Measurements of All-Particle Energy Spectrum and Mean Logarithmic Mass of Cosmic Rays from 0.3 to 30 PeV with LHAASO-KM2A.

We present the measurements of all-particle energy spectrum and mean logarithmic mass of cosmic rays in the energy range of 0.3-30 PeV using data collected from LHAASO-KM2A between September 2021 and December 2022, which is based on a nearly composition-independent energy reconstruction method, achieving unprecedented accuracy. Our analysis reveals the position of the knee at 3.67±0.05±0.15 PeV. Below the knee, the spectral index is found to be -2.7413±0.0004±0.0050, while above the knee, it is -3.128±0.005±0.027, with the sharpness of the transition measured with a statistical error of 2%. The mean logarithmic mass of cosmic rays is almost heavier than helium in the whole measured energy range. It decreases from 1.7 at 0.3 PeV to 1.3 at 3 PeV, representing a 24% decline following a power law with an index of -0.1200±0.0003±0.0341. This is equivalent to an increase in abundance of light components. Above the knee, the mean logarithmic mass exhibits a power law trend towards heavier components, which is reversal to the behavior observed in the all-particle energy spectrum. Additionally, the knee position and the change in power-law index are approximately the same. These findings suggest that the knee observed in the all-particle spectrum corresponds to the knee of the light component, rather than the medium-heavy components.

[Promoting implementation research and One Health approach to respond the four global health challenges: an interpretation of the Special Programme for Research and Training in Tropical Diseases (TDR) Strategy 2024-2029].

Tropical diseases, notably neglected tropical diseases and infectious diseases of poverty, remain major health problems endangering the poorest and most-marginalized people in the world. The Special Programme for Research and Training in Tropical Diseases (TDR), which is co-sponsored by the World Health Organization, the United Nations Children's Fund (UNICEF), the United Nations Development Programme (UNDP) and the World Bank, is an important programme that helps facilitate, support, guide and coordinate global efforts to combat tropical diseases. On July 2023, TDR formally issued its 2024-2029 strategy, which proposed the direction and proprieties of global tropical disease prevention and control in the next six years. Based on its original focus on supporting researchers and research institutions from low and middle-income countries to conduct research on tropical diseases and building their research capabilities, this strategy proposed some new developments, which mainly included incorporating tropical disease prevention and control into the overall framework of addressing major global health challenges and achieving the health goals set by the United Nations Sustainable Development Goals (SDGs) to combat tropical diseases and contribute to achieving health goals of SDGs in a collaborative and integrated manner; supporting implementation research and encouraging practitioners and social innovators to participate in research to enable generation of solutions that may be used to solve local health problems; promoting and encouraging the One Health concept and interdisciplinary and cross-departmental collaboration; shifting gradually its focus from disease prevention and control to addressing the health needs of the poorest and most-marginalized populations. These new developments deserve the attention of personnel and institutions in China dedicated to the prevention and control of tropical diseases in order to help their future researches and activities.

[Key microbial monitoring and clinical analysis of bloodstream infections and CRO colonization after hematopoietic stem cell transplantation in hematological patients].

Objective: To investigate the distribution and clinical characteristics of pathogenic bacteria following hematopoietic stem cell transplantation (HSCT), as well as to provide a preliminary research foundation for key microbial monitoring, and clinical diagnosis and treatment of infections after HSCT in hematological patients. Methods: We retrospectively analyzed the clinical data of 190 patients who tested positive for microbial testing [G-bacteria blood culture and/or carbapenem-resistant organism (CRO) screening of perianal swabs] at our center from January 2018 to December 2022. Patients were divided into blood culture positive, perianal swab positive, and double positive groups based on the testing results. The three patient groups underwent statistical analysis and comparison. Results: The top four pathogenic bacteria isolated from sixty-three patients with G-bacteria bloodstream infection (BSI) were Escherichia coli (28 strains, 43.75% ), Klebsiella pneumonia (26 strains, 40.63% ), Pseudomonas aeruginosa (3 strains, 4.69% ), and Enterobacter cloacae (3 strains, 4.69% ). The top three pathogenic bacteria isolated from 147 patients with CRO perianal colonization were carbapenem-resistant Klebsiella pneumoniae (58 strains, 32.58% ), carbapenem-resistant Escherichia coli (49 strains, 27.53% ), and carbapenem-resistant Enterobacter cloacae (20 strains, 11.24% ). The 3-year disease-free survival (DFS ) and overall survival (OS) of double positive group patients were significantly lower compared to those in the blood culture and perianal swab positive groups (DFS: 35.6% vs 53.7% vs 68.6%, P=0.001; OS: 44.4% vs 62.4% vs 76.9%, P<0.001), while non-relapse mortality (NRM) was significantly higher (50.0% vs 34.9% vs 10.6%, P<0.001). Failed engraftment of platelets and BSI are independent risk factors for NRM (P<0.001). Using polymyxin and/or ceftazidime-avibactam for more than 7 days is an independent protective factor for NRM (P=0.035) . Conclusion: This study suggests that the occurrence of BSI significantly increases the NRM after HSCT in patients with hematological diseases; CRO colonization into the bloodstream has a significant impact on the DFS and OS of HSCT patients.

