Search

Abstract To evaluate whether radiomics models based on unenhanced paranasal sinuses CT images could be a useful tool for differentiating inverted papilloma (IP) from chronic rhinosinusitis with polyps (CRSwNP). This retrospective study recruited 240 patients with CRSwNP and 106 patients with IP from three centers. 253 patients from Qilu Hospital were randomly divided into the training set (n = 151) and the internal validation set (n = 102) with a ratio of 6:4. 93 patients from the other two centers were used as the external validation set. The patients with the unilateral disease (n = 115) from Qilu Hospital were selected to further develop a subgroup analysis. Lesion segmentation was manually delineated in CT images. Least absolute shrinkage and selection operator algorithm was performed for feature reduction and selection. Decision tree, support vector machine, random forest, and adaptive boosting regressor were employed to establish the differential diagnosis models. 43 radiomic features were selected for modeling. Among the models, RF achieved the best results, with an AUC of 0.998, 0.943, and 0.934 in the training set, the internal validation set, and the external validation set, respectively. In the subgroup analysis, RF achieved an AUC of 0.999 in the training set and 0.963 in the internal validation set. The proposed radiomics models offered a non-invasion and accurate differential approach between IP and CRSwNP and has some significance in guiding clinicians determining the best treatment plans, as well as predicting the prognosis.

Abstract Background Drug use disorders (DUDs) have emerged as one of the most significant public health crises, exerting a substantial influence on both community health and socio-economic progress. The United States (US) also suffers a heavy burden, it is necessary to figure out the situation from multiple perspectives and take effective measures to deal with it. Therefore, using the data from the Global Burden of Diseases, Injuries, and Risk Factors (GBD) 2021, we evaluated this topic. Methods Annual data on DUDs-related burden were collected from the GBD study 2021. We calculated the indicator of estimated annual percentage change (EAPC) to evaluate the changing trend of burden. The Bayesian model for age-period-cohort was introduced to forecast the burden. Results In 2021, the number and age-standardized rate of prevalence were particularly prominent, with 12,146.95 thousand and 3821.43 per 100,000, respectively. Higher burden was also observed in males, 15–45 years old populations, and opioid use disorders subtype. From 1990 to 2021, the DUDs-related burden increased in the US and all states, especially in West Virginia; and the national death-related burden with the highest increase (EAPC = 7.96). Other significant inverse associations were seen between EAPC, age-standardized rates, and socio-demographic index (SDI). Moreover, in the next 14 years, the projected DUDs burden remains exigent. Conclusions The burden of DUDs in the US is heavy and has been enlarging. This study proposes that greater attention should be paid to the strategies in males, the younger population, opioid use disorders, and low-SDI states implemented by decision-makers to achieve goals such as reducing burden.

Abstract Background and aim An increasing amount of research has indicated obesity greatly affects individuals with overactive bladder (OAB). However, traditional anthropometric methods present challenges in accurately assessing the likelihood of OAB. Hence, this study’s objective was to identify the correlation between the body roundness index (BRI) and OAB. Methods The research included 12,401 individuals who participated in the National Health and Nutrition Examination Survey spanning 2005–2018. The correlation between BRI and OAB was explored by using weighted multiple logistic regression and weighted restricted cubic spline (RCS). Subgroup analyses showed the associations based on different population types. The study also analyzed the predictive capability of various anthropometric indices, including BRI, body mass index, waist circumference, and weight, in assessing the likelihood of OAB through Receiver-operating characteristic (ROC) curves. Results An independent positive correlation between OAB and BRI was identified after adjusting for potential confounders in weighted multivariate logistic models[odds ratio (OR) = 1.15, 95% confidence interval (CI), 1.12–1.17]. Weighted RCS analysis found a positive dose-response correlation between OAB and BRI. The effect size of BRI on OAB remained stable across all prespecified subgroups (all P for interactions > 0.05). In ROC analysis, BRI showed better discriminatory ability for OAB compared with other anthropometric measures for both genders (all P

Abstract Background Depressive disorders have been identified as a significant contributor to non-fatal health loss in China. Among the various subtypes of depressive disorders, dysthymia is gaining attention due to its similarity in clinical severity and disability to major depressive disorders (MDD). However, national epidemiological data on the burden of disease and risk factors of MDD and dysthymia in China are scarce. Methods This study aimed to evaluate and compare the incidence, prevalence, and disability-adjusted life-years (DALYs) caused by MDD and dysthymia in China between 1990 and 2019. The temporal trends of the depressive disorder burden were evaluated using the average annual percentage change. The comparative risk assessment framework was used to estimate the proportion of DALYs attributed to risk factors, and a Bayesian age-period-cohort model was applied to project the burden of depressive disorders. Results From 1990 to 2019, the overall age-standardized estimates of dysthymia in China remained stable, while MDD showed a decreasing trend. Since 2006, the raw prevalence of dysthymia exceeded that of MDD for the first time, and increased alternately with MDD in recent years. Moreover, while the prevalence and burden of MDD decreased in younger age groups, it increased in the aged population. In contrast, the prevalence and burden of dysthymia remained stable across different ages. In females, 11.34% of the DALYs attributable to depressive disorders in 2019 in China were caused by intimate partner violence, which has increasingly become prominent among older women. From 2020 to 2030, the age-standardized incidence, prevalence, and DALYs of dysthymia in China are projected to remain stable, while MDD is expected to continue declining. Conclusions To reduce the burden of depressive disorders in China, more attention and targeted strategies are needed for dysthymia. It’s also urgent to control potential risk factors like intimate partner violence and develop intervention strategies for older women. These efforts are crucial for improving mental health outcomes in China.

