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In this Review we examine the progress and challenges of China's ambitious 1998 reform of the world's largest health professional educational system. The reforms merged training institutions into universities and greatly expanded enrolment of health professionals. Positive achievements include an increase in the number of graduates to address human resources shortages, acceleration of production of diploma nurses to correct skill-mix imbalance, and priority for general practitioner training, especially of rural primary care workers. These developments have been accompanied by concerns: rapid expansion of the number of students without commensurate faculty strengthening, worries about dilution effect on quality, outdated curricular content, and ethical professionalism challenged by narrow technical training and growing admissions of students who did not express medicine as their first career choice. In this Review we underscore the importance of rebalance of the roles of health sciences institutions and government in educational policies and implementation. The imperative for reform is shown by a looming crisis of violence against health workers hypothesised as a result of many factors including deficient educational preparation and harmful profit-driven clinical practices.

Background The medicinal material quality of Citrus reticulata ‘Chachi’ differs depending on the bioactive components influenced by the planting area. Environmental factors, such as soil nutrients, the plant-associated microbiome and climatic conditions, play important roles in the accumulation of bioactive components in citrus. However, how these environmental factors mediate the production of bioactive components of medicinal plants remains understudied. Results Here, a multi-omics approach was used to clarify the role of environmental factors such as soil nutrients and the root-associated microbiome on the accumulation of monoterpenes in the peel of C. reticulata ‘Chachi’ procured from core (geo-authentic product region) and non-core (non-geo-authentic product region) geographical regions. The soil environment (high salinity, Mg, Mn and K) enhanced the monoterpene content by promoting the expression of salt stress-responsive genes and terpene backbone synthase in the host plants from the core region. The microbial effects on the monoterpene accumulation of citrus from the core region were further verified by synthetic community (SynCom) experiments. Rhizosphere microorganisms activated terpene synthesis and promoted monoterpene accumulation through interactions with the host immune system. Endophyte microorganisms derived from soil with the potential for terpene synthesis might enhance monoterpene accumulation in citrus by providing precursors of monoterpenes. Conclusions Overall, this study demonstrated that both soil properties and the soil microbiome impacted monoterpene production in citrus peel, thus providing an essential basis for increasing fruit quality via reasonable fertilization and precision microbiota management. 5YLcq9_vpnDnpERRVFZqtN Video Abstract

Apoptosis plays a critical role in controlling the proliferation and differentiation of germ cells during spermatogenesis. Dysregulation of the fine-tuned balance may lead to the onset of testicular diseases. In this study, we investigated the activation status of apoptosis pathways in the testicular tissues under the background of an asthmatic mouse model. Ten BALB/c mice were divided into two groups: the acute asthma group and the control group. In the acute asthma group, ovalbumin (OVA)-sensitized mice were challenged with aerosolized OVA for 7 days, while the control group was treated with physiological saline. After that, both epididymis and testis were collected to determine the sperm count and motility. Apoptosis in the testis was evaluated by DNA ladder, immunochemistry and further by PCR array of apoptosis-related genes. Finally, the cleavage of caspase-3 and poly ADP-ribose polymerase (PARP) was determined by western blot and the enzymatic activities of caspase-9 and 3/7 were assessed using Caspase-Glo kits. Compared with control mice, significant decreases in the body weight, testis weight, sperm count and motility were seen in the experimental group. DNA ladder and immunochemistry showed significant increase in apoptotic index of the asthmatic testis, whereas a decrease in mRNA expression of Bcl-2 and increases in Bax, BNIP3, caspase-9, and AIF were observed in the asthma group. Furthermore, protein levels of AIF were significantly upregulated, while the translational expression of Bcl-2 was downregulated markedly. Consistently, caspase-9 activity in the testis of asthma mice was significantly higher than that of the control group. Collectively, these results showed that Bcl-2-caspase-9 apoptosis pathway was clearly activated in the testis of asthmatic mice with the increased expression of apoptosis-related genes and proteins. To our knowledge, this is the first report demonstrating that asthma could lead to the activation of the mitochondrial apoptosis signaling pathway in the mouse testis.