[Effect of dual fluorescence imaging in identifying central lymph nodes and parathyroid glands during thyroid cancer surgery].

Objective: To investigate the effect of dual fluorescence imaging in identifying central lymph nodes and parathyroid glands during thyroid cancer surgery. Methods: This study was a cross-sectional study. Patients who underwent surgery for papillary thyroid cancer (PTC) at the Department of Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University between January 2022 and September 2023 were included. All patients underwent thyroid lobectomy or total resection, and central lymph node dissection was performed at the same time. During the operation, tracing injection of mitoxantrone hydrochloride and 785 nm and 660 nm dual fluorescence imaging technique were used to measure the fluorescence intensity (FI) of parathyroid glands, central lymph nodes and background. After correcting to obtain the standardized FI, the paired t-test was used to compare the standardized FI of the parathyroid glands and central lymph nodes, and the Spearman's rank correlation analysis was used to analyze the relationship between the standardized FI and various clinical indicators. Results: The study included 30 patients (8 males and 22 females), with a mean age of (41.8±10.4) years. A total of 76 parathyroid glands and 234 central lymph nodes were identified under dual fluorescence imaging, and the standardized FI of parathyroid glands was less than that of central lymph nodes (44.7±16.8 vs 99.5±28.4, P<0.001). The visualization rate, false rate and miscut rate of parathyroid glands under 785 nm wavelength excitation light were 98.7% (76/77), 0 (0/77) and 1.3% (1/77), respectively (one case with no visualization and miscutting parathyroid gland was the encapsulated type). The visualization rate of central lymph nodes under 660 nm wavelength excitation light was 98.7% (234/237). There was no significant correlation between FI and clinical indicators such as gender, age, height, weight, body mass index, preoperative thyroid stimulating hormone, thyroglobulin antibody, thyroid microsomal antibody, serum calcium, parathyroid hormone level and surgical procedure (all P>0.05). Conclusion: Dual fluorescence imaging of central lymph nodes and parathyroid glands can improve the ability to identify parathyroid gland while assisting central lymph node dissection.

Surgical treatment of nasopharyngeal cancer - a consensus recommendation from two Chinese associations.

BACKGROUND: Surgical treatment is playing an increasingly important role in the management of nasopharyngeal carcinoma (NPC). This consensus focuses on the indications for optimal surgery, and surgical methods in the whole process of treatment for NPC to provide a useful reference to assist these difficult clinical decisions. METHODOLOGY: A thorough review of available literature on NPC and surgery was conducted by the Association for the prevention and treatment of nasopharyngeal carcinoma in China, international exchange and promotion Association for medicine and healthcare, and the Committee on nasopharyngeal cancer of Guangdong provincial anticancer association. A set of questions and a preliminary draft guideline was circulated to a panel of 1096 experienced specialists on this disease for voting on controversial areas and comments. A refined second proposal, based on a summary of the initial voting and different opinions expressed, was recirculated to the experts in two authoritative medical science and technology academic groups in the prevention and treatment of NPC in China for review and reconsideration. RESULTS: The initial round of questions showed variations in clinical practice even among similar specialists, reflecting the lack of high-quality supporting data and resulting difficulties in formulating clinical decisions. Through exchange of comments and iterative revisions, recommendations with high-to-moderate agreement were formulated on general treatment strategies and details of surgery, including indications and surgical approaches. CONCLUSION: By standardizing the surgical indications and practice, we hope not only to improve the surgical outcomes, but also to highlight the key directions of future clinical research in the surgical management of NPC.

