OBJECTIVE To explore the application of digital twin technology in modeling and simulating the hospi-tal-associated transmission pathways of multidrug-resistant organisms(MDROs)and propose MDRO transmis-sion prevention and control strategies based on digital twins.METHODS Real-time hospital data and person-nel mobility information from Jun.2023 to Jun.2024 were collected and analyzed.A dynamic model of the hospi-tal's internal environment and MDROs transmission was established by digital modeling and 3D simulation tech-nology of the hospital environment.A simulation platform was utilized to analyze the impact of different preven-tion and control measures on MDROs transmission risks.Digital twin technology was employed for predicting and real-time monitoring of organism transmission pathways.RESULTS Simulation data showed that under initial pre-vention and control conditions,Ward A had 8 infected individuals and a transmission duration of 12 days.Af-ter implementing comprehensive measures of"increased cleaning frequency+enhanced personnel protection",the number of infected individuals reduced to 4,the transmission duration shortened to 6 days and the transmis-sion risk reduction rate reached 45.00％.The digital twin model can effectively reflect the transmission patterns of MDROs within the hospital and provide quantitative risk assessments under different prevention and control strat-egies.CONCLUSIONS Digital twin technology can predict and simulate organism transmission pathways in real-time,providing scientific decision-making support for hospitals.It has the potential to become a new paradigm for MDROs prevention and control.

OBJECTIVE To explore the application of digital twin technology in modeling and simulating the hospi-tal-associated transmission pathways of multidrug-resistant organisms(MDROs)and propose MDRO transmis-sion prevention and control strategies based on digital twins.METHODS Real-time hospital data and person-nel mobility information from Jun.2023 to Jun.2024 were collected and analyzed.A dynamic model of the hospi-tal's internal environment and MDROs transmission was established by digital modeling and 3D simulation tech-nology of the hospital environment.A simulation platform was utilized to analyze the impact of different preven-tion and control measures on MDROs transmission risks.Digital twin technology was employed for predicting and real-time monitoring of organism transmission pathways.RESULTS Simulation data showed that under initial pre-vention and control conditions,Ward A had 8 infected individuals and a transmission duration of 12 days.Af-ter implementing comprehensive measures of"increased cleaning frequency+enhanced personnel protection",the number of infected individuals reduced to 4,the transmission duration shortened to 6 days and the transmis-sion risk reduction rate reached 45.00％.The digital twin model can effectively reflect the transmission patterns of MDROs within the hospital and provide quantitative risk assessments under different prevention and control strat-egies.CONCLUSIONS Digital twin technology can predict and simulate organism transmission pathways in real-time,providing scientific decision-making support for hospitals.It has the potential to become a new paradigm for MDROs prevention and control.

Objectives The combined use of bedaquiline and delamanid(BDQ-DLM)is limited by an increased risk of prolonging the QTc interval.We retrospectively evaluated patients who received DLM/BDQ-containing regimens at a TB-specialized hospital.We aimed to present clinical efficacy and safety data for Chinese patients. Methods This case-control study included patients with multidrug-resistant tuberculosis(MDR-TB)treated with BDQ alone or BDQ plus DLM. Results A total of 96 patients were included in this analysis:64 in the BDQ group and 32 in the BDQ+DLM group.Among the 96 patients with positive sputum culture at the initiation of BDQ alone or BDQ combined with DLM,46 patients(71.9%)in the BDQ group and 29(90.6%)in the BDQ-DLM group achieved sputum culture conversion during treatment.The rate of sputum culture conversion did not differ between the two groups.The time to sputum culture conversion was significantly shorter in the BDQ-DLM group than in the BDQ group.The most frequent adverse event was QTc interval prolongation;however,the frequency of adverse events did not differ between the groups. Conclusion In conclusion,our results demonstrate that the combined use of BDQ and DLM is efficacious and tolerable in Chinese patients infected with MDR-TB.Patients in the BDQ-DLM group achieved sputum culture conversion sooner than those in the BDQ group.