Objective Given the distinct physiological and societal traits between women and men, we propose that there are distinct risk factors for lumbar degenerative disc disease surgeries, including lumbar disc herniation (LDH) and lumbar spinal stenosis (LSS), in middle‐aged and older populations. However, few studies have focused on middle‐aged and older women. This study aims to identify these risk factors specifically in this population. Methods In this case–control study, the study group comprised 1202 women aged ≥ 45 years who underwent operative treatment of lumbar degenerative disc disease (LDH, n = 825; LSS, n = 377), and the control group comprised 1168 women without lumbar disease who visited a health examination clinic during the same period. The study factors included demographics (age, body mass index [BMI], smoking, labor intensity, and genetic history), female‐specific factors (menopausal status, number of deliveries, cesarean section, and simple hysterectomy), surgical history (number of abdominal surgeries, hip joint surgery, knee joint surgery, and thyroidectomy), and systemic diseases (hypercholesterolemia, hypertriglyceridemia, hyper‐low‐density lipoprotein cholesterolemia, hypertension, diabetes, cardiovascular disease, and cerebrovascular disease). Multivariate binary logistic regression analysis was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) of associated factors. Results The risk factors for surgical treatment of LDH in middle‐aged and older women included BMI (OR = 1.603), labor intensity (OR = 1.189), genetic history (OR = 2.212), number of deliveries (OR = 1.736), simple hysterectomy (OR = 2.511), hypertriglyceridemia (OR = 1.932), and hyper‐low‐density lipoprotein cholesterolemia (OR = 2.662). For surgical treatment of LSS, the risk factors were age (OR = 1.889), BMI (OR = 1.671), genetic history (OR = 2.134), number of deliveries (OR = 2.962), simple hysterectomy (OR = 1.968), knee joint surgery (OR = 2.527), hypertriglyceridemia (OR = 1.476), hyper‐low‐density lipoprotein cholesterolemia (OR = 2.413), and diabetes (OR = 1.643). Cerebrovascular disease was a protective factor against surgery for LDH (OR = 0.267). Conclusions BMI, genetic history, number of deliveries, simple hysterectomy, hypertriglyceridemia, and hyper‐low‐density lipoprotein cholesterolemia were independent risk factors for surgical treatment of both LDH and LSS in middle‐aged and older women. Two disparities were found: labor intensity was a risk factor for LDH patients, and knee joint surgery and diabetes were risk factors for LSS patients.

Background: The mechanism underlying human umbilical cord mesenchymal stem cells (hUC-MSCs) regulating the stability of atherosclerotic plaque was explored by establishing mice models of atherosclerosis induced by a high-fat diet and hUC-MSCs intervention. Methods: The ApoE−/− mice atherosclerosis model was constructed using a high-fat diet, and mice were divided into a normal diet group (ND), high-fat diet group (HFD), hUC-MSCs treatment group (HFDM), while the blank control (BC) consisted of C57BL/6J mice. After successful establishment of the model, the feces, hearts, and aorta of mice were collected. Morphological features were detected using HE, oil red O, and Masson staining. Afterward, 16s rRNA gene sequences was used to detect the species and abundance of the intestinal flora in mice, and an atomic force microscope (AFM) was used to detect the Young's modulus of the fibrous cap of atherosclerotic plaques. Lastly, the expression level of the inflammatory factors NLRP3, IL-1β, and IL-18 were detected via immunohistochemistry and immunofluorescence assays. Results: In terms of morphological characteristics, the expression level of NLRP3, Young's modulus of the fibrous cap, and plaque stability were significantly reduced in HFD, whereas the ratio of Firmicutes to Bacteroidetes (F/B) was significantly increased. Interestingly, hUC-MSCs treatment reversed the above indices, thus enhancing plaque stability. Conclusion: HFD led to dysregulation of intestinal flora homeostasis and induced aberrant expression levels of NLRP3, resulting in a decrease in the Young's modulus of plaques. However, hUC-MSCs treatment improved the biomechanical properties of plaque by modulating the intestinal flora and NLRP3, thereby elevating plaque stability and minimizing the risk of plaque rupture.