Multimodel habitats constructed by perfusion and/or diffusion MRI predict isocitrate dehydrogenase mutation status and prognosis in high-grade gliomas.

AIM: To determine whether tumour vascular and cellular heterogeneity of high-grade glioma (HGG) is predictive of isocitrate dehydrogenase (IDH) mutation status and overall survival (OS) by using tumour habitat-based analysis constructed by perfusion and/or diffusion magnetic resonance imaging (MRI). MATERIALS AND METHODS: Seventy-eight HGG patients that met the 2021 World Health Organization WHO Classification of Tumors of the Central Nervous System, 5th edition (WHO CNS5), were enrolled to predict IDH mutation status, of which 32 grade 4 patients with unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter were enrolled for prognostic analysis. The deep-learning-based model nnU-Net and K-means clustering algorithm were applied to construct the Traditional Habitat, Vascular Habitat (VH), Cellular Density Habitat (DH), and their Combined Habitat (CH). Quantitative parameters were extracted and compared between IDH-mutant and IDH-wild-type patients, respectively, and the prediction potential was evaluated by receiver operating characteristic (ROC) curve analysis. OS was analysed using Kaplan-Meier survival analysis and the log-rank test. RESULTS: Compared with IDH-mutants, median relative cerebral blood volume (rCBVmedian) values in the whole enhancing tumour (WET), VH1, VH3, CH1-4 habitats were significantly increased in IDH-wild-type HGGs (all p<0.05). Additionally, the accuracy of rCBVmedian values in CH1 outperformed other habitats in identifying IDH mutation status (p<0.001) at a cut-off value of 4.83 with AUC of 0.815. Kaplan-Meier survival analysis highlighted significant differences in OS between the populations dichotomised by the median of rCBVmedian in WET, VH1, CH1-3 habitats (all p<0.05). CONCLUSIONS: The habitat imaging technique may improve the accuracy of predicting IDH mutation status and prognosis, and even provide a new direction for subsequent personalised precision treatment.

Brusatol attenuated proliferation and invasion induced by KRAS in differentiated thyroid cancer through inhibiting Nrf2.

BACKGROUND: Poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) can be developed from differentiated thyroid cancer, and this dedifferentiated transformation leads to poor prognosis and high mortality. The role of Nrf2 in the dedifferentiation of differentiated thyroid cancer (DTC) induced by KRAS remains unclear. METHODS AND MATERIALS: In this study, two DTC cell lines, BCPAP and WRO, were used to evaluate the function of Nrf2 in the dedifferentiation caused by wild-type KRAS (KRAS-WT) and G12V point mutation KRAS (KRAS-G12V). RESULTS: The overexpression of KRAS-WT and KRAS-G12V increased the proliferative and invasive ability of BCPAP and WRO cells. Aggressive morphology was observed in KRAS-WT and KRAS-G12V overexpressed WRO cells. These results suggested that overexpression of KRAS-WT or KRAS-G12V may induce dedifferentiation in DTC cells. The expression of Nrf2 was increased by KRAS-WT and KRAS-G12V in DTC cells. In addition, compared with normal thyroid tissues, the expression of Nrf2 protein was considerably higher in thyroid cancer tissues on immunohistochemistry (IHC) staining, and the increased expression of Nrf2 indicated a poor prognosis of thyroid cancer. These results indicated that Nrf2 is the KRAS downstream molecule in thyroid cancer. Functional studies showed that the Nrf2 inhibitor Brusatol counteracted the proliferative and invasive abilities induced by KRAS-WT and KRAS-G12V in BCPAP and WRO cells. In addition, the xenograft assay further confirmed that Brusatol inhibits tumor growth induced by KRAS-WT and KRAS-G12V. CONCLUSION: Collectively, this study suggests that Nrf2 could be a promising therapeutic target in KRAS-mediated dedifferentiation of thyroid cancer.

[Performance verification and clinical application evaluation of D-dimer assay].

