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Abstract Introduction Ixekizumab, an interleukin 17A (IL-17A) inhibitor, has demonstrated rapid and sustained improvement in the signs and symptoms in patients with active radiographic axial spondyloarthritis (r-axSpA) in global and Chinese populations. We studied the effect of ixekizumab on patient-reported outcomes (PROs) (including patient global, spinal pain, stiffness, and fatigue) and overall health-related quality of life (HRQoL) of ixekizumab in the phase 3 study in China. Methods In this Chinese phase 3, randomized, double-blind, placebo-controlled study, patients with r-axSpA were randomized (1:1) to receive ixekizumab 80 mg every 4 weeks (IXEQ4W; starting dose 160 mg) or placebo for 16 weeks. At week 16, patients receiving placebo were switched to IXEQ4W, and those receiving IXEQ4W continued, until week 52. Data for patient global, spinal pain, spinal pain at night, stiffness, and fatigue were collected through week 52. Minimally clinical important differences (MCIDs) were determined for spinal pain and spinal pain at night. The subgroup analyses by baseline disease duration since diagnosis and baseline C-reactive protein (CRP) level were conducted post hoc. Results Compared with placebo, patients treated with IXEQ4W reported significantly greater improvement with a rapid onset in changes from baseline of PROs (patient global, spinal pain, spinal pain at night, stiffness, and fatigue) through week 16. Improvements were maintained through week 52. A similar trend of improvement was also observed in MCID response in spinal pain and spinal pain at night. The improvement in overall HRQoL was supported by EQ-5D-5L assessment. Subgroup analyses demonstrated that IXEQ4W provided significantly greater efficacy at week 16 compared with placebo, irrespective of baseline disease duration or baseline CRP level. Conclusion IXEQ4W provided rapid and sustained improvement in clinically relevant PROs and overall HRQoL through 1-year treatment in Chinese patients with r-axSpA. Regardless of the baseline disease duration or baseline CRP level, consistent efficacy was observed. Trial Registration ClinicalTrials.gov identifier NCT04285229.

Lipid-coated perfluorocarbon nanodroplets (lp-NDs) hold great promise in bio-medicine as vehicles for drug delivery, molecular imaging and vaccine agents. However, their clinical utility is restricted by limited targeted accumulation, attributed to the innate immune system (IIS), which acts as the initial defense mechanism in humans. This study aimed to optimize lp-ND formulations to minimize non-specific clearance by the IIS. Ginsenosides (Gs), the principal components of Panax ginseng, possessing complement inhibition ability, structural similarity to cholesterol, and comparable fat solubility to phospholipids, were used as promising candidate IIS inhibitors. Two different types of ginsenoside-based lp-NDs (Gs lp-NDs) were created, and their efficacy in reducing IIS recognition was examined. The Gs lp-NDs were observed to inhibit the adsorption of C3 in the protein corona (PC) and the generation of SC5b-9. Adding Gs to lp-NDs reduced complement adsorption and phagocytosis, resulting in a longer blood circulation time in vivo compared to lp-NDs that did not contain Gs. These results suggest that Gs can act as anti-complement and anti-phagocytosis adjuvants, potentially reducing non-specific clearance by the IIS and improving lifespan.

Abstract Parkinson’s disease (PD) exhibits significant clinical heterogeneity, presenting challenges in the identification of reliable electroencephalogram (EEG) biomarkers. Machine learning techniques have been integrated with resting-state EEG for PD diagnosis, but their practicality is constrained by the interpretable features and the stochastic nature of resting-state EEG. The present study proposes a novel and interpretable deep learning model, graph signal processing-graph convolutional networks (GSP-GCNs), using event-related EEG data obtained from a specific task involving vocal pitch regulation for PD diagnosis. By incorporating both local and global information from single-hop and multi-hop networks, our proposed GSP-GCNs models achieved an averaged classification accuracy of 90.2%, exhibiting a significant improvement of 9.5% over other deep learning models. Moreover, the interpretability analysis revealed discriminative distributions of large-scale EEG networks and topographic map of microstate MS5 learned by our models, primarily located in the left ventral premotor cortex, superior temporal gyrus, and Broca’s area that are implicated in PD-related speech disorders, reflecting our GSP-GCN models’ ability to provide interpretable insights identifying distinctive EEG biomarkers from large-scale networks. These findings demonstrate the potential of interpretable deep learning models coupled with voice-related EEG signals for distinguishing PD patients from healthy controls with accuracy and elucidating the underlying neurobiological mechanisms.

In order to investigate the effects of different drying methods on the properties of porous starch. The present study used four drying methods, namely hot air drying (HD), spray drying (SPD), vacuum freeze drying (FD) and supercritical carbon dioxide drying (SCD) to prepare maize and kudzu porous starch. Findings indicated that the physicochemical properties (e.g., morphology, crystallinity, enthalpy value, porosity, surface area and water absorption capacity as well as dye absorption capacity, particle size) of porous starch were significantly affected by the drying method. Compared with other samples, SCD-treated porous starch exhibited the highest surface areas of the starch (2.943 and 3.139 m2/g corresponding to kudzu and maize, respectively), amylose content (22.02 % and 16.85 % corresponding to kudzu and maize, respectively), MB and NR absorption capacity (90.63 %, 100.26 % and 90.63 %, 100.26 %, corresponding to kudzu ad maize, respectively), and thermal stability, whereas HD-treated porous starch showed the highest water-absorption capacity (123.8 % and 131.31 % corresponding to kudzu and maize, respectively). The dye absorption of the maize and kudzu porous starch was positively correlated with surface area, according to Pearson's correlation analysis. Therefore, in this study, our aim was to explore the effects of different drying methods on the Structure and properties of porous starch, and provide reference for selecting the best drying method for its application in different fields.

Abstract Background With the aging of the population, the number of total hip replacement surgeries is increasing globally. Hip replacement has undergone revolutionary advancements in surgical methods and materials. Due to the short length of hospitalization, rehabilitation care is mainly home-based. The needs and concerns about such home-based rehabilitation are constantly changing, requiring continuous attention. Objective To explore effective methods for comprehensively identifying older patients’ self-reported outcomes after home-based rehabilitation for hip replacement, in order to develop appropriate intervention strategies for patient rehabilitation care in the future. Methods This study constructed a corpus of patients’ self-reported rehabilitation care problems after hip replacement, based on the Omaha classification system. This study used the Python development language and implemented artificial intelligence to match the corpus data on the cooperation platform, to identify the main health-related problems reported by the patients, and to perform statistical analyses. Results Most patients had physical health-related problems. More than 80% of these problems were related to neuromusculoskeletal function, interpersonal relationships, pain, health care supervision, physical activity, vision, nutrition, and residential environment. The most common period in which patients’ self-reported problems arose was 6 months post-surgery. The relevant labels that were moderately related to these problems were: Physiology-Speech and Language and Physiology-Mind (r = 0.45), Health-Related Behaviors-Nutrition and Health-Related Behaviors-Compliance with Doctors’ Prescription (r = 0.40). Conclusion Physiological issues remain the main health-related issues for home-based rehabilitation after hip replacement in older patients. Precision care has become an important principle of rehabilitation care. This study used a machine learning method to obtain the largest quantitative network data possible. The artificial intelligence capture was fully automated, which greatly improved efficiency, as compared to manual data entering.