ABSTRACTLike insulin, glucagon-like peptide 1 (GLP-1) may have direct trophic actions on the nervous system, but its potential role in supporting diabetic sensory neurons is uncertain. We identified wide expression of GLP-1 receptors on dorsal root ganglia sensory neurons of diabetic and nondiabetic mice. Exendin-4, a GLP-1 agonist, increased neurite outgrowth of adult sensory neurons in vitro. To determine the effects ofexendin-4 in comparison with continuous low- or high-dose insulin in vivo, we evaluated parallel cohorts of type 1 (streptozotocin-induced) and type 2 (db/db) mice of 2 months’ diabetes duration with established neuropathy during an additional month of treatment. High-dose insulin alone reversed hyperglycemia in type 1 diabetic mice, partly reversed thermal sensory loss, improved epidermal innervation but failed to reverse electrophysiological abnormalities. Exendin-4 improved both sensory electrophysiology and behavioral sensory loss. Low-dose insulin was ineffective. In type 2 diabetes, hyperglycemia was uncorrected, and neither insulin nor exendin-4 reversed sensory electrophysiology, sensory behavior, or loss of epidermal axons. However, exendin-4 alone improved motor electrophysiology. Receptor for advanced glycosylated end products and nuclear factor-κB neuronal expression were not significantly altered by diabetes or treatment. Taken together, these results suggest that although GLP-1 agonists and insulin alone are insufficient to reverse all features of diabetic neuropathy, in combination, they might benefit some aspects of established diabetic neuropathy.

This paper presents a safe A* algorithm for the path planning of automated guided vehicles (AGVs) operating in storage environments. Firstly, to overcome the problems of great collision risk and low search efficiency in the path produced by traditional A* algorithm, a new evaluation function is designed by introducing repulsive term and assigning dynamic adjustment weights to heuristic items. Secondly, a Floyd deletion algorithm based on the safe distance is proposed to remove redundant path points for reducing the path length. Moreover, the algorithm replaces the broken line segments at the turns with a cubic B-spline to ensure the smoothness of turning points. The simulation applied to different scenarios and different specifications showed that, compared with other three typical path planning algorithms, the path planned by the proposed safe A* algorithm always keeps a safe distance from the obstacle and the path length is reduced by 1.95 % , while the planning time is reduced by 25.03 % and the number of turning point is reduced by 78.07 % on average.

Background Both inflammatory bowel disease (IBD) and hepato‐pancreato‐biliary cancers (HPBC) have been established to cause a huge socioeconomic burden. Epidemiological studies have revealed a close association between IBD and HPBC. Methods Herein, we utilized inverse‐variance weighting to conduct a two‐sample Mendelian randomization analysis. We sought to investigate the link between various subtypes of IBD and HPBC. To ensure the accuracy and consistency of our findings, we conducted heterogeneity tests, gene pleiotropy tests, and sensitivity analyses. Results Compared to the general population, IBD patients in Europe exhibited a 1.22‐fold increased incidence of pancreatic cancer (PC) with a 95% confidence interval (CI) of 1.0022–1.4888 (p = 0.0475). We also found a 1.14‐fold increased incidence of PC in Crohn's disease (CD) patients with (95% CI: 1.0017–1.3073, p = 0.0472). In the East Asian population, the incidence of hepatocellular carcinoma (HCC) was 1.28‐fold higher (95% CI = 1.0709–1.5244, p = 0.0065) in IBD patients than in the general population. Additionally, ulcerative colitis (UC) patients displayed 1.12‐fold (95% CI: 1.1466–1.3334, p < 0.0001) and 1.31‐fold (95% CI: 1.0983–1.5641, p = 0.0027) increased incidences of HCC and cholangiocarcinoma (CCA), respectively. Finally, the incidence of PC was 1.19‐fold higher in CD patients than in the general population (95% CI = 1.0741–1.3132, p = 0.0008). Conclusion Our study validated that IBD is a risk factor for HPBC. This causal relationship exhibited significant heterogeneity in different European and East Asian populations.

Background The modified Glasgow Prognostic Score (mGPS) and the neutrophil-to-lymphocyte ratio (NLR) are conventional inflammation-based scores for colorectal cancer (CRC). The systemic inflammation score (SIS) has been shown to be more informative than the mGPS in CRC. The albumin-NLR, composed of albumin and the NLR, can also be a candidate for a valuable inflammation score. However, about the utility of the mGPS, SIS, and albumin-NLR for CRC patients who have received radical resections remains unclear. Methods This study enrolled 877 CRC patients, who underwent radical surgical resection between January 1, 2007 and December 31, 2014. The prognostic values of the mGPS, SIS, and albumin-NLR were compared by the Kaplan-Meier survival analysis, multivariate Cox regression modelling, and the time-dependent receiver operating characteristic curve analysis (ROC). Results In the Kaplan-Meier analysis, all three inflammation scores were significantly associated with overall survival (OS) in the group including all the patients (mGPS, p  = 0.016; SIS, p  < 0.001; albumin-NLR, p  = 0.007) and in the left-sided colon tumour subgroup (mGPS, p  = 0.029; SIS p  = 0.0013; albumin-NLR, p  = 0.001). In the right-sided colon tumour subgroup, only the albumin-NLR was associated with OS ( p  = 0.048). The albumin-NLR was the only independent prognostic factor of the three scores for OS in the multivariate survival analysis. Conclusions The albumin-NLR outperformed both the SIS and mGPS in predicting OS in CRC patients undergoing radical resection.