Accumulating observational studies have linked particulate air pollutants to neurodegenerative diseases (NDDs). However, the causal links and the direction of their associations remain unclear. Therefore, we adopted a two-sample Mendelian randomization (TSMR) design using the GWAS-based genetic instruments of particulate air pollutants (PM2.5 and PM10) from the UK Biobank to explore their causal influence on four common neurodegenerative diseases. Estimates of causative relationships were generated by the Inverse variance weighted (IVW) method with multiple sensitive analyses. The heterogeneity and pleiotropy tests were additionally performed to verify whether our findings were robust. Genetically predicted PM2.5 and PM10 could elevate the occurrence of AD (odds ratio [OR] = 2.22, 95 % confidence interval [CI] 1.53–3.22, PIVW = 2.85×10−5, PFalse discovery rate [FDR] = 2.85×10−4 and OR = 2.41, 95 % CI: 1.26–4.60, PIVW = 0.008, PFDR =0.039, respectively). The results were robust in sensitive analysis. However, no evidence of causality was found for other NDDs. Our present study suggests that PM2.5 and PM10 have a detrimental effect on AD, which indicates that improving air quality to prevent AD may have pivotal public health implications.

Abstract Background To analyze the impact of the time of natural cessation of the umbilical cord on maternal and infant outcomes in order to explore the time of clamping that would be beneficial to maternal and infant outcomes. Methods The study was a cohort study and pregnant women who met the inclusion and exclusion criteria at the Obstetrics and Gynecology Department of Qilu Hospital of Shandong University from September 2020 to September 2021. Analysis using Kruskal-Wallis rank sum test, Pearson’s Chi-squared test, generalized linear mixed model (GLMM) and repeated measures ANOVA. If the difference between groups was statistically significant, the Bonferroni test was then performed. A two-sided test of P 0.05). The weight of the newborns in the three groups was (3316.27 ± 356.70) g, (3387.26 ± 379.20) g, and (3455.52 ± 363.78) g, respectively, and the number of days of cord detachment was 12.00 (8.00, 15.75) days, 10.00 (7.00, 15.00) days and 9.00 (7.00, 13.00) days, respectively, as the time of natural cessation of the cord increased. The neonatal lymphocyte ratio, erythrocyte pressure, and hemoglobin reached a maximum in the 61–89 s group at (7.41 ± 2.16) %, (61.77 ± 8.17) % and (194.52 ± 25.84) g/L, respectively. Lower incidence of neonatal hyperbilirubinemia in the 61–89 s group compared to the ≥90s group 0 vs 4.8 (P

Abstract Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive types of squamous cell carcinoma and represents a significant proportion of esophageal cancer. Metabolic reprogramming plays a key role in the occurrence and development of ESCC. Unsupervised clustering analysis was employed to stratify ESCC samples into three clusters: MPC1-lipid type, MPC2-amino acid type, and MPC3-energy type, based on the enrichment scores of metabolic pathways extracted from the Reactome database. The MPC3 cluster exhibited characteristics of energy metabolism, with heightened glycolysis, cofactors, and nucleotide metabolism, showing a trend toward increased aggressiveness and poorer survival rates. On the other hand, MPC1 and MPC2 primarily involved lipid and amino acid metabolism, respectively. In addition, liquid chromatography‒mass spectrometry-based metabolite profiles and potential therapeutic agents were explored and compared among ESCC cell lines with different MPCs. MPC3 amplified energy metabolism markers, especially carnitines. In contrast, MPC1 and MPC2 predominantly had elevated levels of lipids (primarily triacylglycerol) and amino acids, respectively. Furthermore, MPC3 demonstrated a suboptimal clinical response to PD-L1 immunotherapy but showed increased sensitivity to the doramapimod chemotherapy regimen, as evident from drug sensitivity evaluations. These insights pave the way for a more personalized therapeutic approach, potentially enhancing treatment precision for ESCC patients.