Objective: To evaluate the clinical application performance of a domestic D-dimer assay reagent (ADX D-dimer). Methods: A total of 546 residual sodium citrate anticoagulated plasma samples (530 of which were used for comparability validation and 16 for sample preparation of other validation components) were selected after the completion of clinical testing at Peking Union Medical College Hospital from Jun 2022 to May 2023. According to the American Clinical Laboratory Standards Institute (CLSI) guidelines, national health industry standards and relevant references, the performance of ADX D-dimer used in Sysmex CS 5100 fully automated coagulation analyzer which included accuracy, precision, linear range, carryover rate, interference resistance capability and reference interval were validated and the agreement compared with two mainstream imported detection reagents (reagent A: Vidas D-dimer reagent; reagent B: Innovance D-dimer detection reagent) was evaluated. The clinical diagnostic efficacy of the ADX D-dimer was evaluated using the ELISA D-dimer (reagent A) test results as criteria. Results: The linear correlation coefficient of the 6-point calibrated absorbance and target value was 0.998, the bias of accuracy met the requirements (-2.8%-8.4%), and the coefficient of variation (CV) of within-run and between-day precision of the two levels were 1.0%-2.7% and 2.7%-4.1%, respectively, which were less than the requirements of the manufacturer's statement and the national health industry standard. The linear range within 0.33-9.69 mg/L FEU was verified and the carryover rate was 0. There was no significant interference with the assay results at bilirubin F≤0.22 g/L, bilirubin C≤0.22 g/L, hemoglobin≤5.5 g/L and celiac≤2 800 FTU. The manufacturer's reference interval≤0.5 mg/L FEU was verified suitable for this laboratory. For 358 samples without suspicious heterophilic antibody whose D-dimer levels range from 0.06 to143.63 mg/L FEU, the correlation between ADX D-dimer and another two assay was good, with r values being 0.968 and 0.975, respectively, the percentage of deviation and relative deviation beyond the 95% confidence interval was 3.4%-4.5% and 5.3%-7.0%. The correlation between ADX D-dimer and ELISA D-dimer was better than that of reagent B in the concentration range of 0.06-1.00 mg/L FEU (r=0.858, 0.134). For 172 samples with heterophilic antibody, the correlation between ADX D-dimer and ELISA D-dimer was still good(r=0.827), with the percentage of deviation and relative deviation being 6.4% (11/172). The diagnostic efficacy was evaluated using 530 samples, and the sensitivity, specificity, positive predictive value, negative predictive value of ADX D-dimer was 97.4%, 77.6%, 91.9%, 91.9%. The area under the curve was 0.976 (95%CI: 0.964-0.987, P<0.001). Conclusion: The ADX D-dimer reagent has superior assay and diagnostic performance, and can meet the needs of clinical laboratories.

[Study on formulation and revision of standard limits for inhalable particulate matter (PM10) and fine particulate matter (PM2.5) in "Standards for indoor air quality（GB/T 18883-2022）" in China].

The pollution and health effects of indoor inhalable particulate matter (PM10) and fine particulate matter (PM2.5) are increasingly receiving public attention. The"Standards for indoor air quality (GB/T 18883-2022)"has revised the standard limit for PM10 and added the standard limit for PM2.5. This study analyzed and interpreted the relevant technical contents of the revision of the standard limits for two indicators, including the exposure status, health effects, and the basis for the determination of the limit value. It also proposed prospects for the future development and revision of standard limits for indoor particulate matters.

Measurement of Ultra-High-Energy Diffuse Gamma-Ray Emission of the Galactic Plane from 10 TeV to 1 PeV with LHAASO-KM2A.

The diffuse Galactic γ-ray emission, mainly produced via interactions between cosmic rays and the interstellar medium and/or radiation field, is a very important probe of the distribution, propagation, and interaction of cosmic rays in the Milky Way. In this Letter, we report the measurements of diffuse γ rays from the Galactic plane between 10 TeV and 1 PeV energies, with the square kilometer array of the Large High Altitude Air Shower Observatory (LHAASO). Diffuse emissions from the inner (15°10 TeV). The energy spectrum in the inner Galaxy regions can be described by a power-law function with an index of -2.99±0.04, which is different from the curved spectrum as expected from hadronic interactions between locally measured cosmic rays and the line-of-sight integrated gas content. Furthermore, the measured flux is higher by a factor of ∼3 than the prediction. A similar spectrum with an index of -2.99±0.07 is found in the outer Galaxy region, and the absolute flux for 10≲E≲60 TeV is again higher than the prediction for hadronic cosmic ray interactions. The latitude distributions of the diffuse emission are consistent with the gas distribution, while the longitude distributions show clear deviation from the gas distribution. The LHAASO measurements imply that either additional emission sources exist or cosmic ray intensities have spatial variations.