Abstract Background Despite significant progress in sanitation status and public health awareness, intestinal infectious diseases (IID) have caused a serious disease burden in China. Little was known about the spatio-temporal pattern of IID at the county level in Zhejiang. Therefore, a spatio-temporal modelling study to identify high-risk regions of IID incidence and potential risk factors was conducted. Methods Reported cases of notifiable IID from 2008 to 2021 were obtained from the China Information System for Disease Control and Prevention. Moran’s I index and the local indicators of spatial association (LISA) were calculated using Geoda software to identify the spatial autocorrelation and high-risk areas of IID incidence. Bayesian hierarchical model was used to explore socioeconomic and climate factors affecting IID incidence inequities from spatial and temporal perspectives. Results From 2008 to 2021, a total of 101 cholera, 55,298 bacterial dysentery, 131 amoebic dysentery, 5297 typhoid, 2102 paratyphoid, 27,947 HEV, 1,695,925 hand, foot and mouth disease (HFMD), and 1,505,797 other infectious diarrhea (OID) cases were reported in Zhejiang Province. The hot spots for bacterial dysentery, OID, and HEV incidence were found mainly in Hangzhou, while high-high cluster regions for incidence of enteric fever and HFMD were mainly located in Ningbo. The Bayesian model showed that Areas with a high proportion of males had a lower risk of BD and enteric fever. People under the age of 18 may have a higher risk of IID. High urbanization rate was a protective factor against HFMD (RR = 0.91, 95% CI: 0.88, 0.94), but was a risk factor for HEV (RR = 1.06, 95% CI: 1.01–1.10). BD risk (RR = 1.14, 95% CI: 1.10–1.18) and enteric fever risk (RR = 1.18, 95% CI:1.10–1.27) seemed higher in areas with high GDP per capita. The greater the population density, the higher the risk of BD (RR = 1.29, 95% CI: 1.23–1.36), enteric fever (RR = 1.12, 95% CI: 1.00–1.25), and HEV (RR = 1.15, 95% CI: 1.09–1.21). Among climate variables, higher temperature was associated with a higher risk of BD (RR = 1.32, 95% CI: 1.23–1.41), enteric fever (RR = 1.41, 95% CI: 1.33–1.50), and HFMD (RR = 1.22, 95% CI: 1.08–1.38), and with lower risk of HEV (RR = 0.83, 95% CI: 0.78–0.89). Precipitation was positively correlated with enteric fever (RR = 1.04, 95% CI: 1.00–1.08), HFMD (RR = 1.03, 95% CI: 1.00–1.06), and HEV (RR = 1.05, 95% CI: 1.03–1.08). Higher HFMD risk was also associated with increasing relative humidity (RR = 1.20, 95% CI: 1.16–1.24) and lower wind velocity (RR = 0.88, 95% CI: 0.84–0.92). Conclusions There was significant spatial clustering of IID incidence in Zhejiang Province from 2008 to 2021. Spatio-temporal patterns of IID risk could be largely explained by socioeconomic and meteorological factors. Preventive measures and enhanced monitoring should be taken in some high-risk counties in Hangzhou city and Ningbo city.

Abstract Background Radioresistance hinders radiotherapy for the treatment of lung cancer. Kinesin light chain‐2 (KLC2) has been found to be upregulated in lung cancer and also to be associated with poor prognosis. This study aimed to investigate the effect of KLC2 on radiosensitivity in lung cancer. Methods The radioresistant role of KLC2 was determined by colony formation, neutral comet assay, and γH2AX immunofluorescent staining assay. We further verified the function of KLC2 in a xenograft tumor model. The downstream of KLC2 was identified through gene set enrichment analysis and validated by western blot. Finally, we analyzed clinical data from the TCGA database to reveal the upstream transcription factor of KLC2, which was validated by RNA binding protein immunoprecipitation assay. Results Here, we found that downregulation of KLC2 could significantly reduce colony formation, increase γH2AX level, and double‐stranded DNA breaks in vitro. Meanwhile, overexpressed KLC2 significantly increased the proportion of the S phase in lung cancer cells. KLC2 knockdown could activate P53 pathway, and ultimately promoting radiosensitivity. The mRNA of KLC2 was observed to bind with Hu‐antigen R (HuR). The mRNA and protein expression of KLC2 in lung cancer cells was significantly reduced when combined with siRNA‐HuR. Interestingly, KLC2 overexpression significantly increased the expression of HuR in lung cancer cells. Conclusion Taken together, these results indicated that HuR‐KLC2 forms a positive feedback loop, which decreases the phosphorylation of p53 and thereby weaken the radiosensitivity of lung cancer cells. Our findings highlight the potential prognosis and therapeutic target value of KLC2 in lung cancer patients treated with radiotherapy.

Abstract Background We aimed to prepare a non‐invasive, reproducible, and controllable rat model of intracerebral hemorrhage with focused ultrasound (FUS). Methods A rat intracerebral hemorrhage (ICH) model was established by combining FUS and microbubbles (μBs), and edaravone was used to verify whether the free radical scavenger had a protective effect on the model. The brain tissue of each group was sectioned to observe the gross histology, blood–brain barrier (BBB) permeability, cerebral infarction volume, and histopathological changes. Results Compared with the FUS group, the BBB permeability was significantly increased in the FUS + μBs (F&B) group (p = 0.0021). The second coronal slice in the F&B group had an obvious hemorrhage lesion, and the FUS + μBs + edaravone (F&B&E) group had smaller hemorrhage areas; however, ICH did not occur in the FUS group. The cerebral infarction volume in the F&B group was significantly larger than that in the FUS group (p = 0.0030) and F&B&E group (p = 0.0208). HE staining results showed that nerve fibrinolysis, neuronal necrosis, microglia production, and erythrocytes were found in both the F&B group and the F&B&E group, but the areas of the nerve fibrinolysis and neuronal necrosis in the F&B group were larger than the F&B&E group. Conclusions A rat ICH model was successfully prepared using the μBs assisted FUS treatment, and edaravone had a therapeutic effect on this model. This model can be used to study the pathophysiological mechanism of ICH‐related diseases and in preclinical research on related new drugs.

Porous starch is a denatured starch product with high porosity, a large specific surface area, and strong adsorption. It is widely used in medicine, food, and chemical industries. Native starch includes types A, B, and C. In this study, the various starch materials, including potato maize, and kudzu starch, were used to prepare different crystal types of porous starch with α-amylase and glucoamylase. The structural and chemical characteristics of the porous starch were measured using Fourier-transform infrared spectroscopy, scanning electron microscopy, X-ray diffraction, and differential scanning calorimetry. The results showed that maize , potato and kudzu starches were typically A, B, and C types, respectively. Compared to the native starch, the three types of porous starch treated with α-amylase and Glucoamylase cause varying degrees of destruction of the surface of the starch. Moreover, investigating the reaction factors which are expected to affect the water adsorption capacity were studied systematically, including the mass ratio of α-amylase to glucoamylase (m α-amylase/m glucoamylase), the mass ratio of the total amount of enzymes to starch (m enzyme/m St), enzymatic reaction temperature, and enzymatic reaction time. The results suggested that A-type starch has higher enzymolysis efficiency than other types of starch and can be used to produce ideal cavity and pore-size starch granules with potential applications in many fields.

Background As a three-dimensional network involving glycosaminoglycans (GAGs), proteoglycans (PGs) and other glycoproteins, the role of extracellular matrix (ECM) in tumorigenesis is well revealed. Abnormal glycosylation in liver cancer is correlated with tumorigenesis and chemoresistance. However, the role of galactosyltransferase in HCC (hepatocellular carcinoma) is largely unknown. Methods Here, the oncogenic functions of B4GALT7 (beta-1,4-galactosyltransferase 7) were identified in HCC by a panel of in vitro experiments, including MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), colony formation, transwell and flow cytometry assay. The expression of B4GALT7 in HCC cell lines and tissues were examined by qPCR (real-time quantitative polymerase chain reaction) and western blot assay. The binding between B4GALT7 and miR-338-3p was examined by dual-luciferase reporter assay. Results B4GALT7 encodes galactosyltransferase I and it is highly expressed in HCC cells and human HCC tissues compared with para-tumor specimens. MiR-338-3p was identified to bind the 3′ UTR (untranslated region) of B4GALT7. Highly expressed miR-338-3p suppressed HCC cell invasive abilities and rescued the tumor-promoting effect of B4GALT7 in HCC. ShRNA (short hairpin RNA) mediated B4GALT7 suppression reduced HCC cell invasive abilities, and inhibited the expression of MMP-2 and Erk signaling. Conclusion These findings identified B4GALT7 as a potential prognostic biomarker and therapeutic target for HCC.