Although various strategies have been reported for the synthesis of gold nanoparticles (AuNPs) for possible anticancer effects, green synthesis can be considered an efficient strategy for the production of efficient NPs with minimal toxic effects. In this study, we investigate the green synthesis of gold nanoparticles (AuNPs) using an aqueous leaf extract of Nicotiana plumbaginifolia and evaluated their protein/DNA binding, hemolysis characteristics, and anticancer properties against HeLa cervical cancer cells, while normal HUVECs were used as the control sample. Different techniques were utilized to characterize the development of AuNPs. Then, the interaction properties of biosynthesized AuNPs with HeLa cancer cells and HUVECs were assessed by cellular assays. The results showed that the Au nanosphere had an average particle size of 18 nm with four distinctive X-ray diffraction (XRD) peaks at 38.00°, 44.10°, 63.75° and 77.10°. Moreover, the UV–Vis spectrum showed a maximum absorption peak at about 538 nm, corresponding to the surface Plasmon resonance (SPR) characteristics of the AuNPs. Furthermore, an observed Fourier-transform infrared spectroscopy (FTIR) peak at about 769 cm−1 was attributed to the AuO stretching vibration. Dynamic light scattering (DLS) analysis also showed that the maximum size and zeta potential values for colloid AuNPs were 68.69 nm and −47.92 mV, respectively. Then, it was detected that after incubation of maximum % solution of AuNPs, 0.1, % BSA and %DNA binding values were 58.76 % and 32.15 %, respectively. It was also determined that following incubation of red blood cells (RBC) with maximum concentrations of AuNPs, 20 μM, the hemolysis value was 2.29 %. Cellular assays showed that the IC50 value of AuNPs was 1.53 μM in HeLa cells, whereas this value for HUVEC normal cells was 30.55 μM. It was also shown that incubation of cells with AuNPs for 24 h led to a higher upregulation in the levels of released Cytc. C, caspase-9, and caspase-3 in HeLa cancer cells compared with HUVECs. Then, it was determined that stimulation of ROS generation and subsequent apoptosis, upregulation of Bax/Bcl-2, caspase-9, and caspase-3 mRNA, induced by AuNPs can be reversed by pretreatment of cells with NAC, a potential antioxidant. Finally, it was demonstrated that although the exposure of HeLa cells to AuNPs after 24 h caused a significant reduction in cell viability mediated by apoptosis, pre-treatment of cells with caspase-9 and caspase-3 inhibitors, significantly mitigated apoptosis induction and recovered cell viability. In conclusion, this paper might provide useful information about the medicinal purposes enabled by AuNPs.

In plants, carbohydrates are central products of photosynthesis. Rice is a staple that contributes to the daily calorie intake for over half of the world’s population. Hence, the primary objective of rice cultivation is to maximize carbohydrate production. The “source-sink” theory is proposed as a valuable principle for guiding crop breeding. However, the “flow” research lag, especially in sugar transport, has hindered high-yield rice breeding progress. This review concentrates on the genetic and molecular foundations of sugar transport and its regulation, enhancing the fundamental understanding of sugar transport processes in plants. We illustrate that the apoplastic pathway is predominant over the symplastic pathway during phloem loading in rice. Sugar transport proteins, such as SUTs and SWEETs, are essential carriers for sugar transportation in the apoplastic pathway. Additionally, we have summarized a regulatory pathway for sugar transport genes in rice, highlighting the roles of transcription factors (OsDOF11, OsNF-YB1, OsNF-YC12, OsbZIP72, Nhd1), OsRRM (RNA Recognition Motif containing protein), and GFD1 (Grain Filling Duration 1). Recognizing that the research shortfall in this area stems from a lack of advanced research methods, we discuss cutting-edge analytical techniques such as Mass Spectrometry Imaging and single-cell RNA sequencing, which could provide profound insights into the dynamics of sugar distribution and the associated regulatory mechanisms. In summary, this comprehensive review serves as a valuable guide, directing researchers toward a deep understanding and future study of the intricate mechanisms governing sugar transport.

An ultrasensitive electrochemical immunosensor was developed for detection of the cervical squamous cell carcinoma antigen (SCCA) biomarker using graphene-chitosan nanocomposites. Graphene oxide (GO) synthesized by a modified Hummer’s method was functionalized with chitosan biopolymer (CS) to produce CS-GO nanocomposites. Characterization by SEM, FTIR, Raman, XPS confirmed successful grafting of CS onto GO by electrostatic interactions. The CS-GO composite exhibited improved conductivity and biocompatibility. After optimizing the GO:CS ratio to 1:1, the nanocomposite was deposited on glassy carbon electrodes (GCE). Anti-SCCA antibodies were then immobilized covalently using pyrenebutyric acid crosslinker. The immunosensor fabrication was analyzed by EIS, CV, and DPV electrochemical techniques. The conditions including CS-GO ratio, antibody concentration, incubation time, pH, and voltage parameters were systematically optimized using orthogonal experimental design. Under optimal conditions, the immunosensor showed a linear detection range from 1 pg/mL to 100 ng/mL with a sensitivity of 196 μA/(ng/mL/cm2). The low limit of detection of 1 pg/mL was attributed to the high surface area and conductivity of the CS-GO transducer. Analysis of human serum samples spiked with SCCA demonstrated the reliability of the immunosensor for clinical applications. The graphene-nanocomposite electrochemical biosensing platform provides a rapid, low-cost, and ultrasensitive alternative to ELISA for SCCA detection in cervical cancer diagnostics.