[Standardized and individualized treatment improves survival rate and quality of life for advanced thyroid cancer].

The overall prognosis of differentiated thyroid carcinoma is favorable, but some patients still progress to a locally advanced stage. At present, there are still some problems in the diagnosis and treatment of locally advanced thyroid cancer, which have not been completely clarified, and have caused some problems to the clinical treatment. This article provides a comprehensive analysis and elaboration on the selection of surgical methods for local advanced thyroid cancer, management of recurrent laryngeal nerve and trachea, timing selection of staging surgery, and targeted therapy, aiming at promoting standardized and individualized treatment for advanced thyroid cancer and improving the survival rate and quality of life.

[Preliminary analysis of neuroprotective effects of capillary fascia preservation recurrent laryngeal nerve anatomical method in right level â ¥ dissection].

Objective: To investigate the application and effect of capillary fascia preservation between the recurrent laryngeal nerve (RLN) and common carotid artery (fascia preservation method) in nerve protection when dissecting right level Ⅵ lymph nodes for patients with papillary thyroid carcinoma. Methods: A retrospective cohort study enrolling 195 patients with papillary thyroid carcinoma undergoing right level Ⅵ lymph node dissection in Beijing Tongren Hospital from March 2021 to August 2022 was carried out. The RLN was dissected by fascia preservation method in study group and by routine method in control group. The intraoperative electrical signal amplitude of the RLN, the number of dissected lymph nodes, and the postoperative complications were recorded and analyzed. Results: A total of 195 patients (study group: 94 cases, control group: 101 cases) were collected. There were 71 males and 124 females, with the median age of 32 (39, 51) years. In the study group, the total number of right level Ⅵ lymph nodes was significantly larger than the number of right Ⅵa level lymph nodes [8 (6, 11) vs 6 (4, 8), P<0.001]. There were no significant differences between the two groups in the number of level Ⅵa or level Ⅵb lymph nodes [Ⅵa: 6 (4, 8) vs 5 (3, 7), P=0.373; Ⅵb: 3 (1, 4) vs 2 (1, 4), P=0.337] and metastasis rate [Ⅵa: 51.1% (48/94) vs 52.5% (53/101), P=0.844; Ⅵb: 12.8% (12/94) vs 15.8% (16/101), P=0.541]. The ratio of electromyography (EMG) amplitude R2 in lower level Ⅵ and entry into larynx (grouped as>90%, 50%~90%,<50%) in the study group was significantly higher than that in the control group (P<0.001). No significant differences were detected between the two groups in temporary RLN paralysis [1.1% (1/94) vs 2.0% (2/101), P=1.000]. Conclusions: Fascia preservation method can decrease the stimulus and traction to RLN and preserve the capillary network serving RLN. It can thoroughly dissect lymph nodes and decrease the injury of RLN.

[Application of near-infrared autofluorescence imaging-based convolution neural network in recognition of parathyroid gland].

Objective: To investigate the application value of near-infrared autofluorescence imaging-based convolution neural network (CNN) for automatic recognition of parathyroid gland. Methods: The data of 83 patients who underwent thyroid papillary cancer surgery in the Department of Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University from August 2020 to March 2022 were retrospectively analyzed, and a total of 725 autofluorescence images of parathyroid gland were collected during the surgery. Meanwhile, non-parathyroid fluorescence imaging videos in the operation area of 10 patients were also collected, and 928 non-parathyroid fluorescence images were captured from those videos. The fluorescence images of parathyroid and non-parathyroid glands were directly used as input features for deep learning to construct ResNet 34, VGGNet 16 and GoogleNet models for automatic parathyroid identification. The ability of different models to identify parathyroid glands was tested by indicators such as accuracy, specificity, sensitivity, precision, receiver operating characteristic curve and area under the curve (AUC). In addition, 30 fluorescence images of parathyroid and 35 fluorescence images of non-parathyroid glands in 13 patients with papillary thyroid cancer from March to May 2022 were collected to prospectively test the best performing CNN model. Results: Among the 83 patients, there were 25 males and 58 females, with the mean age of (46.7±12.4) years. In the binary classification (parathyroid gland and non-parathyroid gland), the ResNet 34 model performed the best in different CNN models, the accuracy, specificity, sensitivity and precision of the identification test set were 97.6%, 96.3%, 99.3% and 95.5%, and the AUC reached 0.978 (95%CI: 0.956-0.991). In the prospective test, the prediction accuracy of the ResNet 34 model reached 93.8%, and the AUC was 0.938 (95%CI: 0.853-0.984). Conclusion: The near-infrared autofluorescence imaging-based deep CNN has good application value in the automatic recognition of parathyroid gland, and can be used to assist the recognition and protection of parathyroid gland in thyroid cancer surgery.