Abstract Stage III non‐small cell lung cancer (NSCLC) encompasses a group of diseases with high heterogeneity. Such patients should actively receive comprehensive treatments. It is imperative for all stage III NSCLC patients to receive consultation with a multiple disciplinary team, which allows the development of a proposal for clinical diagnosis and treatment. In this consensus, stage III NSCLC is divided into two types (operable and inoperable) according to different clinical conditions. Resectable NSCLC is further subdivided into two conditions (with or without driver genes). For each clinical scenario, this consensus emphasizes that the foundation of any medical decisions regarding the optimal diagnostic or therapy procedure is scientific evidence from clinical research. Finally, based on the level of evidence and strength of recommendations, this consensus provides recommendations for the management of stage III NSCLC from six perspectives. The objective of this consensus is to help clinicians choose the best treatment and promote the standardization of stage III NSCLC diagnosis and treatment in China.

The fabrication of freestanding 3D lattice structures with beam diameters less than 100 nm is a considerable challenge. Here, the authors report quasi-BCC nanolattices of gold and copper, featuring beam diameters as low as 34 nm, that demonstrate an exceptionally high capacity for energy absorption.

Abstract Background During the last decades, radiotherapy (RT) for non-small cell lung cancer (NSCLC) with brain metastases (BM) has been developed. However, the lack of predictive biomarkers for therapeutic responses has limited the precision treatment in NSCLC-BM. Patients and methods In order to find the predictive biomarkers for RT, we investigated the influence of RT on the cell-free DNA (cfDNA) from cerebrospinal fluid (CSF) and the frequency of T cell subsets of NSCLC patients with BM. A total of 19 patients diagnosed as NSCLC with BM were enrolled. The CSF from 19 patients and matched plasma samples from 11 patients were collected before RT, during RT, and after RT. The cfDNA from CSF and plasma were extracted, and the cerebrospinal fluid tumor mutation burden (cTMB) was calculated after through next-generation sequencing. The frequency of T cell subsets in peripheral blood was using flow cytometry. Results The detection rate of cfDNA was higher in CSF compared to plasma in the matched samples. The mutation abundance of cfDNA in CSF was decreased after RT. However, no significant difference was observed in cTMB before and after RT. Although the median intracranial progression-free survival (iPFS) has not yet been reached in patients with decreased or undetectable cTMB, there was a trend that these patients possessed longer iPFS compared to those with stable or increased cTMB (HR 0.28, 95% CI 0.07–1.18, P = 0.067). The proportion of CD4+T cells in peripheral blood was decreased after RT. Conclusion: Our study indicates that cTMB can serve as a prognostic biomarker in NSCLC patients with BMs.

Abstract Introduction Efficient and complete debridement of intra-articular deposits of monosodium urate crystals is rarely achieved by existing arthroscopic tools such as shavers or radiofrequency ablation, while cavitation technology represents a prospective solution for the non-invasive clearance of adhesions at intra-articular interfaces. Methods Simulation modeling was conducted to identify the optimal parameters for the device, including nozzle diameters and jet pressures. Gouty arthritis model was established in twelve rats that were equally and randomly allocated into a cavitation debridement group or a curette debridement group. A direct injection nozzle was designed and then applied on animal model to verify the effect of the cavitation jet device on the removal of crystal deposits. Image analysis was performed to evaluate the clearance efficiency of the cavitation device and the pathological features of surrounding tissue were collected in all groups. Results To maximize cavitation with the practical requirements of the operation, an experimental rig was applied, including a 1 mm direct injection nozzle with a jet pressure of 2.0 MPa at a distance of 20 mm and a nitrogen bottle as high-pressure gas source. With regards to feasibility of the device, the clearance rates in the cavitation group were over 97% and were significantly different from the control group. Pathological examination showed that the deposition of monosodium urate crystals was removed completely while preserving the normal structure of the collagen fibers. Conclusions We developed a promising surgical device to efficiently remove intra-articular deposits of monosodium urate crystals. The feasibility and safety profile of the device were also verified in a rat model. Our findings provide a non-invasive method for the intraoperative treatment of refractory gouty arthritis.

Plant growth-promoting bacteria (PGPB) have growth-promoting and disease-resisting effects and can be used as new types of plant growth promoters. This study was conducted to determine the plant growth-promoting traits of five strains and follow a 2-year field trial to evaluate their effects on grape growth and fruit quality. The five PGPB were combined with two organic fertilizers (cow dung fertilizer and distillers’ grain fertilizer) for application on grape fields; the control group only received the corresponding organic fertilizer. The five strains showed different growth promoting abilities, as indicated by their differing production of indole acetic acid (IAA) and siderophores and ability to dissolve phosphorus and potassium, fix nitrogen, and resist saline and alkali. During the field trial, vine growth and fruit quality were significantly better in the distillers’ grain fertilizer (high nutrient content) alone treatment than in the cow dung fertilizer (low nutrient content) alone treatment. However, after the two fertilizers were inoculated with the five different PGPB, only the five treatments with cow dung fertilizer inoculated with PGPB showed significant improvement. The five treatments of cow dung fertilizer inoculated with PGPB exhibited varied impacts on plant growth and fruit quality. And the promotion effects persisted significantly after two consecutive years. Among the PGPB, Bacillus velezensis 18, B. velezensis 20, and Rahnella aquatilis 5 emerged as consistently effective performers over the two-year period, demonstrating stable and commendable outcomes. These strains are recommended for prolonged application in grape cultivation to optimize growth and yield. This study provides a theoretical reference and an experimental basis for organic fertilizer inoculated with PGPB to improve grape production.

Sepsis ranks among the most common health problems worldwide, characterized by organ dysfunction resulting from infection. Excessive inflammatory responses, cytokine storms, and immune-induced microthrombosis are pivotal factors influencing the progression of sepsis. Our objective was to identify novel immune-related hub genes for sepsis through bioinformatic analysis, subsequently validating their specificity and potential as diagnostic and prognostic biomarkers in an animal experiment involving a sepsis mice model. Gene expression profiles of healthy controls and patients with sepsis were obtained from the Gene Expression Omnibus (GEO) and analysis of differentially expressed genes (DEGs) was conducted. Subsequently, weighted gene co-expression network analysis (WGCNA) was used to analyze genes within crucial modules. The functional annotated DEGs which related to the immune signal pathways were used for constructing protein–protein interaction (PPI) analysis. Following this, two hub genes, FERMT3 and CD3G, were identified through correlation analyses associated with sequential organ failure assessment (SOFA) scores. These two hub genes were associated with cell adhesion, migration, thrombosis, and T-cell activation. Furthermore, immune infiltration analysis was conducted to investigate the inflammation microenvironment influenced by the hub genes. The efficacy and specificity of the two hub genes were validated through a mice sepsis model study. Concurrently, we observed a significant negative correlation between the expression of CD3G and IL-1β and GRO/KC. These findings suggest that these two genes probably play important roles in the pathogenesis and progression of sepsis, presenting the potential to serve as more stable biomarkers for sepsis diagnosis and prognosis, deserving further study.

LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonlinear PK characteristics of LR004 within the dose range of 6–54 mg/kg. The radiochemical purity of 125I-LR004 was approximately 98.54%, and iodination of LR004 did not affect its specific binding activity to the EGFR antigen. In a classical biodistribution study, 125I-LR004 exhibited higher uptake in highly perfused organs than in poorly perfused organs. Prolonged retention properties of 125I-LR004 in tumors were observed at 4 and 10 days. Autoradiography and NanoSPECT/CT confirmed the sustained retention of 125I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of 125I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development.

Fibrosis is a common pathological process that must take place for multiple chronic liver diseases to develop into cirrhosis and liver cancer. Liver fibrosis (LF) is regulated by various cytokines and signaling pathways in its occurrence and development. Ferroptosis is an important mode of cell death caused by iron-dependent oxidative damage and is regulated by iron metabolism and lipid peroxidation signaling pathways. In recent years, numerous studies have shown that ferroptosis is closely related to LF. As the main material secreted by the extracellular matrix, hepatic stellate cells (HSCs) are a general concern in the development of LF. Therefore, targeting HSC ferroptosis against LF is crucial. This review describes the current status of treating LF by inducing HSC ferroptosis that would aid studies in better understanding the current knowledge on ferroptosis in HSCs and the future research direction in this field.