Background: Studies have shown that the stimulator of interferon genes (STING) is critical in tumorigenesis, and development. This study aimed to investigate the immune profile and prognostic significance of STING-mediated immune senescence in bladder cancer (BLCA). Methods: We identified differential genes between tumor and normal tissue based on the Cancer Genome Atlas database, and used consensus clustering to identify BLCA subtypes. The genes most associated with overall survival were screened by further analysis and used to construct risk models. Then, comparing the immune microenvironment, tumor mutational load (TMB), and microsatellite instability (MSI) scores between different risk groups. Eventually, a nomogram was constructed based on clinical information and risk scores. The model was validated using receiver operating curves (ROC) and calibration plots. Results: We identified 160 differential genes, including 13 genes most associated with prognosis. Three subtypes of bladder cancer with different clinical and immunological features were identified. Immunotherapy was more likely to benefit the low-risk group, which had higher TMB and MSI scores. The nomogram was found to be highly predictive based on ROC analysis and calibration plots. Conclusion: The risk model and nomogram not only predict the prognosis of BLCA patients but also can guide the treatment.

ObjectivePrevious studies reported possible connections between inflammatory bowel disease (IBD) and several neurodegenerative disorders. However, the comprehensive relationships between IBD and various neurodegenerative disorders were not summarized. We executed a meta-analysis of longitudinal studies to provide an estimate of the strength of the two-directional prospective association between IBD and neurodegenerative disorders.MethodsWe accomplished a thorough bibliographic search of PubMed, Web of Science, Embase, PsycINFO, and Cochrane Library databases until June 2023 to locate relevant longitudinal studies. The extracted data were then analyzed via meta-analysis using either a fixed or random effects model.ResultsThe final analysis encompassed 27 studies. Individuals with IBD faced an increased risk of developing four neurodegenerative disorders than the general public, namely, Alzheimer’s disease (hazard ratio[HR] = 1.35, 95% confidence interval [CI]: 1.03–1.77, P=0.031), dementia (HR =1.24, 95% CI: 1.13–1.36, P

Rhubarb contains an abundance of compounds and nutrients that promote health through various activities; however, these activities are affected by the harvest season. In this paper, the changes in nutrients, phytochemical profiles and antioxidant activity of Rheum officinale leaf blades (LRO) during different growth periods were investigated. The results showed that LRO is a good source of protein, fiber, and minerals and contains abundant fatty acids; however, as the harvest time increased from March to July, the levels of protein and amino acid decreased, and the levels of other nutrients reached a maximum in May or June. LRO also contains flavonoids, terpenoids, and quinones. As the harvest time increased, the quinone content decreased, possibly due to the unstable chemical properties of quinones at high temperatures. The flavonoid contents reached a maximum in May or June. This study indicated that LRO is a source of nutrients and chemical components and can be used for functional food production. In addition, the nutrients and chemical components related to the antioxidant activity of LRO changed according to the harvest season.

While BRAF alterations have been established as a driver in various solid malignancies, the characterization of BRAF alterations in prostate cancer (PCa) has not been thoroughly interrogated. By bioinformatics analysis, we first found that BRAF alterations were associated with advanced PCa and exhibited mutually exclusive pattern with ERG alteration across multiple cohorts. Of the most interest, recurrent non-V600 BRAF mutations were found in 3 of 21 (14.3 %) PCa patients demonstrating IDC-P morphology. Furthermore, experimental overexpression of BRAFK601E and BRAFL597R exhibited emergence of oncogenic phenotypes with intensified MAPK signaling in vitro, which could be targeted by MEK inhibitors. Comparison of the incidence of BRAF alterations in IDC-P between western and Chinese ancestry revealed an increased prevalence in the Chinese population. The BRAF mutation may represent important genetic alteration in a subset of IDC-P, highlighting the role of MAPK signaling pathway in this subtype of PCa. To the best of knowledge, this is the first description of non-V600 BRAF mutation in setting of IDC-P, which may in part explain the aggressive phenotype seen in IDC-P and could also bring more treatment options for PCa patients with IDC-P harboring such mutations.

Abstract Background The therapeutic effect of poly (ADP-ribose) polymerase inhibitors (PARPi) monotherapy compared with platinum-based chemotherapy, and the impact to subsequent platinum-based chemotherapy after PARPi resistance were inconclusive in breast cancer susceptibility genes (BRCA)1/2-mutated ovarian cancer patients with secondary platinum-sensitive relapse. Methods BRCA1/2-mutated patients with secondary platinum-sensitive relapse included in this study did not receive any maintenance regimen after first- and second-line platinum-based chemotherapy, and the secondary platinum-free interval (PFI) was more than 6 months. Patients in study group were treated with PARPi monotherapy until disease progression, and patients in control group were treated with platinum-based chemotherapy without restriction. Progression-free survival (PFS) was defined as the time from third-line therapy to disease progression or death, PFS2 was defined as the time from platinum-based chemotherapy after PARPi resistance to next subsequent therapy or death. Post-recurrence survival (PRS) refers to the survival time after secondary platinum-sensitive relapse. Results A total of 119 patients were retrospectively analyzed, including 71 (59.7%) in study group and 48 (40.3%) in control group. The objective response rate (ORR: 77.5% vs. 80.0%, p=0.766) and PFS (median: 11.2 vs. 11.0 months, p=0.962) were comparable. The benefit of subsequent platinum-based chemotherapy after PARPi resistance was more pronounced in patients with PARPi treatment for more than 12 months (median PFS2: 8.6 vs. 4.3 months, p=0.040). PARPi monotherapy had no adverse effect on PRS compared with platinum-based chemotherapy (median PRS:41.2 vs. 42.8 months, p=0.323). Compared to patients in control group who had never received PARPi, PARPi monotherapy (median PRS: 41.2 vs. 33.7 months, p=0.019) and post-line treatment with PARPi in the control group (median PRS: 48.1 vs. 33.7 months, p=0.002) could prolong PRS for patients with secondary platinum-sensitive relapse. Conclusions PARPi monotherapy was similar to platinum-based chemotherapy for BRCA1/2-mutated ovarian cancer patients with secondary platinum-sensitive recurrence, and could improve prognosis.

