.61, 95% CI: 0.39–0.95, P = 0.028) in the multivariable models. Conclusion::Ingesting 400 mL of CFD 2 h before ERCP is safe, with a reduction in post-ERCP fatigue, abdominal pain, and cholangitis during recovery.Trail Registration::ClinicalTrials.gov, No. NCT03075280.

Acute hepatic porphyria （AHP） is a rare disease with abnormal heme metabolism， and breakthroughs have been made in the treatment of this disease in recent years. In addition to conventional treatment methods， this article reviews new therapies for AHP that are in the stage of initial clinical application or are still in the research stage， including RNAi therapy， enzyme replacement therapy， genetic supplementation of DNA or mRNA， drug molecular chaperones， and glycine transporter inhibitors for reducing heme synthesis. Moreover， this article also reviews the treatment of AHP-related comorbidities and complications， such as hyponatremia and posterior reversible encephalopathy syndrome. High glucose infusion is the main treatment method for AHP in China， and the improvement in diagnosis and increased attention to rare diseases in China has promoted the development of the diagnosis and treatment of AHP， and it is expected to explore more suitable treatment methods for AHP in the Chinese population in the future.

Objective:To analyze the clinical features of MDA5 antibody positive dermatomyositis (MDA5-DM) and to provide evidence for early diagnosis and treatment.Methods:From March 2019 to June 2021, 272 patients with anti-MDA5-DM from the Nanjing Medical University myositis-associated interstitial lung disease cohort were enrolled, with 76 patients with anti-synthetase syndrome (ASS) as the control group. The clinical characteristics and the occurrence of interstitial lung disease were analyzed. T-test was used for normally distributed and variance-homogeneous independent samples, Mann-Whitney U test for non-normally distributed data, and chi-square test or Fisher′s exact test for dichotomous variables. Results:Among the 272 anti-MDA5-DM patients, 88.6% (241/272) developed interstitial lung disease (ILD), and 33.8% (92/272) developed rapidly progressive ILD (RP-ILD). The six-month all-cause mortality rate of anti-MDA5-DM patients was 16.9% (46/272), and it was as high as 47.8% (44/92) for those with RP-ILD. Compared with ASS patients, anti-MDA5-DM patients had a significantly higher proportion of males, arthritis, Gottron's sign, heliotrope rash, V-sign, periungual erythema, and skin ulcers ( P<0.05). The levels of ALT, AST, and ferritin were significantly increased ( P<0.05). Compared with non-RP-ILD patients, RP-ILD patients had a significantly higher proportion of males [35.9%(33/92) vs. 23.3%(42/180), χ2=4.79, P=0.029], higher levels of LDH [387 (276, 547) U/L vs. 310 (245, 400) U/L, Z=-3.67, P<0.001], ESR [45.5 (29.25, 63.25) mm/1 h vs. 31.2 (20, 51) mm/1 h, Z=-3.71, P<0.001], CRP [10.9 (4.1, 25.2) mg/L vs. 4.54 (2.58, 9.08) mg/L, Z=-4.97, P<0.001], ferritin [1 340 (650, 2 000) ng/ml vs. 556 (203, 1 186) ng/ml, Z=-4.40, P<0.001], and a higher proportion of anti-Ro52 antibody and anti-MDA5 antibody co-positivity [87.0%(80/92) vs. 52.2%(94/180), χ2=31.87, P<0.001]. Conclusion:Anti-MDA5-DM patients are prone to develop RP-ILD and have poor prognosis.

Objective:To investigate the protective effect of racanisodamine (654-2) on lung epithelial cell injury induced by X-ray in mice and unravel the underlying mechanism.Methods:Mouse alveolar epithelial cells MLE-12 were used to establish radiation-induced lung injury (RILI) model in vitro and divided into 4 groups as follows: control (no irradiation), radiation (16 Gy radiation), treatment 1 (16 Gy radiation + 2 μmol/L 654-2), treatment 2 (16 Gy radiation + 10 μmol/L 654-2), and inhibitor (16 Gy radiation + 10 μmol/L 654-2 + 2 μmol/L ML385), respectively. Cells were sampled at different time points after radiation. Cell senescence was detected with senescence-associated β-galactosidase (SA-β-Gal) staining. Cell colony-forming ability was detected to observe the recovery capability of cells after treatment. The expression levels of p21, p16, phosphorylated histone H2AX(γH2AX), nuclear factor erythroid-2 related factor 2 (Nrf2), Nrf2 Ser40 site phosphorylation (p-Nrf2), p62, heme oxygenase-1 (HO-1) and NAD(P)H quinone oxidoreductase 1 (NQO1) proteins were measured by Western blot. Cell apoptosis and the production of intracellular reactive oxygen species (ROS) were determined by flow cytometry. The expression levels of glutathione (GSH) and superoxide dismutase (SOD) were detected according to the manufectuer instructions. The expression levels of glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) mRNA were determined by real time reverse transcription PCR. Measurement data were expressed as Mean ±SD. Comparison between two groups was conducted by independent sample t-test, and comparison among multiple groups was performed by one-way ANOVA. Results:Compared with the radiation group, the proportion of cells with positive staining of SA-β-Gal was significantly lower and cell senescence were alleviated in the treatment 1 and 2 groups (all P<0.001). Compared with the radiation group, the expression level of γH2AX protein was significantly down-regulated ( P=0.037), cell apoptosis rate was significantly decreased ( P=0.026), the proliferation capacity of MLE-12 was enhanced ( P=0.004), GSH ( P=0.002) and SOD ( P<0.001) activity was enhanced and ROS production was declined ( P=0.001) in the treatment 2 group. The expression levels of Nrf2 and p-Nrf2 in total protein were up-regulated over the time of 654-2 intervention. Meanwhile, the expression levels of antioxidant proteins of NQO1 and HO-1 were up-regulated and that of GCLC and GCLM mRNA was also up-regulated. There were no significant differences in the number of cells with positive staining of SA-β-Gal ( P=0.145) and ROS production ( P=0.317) between the inhibitor and radiation groups after supplement of ML385, small-molecule inhibitor of Nrf2. Conclusion:654-2 can activate the Nrf2 pathway, enhance cell antioxidant capacity and inhibit cell senescence, thereby playing a protective role on radiation- induced lung injury.