The E26 transformation-specific (ETS) transcription factor family is widely expressed and implicated in tumorigenesis. Among them, ETV4 plays a crucial role in cancer progression. However, its broader impact on prognosis and immune regulation across different malignancies remains insufficiently understood. Based on public databases and our experimental validation, we systematically investigated the role of ETV4 in various cancers. Cytoscape, GSCALite, CancerSEA, STRING, HPA, TIGER, TISIDB, and R were used to assess ETV4's expression and functional impact on basis of the TCGA and GTEx databases. Experimental validation included a range of methods such as CCK8 assays, clonogenic assays, migration assays, flow cytometry, RT-qPCR, immunohistochemistry (IHC), lentiviral transfection, and tumor formation assays. ETV4 overexpression was detected in several cancer types and was associated with poor prognosis and specific molecular and immune subtypes. ETV4 was linked to overall survival in 10 of them. Furthermore, ETV4 played a key role in modulating multiple signaling pathways and was associated with immune regulation, particularly in melanoma and renal cell carcinoma, where its expression predicted immune responses. Knockdown of ETV4 in digestive tumors inhibited cell proliferation and migration, promoted apoptosis, and altered the expression of immune-related molecules. Further and analyses revealed that knockdown of ETV4 led to significant downregulation of FGL1 expression in BxPC3 cells and in tumors from Panc02 xenograft models. Kaplan-Meier Plotter analysis showed that lower FGL1 expression was associated with longer overall survival in patients receiving anti-PD1 therapy. In silico analysis using NCBI and UCSC genome databases further identified ETV4 as a putative transcription factor that may bind to the FGL1 promoter region, suggesting a potential regulatory relationship. ETV4 shows differential expression across various cancer types and may serve as a potential prognostic biomarker in certain tumor types. Further validation in clinical samples and functional studies is warranted to clarify the biological role of ETV4 and its potential utility as a therapeutic target or prognostic indicator in pan-cancer.

The prognostic, especially predictive, values of inflammation indexes in advanced colorectal cancer were not established. Therefore, the both values of neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) in patients with initially metastatic colorectal cancer (mCRC) were investigated and compared. Samples were collected from 243 patients who were initially diagnosed with mCRC between 2005 and 2010 in the Sun Yat-sen University Cancer Center. Elevated NLR ( p  < 0.001), PLR ( p  = 0.008), and CEA ( p  < 0.001) were identified as statistically significant poor prognostic factors for overall survival (OS), while only NLR ( p  = 0.029) and CEA ( p  < 0.001) were validated as independent predictors. Univariate analysis identified elevated NLR ( p  < 0.001), PLR ( p  = 0.023), and CEA ( p  < 0.001) as statistically significant poor predict factors for the progression-free survival (PFS) of first-line chemotherapy, while NLR ( p  = 0.013) and CEA ( p  = 0.001) were independent. In addition, we observed significantly different OS ( p  < 0.001) and PFS ( p  < 0.001) among patients who had elevations in both NLR and CEA levels and those having one elevation or neither elevation. NLR, PLR, and CEA were significant predictors of OS and PFS in mCRC. However, only NLR and CEA play as independent. When coupled with CEA, NLR may lead to improved prognostic predictors.

Background The consensus is that a minimum of 12 lymph nodes should be analyzed at colectomy for colon cancer. However, right colon cancer and left colon cancer have different characteristics, and this threshold value for total number of lymph nodes retrieved may not be universally applicable. Methods The data of 63,243 patients with colon cancer treated between 2004 and 2012 were retrieved from the National Cancer Institute’s Surveillance, Epidemiology, and End Results database. Multivariate Cox regression analysis was used to determine the predictive value of total number of lymph nodes for survival after adjusting for lymph nodes ratio. The predictive value in left-sided colon cancer and right-sided colon cancer was compared. The optimal total number of lymph nodes cutoff value for prediction of overall survival was identified using the online tool Cutoff Finder. Survival of patients with high total number of lymph nodes (≥12) and low total number of lymph nodes (< 12) was compared by Kaplan–Meier analysis. Results After stratifying by lymph nodes ratio status, total number of lymph nodes≥12 remained an independent predictor of survival in the whole cohort and in right-sided colon cancer, but not in left-sided colon cancer. The optimal cutoff value for total number of lymph nodes was determined to be 11. Low total number of lymph nodes (< 11) was associated with significantly poorer survival after adjusting for lymph nodes ratio in all subgroups except in the subgroup with high lymph nodes ratio (0.5–1.0). Conclusions Previous reports of the prognostic significance of total number of lymph nodes on node-positive colon cancer were confounded by lymph nodes ratio. The 12-node standard for total number of lymph nodes may not be equally applicable in right-sided colon cancer and left-sided colon cancer.