The phenomenon of "information islands" in medical studies is becoming increasingly prevalent since healthcare information resources are generally characterized by multiple sources, multiple types, and non-standardization. The data from large cohort studies in China have complex sources and multiple types and it is difficult for the data from different cohorts to be integrated, shared and utilized. For promoting the standardized integration of healthcare resource data in China, we conduct an in-depth literature analysis on the research on common medical data models (CDM) at home and abroad and patterns of CDM establishment for cross-cohort studies. The study also proposes some recommendations regarding the problems of medical data integration and sharing in the context of precision medicine in China for effective integration, consolidation, sharing, and utilization of cross-cohorts data.

Pathogenic Salmonella strains causing gastroenteritis typically can colonize and proliferate in the intestines of multiple host species. They retain the ability to form red dry and rough (rdar) biofilms, as seen in Salmonella enterica serovar Typhimurium. Conversely, Salmonella serovar like Typhi, which can cause systemic infections and exhibit host restriction, are rdar-negative. In this study, duck-derived strains and swine-derived strains of S. Typhimurium locate on independent phylogenetic clades and display relative genomic specificity. The duck isolates appear more closely related to human blood isolates and invasive non-typhoidal Salmonella (iNTS), whereas the swine isolates were more distinct. Phenotypically, compared to duck isolates, swine isolates exhibited enhanced biofilm formation that was unaffected by the temperature. The transcriptomic analysis revealed the upregulation of csgDEFG transcription as the direct cause. This upregulation may be mainly attributed to the enhanced promoter activity caused by the G-to-T substitution at position −44 of the csgD promoter. Swine isolates have created biofilm polymorphisms by altering a conserved base present in Salmonella Typhi, iNTS, and most Salmonella Typhimurium (such as duck isolates). This provides a genomic characteristics perspective for understanding Salmonella transmission cycles and evolution.

ObjectiveObservational studies have shown an association between systemic autoimmune disease (AD) and multiple malignancies. However, due to the difficulty indetermining the temporal nature of the order, their causal relationship remains elusive. Based on pooled data from a large population-wide genome-wide association study (GWAS), this study explores the genetic causality between systemic autoimmune disease and renal malignancy.MethodsWe took a series of quality control steps from a large-scale genome-wide association study to select single nucleotide polymorphisms (SNPs) associated with systemic autoimmune disease as instrumental variables(IVs) to analyze genetic causality with renal malignancies. Inverse variance weighting (IVW), MR- Egger, weighted median, simple model and weighted model were used for analysis. The results were mainly based on IVW (Random Effects), followed by sensitivity analysis. Inverse-Variance Weighted(IVW) and MR-Egger were used to test for heterogeneity. MR- Egger is also used for pleiotropic testing. A single SNP analysis was used to identify single nucleotide polymorphisms (SNPs) with potential impact. Odds ratio (OR) and 95% confidence interval (CI) were used to evaluate causality, and sensitivity analysis was performed to evaluate pleiotropy and instrumental validity.ResultsAcute and subacute iridocylitis (P = 0.006, OR = 1.077), Ankylosing spondylitis (P = 0.002, OR = 1.051), and spondyloarthritis (P = 0.009, OR = 1.073) were positively associated with an increased risk of renal malignancy. Coxarthrosis (P = 0.008, OR = 0.483), Juvenile rheumatism (P = 0.011, OR = 0.897), and Systemic lupus erythematosus (P = 0.014, OR = 0.869) were negatively associated with an increased risk of renal malignancy. The results of sensitivity analysis were consistent without heterogeneity or pleiotropy.ConclusionOur study suggests a causal relationship between different systemic autoimmune diseases and renal malignancies. These findings prompt health care providers to take seriously the potential risk of systemic autoimmune disease and provide new insights into the genetics of kidney malignancies.