BackgroundSpeech impairment is a common symptom of Parkinson’s disease (PD) that worsens with disease progression and affects communication and quality of life. Current pharmacological and surgical treatments for PD have inconsistent effects on speech impairment. The cerebellum is an essential part of sensorimotor network that regulates speech production and becomes dysfunctional in PD. Continuous theta-burst stimulation (cTBS) is a non-invasive brain stimulation technique that can modulate the cerebellum and its connections with other brain regions.ObjectiveTo investigate whether cTBS over the right cerebellum coupled with speech-language therapy (SLT) can improve speech impairment in PD.MethodsIn this randomized controlled trial (RCT), 40 patients with PD will be recruited and assigned to either an experimental group (EG) or a control group (CG). Both groups will receive 10 sessions of standard SLT. The EG will receive real cTBS over the right cerebellum, while the CG will receive sham stimulation. Blinded assessors will evaluate the treatment outcome at three time points: pre-intervention, post-intervention, and at a 12-week follow-up. The primary outcome measures are voice/speech quality and neurobehavioral parameters of auditory-vocal integration. The secondary outcome measures are cognitive function, quality of life, and functional connectivity determined by resting-state functional magnetic resonance imaging (fMRI).SignificanceThis trial will provide evidence for the efficacy and safety of cerebellar cTBS for the treatment of speech impairment in PD and shed light on the neural mechanism of this intervention. It will also have implications for other speech impairment attributed to cerebellar dysfunctions.Clinical trial registrationwww.chictr.org.cn, identifier ChiCTR2100050543.

BackgroundDietary factors may affect the incidence of colorectal serrated polyps (SP). However, its effects on SP are unclear as epidemiological studies on this topic have showed inconsistent results. The present systematic review and meta-analysis sought to evaluate the effects of dietary factors on SPs.MethodsStudies regarding the association between dietary factors and SPs were identified by searching PubMed, Cochrane library, Embase and Chinese Biomedical Literature database from inception until 27 February 2023. Search terms include serrated, hyperplastic, adenoma, polyps, colorectal, rectal, rectum and risk. Heterogeneity was assessed using I2 statistics. The meta-analysis was conducted by using a random-effects model, and the pooled effects were expressed with odds ratios (OR) and 95% confidence intervals (95% CI). Probable sources of heterogeneity were identified through meta-regression. Subgroup analysis were based on lesion types, study designs, countries, and so on.Results28 studies were ultimately eligible after scanning, and five dietary factors including vitamin D, calcium, folate, fiber and red or processed meat were excerpted. Higher intakes of vitamin D (OR = 0.95, 95%CI:0.90–1.02), calcium (OR = 0.97, 95%CI: 0.91–1.03) and folate (OR = 0.82, 95% CI: 0.6–1.13) were not significantly associated with SP. Fiber intake (OR = 0.90, 95% CI: 0.82–0.99) was a protective factor against SPs. Red meat intake increased the risk of SPs by 30% for the highest versus lowest intakes (OR = 1.30, 95% CI: 1.13–1.51). For different lesion types, higher folate intake was associated with a decreased risk of HPs (OR = 0.59, 95%CI: 0.44–0.79), and higher vitamin D intake decreased the risk of SPs including SSA/P (OR = 0.93, 95%CI: 0.88–0.98).ConclusionsHigher dietary fiber intake plays an effective role in preventing SP, while red meat intake is associated with an increased risk of SP. This evidence provides guidance for us to prevent SP from a dietary perspective.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?, RecordID=340750.

Abstract Background Systemic sclerosis (SSc) is an incurable autoimmune disease characterized by progressive skin fibrosis and organ failure. Tenosynovitis is a common musculoskeletal manifestation, but tendon rupture has seldom reported in SSc. Case presentation We present a rare case of a 49-year-old female with SSc who has suffered from bilateral tendon rupture of the fourth and fifth digits with positive antinuclear antibody (ANA) and anti-centromere B antibody, but negative rheumatoid factor in serum. In the extensor tendons of the patient’s hands, inflammation, edema, hypertrophy and tendon interruption were detected with ultrasound and magnetic resonance imaging(MRI). Tendon transfer repair surgery was performed and 10 mg/week methotrexate was then used in this patient. Her hand function was improved well with methotrexate and rehabilitation treatment postoperatively. Conclusions Early detection of tenosynovitis is necessary to prevent tendon rupture in SSc patients. Ultrasound and Magnetic Resonance Imaging appear to be useful examinations for evaluating tendon pathology for early detection.

Abstract Overproduction of reactive oxygen species (ROS) and aberrant lipid metabolism are established hallmarks of cancer; however, the role of ROS in lipid synthesis during tumorigenesis is almost unknown. Herein, we show that ROS regulates lipid synthesis and thus controls colorectal tumorigenesis through a p53-dependent mechanism. In p53 wild-type colorectal cancer (CRC) cells, hydrogen peroxide (H2O2)-induced p53 expression represses the transcription of deubiquitinase USP22, which otherwise deubiquitinates and stabilizes Fatty Acid Synthase (FASN), and thus inhibits fatty acid synthesis. Whereas, in p53-deficient CRC cells, ROS-mediated inhibition of USP22 is relieved, leading to FASN stabilization, which thus promotes lipid synthesis and tumor growth. In human CRC specimens, USP22 expression is positively correlated with FASN expression. Our study demonstrates that ROS critically regulates lipid synthesis and tumorigenesis through the USP22-FASN axis in a p53-dependent manner, and targeting the USP22-FASN axis may represent a potential strategy for the treatment of colorectal cancer.

PEP06 is a novel endostatin-Arg-Gly-Asp-Arg-Gly-Asp (RGDRGD) 30-amino-acid polypeptide featuring a terminally fused RGDRGD hexapeptide at the N terminus. The active endostatin fragment of PEP06 directly targets tumor cells and exerts an antitumoral effect. However, little is known about the kinetics and degradation products of PEP06 in vitro or in vivo. In this study, we investigated the in vitro metabolic stability of PEP06 after it was incubated with living cells obtained from animals of different species; we further identified the degradation characteristics of its cleavage products. PEP06 underwent rapid enzymatic degradation in multiple types of living cells, and the liver, kidney, and blood play important roles in the metabolism and clearance of the peptides resulting from the molecular degradation of PEP06. We identified metabolites of PEP06 using full-scan mass spectrometry (MS) and tandem MS (MS2), wherein 43 metabolites were characterized and identified as the degradation metabolites from the parent peptide, formed by successive losses of amino acids. The metabolites were C and N terminal truncated products of PEP06. The structures of 11 metabolites (M6, M7, M16, M17, M21, M25, M33, M34, M39, M40, and M42) were further confirmed by comparing the retention times of similar full MS spectrum and MS2 spectrum information with reference standards for the synthesized metabolites. We have demonstrated the metabolic stability of PEP06 in vitro and identified a series of potentially bioactive downstream metabolites of PEP06, which can support further drug research.

Abstract Systemic sclerosis (SSc) is an autoimmune rheumatic disease with high mortality, which is featured by inflammation, vascular damage, and aggressive fibrosis. To date, the pathogenesis of SSc remains unclear and effective treatments are still under research. Active NLRP3 recruits downstream proteins such as ASC and caspase-1 and assembles into inflammasome, resulting in excretion of inflammatory cytokines including IL-1β and IL-18, as well as in pyroptosis mediated by gasdermin D. Various studies demonstrated that NLRP3 inflammasome might be involved in the mechanism of tenosynovitis, arthritis, fibrosis, and vascular damage. The pathophysiological changes might be due to the activation of proinflammatory Th2 cells, profibrotic M2 macrophages, B cells, fibroblasts, and endothelial cells. Here, we review the studies focused on NLRP3 inflammasome activation, its association with innate and adaptive immune cells, endothelium injury, and differentiation of fibroblasts in SSc. Furthermore, we summarize the prospect of therapy targeting NLRP3 pathway.