Objective:To observe the expression and significance of Jagged1 in fibrovascular membranes of proliferative diabetic retinopathy (PDR).Methods:Sixty preretinal fibrovascular membrane specimens collected from fifty-seven patients (60 eyes) with PDR during vitrectomy in The Affiliated Hospital of Qingdao University from July 2014 to July 2015 were set as the PDR group.The patients were divided into the injection group (30 cases, 32 eyes) and non-injection group (27 cases, 28 eyes) according to whether they received anti-vascular endothelial factor drug intravitreally before surgery.Ranibizumab injections were administered to the patients in the injection group intravitreally 2-7 days before surgery.Eighteen macular epiretinal membrane specimens obtained from 18 non-diabetic patients were served as the control group.Hematoxylin-eosin staining was applied to observe the structural festures of specimers. The immunohistochemical staining was used to detect the expression levels of Jagged1, Delta-like 4(Dll4) and Notch1 in the injection and non-injection groups, and the real-time fluorescent quantitative polymerase chain reaction was performed to detect the relative expression levels of Jagged1, Dll4 and Notch1 mRNA in the three groups.Pearson linear correlation analysis was used to evaluate the relationships between the expression of Jagged1 mRNA and both Dll4 mRNA or Notch1 mRNA in the PDR fibrovascular membranes.This study protocol adhered to the Declaration of Helsinki and was approved by an Ethics Committee of The Affiliated Hospital of Qingdao University (No.QYFYWZLL25645). Written informed consent was obtained from each patient.Results:The neovascularization was found in fibrovascular membranes of PDR with a light microscope, and the lumen of the new blood vessels in the injection group was narrow, but relatively dilated in the non-injection group.There was no neovascularization found in the macular epiretinal membranes.The immunohistochemical staining revealed that there was the positive expression of Jagged1, Dll4 and Notch1 proteins in all PDR membranes, mainly located in the vascular endothelium during neovascularization.The absorbance values of Jagged1, Dll4 and Notch1 proteins were 6.25±1.82, 6.87±1.89 and 5.12±2.14 respectively in the non-injection group, which were all higher than 1.46±0.37, 1.55±0.24 and 1.32±0.53 respectively in the injection group, showing statistically significant differences ( t=5.168, P=0.014; t=6.012, P=0.008; t=3.453, P=0.030). There were statistically significant differences in Jagged1, Dll4 and Notch1 mRNA relative expression levels among the three groups ( F=77.337, 62.305, 51.869; all at P<0.01). The relative expression levels of Jagged1, Dll4 and Notch1 mRNA in the fibrovascular membranes with PDR were significantly higher than those of control macular epiretinal membranes, and the relative expression levels of Jagged1, Dll4 and Notch1 mRNA of the injection group were significantly lower than those of the non-injection group (all at P<0.05). The expression level of Jagged1 mRNA was positively correlated with expression levels of both Dll4 and Notch1 mRNA ( r=0.925, 0.950; both at P<0.05). Conclusions:There is a high expression of Jagged1 in the vascular endothelium of fibrovascular membranes with PDR and the Jagged1 expression is positively correlated with the expression of Dll4 and Notch1.The effect of Jagged1 on the neovascularization in PDR may be related to Dll4 and Notch1.