BackgroundMyocarditis is characterized by high disability and mortality, and imposes a severe burden on population health globally. However, the latest global magnitude and secular trend of myocarditis burden have not been reported. ObjectiveThis study aimed to delineate the epidemiological characteristics of myocarditis burden globally for optimizing targeted prevention and research. MethodsBased on the Global Burden of Disease Study 2019, the myocarditis burden from 1990 to 2019 was modeled using the Cause of Death Ensemble tool, DisMod-MR, and spatiotemporal Gaussian regression. We depicted the epidemiology and trends of myocarditis by sex, age, year, region, and sociodemographic index (SDI). R program version 4.2.1 (R Project for Statistical Computing) was applied for all statistical analyses, and a 2-sided P-value of

Abstract Objective To investigate the predictive value of the systemic immune inflammation (SII) index on the occurrence of stroke‐associated pneumonia (SAP) in patients with acute stroke. Methods Data of patients with or without a previous history of pulmonary who visited the First Affiliated Hospital of Kunming Medical University within 24 h of the onset of stroke were collected between January 2017 and December 2019. Patient's demographic data, stroke type, past medical history, National Institutes of Health Stroke Scale score, Glasgow Coma score, and laboratory tests were collected. Logistic regression models and receiver‐operating characteristic (ROC) curves were used to investigate the predictive value of SII for the development of SAP in patients with stroke. Results We included 395 patients with acute stroke, with a mean age of 63.89 ± 13.42 years, of whom 340 (86.1%) had ischemic stroke, and 55 (13.9%) had hemorrhagic stroke. Out of 395, 113 (28.6%) had SAP and 282 (71.4%) did not, and the SII level in the SAP group was higher than that of the non‐SAP group (p

Abstract Background Defects in DNA damage repair (DDR) pathways lead to genomic instability and oncogenesis. DDR deficiency is prevalent in esophageal squamous cell carcinoma (ESCC), but the effects of DDR alterations on mutational processes and tumor immune microenvironment in ECSS remain unclear. Methods Whole‐exome and transcriptome sequencing data of 45 ESCC samples from Taizhou, China, were used to identify genomic variations, gene expression modulation in DDR pathways, and the abundance of tumor‐infiltrating immune cells. Ninety‐six ESCC cases from The Cancer Genome Atlas (TCGA) project were used for validation. Results A total of 57.8% (26/45) of the cases in the Taizhou data and 70.8% (68/96) of the cases in the TCGA data carried at least one functional impact DDR mutation. Mutations in the DDR pathways were associated with a high tumor mutation burden. Several DDR deficiency‐related mutational signatures were discovered and were associated with immune cell infiltration, including T cells, monocytes, dendritic cells, and mast cells. The expression levels of two DDR genes, HFM1 and NEIL1, were downregulated in ESCC tumor tissues and had an independent effect on the infiltration of mast cells. In the Taizhou data, increased expression of HFM1 was associated with a poor prognosis, and the increased expression of NEIL1 was associated with a good outcome, but no reproducible correlation was observed in the TCGA data. Conclusion This research demonstrated that DDR alterations could impact mutational processes and immune cell infiltration in ESCC. The suppression of HFM1 and NEIL1 could play a crucial role in ESCC progression and may also serve as prognostic markers.

Abstract Background Pericardial calcification is usually a marker of chronic diseases, and its occurrence in rapidly progressing malignant primary pericardial mesothelioma (PPM) is extremely rare. Therefore, this atypical imaging appearance contributes to more frequent misdiagnosis of PPM. However, no systematic summary currently exists of the imaging characteristics of malignant pericardial calcification in PPM. In our report, its clinical characteristics are discussed in detail, to provide a reference to reduce the misdiagnosis rates of PPM. Case presentation A 50-year-old female patient was admitted to our hospital, presenting primarily with features suggestive of cardiac insufficiency. Chest computed tomography revealed significant pericardial thickening and localized calcification, suspicious of constrictive pericarditis. A chest examination performed through a midline incision showed a chronically inflamed and easily-ruptured pericardium that was closely adherent to the myocardium. Post-operative pathological examination confirmed a diagnosis of primary pericardial mesothelioma. Six weeks postoperatively, the patient experienced symptom recurrence and abandoned chemotherapy and radiation therapy. Nine months postoperatively, the patient died of heart failure. Conclusion We report this case to highlight the rare finding of pericardial calcification in patients with primary pericardial mesothelioma. This case illustrated that confirmation of pericardial calcification cannot completely rule out rapidly developing PPM. Therefore, understanding the different radiological features of PPM can help to reduce its rate of early misdiagnosis.