Objective:To construct an evidence-based prediction model for early recurrence after surgery of hepatocellular carcinoma (HCC) based on Meta-analysis and to do external validation study.Methods:The literatures in Chinese National Knowledge Infrastructure, Wanfang, VIP, Chinese Science Citation Database (CSCD), Chinese Social Science Citation System (CCSCI), PubMed, Web of Science and IEEE databases between January 2019 and December 2023 were searched based on the subject words. According to the inclusion and exclusion criteria, 9 literatures were included to screen the risk factors affecting the early recurrence of HCC. When the same risk factor was found in ≥5 included literatures, Meta-analysis was performed by using Review Manager 5.4.1 software. External validation data were collected from 401 patients with primary HCC who underwent surgery in Liaoning Cancer Hospital between March 2014 and March 2017. The patients were divided into early recurrence group (176 cases) and early non-recurrence group (225 cases) according to whether they relapsed 2 years after surgery. The OR values of all risk factors obtained in the Meta-analysis were converted into modeling, and postoperative early recurrence rate of HCC in the Meta-analysis was used to calculate β 0, and finally the logistic model was obtained. The OR value was incorporated into the logit (P) model, and the morbidity (P) of the external validation data was calculated. Taking the recurrence 2 years after surgery or not as the dependent variable and P as the independent variable, the receiver operating characteristic (ROC) curve was drawn to calculate the area under the curve (AUC). Results:A total of 8 risk factors for early HCC recurrence were screened out from 9 literatures (x 1: alpha-fetoprotein ≥ 400 ng/ml; x 2: tumor number ≥ 2; x 3: the longest tumor diameter ≥ 5 cm; x 4: Barcelona staging B-C; x 5: microvascular invasion; x 6: moderate to low differentiation; x 7: incomplete capsule; x 8: nonanatomic hepatectomy). The Meta-analysis included 1 757 HCC cases, with 960 postoperative early recurrences and an early recurrence rate of 45.36%, finally the β 0 value was -0.201. The predictive model for 2-year recurrence of HCC was constructed and calculated as logit (P) = -0.201+0.835x 1+0.905x 2+0.783x 3+1.008x 4+0.765x 5+0.831x 6+1.533x 7+0.940x 8. Analysis of variance by external validation data showed that the differences in ascites, alpha-fetoprotein, tumor number, tumor diameter, Barcelona staging, microvascular invasion, tumor differentiation degree, capsule invasion, resection type, and systemic inflammation index were statistically significant between early recurrence group and early non-recurrence group (all P < 0.05). ROC curve analysis showed that AUC of postoperative early recurrence of HCC predicted by the model was 0.718, (95% CI: 0.689-0.753), the optimal cut-off value was 3.11, the Yoden index was 0.288, the sensitivity was 69.32%, and the specificity was 69.56%. Conclusions:The evidence-based prediction model constructed based on Meta-analysis for postoperative early recurrence of HCC has a high predictive value. However, further verification and optimization with big data is still needed.