Objective:To investigate the radiosensitizing effect of Ta 4C 3-PVP nanosheets on the tumor of 4T1 murine triple-negative breast cancer cells planted in mice. Methods:4T1 tumor-bearing mice model was established by subcutaneous injection of 4T1 cells into the right flank of the female BALB/c mice. The mice were divided into four groups uniformly according to their tumor size: blank control group, Ta 4C 3-PVP group, ionizing radiation (IR) group and Ta 4C 3-PVP plus IR group. A single dose of 8 Gy X-ray local irradiation was given to xenograft tumor at 24 h after tail intravenous injection of Ta 4C 3-PVP (20 mg/kg). The xenograft tumor volume and weight, the pathological changes of tumor tissue, the expression of tumor proliferative marker Ki-67 protein, and the formation of γ-H2AX foci [a DNA double-strand breaks (DSBs) molecular marker] were detected. Tumor growth curve was established, and enhancement factor (EF) and tumor inhibition rate were calculated. Results:Compared with the blank control group, tumor growth was significantly inhibited ( t=5.41, 9.59, P < 0.05) and tumor weight was markedly decreased ( t=2.67, 4.40, P < 0.05) in both IR group and Ta 4C 3-PVP plus IR group at day 16 after IR. The EF in Ta 4C 3-PVP plus IR group was 1.57, and tumor inhibition rate in Ta 4C 3-PVP plus IR group were about 64%, which was much higher than that of IR group alone(42%). Immunohistochemistry and immunofluorescence histochemistry assays showed that the expression of Ki-67 protein was obviously decreased and the amount of γ-H2AX foci was significantly increased in both IR group and Ta 4C 3-PVP plus IR group in comparison with the blank control group ( t=5.73, 8.02, 2.97, 9.86, P < 0.05). Moreover, the inhibition of Ki-67 protein expression and the increase of γ-H2AX foci were much higher in Ta 4C 3-PVP plus IR group than that in IR group ( t=4.75, 4.42, P < 0.05). Conclusions:Ta 4C 3-PVP nanosheets could enhance radiosensitivity of xenograft tumor in 4T1 tumor-bearing mice through increasing the IR-induced DNA DSBs.

Objective:To assess the radiosensitivity of polyvinylpyrrolidone (PVP) modified tantalum carbide (Ta 4C 3) nanosheets in human triple-negative breast cancer MDA-MB-231 cells in vitro. Methods:PVP-modified Ta 4C 3 nanosheets were synthesized and characterized. The uptake of fluoresceine isothiocyanate(FITC) labeled Ta 4C 3-PVP nanosheets in MDA-MB-231 cells was examined by fluorescent microscope. The toxicity of Ta 4C 3-PVP in the cells was measured by CCK-8 assay.These cells were divided into 4 groups: control group, Ta 4C 3-PVP group, irradiation group alone and Ta 4C 3-PVP plus irradiation group. The colony formation assay was used to evaluate the radiosensitivity. The levels of intracellular reactive oxygen species (ROS) and lipid oxidation production, malondialdehyde (MDA), were detected with an automatic microplate reader.γH2AX foci and mitotic catastrophe were observed by immunofluorescence staining. Results:Ta 4C 3-PVP nanosheets with a single-layer flaky shape were successfully synthesized. The hydrodynamic diameter and thick of Ta 4C 3-PVP nanosheets were about 143.93 nm and 1.35 nm, respectively. The FITC labeled Ta 4C 3-PVP nanosheets were uptaken by MDA-MB-231 cells, which was mainly distributed in the cytoplasm.Treatment of Ta 4C 3-PVP nanosheets at concentrations up to 400 μg/ml was noncytotoxic to MDA-MB-231 cells. The colony formation assay showed that pretreatment with Ta 4C 3-PVP at 50 and 100 μg/ml moved the survival curve of the irradiated cells downward in a concentration-dependent manner, compared to irradiation group alone. The sensitization enhancement ratio (SER D0 ) of Ta 4C 3-PVP at 50 and 100 μg/ml were 1.21 and 1.45, respectively.The intracellular ROS level in Ta 4C 3-PVP plus irradiation group was significantly higher than that in irradiation group alone at 2 and 12 h after irradiation ( q=20.01, 7.193, P<0.05). The percentage of positive cells with more than five γH2AX foci in Ta 4C 3-PVP plus irradiation group was higher than that of irradiation group alone at 1, 4 and 8 h after irradiation ( q=36.78, 14.87, 8.217, P<0.05). The content of MDA in Ta 4C 3-PVP plus irradiation group was significantly higher than that of irradiation group alone at 24 and 48 h after irradiation ( q=14.02, 7.015, P<0.05). The percentage of cells that succumbed to mitotic catastrophe in Ta 4C 3-PVP plus irradiation group was significantly higher than that in irradiation group alone at 72 h after irradiation ( q=16.33, P<0.05). Conclusions:Ta 4C 3-PVP nanosheets could enhance the radiosensitivity of human triple-negative breast cancer MDA-MB-231 cells through an increase of the intracellular ROS induced by irradiation.