Testicular torsion (TT) is a medical emergency that requires immediate diagnostic evaluation. Photoacoustic imaging (PAI) has the potential to provide spatially resolved oxygen saturation (sO2), which can serve as a valuable marker in TT diagnosis. We investigated the potential of PAI as an alternative method for TT diagnosis and testicular injury assessment. We measured sO2 levels in different degrees of TT models using PAI at various time points. Based on histopathological results, we found that the averaged sO2 per pixel (sO2̅) and reduction of sO2̅ (rsO2) in twisted testicles had significant correlations with hypoxic conditions. Both sO2̅ and rsO2 exhibited excellent diagnostic abilities in detecting TT and identifying ischemia/hypoxia injury following TT. Furthermore, PAI-measured sO2 demonstrated favorable diagnostic capabilities in discriminating if the testicle had suffered irreversible injury. In summary, PAI presents a potentially promising novel approach in evaluating TT and warrants further clinical investigation.

In recent years, the coagulation properties of inorganic minerals such as kaolin and zeolite have been demonstrated. This study aimed to assess the hemostatic properties of three local clays from China: natural kaolin from Hainan, natural halloysite from Yunnan, and zeolite synthesized by our group. The physical and chemical properties, blood coagulation performance, and cell biocompatibility of the three materials were tested. The studied materials were characterized by using scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), X-ray fluorescence spectroscopy (XRF), thermogravimetric analysis (TGA), and differential scanning calorimetry (DSC). All three clays showed different morphologies and particle size, and exhibited negative potentials between pH 6 and 8. The TGA and DSC curves for kaolin and halloysite were highly similar. Kaolin showed the highest water absorption capacity (approximately 93.8% ± 0.8%). All three clays were noncytotoxic toward L929 mouse fibroblasts. Kaolin and halloysite showed blood coagulation effects similar to that exhibited by zeolite, indicating that kaolin and halloysite are promising alternative hemostatic materials.

Approximately one-third of agricultural land worldwide is affected by salinity, which limits the productivity and sustainability of crop ecosystems. Plant-growth-promoting rhizobacteria (PGPR) are a potential solution to this problem, as PGPR increases crop yield through improving soil fertility and stress resistance. Previous studies have shown that Priestia megaterium ZS-3(ZS-3) can effectively help plants tolerate salinity stress. However, how ZS-3 regulates its metabolic adaptations in saline environments remains unclear. In this study, we monitored the metabolic rearrangement of compatibilisers in ZS-3 and combined the findings with genomic data to reveal how ZS-3 survives in stressful environments, induces plant growth, and tolerates stress. The results showed that ZS-3 tolerated salinity levels up to 9%. In addition, glutamate and trehalose help ZS-3 adapt to osmotic stress under low NaCl stress, whereas proline, K+, and extracellular polysaccharides regulate the osmotic responses of ZS-3 exposed to high salt stress. Potting experiments showed that applying the ZS-3 strain in saline and neutral soils could effectively increase the activities of soil acid phosphatase, urease, and invertase in both soils, thus improving soil fertility and promoting plant growth. In addition, strain ZS-3-GFP colonised the rhizosphere and leaves of Cinnamomum camphora well, as confirmed by confocal microscopy and resistance plate count analysis. Genomic studies and in vitro experiments have shown that ZS-3 exhibits a variety of beneficial traits, including plant-promoting, antagonistic, and other related traits (such as resistance to saline and heavy metal stress/tolerance, amino acid synthesis and transport, volatile compound synthesis, micronutrient utilisation, and phytohormone biosynthesis/regulatory potential). The results support that ZS-3 can induce plant tolerance to abiotic stresses. These data provide important clues to further reveal the interactions between plants and microbiomes, as well as the mechanisms by which micro-organisms control plant health.

Background/ObjectiveThe efficacy of transcranial magnetic stimulation (TMS) on Parkinson’s disease (PD) varies across the stimulation targets. This study aims to estimate the effect of different TMS targets on motor symptoms in PD.MethodsA Bayesian hierarchical model was built to assess the effects across different TMS targets, and the rank probabilities and the surface under the cumulative ranking curve (SUCRA) values were calculated to determine the ranks of each target. The primary outcome was the Unified Parkinson’s Disease Rating Scale part-III. Inconsistency between direct and indirect comparisons was assessed using the node-splitting method.ResultsThirty-six trials with 1,122 subjects were included for analysis. The pair-wise meta-analysis results showed that TMS could significantly improve motor symptoms in PD patients. Network meta-analysis results showed that the high-frequency stimulation over bilateral M1, bilateral DLPFC, and M1+DLPFC could significantly reduce the UPDRS-III scores compared with sham conditions. The high-frequency stimulation over both M1 and DLPFC had a more significant effect when compared with other parameters, and ranked first with the highest SCURA value. There was no significant inconsistency between direct and indirect comparisons.ConclusionConsidering all settings reported in our research, high-frequency stimulation over bilateral M1 or bilateral DLPFC has a moderate beneficial effect on the improvement of motor symptoms in PD (high confidence rating). High-frequency stimulation over M1+DLPFC has a prominent beneficial effect and appears to be the most effective TMS parameter setting for ameliorating motor symptoms of PD patients (high confidence rating).

Abstract Background Pregnant women in Shanghai have long been at risk for mild iodine deficiency. Because thyroid autoimmunity in pregnant women can lead to premature birth and miscarriage as well as neurodevelopmental deficits in the fetus, the aim of this study was to explore the association of iodine nutrition status with thyroid antibodies during pregnancy. Methods A pregnancy-birth cohort was conducted including 4635 pregnant women in Shanghai, China. The eligible participants underwent a face-to-face interview and completed questionnaire surveys to collect baseline information and diet intake. Spot urine samples were collected to test urine iodine. Thyroid antibodies including thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyrotrophic antibodies (TRAb) were tested. Single-factor analysis and logistic regression were used to evaluate the association between iodine status and thyroid autoimmunity during pregnancy. Results The median urinary iodine excretion level in the sample was 138.14 μg/L (interquartile range [IQR] 80.90–219.00 μg/L). Among all the subjects, 25.9% consumed non-iodized salt, 54.5% had iodine deficiency, and 31.0% had thyroid autoimmunity. The proportion of patients with iodine deficiency was significantly higher among those who consumed non-iodized salt (36.9% vs. 33.1%; p = 0.04). After adjusting for age, educational status, former smoker status, former drinker status, first pregnancy, and previous thyroid disease, non-iodized salt (odds ratio [OR] = 1.394 [confidence interval, CI, 1.165–1.562]; p = 0.003), iodine-rich food (OR = 0.681 [CI 0.585–0.793]; p = 0.003), iodized nutritional supplements (OR = 0.427 [CI 0.347–0.526]; p = 0.003), were found to be individually associated with thyroid autoimmunity in all participants. The results of the multivariable restricted cubic spline regression analysis showed a non-linear relationship between the continuous change in iodine intake and thyroid autoimmunity (p = 0.019). Participants with iodine deficiency (urinary iodine concentration, UIC,

Unfractionated heparin (UFH) is an anionic glycosaminoglycan that is widely used to prevent blood clotting. However, in certain cases, unwanted side effects can require it to be neutralized. Protamine sulfate (PS), a basic peptide rich in arginine, is the only approved antagonist for UFH neutralization. Many adverse reactions occur with the clinical application of PS, including systemic hypotension, pulmonary hypertension, and anaphylaxis. We previously described R15, a linear peptide composed of 15 arginine molecules, as a potential UFH antagonist. In this study, the in‐depth safety of R15 was explored to reveal its merits and associated risks in comparison with PS. In vitro safety studies investigated the interactions of R15 with erythrocytes, fibrin, complement, and rat plasma. In vivo safety studies explored potential toxicity and immunogenicity of R15 and the UFH–R15 complex. Results showed that both PS and R15 can induce erythrocyte aggregation, thicken fibrin fibers, activate complement, and cause anticoagulation in a concentration‐dependent manner. However, those influences weakened in whole blood or in live animals and were avoided when R15 was in a complex with UFH. We found dramatically enhanced complement activation when there was excess UFH in analyses involving UFH–PS complexes, and a slight increase in those involving UFH–R15 complexes. Within 2 h, R15 was degraded in rat plasma in vitro, whereas PS was not. Enhanced creatinine was found after a single intravenous injection of PS or R15 (900 U·kg−1, body weight), suggesting possible abnormal renal function. The UFH–PS complex, but not the UFH–R15 complex, exhibited obvious immunogenicity. In conclusion, R15 is nonimmunogenic and potentially safe at a therapeutic dose to reverse the effects of UFH.