[Effects of three-dimensional computed tomography angiography-assisted free medial sural artery perforator flap in repairing foot wounds].

Objective: To investigate the effects of three-dimensional computed tomography angiography (3D-CTA)-assisted free medial sural artery perforator flap in repairing foot wounds. Methods: A retrospective observational study was conducted. From May 2018 to August 2021, 18 patients with foot soft tissue defects who met the inclusion criteria were admitted to the Department of Spine and Trauma Orthopedics of the Yidu Central Hospital of Weifang, including 13 males and 5 females, aged 19 to 55 years, with a wound area of 4.0 cm×3.0 cm-9.0 cm×8.0 cm at admission. Before the operation, CT scanner was used to scan the area from the supracondylar femur to the middle segment of the fibula of patients, and the obtained data were extracted into the Mimics16.0 software and analyzed to determine the pre-selected perforator, and then the image data of the pre-selected perforator side were analyzed further, and the body surface projection position of the perforating point of the medial sural artery in the calf region was marked. Based on the above examination, the flap was designed and cut according to the shape and area of the patient's foot tissue defect, and the area of flaps ranged from 5.0 cm×4.0 cm to 10.0 cm×9.0 cm. The donor sites were sutured directly or covered by skin grafting. The type of perforator, the diameters of perforator at the beginning and outlet point, and the location of the outlet point of perforator of the medial sural artery were observed under 3D-CTA examination before operation and compared to see if they were consistent with the observation under intraoperative condition. The survival of the flaps after operation was recorded. During follow-up, the satisfaction of patients with the wound repair effects, the sensory recovery of the recipient flaps, the healing of the donor wound, and whether there were complications affecting limb functions were recorded. Data were statistically analyzed with Kappa consistency test and equivalence test, and the 95% confidence intervals of measurement difference of perforator diameter and outlet point position of perforator were -0.50-0.50 mm and -2.0-2.0 cm, respectively. Results: The types of medial sural artery perforators observed during operation were type Ⅰ in 3 cases, type ⅡA in 6 cases, type ⅡB in 8 cases, and type Ⅲ in 1 case, which was consistent with the results of 3D-CTA before operation (Kappa=1.00, P<0.05). The blood vessel diameter detected by 3D-CTA before operation at the beginning of perforator of medial sural artery was (1.81±0.39) mm, and the blood vessel diameter at the outlet point of the perforator was (0.83±0.21) mm, which were close to the actual intraoperative measurement of (1.83±0.43) and (0.86±0.22) mm, respectively; equivalence test showed that the 95% confidence intervals of the measurement differences of diameter of medial sural artery perforator at beginning and outlet point were -0.18-0.22 and -0.08-0.14 mm, respectively, with both P values <0.05. The preoperative 3D-CTA detected that the perforating position at the deep fascia of the perforator of the medial sural artery, namely the vertical distance with the popliteal fold was (12.2±1.4) cm, and the horizontal distance with the posterior midline was (2.6±0.7) cm, which were respectively close to the actual intraoperative measurement of (12.4±1.4) and (2.6±0.7) cm; equivalence test showed that the 95% confidence intervals of the measurement differences in the vertical distance with the popliteal fold and the horizontal distance with the posterior midline of the outlet point of medial sural artery perforator were -1.06-1.26 and -0.46-0.66 cm, respectively, with both P values <0.05. After surgery, all flaps of 18 patients survived without vascular crisis. After 1 year of follow-up, the satisfaction degree of 16 patients was excellent and 2 patients was good with the wound repair effects, with a satisfaction ratio of 16/18; the sensory recovery of flap was evaluated as S3 in 11 cases and S2 in 7 cases; the donor wounds healed well without obvious scar or contracture, with no effect on limb joint functions. Conclusions: The medial sural artery perforator flap achieved good results in repairing foot wound with high degree of patient satisfaction. Preoperative application of 3D-CTA can realize the standardization, systematization, and visualization of artery perforator flap.

[ARHGAP21 inhibits epithelial-mesenchymal transition by inactivating the WNT signaling pathway in non-small cell lung cancer].