Objective To assess the value of multimodal ultrasonography for diagnosing thyroid nodules—atypia of undetermined significance (AUS) of thyroid imaging reporting and data system (TI-RADS) categories 3 to 5. Methods A total of 90 AUS thyroid nodules in TI-RADS 3-5 categories from 88 patients underwent conventional ultrasonography, ultrasound elastography, superb microvascular imaging, and multimodal ultrasonography at the same time. With fine needle aspiration biopsy results as the gold standard, the methods were compared in terms of the sensitivity, specificity, accuracy, false positive rate (FPR), false negative rate (FNR), and area under the receiver operating characteristic curve (AUC) for diagnosing thyroid nodules. Results There were no significant differences between patients with benign and those with malignant thyroid nodules in terms of sex, age, and nodule locations (all P > 0.05), but the proportion of thyroid nodules ≤ 1 cm in diameter was significantly higher for malignant thyroid nodules than for benign thyroid nodules (χ²=9.610, P=0.002). Compared with benign nodules, malignant nodules were significantly more frequent to have low-level echoes or very low-level echoes, a blurred margin, a vertical diameter/horizontal diameter ratio of > 1, and microcalcifications or no calcifications (all P < 0.05). An ultrasound elastography score of ≥ 3 and type III vascularity on superb microvascular imaging indicated a higher possibility of malignant thyroid nodules (both P < 0.001). The multivariable logistic regression analysis showed that the size, echogenicity, margin, and vertical diameter/horizontal diameter ratio, and superb microvascular imaging type of thyroid nodules were not significant markers for benign or malignant thyroid nodules (all P > 0.05), while microcalcifications/no calcifications and an ultrasound elastography score of ≥ 3 were independent risk factors for malignant AUS nodules (both P < 0.05). The diagnostic sensitivity, specificity, accuracy, FPR, and FNR of conventional ultrasonography for AUS nodules were 91.30%, 71.40%, 62.70%, 28.60%, and 8.70%, respectively; the values for ultrasound elastography were 85.50%, 66.70%, 52.20%, 33.30%, and 14.50%, respectively; the values for superb microvascular imaging were 66.70%, 76.20%, 42.90%, 23.80%, and 33.30%, respectively; and the values for multimodal ultrasonography were 75.20%, 92.50%, 67.70%, 24.80%, and 7.50%, respectively. For distinguishing between benign and malignant AUS nodules, the AUC values of conventional ultrasonography, ultrasound elastography, superb microvascular imaging, and multimodal ultrasonography were 0.866, 0.745, 0.774, and 0.918, respectively. Conclusion Multimodal ultrasonography shows better diagnostic efficacy for AUS nodules of TI-RADS 3-5 compared with conventional ultrasonography, ultrasound elastography, and superb microvascular imaging, which can facilitate the malignancy risk stratification and management of AUS thyroid nodules.

Objective To explore the distribution of common syndromes in sepsis based on literature data mining.Methods The literature related to sepsis symptoms analysis included in China National Knowledge Infrastructure(CNKI),Chinese Biomedical Literature Database(CBM),VIP database(VIP)and Wanfang Data were searched by computer to extract relevant information and establish a database.Analysis of common syndromes and symptoms of sepsis by frequency statistics.Based on LTM-EAST algorithm of two-step hidden tree analysis,a symptom hidden structure model with frequency≥10 was constructed by Latern 5.0 software,and potential syndromes were inferred through comprehensive clustering.Symptoms with frequency＞5%were selected for factor analysis,common factors were extracted for further systematic cluster analysis,and potential syndromes were inferred according to the results.Based on the above results,the common syndromes and clinical characteristics of sepsis were analyzed.Results A total of 792 literatures and 961 syndromes records and 877 symptoms records were included,involving 48 syndromes after the regulation,with high frequency of pattern of blood stasis,pattern of yangming fu-organ excess,pattern of internal block of the heart orifices due to phlegm and heat,pattern of yang prostration,etc.The frequencies were 12.70%(122/961),9.68%(93/961),9.47%(91/961)and 7.80%(75/961).It involved 179 symptoms after the regulation,including high fever,red tongue,thirst,dysphoria,etc.The frequencies were 27.82%(244/877),27.36%(240/877),27.25%(239/877),25.54%(244/877).Forty-three hidden variables were obtained through implicit structure analysis,according to professional knowledge,12 potential syndromes were obtained by comprehensive clustering,including pattern of blood stasis,pattern of yangming fu-organ excess,pattern of phlegm and heat congesting in the lung,pattern of fire toxin entering the nutrient phase,pattern of Yin deficiency with exuberant heat,pattern of Yang prostration,pattern of Qi deficiency,pattern of Yang deficiency,pattern of turbid phlegm obstructing the lung,pattern of damp-heat encumbering the spleen,pattern of intense exuberant heat toxin,pattern of pathogenic factors repressing defensive Qi of lung.Twenty-five common factors were obtained by factor analysis,and 12 potential syndromes were inferred by systematic clustering,including pattern of heart-Yang deficiency,pattern of phlegm and heat congesting in the lung,pattern of yangming fu-organ excess,pattern of Yang prostration,pattern of intense exuberant heat toxin,pattern of Yang deficiency in spleen and kidney,pattern of Qi deficiency,pattern of phlegm and heat damaging Yin,pattern of Qi deficiency with blood stasis,pattern of Qi and Yin deficiency,pattern of pathogenic factors repressing defensive Qi of lung,and pattern of heat sinking into the pericardium.According to the standard of common traditional Chinese medicine(TCM)syndromes and their symptom characteristics,9 common syndromes of sepsis were finally obtained,including pattern of intense exuberant heat toxin,blood stasis,pattern of yangming fu-organ excess,pattern of phlegm and heat congesting in the lung,pattern of fire toxin entering,pattern of pathogenic factors repressing defensive Qi of lung,pattern of Qi and Yin deficiency,pattern of Qi deficiency,pattern of Yang prostration.Conclusion The symptoms and characteristics of common syndromes of sepsis are significant,which can provide evidence for the syndrome diagnosis standard of sepsis.