The floating population has been growing rapidly in China, and their fertility behaviors do affect urban management and development. Based on the data set of the China Migrants Dynamic Survey in 2016, the logistic regression model and multiple linear regression model were used to explore the related factors of fertility behaviors among the floating populace. The artificial neural network model, the naive Bayes model, and the logistic regression model were used for prediction. The findings showed that age, gender, ethnic, household registration, education level, occupation, duration of residence, scope of migration, housing, economic conditions, and health services all affected the reproductive behavior of the floating population. Among them, the improvement duration of post-migration residence and family economic conditions positively impacted their fertility behavior. Non-agricultural new industry workers with college degrees or above living in first-tier cities were less likely to have children and more likely to delay childbearing. Among the prediction models, both the artificial neural network model and logistic regression model had better prediction effects. Improving the employment and income of new industry workers, and introducing preferential housing policies might improve their probability of bearing children. The artificial neural network and logistic regression model could predict individual fertility behavior and provide a scientific basis for the urban population management.

BackgroundPyroptosis is a critical type of programmed cell death that is strongly associated with the regulation of tumor and immune cell functions. However, the role of pyroptosis in tumor progression and remodeling of the tumor microenvironment in gliomas has not been extensively studied. Thus, in this study, we aimed to establish a comprehensive pyroptosis-related signature and uncover its potential clinical application in gliomas.MethodsThe TCGA glioma cohort was obtained and divided into training and internal validation cohorts, while the CGGA glioma cohort was used as an external validation cohort. Unsupervised consensus clustering was performed to identify pyroptosis-related expression patterns. A Cox regression analysis was performed to establish a pyroptosis-related risk signature. Real-time quantitative PCR was performed to analyze the expression of signature genes in glioma tissues. Immune infiltration was analyzed and validated by immunohistochemical staining. The expression patterns of signature genes in different cell types were analyzed using single-cell RNA sequencing data. Finally, therapeutic responses to chemotherapy, immunotherapy, and potential small-molecule inhibitors were investigated.ResultsPatients with glioma were stratified into clusters 1 and 2 based on the expression patterns of pyroptosis-related genes. Cluster 2 showed a longer overall (P

BackgroundAccurate incidence prediction of sexually transmitted diseases (STDs) is critical for early prevention and better government strategic planning. In this paper, four different forecasting models were presented to predict the incidence of AIDS, gonorrhea, and syphilis.MethodsThe annual percentage changes in the incidence of AIDS, gonorrhea, and syphilis were estimated by using joinpoint regression. The performance of four methods, namely, the autoregressive integrated moving average (ARIMA) model, Elman neural network (ERNN) model, ARIMA-ERNN hybrid model and long short-term memory (LSTM) model, were assessed and compared. For 1-year prediction, the collected data from 2011 to 2020 were used for modeling to predict the incidence in 2021. For 5-year prediction, the collected data from 2011 to 2016 were used for modeling to predict the incidence from 2017 to 2021. The performance was evaluated based on four indices: mean square error (MSE), mean absolute error (MAE), and mean absolute percentage error (MAPE).ResultsThe morbidities of AIDS and syphilis are on the rise, and the morbidity of gonorrhea has declined in recent years. The optimal ARIMA models were determined: ARIMA(2,1,2)(0,1,1)12, ARIMA(1,1,2)(0,1,2)12, and ARIMA(3,1,2)(1,1,2)12 for AIDS, gonorrhea, and syphilis 1-year prediction, respectively; ARIMA (2,1,2)(0,1,1)12, ARIMA(1,1,2)(0,1,2)12, and ARIMA(2,1,1)(0,1,0)12 for AIDS, gonorrhea and syphilis 5-year prediction, respectively. For 1-year prediction, the MAPEs of ARIMA, ERNN, ARIMA-ERNN, and LSTM for AIDS are 23.26, 20.24, 18.34, and 18.63, respectively; For gonorrhea, the MAPEs are 19.44, 18.03, 17.77, and 5.09, respectively; For syphilis, the MAPEs are 9.80, 9.55, 8.67, and 5.79, respectively. For 5-year prediction, the MAPEs of ARIMA, ERNN, ARIMA-ERNN, and LSTM for AIDS are 12.86, 23.54, 14.74, and 25.43, respectively; For gonorrhea, the MAPEs are 17.07, 17.95, 16.46, and 15.13, respectively; For syphilis, the MAPEs are 21.88, 24.00, 20.18 and 11.20, respectively. In general, the performance ranking of the four models from high to low is LSTM, ARIMA-ERNN, ERNN, and ARIMA.ConclusionThe time series predictive models show their powerful performance in forecasting STDs incidence and can be applied by relevant authorities in the prevention and control of STDs.

BackgroundSyphilis has spread throughout China, especially in Zhejiang Province which endangers the health and lives of people. However, the spatial and temporal epidemiological studies of syphilis in Zhejiang are not thorough enough. The temporal and spatial variation and the relevant factors of syphilis incidence should be analyzed for more effective prevention and control in Zhejiang, China.MethodsData on confirmed cases of syphilis in Zhejiang Province from 2005 to 2018 was used and the spatio–temporal distributions were described. The spatial autocorrelation analysis and SaTScan analysis were performed to identify spatio–temporal clusters. A Bayesian spatial Conditional Autoregression (CAR) model was constructed to explore the relationships between syphilis incidence and common social and natural indicators.Results474,980 confirmed cases of syphilis were reported between 2005 and 2018 with a large peak in 2010. Farmers and unemployed people accounted for the largest proportion of confirmed cases. And the significant spatial clusters of syphilis were concentrated in the north of Zhejiang Province, especially in more economically developed regions. Seven spatio–temporal clusters were identified and the main three high–risk areas were located in Hangzhou (RR = 1.62, P < 0.05), Zhoushan and Ningbo (RR = 1.99, P < 0.05), and Lishui (RR = 1.68, P < 0.05). The findings showed that the morbidity of syphilis was positively correlated with the Gross Domestic Product (GDP) per capita, the number of health technicians per 10,000 people, the proportion of the elderly and air temperature were negatively correlated with the proportion of the urban population, the proportion of men and precipitation.ConclusionsThe spatio–temporal analysis revealed that the prevalence of syphilis was still serious in Zhejiang Province. Syphilis high–risk areas were mainly located in the more developed coastal regions where more targeted intervention measures were required to be implemented. The study highlighted the need to strengthen Sexually Transmitted Diseases (STD) screening and health education for high–risk groups and improve the coverage of syphilis testing to reduce hidden syphilis cases.

Objective: To develop an UPLC-MS/MS method for the accurate quantification of Estriol (E3), a new radioprotective agent, and observe the variation in pharmacokinetic characteristics of E3 after irradiation. As a hormone drug, the gender differences of E3 metabolism were also concerned here. Methods: Various chromatographic and mass spectrometric conditions of E3 were optimized. The specificity, linearity, precision and accuracy of UPLC-MS/MS method were validated. Twenty SD rats, half male and half female, were administered with intramuscular (im) injection of 2.7 ​mg/kg E3, and then divided randomly into two groups, sham-irradiated group (Con) and irradiated group (IR). IR group was irradiated to 7 ​Gy of γ-rays. Blood samples were collected at different times post-irradiation and E3 concentrations were detected. The changes of concentration-time variation and pharmacokinetic parameters for E3 after irradiation were investigated, together with metabolic differences between male and female rats. Results: The range of the calibration curve of UPLC-MS/MS for E3 was 1.00–200.0 ​ng/mL. Con group reached maximum concentration (Cmax) (77.57 ​± ​18.71) ng/mL at (0.68 ​± ​0.29) h (Tmax) after im injection. The drug concentration-time profiles and pharmacokinetic parameters of E3 were consistent before and after irradiation. The areas under time curve (AUC0-t) of E3 were (353 ​± ​74) h·ng/mL for Con group, and (299 ​± ​74) h·ng/mL for IR group (P ​> ​0.05). There were also no statistical differences in pharmacokinetic parameters between female and male rats. The elimination half-lifes (T1/2) of males and females were (3.02 ​± ​0.68) h and (3.01 ​± ​0.42) h in Con group, and (3.64 ​± ​0.51) h and (3.38 ​± ​0.60) h in IR group, respectively (P ​> ​0.05). Conclusion: A rapid and sensitive UPLC-MS/MS method for determination of E3 was established. The pharmacokinetic characteristics of E3 in rat were not affected by 7 ​Gy irradiation and gender differences. This study provided a theoretical basis for the development and application of new radiation injury treatment drug.