OBJECTIVE: To investigate the role of Rho GTPase-activating protein 21 (ARHGAP21) in regulating the migration and metastasis of non-small cell lung cancer (NSCLC) cells. METHODS: TCGA, CPTAC database were used to analyze the correlation of ARHGAP21 expression level in NSCLC and the patients' prognosis. The expression of ARHGAP21 in clinical specimens of NSCLC tissues was examined using Western blotting and immunohistochemistry. The effect of ARHGAP21 knockdown on migration ability of lung cancer cell lines was examined using Transwell assay and wound healing assay. A nude mouse model with injection of lung cancer H1299 cells via the tail vein was used to examine the effect of ARHGAP21 knockdown on the metastatic ability of the tumor cells. The possible mechanism of ARHGAP21 was predicted by bioinformatics analysis and verified using Western blotting. RESULTS: A low ARHGAP21 expression was associated with poor prognosis of patients with NSCLC (P < 0.05). ARHGAP21 expression was significantly downregulated in lung cancer tissues as compared with the adjacent tissues (P < 0.001). In cultured lung cancer cells, ARHGAP21 knockdown obviously promoted the migration ability of the cells (P < 0.001). In the nude mouse models, injection of H1299 cells with ARHGAP21 knockdown, as compared with the negative control cells, resulted in a greater number of metastatic lung cancer nodules (P < 0.05), which expressed higher levels of N-cadherin and vimentin. Bioinformatic analysis showed a close correlation of ARHGAP21 with APC, GSK3ß, and Axin (P < 0.001). Western blotting showed that ARHGAP21 knockdown significantly decreased ubiquitination of ß-catenin, upregulated N-cadherin and activated the WNT signaling pathway in the lung cancer cells. CONCLUSION: ARHGAP21 downregulation can significantly promote the migration and metastatic ability of NSCLC possibly as a result of WNT signaling pathway activation, which reduces the ubiquitination of ß-catenin by affecting the expressions of APC, GSK3ß, and Axin.

Adaptable polymerization platform for therapeutics with tunable biodegradability.

Biodegradable polymer-based therapeutics have recently become essential drug delivery biomaterials for various bioactive compounds. Biodegradable and biocompatible polymer-based biomaterials fulfill the requirements of these therapeutics because they enable to obtain polymer biomaterials with optimized blood circulation, pharmacokinetics, biodegradability, and renal excretion. Herein, we describe an adaptable polymerization platform employed for the synthesis of long-circulating, stimulus-sensitive and biodegradable biomaterials, therapeutics, or theranostics. Four chain transfer agents (CTA) were designed and successfully synthesized for the reversible addition-fragmentation chain transfer polymerization, allowing the straightforward synthesis of hydrolytically biodegradable structures of block copolymers-based biomaterials. The controlled polymerization using the CTAs enables controlling the half-life of the hydrolytic degradation of polymer precursors in a wide range from 5 h to 21 days. Moreover, the antitumor drug pirarubicin (THP) was successfully conjugated to the polymer biomaterials via a pH-sensitive hydrazone bond for in vitro and in vivo experiments. Polymer conjugates demonstrated superior antitumor efficacy compared to basic linear polymer-based conjugates. Notably, the biodegradable systems, even though those with degradation in the order of hours were selected, increased the half-life of THP in the bloodstream almost two-fold. Indeed, the presented platform design enables the main chain-end specific attachment of targeting ligands or diagnostic molecules. The adaptable polymerization platform design allows tuning of the biodegradability rate, stimuli-sensitive drug bonding, and optimized pharmacokinetics to increase the therapy outcome and system targeting, thus allowing the preparation of targeted or theranostic polymer conjugates. STATEMENT OF SIGNIFICANCE: Biodegradable and biocompatible polymer-based biomaterials are recognized as potential future bioactive nanomedicines. To advance the development of such biomaterials, we developed polymerization platforms utilizing tailored chain transfer agents allowing the straightforward synthesis of hydrolytically degradable polymer biomaterials with tuned biodegradability from hours to several days. The platform allows for the synthesis of long-circulating, stimulus-sensitive and biodegradable biomaterial serving as drug carriers or theranostics. The therapeutic potential was validated by preparation of polymer biomaterials containing pirarubicin, anticancer drug, bound via pH sensitive bond and by showing prolonged blood circulation and increased antitumor activity while keeping the drug side effects low. This work paves the way for future development of biodegradable polymer biomaterials with advanced properties in drug delivery.