Objective:To observe and investigate the effect of HIF-2α in the process of neovascularization of proliferative diabetic retinopathy (PDR).Methods:Retrospective clinical study. From July 2014 to July 2015, 60 eyes of 57 PDR patients diagnosed in Ophthalmology Department of Affiliated Hospital of Qingdao University were included in the study. Twenty-eight eyes of 27 patients received intravitreal injections of 0.5 mg ranibizumab (0.05 ml) at 2-7 days before surgery (ranibizumab group) and other 32 eyes of 30 patients did not (group without ranibizumab). Eighteen eyes of 18 patients with epiretinal membranes were included as controls. Pathological specimens of PDR fibrovascular membrane and premacular membrane were obtained during vitrectomy. The immunohistochemical staining and real-time PCR (RT-PCR) were used to detecting the expression of HIF-2α, Dll4 and VEGF. Kruskal-wallis test was used to compare the expression differences of correlation factors between groups. Spearman correlation analysis was used to analyze the relationship between the two variables.Results:The immunohistochemical staining revealed that there were positive expression of HIF-2α, Dll4 and VEGF in all PDR membranes, regardless of the injection of the ranibizumab. The levels of HIF-2α, Dll4 and VEGF protein in the group without ranibizumab were higher than those of the ranibizumab group ( t=4.36, 6.01, 4.82; P=0.000, 0.008, 0.016). RT-PCR showed that the differences of the mRNA expression of HIF-2α, Dll4 and VEGF were all statistically significant among the PDR patients and controls ( H=18.81,19.60, 20.50; P=0.000, 0.000, 0.000). The expression of HIF-2α, Dll4 and VEGF in the PDR membranes was higher than that of epiretinal membranes from non-diabetic patients. In the PDR patients,the expression of HIF-2α, Dll4 and VEGF of the group without ranibizumab was higher than that of the ranibizumab group. The spearman correlation analysis showed that the expression of mRNA between HIF-2α and Dll4, HIF-2α and VEGF were both significantly correlated ( r=0.95, 0.87; P<0.05). Conclusions:The expression of HIF-2α in the PDR membranes was higher than that of the controls. It is positively correlated with the expression of the DLL4 and VEGF.

Objective To observe the effect of Delta-like ligand 4 (Dll-4) on the pathological structure of retina in early diabetic rats (DM) and its relationship with vascular endothelial growth receptor-2 (VEGFR-2).Methods A total of 70 male Sprague-Dawley rats were randomly divided into normal group and DM group,with 10 and 60 rats in each group,respectively.The rats of DM group was induced by intraperitoneal injection of streptozotocin to established DM model.The rats with blood glucose recovery and death were excluded,and the final 60 rats were included in the statistics.Rats in the normal group were injected with an equal volume of citric acid-sodium citrate buffer.Rats in the DM group were divided into DM 1 month (DM lm) group,DM 2 months (DM 2m) group,DM 3 months (DM 3m) group and DM 3m + Anti group,DM 3m + phosphate buffer solution (PBS) group by random number table method,and 10 rats in each group.In the DM 3m+Anti group,4 μl ofantiDll-4 polyclonal antibody was injected into the vitreous cavity,and the antibody concentration was 0.25 mg/ml.The DM 3m+PBS group was intravitreally injected with an equal volume of PBS.Five days after the injection,the rats were sacrificed.Rats in the DM 3m group and the normal group were not treated,and were sacrificed 3 months after the model was established.The structure and microvascular changes of the retina were observed by hematoxylin-eosin staining,and the total thickness of the retina was measured.The expression of Dll-4 and VEGFR-2 in the retina was detected by immunohistochemistry and fluorescence quantitative polymerase chain reaction (PCR).One-way analysis of variance was used to compare the expression of Dll-4 and VEGFR-2 in the retina of each group.The least significant difference t test was used to compare the two groups.Results Light microscopy showed that the retinal ganglion cells layer in the DM 3m group were obviously edematous,the inner and outer nuclear layers were thinner,the number of cells was reduced,the arrangement was disordered,the edema of outer plexiform layer was obvious,and the microvessels were abnormally dilated.In the DM 3m+Anti group,the edema of outer plexiform layer was lessened than that of the DM 3m group,and the other layers were not significantly different from the DM 3m group.Compared with the normal group,the total retinal thickness of the DM 3m group,the DM 3m+Anti group and the DM 3m+PBS group increased (t=5.596,3.290,4.286;P=0.000,0.008,0.002).Immunohistochemical staining showed that a small amount of Dl14 was positively expressed in the retinal ganglion cell layer of the normal group;a small amount of VEGFR-2 was positively expressed in the ganglion cell layer and the inner and outer nuclear layers.The positive expression of Dll-4 and VEGFR-2 in retinal vascular endothelial cells of DM 3m group increased significantly.The expression of Dll-4 was significantly decreased in the retinal layers and vascular endothelial cells ofDM 3m+Anti group,while the expression of VEGFR-2 was significantly increased.There was no significant difference between the positive expression of Dll4 and VEGFR-2 in the DM 3m+PBS group and the DM 3m group.The results of real-time PCR showed that the relative expression of Dll-4 and VEGFR-2 mRNA in the DM 3m group was significantly higher than that in the normal group (t=6.705,20.871;P＜0.05).Compared with DM 3m group,the relative expression of Dll-4 mRNA in DM 3m+Anti group decreased,and the relative expression of VEGFR-2 mRNA increased (t=2.681,3.639;P＜0.05).The relative expressions of Dll-4 and VEGFR-2 mRNA in the DM 3m+PBS group and DM 3m group were not statistically significant (t=0.513,0.657;P＜0.05).Conclusions The expression of Dll-4 in retinal vascular endothelial cells is gradually increased during the early retinopathy of DM rats.The expression of Dll-4 is inhibited,the expression of VEGFR-2 is up-regulated,and the plexus edema is alleviated.