Abstract Objectives The study of sex differences in hyperuricemia can provide not only a theoretical basis for this clinical phenomenon but also new therapeutic targets for urate-lowering therapy. In the current study, we aimed to confirm that estradiol can promote intestinal ATP binding cassette subfamily G member 2 (ABCG2) expression to increase urate excretion through the PI3K/Akt pathway. Methods The estradiol levels of hyperuricemia/gout patients and healthy controls were compared, and a hyperuricemia mouse model was used to observe the urate-lowering effect of estradiol and the changes in ABCG2 expression in the kidney and intestine. In vivo and in vitro intestinal urate transport models were established to verify the urate transport function regulated by estradiol. The molecular pathway by which estradiol regulates ABCG2 expression in intestinal cells was explored. Results The estradiol level of hyperuricemia/gout patients was significantly lower than that of healthy controls. Administering estradiol benzoate (EB) to both male hyperuricemic mice and female mice after removing the ovaries confirmed the urate-lowering effect of estradiol, and hyperuricemia and estradiol upregulated the expression of intestinal ABCG2. Estradiol has been confirmed to promote urate transport by upregulating ABCG2 expression in intestinal urate excretion models in vivo and in vitro. Estradiol regulates the expression of intestinal ABCG2 through the PI3K/Akt pathway. Conclusion Our study revealed that estradiol regulates intestinal ABCG2 through the PI3K/Akt pathway to promote urate excretion, thereby reducing serum urate levels.

To improve the problems of inconvenient communication in the manufacturing industry, the ineffective use of resources, and the inability to efficiently complete manufacturing tasks, resource sharing has become an important model to promote the transformation and upgrading of the manufacturing industry. We used multiagent modeling to construct a resource-sharing model and take Baosteel as the micro background and the manufacturing industry as the macro background. Under this model, we discovered the effect of resource sharing on the efficiency of intelligent manufacturing under network collaboration through system dynamics research. We built and simulated a dynamic model of system dynamics that couples the two backgrounds and have given policy suggestions according to the simulation result.

MicroRNAs (miRNAs) are important regulators in the process of cardiac hypertrophy and heart failure. Previous studies have shown that miR-199a is upregulated in pressure-overload cardiac hypertrophy and that inhibition of miR-199a attenuates cardiac hypertrophy in vitro. However, the therapeutic role of anti-miR-199a treatment in the cardiac hypertrophy in vivo model is less known. Here, we show an efficient and useful method to treat mouse cardiac hypertrophy and restore cardiac function through injection of adeno-associated virus (AAV)-mediated anti-miR-199a tough decoys (TuDs). RNA-seq transcriptome analysis indicated that genes related to cytoplasmic translation and mitochondrial respiratory chain complex assembly were upregulated in anti-miR-199a-treated recovered hearts. We further validated that PGC-1α is the direct target of miR-199a involved in the therapeutic effect and the regulation of the PGC-1α/ERRα axis and that the downstream pathway of mitochondrial fatty acid oxidation and oxidative phosphorylation constitute the underlying mechanism of the restored mitochondrial structure and function in our anti-miR-199a-treated mice. Our study highlights the important regulatory role of miR-199a in cardiac hypertrophy and the value of the AAV-mediated miRNA delivery system.

Abstract Background Carpal tunnel syndrome (CTS) is a common cause of pain, numbness and tingling in the wrist and hand region and is associated with repetitive wrist and hand use in office workers. However, scarce knowledge exists about the epidemiology of clinically confirmed CTS among Chinese office workers. This study aimed to investigate the prevalence of wrist/hand symptoms and CTS in office workers in China and to identify associated risk factors. Methods A cross-sectional survey was carried out in a metropolitan city in China involving 969 respondents (aged 17–49 years) from 30 workplaces. A questionnaire was distributed to each participant to collect their demographic, work-related physical and psychosocial factors, and wrist and hand symptoms. The wrist and hand pain/numbness symptoms were marked on a body chart and the nature and intensity of symptoms, nocturnal symptoms, as well as aggravating activities were also recorded. Clinically confirmed CTS cases were screened based on the history, Phalen’s test, Tinel Sign and skin sensation testing among symptomatic respondents. Logistic regression was employed to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for the occurrence of self-reported wrist and hand symptoms and clinically confirmed CTS. Results The clinically confirmed CTS prevalence was 9.6%. The prevalence of wrist and hand symptoms were 22 and 15%, respectively. Frequently working in pain was associated with higher odds of CTS. Multivariate modelling adjusted for age and gender showed that prolonged computer use time and working without breaks were associated with presence of wrist/hand symptoms (adjusted ORs: 1.11 (95% CI 1.02–1.22) and 1.88 (95% CI 1.12–3.14)). Educational level was inversely associated with CTS and smoking was associated with wrist/hand complaints (adjusted OR: 2.20 (95% CI 1.19–4.07)). Conclusions The prevalence of work-related clinically confirmed CTS symptoms among young office workers in China is high. Frequently working in pain is closely associated with clinically confirmed CTS. Intense computer use and no breaks at work are associated with wrist and hand symptoms.

Pulmonary fibrosis (PF) is one of the sequelae of Corona Virus Disease 2019 (COVID-19), and currently, lung transplantation is the only viable treatment option. Hence, other effective treatments are urgently required. We investigated the therapeutic effects of an approved botanical drug, cepharanthine (CEP), in a cell culture model of transforming growth factor-β1 (TGF-β1) and bleomycin (BLM)-induced pulmonary fibrosis rat models both in vitro and in vivo. In this study, CEP and pirfenidone (PFD) suppressed BLM-induced lung tissue inflammation, proliferation of blue collagen fibers, and damage to lung structures in vivo. Furthermore, we also found increased collagen deposition marked by α-smooth muscle actin (α-SMA) and Collagen Type I Alpha 1 (COL1A1), which was significantly alleviated by the addition of PFD and CEP. Moreover, we elucidated the underlying mechanism of CEP against PF in vitro. Various assays confirmed that CEP reduced the viability and migration and promoted apoptosis of myofibroblasts. The expression levels of myofibroblast markers, including COL1A1, vimentin, α-SMA, and Matrix Metallopeptidase 2 (MMP2), were also suppressed by CEP. Simultaneously, CEP significantly suppressed the elevated Phospho-NF-κB p65 (p-p65)/NF-κB p65 (p65) ratio, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels, and elevated inhibitor of NF-κB Alpha (IκBα) degradation and reversed the progression of PF. Hence, our study demonstrated that CEP prevented myofibroblast activation and treated BLM-induced pulmonary fibrosis in a dose-dependent manner by regulating nuclear factor kappa-B (NF-κB)/ NLRP3 signaling, thereby suggesting that CEP has potential clinical application in pulmonary fibrosis in the future.