[Recompensation of complications in patients with hepatitis B virus-related decompensated cirrhosis treated with entecavir antiviral therapy].

Objective: To analyze the occurrence of recompensation conditions in patients with chronic hepatitis B virus-related decompensated cirrhosis after entecavir antiviral therapy. Methods: Patients with hepatitis B virus-related decompensated cirrhosis with ascites as the initial manifestation were prospectively enrolled. Patients who received entecavir treatment for 120 weeks and were followed up every 24 weeks (including clinical endpoint events, hematological and imaging indicators, and others) were calculated for recompensation rates according to the Baveno VII criteria. Measurement data were compared using the Student t-test or Mann-Whitney U test between groups. Categorical data were compared by the χ (2) test or Fisher's exact probability method between groups. Results: 283 of the 320 enrolled cases completed the 120-week follow-up, and 92.2% (261/283) achieved a virological response (HBV DNA 20 IU/ml). Child-Pugh and MELD scores were significantly improved after treatment (8.33 ± 1.90 vs. 5.77 ± 1.37, t = 12.70, P < 0.001; 13.37 ± 4.44 vs. 10.45 ± 4.58, t = 5.963, P < 0.001). During the 120-week follow-up period, 14 cases died, two received liver transplants, 19 developed hepatocellular cancer, 11 developed gastroesophageal variceal bleeding, and four developed hepatic encephalopathy. 60.4% (171/283) (no decompensation events occurred for 12 months) and 56.2% (159/283) (no decompensation events occurred for 12 months and improved liver function) of the patients had achieved clinical recompensation within 120 weeks. Patients with baseline MELD scores > 15 after active antiviral therapy achieved higher recompensation than patients with baseline MELD scores ≤15 [50/74 (67.6%) vs. 109/209 (52.2%), χ (2) = 5.275, P = 0.029]. Conclusion: Antiviral therapy can significantly improve the prognosis of patients with hepatitis B virus-related decompensated cirrhosis. The majority of patients (56.2%) had achieved recompensation. Patients with severe disease did not have a lower probability of recompensation at baseline than other patients.

[Pre- and post-diagnosis body mass index in association with colorectal cancer death in a prospective cohort study].

Objective: To evaluate the association between pre-and post-diagnosis body mass index (BMI) and risk of colorectal cancer (CRC) death. Methods: The cohort consisted of 3, 057 CRC patients from Shanghai who were diagnosed from Jan. 1, 2009 to Dec. 31, 2011 and aged from 20 to 74 years. The pre- and post-diagnosis BMI and clinical and lifestyle factors were collected at baseline. Death information was collected using record linkage with the Shanghai Cancer Registry and telephone confirmation during follow-up by the end of 2019. The Cox proportional regression model was used to estimate HR with 95% CI. Results: Analysis by multivariable Cox model showed no association between pre-diagnosis BMI and death risk in both male and female patients. Male patients with a post-diagnosis underweight BMI had an elevated risk of death compared to those in normal weight (HR=1.69, 95% CI: 1.21-2.37), especially in early stage cases. Overweight patients (HR=0.74, 95% CI: 0.61-0.89) and patients with obesity class Ⅰ (HR=0.63, 95% CI: 0.45-0.89)had better survival with decreased risks of death, especially in advanced stage cases. The decreased death risk in patients with obesity class Ⅱ was not significant (HR=0.57, 95% CI: 0.24-1.39). The P(trend) value for decreased risk of death with increased BMI in female patients was statistically significant (P<0.001), and the overweight and obesity class Ⅰ categories had better survival in advanced stage(HR(overweight)=0.62, 95% CI: 0.42-0.93; HR(obesity class Ⅰ)=0.39, 95% CI: 0.16-0.98). Both male and female patients with post-diagnosis BMI loss >2.0 kg/m(2) had an increased death risk when compared with those with stable BMI (change≤1.0 kg/m(2)) between pre- and post-diagnosis. BMI gain after diagnosis did not change death risk. Conclusions: Post-diagnosis BMI in the overweight or obesity class Ⅰ groups might be conducive to prolonging male CRC patients' survival, while underweight might result in poor prognosis. Keeping weight and avoiding excessive weight loss should be suggested for all CRC patients after diagnosis.