Objective: To describe the clinicopathologic features, diagnosis and differential diagnosis of ovarian carcinoid tumors. Methods: A retrospective chart review was performed of all patients diagnosed with primary ovarian carcinoid tumors at Fudan University Shanghai Cancer Centre from 2007 to 2017. Results: The histologic analysis of these carcinoid tumors revealed 3 were insular, 1 was trabecular, 1 was mucinous, and 10 were strumal. Histologic features of insular and trabecular carcinoid were similar to other parts of the neuroendocrine tumor. Strumal carcinoid was composed of thyroid tissue intimately admixed with carcinoid tumor, showing trabecular pattern. Mucinous carcinoid was resembles Krukenberg tumor. Most ovarian carcinoid tomours were diffusely positive with at least one neuroendocrine marker, especially synaptophysin (14/14) and CD56(9/10). The median follow-up time was 53 months, 1 patient with squamous-cell carcinoma of cervixrecur rence in vaginal after 37 months, and only 1 patient died of disease. The remaining patients were disease-free survival. Conclusions Primary carcinoid of the ovary is a very rare low grade malignant monodermal teratomas and somatic-type tumours arising from a dermoid. The diagnosis and differential diagnosis mainly relies on the histopathologic characteristics and the immuno-phenotype. Primary ovarian carcinoid almost always exhibit a benign clinical behavious except mucinous carcinoid.

Objective:To observe the effect of Da Huang (Rheum Officinale) application at Shenque (CV 8) on constipation after operation for lumbar vertebral fracture. Methods:Seventy-four patients with constipation after operation for lumbar vertebral fracture were divided into an observation group and a control group by the random number table, 37 cases in each group. The two groups both received ordinary treatment (including healthcare guidance, emotional care, diet arrangement, and defecation nursing), while the observation group was additionally givenDa Huang (Rheum Officinale) application at Shenque (CV 8) for 6 h each day. The therapeutic efficacy was evaluated after successive 3-day treatment. Results:After 3-day treatment, it took significantly less time for the observation group to conduct the first flatulence and defecation than for the control group (P<0.05); the therapeutic efficacy of the observation group was significantly higher than that of the control group (P<0.01). Conclusion:Da Huang (Rheum Officinale) application at Shenque (CV 8) is effective in treating constipation after lumbar vertebral fracture operation, and it’s easy-to-operate and well accepted by patients, hence it’s proper to promote this method in clinic.