ObjectiveTo determine the nationwide prevalence of hyperuricemia in China and evaluate its trends and associated risk factors.MethodsUsing a multi-stage, stratified, cluster-randomized sampling design, two cross-sectional surveys (representative of national and provincial information) were conducted in 31 provinces (autonomous regions and municipalities) in mainland China, with 166, 861 Chinese adults in 2015–16 and 168, 351 in 2018–19. Serum uric acid (SUA) levels of all participants were measured after a >10-hour overnight fast. Hyperuricemia (HUA) was defined when SUA was >420 μmol/L. Prevalence estimates were weighted to represent the total population considering the complex sampling design. Multivariable logistic regression models was used to estimate factors associated with HUA.ResultsThe overall hyperuricemia prevalence in the Chinese adult population was 11.1% (95% confidence interval 10.3% to 11.8%) in 2015–16 and 14.0% (13.1% to 14.8%) in 2018–19; an alarming rise was observed in the three years. Hyperuricemia was more common in men with 19.3% (17.9% to 20.7%) in 2015–16 and 24.4% (23.0% to 25.8%) in 2018–19, although the prevalence also escalated from 2.8% (2.5% to 3.0%) in 2015–16 to 3.6% (3.2% to 4.0%) in 2018–19 in women. The hyperuricemia risk factors include the urban culture, settlement in the East, Zhuang descent, high education, heavy or frequent beer drinking, high red meat intake, physical inactivity, high body mass index, central obesity, hypertension, hyperlipidemia, and low glomerular filtration rate.ConclusionThe estimated hyperuricemia prevalence among Chinese adults was 14.0% in 2018-19; significant escalating trends were observed between 2015-16 and 2018-19.

BackgroundSi-Miao-San (SMS) is a well-known traditional Chinese medicine. This study aims to evaluate the anti-inflammatory effects of SMS on gouty arthritis and its potential mechanism of action.MethodsThe effects and mechanism of SMS were evaluated in monosodium urate (MSU)-treated mice or macrophages. The expression of cytokines and PI3K/Akt was analyzed using real-time PCR and Western blotting analyses. Macrophage polarization was assessed with immunofluorescence assays, real-time PCR, and Western blotting. Mass spectrometry was used to screen the active ingredients of SMS.ResultsPretreatment with SMS ameliorated MSU-induced acute gouty arthritis in mice with increased PI3K/Akt activation and M2 macrophage polarization in the joint tissues. In vitro, SMS treatment significantly inhibited MSU-triggered inflammatory response, increased p-Akt and Arg-1 expression in macrophages, and promoted M2 macrophage polarization. These effects of SMS were inhibited when PI3K/Akt activation was blocked by LY294002 in the macrophages. Moreover, SMS significantly reduced serum uric acid levels in the hyperuricemia mice. Using mass spectrometry, the plant hormones ecdysone and estrone were detected as the potentially effective ingredients of SMS.ConclusionSMS ameliorated MSU-induced gouty arthritis and inhibited hyperuricemia. The anti-inflammatory mechanism of SMS may exert anti-inflammatory effects by promoting M2 polarization via PI3K/Akt signaling. Ecdysone and estrone might be the potentially effective ingredients of SMS. This research may provide evidence for the application of SMS in the treatment of gout.

Background: Vitamin D supplementation improves the immune function of human body and can be a convenient way to prevent influenza. However, evidence on the protective effect of vitamin D supplementation on influenza from Randomized Controlled Trials (RCTs) is inconclusive.Methods: RCTs regarding the association between vitamin D supplementation and influenza were identified by searching PubMed, Cochrane library, Embase and Chinese Biomedical Database (CBM) from inception until present (last updated on 10 November 2021). Studies that reported dosages and durations of vitamin D supplementation and number of influenza infections could be included. Heterogeneity was assessed using Cochran's Q test and I2 statistics, the meta-analysis was conducted by using a random-effects model, the pooled effects were expressed with risk ratio (RR) with 95% confidence interval (95% CI).Results: 10 trials including 4859 individuals were ultimately eligible after scanning. There was no evidence of a significant heterogeneity among studies (I2 = 27%, P = 0.150). Meta-regression analysis finding indicated that country, latitude, average age, economic level, follow-up period and average daily vitamin D intake did not cause the statistical heterogeneity. The study finding indicates that substitution with vitamin D significantly reduces the risk of influenza infections (RR = 0.78, 95% CI:0.64–0.95). No evidence of publication bias was observed. Omission of any single trial had little impact on the pooled risk estimates.Conclusions: The meta-analysis produced a corroboration that vitamin D supplement has a preventive effect on influenza. Strategies for preventing influenza can be optimized by vitamin D supplementation.

Abstracts Background Ultrasound is a useful tool to evaluate and quantify skin lesions. Few studies have assessed the criterion validity of skin ultrasound in systemic sclerosis (SSc). The aims of the study were to investigate skin thickness and stiffness using ultrasound and shear wave elastography (SWE) in SSc and to validate skin ultrasound measurements against histological skin thickness. Methods A total of 22 patients with diffuse cutaneous SSc (dcSSc), 22 with limited cutaneous SSc (lcSSc), and 22 age- and gender-matched healthy controls were enrolled. Skin thickness and stiffness were measured by B-mode ultrasound with SWE imaging on the bilateral fingers and hands. Additional ultrasound evaluation was carried out in 13 patients (9 dcSSc and 4 lcSSc) on their dorsal forearms, followed by skin biopsy conducted in the same skin areas. Correlations between ultrasound measurements and histological skin thickness and modified Rodnan skin score (mRSS) were investigated using Spearman’s correlation. Results Compared with controls, ultrasound-measured skin thickness and skin stiffness were significantly higher in patients with SSc (p

Abstract Background Endocrown restoration is widely used to restore endodontically treated teeth. However, the clinical effects of different computer-aided design/computer-aided manufacturing (CAD/CAM) materials for endocrown restoration are not clear. The primary objective of this trial is to compare the clinical efficacy of resin-based bloc and ceramic endocrowns for restoring endodontically treated teeth. Methods The proposed resin-based bloc and ceramic endocrown assessment trial is a parallel group-designed randomized controlled trial. We will recruit 156 adults between 18 and 75 years old with a minimum of one such molar. The inclusion criteria were good oral hygiene habits, root apex of molar without evident damage, receipt of standard endodontic treatment, need for endocrown restoration, and only one endocrown restoration performed per patient. Patients participating in another study or those with systemic diseases, disabilities, or known allergies to used materials will be excluded. All patients will be randomized and restored with resin-based bloc and ceramic endocrown according to a random number table. Clinical evaluations will be performed at baseline and after treatment at 6, 12, and 24 months, in accordance with the modified Federation Dentaire Internationale (FDI) criteria, by two independent evaluators. The primary outcome is marginal adaptation; secondary outcomes include wear, tooth integrity, fracture of material and retention, marginal staining, and patient view. All data will be analyzed by an independent statistician. Signed rank-sum tests will be used for intragroup comparisons. Wilcoxon rank-sum tests will be used for intergroup comparisons. Hierarchical logistic regression will be used to adjust the baseline and other important indicators. Discussion This study will investigate endocrowns of two CAD/CAM materials for endodontically treated molars. The results may help clinicians choose the better CAD/CAM material option and explain to patients the advantages and disadvantages of these two materials with evidence-based support. For patients, the results may lead to improvement in long-term restoration. Trial registration ClinicalTrials.gov NCT04033380 . Registered on 24 July 2019

Lung cancer is the leading cause of cancer death worldwide as well as in China. For many years, conventional oncologic treatments such as surgery, chemotherapy, and radiotherapy (RT) have dominated the field of non-small cell lung cancer (NSCLC). The recent introduction of immunotherapy in clinical practice, led to a paradigm shift in lung cancer as in many other solid tumors. Recent pre-clinical and clinical data have shown RT may also modify antitumor immune responses through induction of immunogenic cell death and reprogramming of the tumor microenvironment. This has led many to reexamine RT as a partner therapy to immuno-oncology treatments and investigate their potential synergy in an exponentially growing number of clinical trials. Clinical trials combining radiotherapy and immunotherapy are attracting major attention, experts were invited to discuss frontier and controversial academic topics: (1) Recent developments of clinical synergy between radiation and immune checkpoint inhibitors (ICIs) in the treatment of NSCLC; (2) Will immunotherapy and radiotherapy increase the toxicity risk for cancer patients; (3) How to cope the mixed responses/disassociated responses phenomenon in checkpoint inhibition therapy to NSCLC with local ablative therapy; (4) Combining radiotherapy and immunotherapy in the treatment of NSCLC brain metastases.