Abstract Background Cuproptosis, as a copper-induced mitochondrial cell death, has attracted extensive attention recently, especially in cancer. Although some key regulatory genes have been identified in cuproptosis, the related lncRNAs have not been further studied. Exploring the prognostic and diagnostic value of cuproptosis-related lncRNAs (CRLs) in colon adenocarcinoma and providing guidance for individualized immunotherapy for patients are of great significance. Results A total of 2003 lncRNAs were correlated with cuproptosis genes and considered as CRLs. We screened 33 survival-associated CRLs and established a prognostic signature base on 7 CRLs in the training group. The patients in the low-risk group had better outcomes in both training group (P

Abstract Background Renal carcinoma is a common malignant tumor of the urinary system. Advanced renal carcinoma has a low 5-year survival rate and a poor prognosis. More and more studies have confirmed that chromatin regulators (CRs) can regulate the occurrence and development of cancer. This article investigates the functional and prognostic value of CRs in renal carcinoma patients. Methods mRNA expression and clinical information were obtained from The Cancer Genome Atlas database. Univariate Cox regression analysis and LASSO regression analysis were used to select prognostic chromatin-regulated genes and use them to construct a risk model for predicting the prognosis of renal cancer. Differences in prognosis between high-risk and low-risk groups were compared using Kaplan–Meier analysis. In addition, we analyzed the relationship between chromatin regulators and tumor immune infiltration, and explored differences in drug sensitivity between risk groups. Results We constructed a model consisting of 11 CRs to predict the prognosis of renal cancer patients. We not only successfully validated its feasibility, but also found that the 11 CR-based model was an independent prognostic factor. Functional analysis showed that CRs were mainly enriched in cancer development-related signalling pathways. We also found through the TIMER database that CR-based models were also associated with immune cell infiltration and immune checkpoints. At the same time, the genomics of drug sensitivity in cancer database was used to analyze the commonly used drugs of renal clear cell carcinoma patients. It was found that patients in the low-risk group were sensitive to medicines such as axitinib, pazopanib, sorafenib, and gemcitabine. In contrast, those in the high-risk group may be sensitive to sunitinib. Conclusion The chromatin regulator-related prognostic model we constructed can be used to assess the prognostic risk of patients with clear cell renal cell carcinoma. The results of this study can bring new ideas for targeted therapy of clear cell renal carcinoma, helping doctors to take corresponding measures in advance for patients with different risks.

BackgroundThe brain-gut axis link has attracted increasing attention, with observational studies suggesting that the relationship between common mental disorders and inflammatory bowel disease (IBD) may run in both directions. However, so far, it is not clear whether there is causality and in which direction.MethodsWe conducted a bidirectional 2-sample Mendelian randomization study to investigate the relationship between IBD, including Crohn’s disease (CD) and ulcerative colitis (UC), and mental disorders, using summary-level GWAS data. The main analysis was the inverse variance weighted method. IBD (including CD and UC), and nine mental disorders were used as both exposures and outcomes.ResultsWe found that UC could significantly lead to obsessive-compulsive disorder, attention deficit hyperactivity disorder, and autism spectrum disorder, with odds ratio (OR) of 1.245 (95% confidence intervals [CI]: 1.069-1.450; P=0.008), 1.050 (95%CI: 1.023-1.077; P=2.42×10-4), and 1.041 (95%CI: 1.015-1.068; P=0.002) respectively. In addition, we found that bipolar disorder and schizophrenia could increase the odds of IBD, with OR values of 1.138 (95%CI: 1.084-1.194; P=1.9×10-7), and 1.115 (95%CI: 1.071-1.161; P=1.12×10-7), respectively. Our results also indicate that obsessive-compulsive disorder could lead to IBD, especially for UC, with OR values of 1.091 (95%CI: 1.024-1.162; P=0.009), and 1.124 (95%CI: 1.041-1.214; P=0.004), respectively.ConclusionsOur findings indicate that the brain-gut axis involves the association between IBD, especially UC, and some mental disorders, which guides the targeted prevention, management, and mechanism exploration of these diseases.

The fourth mobile sulfonamide resistance gene sul4 has been discovered in many metagenomic datasets. However, there is no reports of it in cultured bacteria. In this study, a sul4 positive clinical Salmonella enterica SC2020597 was obtained by conventional Salmonella isolation methods and characterized by species identification and antimicrobial susceptibility testing. Meanwhile, the genomic DNA was sequenced using both long-read and short-read methods. Following that, the complete genome was analyzed by bioinformatic methods. The sul4 gene in S. enterica SC2020597 differed from the sul4 identified in metagenomic data by one amino acid and could confer full resistance to sulfamethoxazole. Genetic location analysis showed that the sul4 in SC2020597 was carried by a complex chromosomally integrated hybrid plasmid. ISCR20-like was strongly associated with the mobilization of sul4 by core genetic context analysis. To the best of our knowledge, this is the first report of the emergence of sul4 in clinically cultured S. enterica. More important, the sul4 has the potential to spread to other bacteria with the help of mobile elements.

In this study, the effects of different Li₂O/Al₂O₃ ratios on the structure, phase composition and properties of Li₂O-Al₂O₃-SiO₂ glass-ceramics were investigated. The crystallisation behaviour and structure of the glass samples were investigated using differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Raman spectroscopy, field-emission scanning electron microscopy (FE-SEM) and other characterisation methods. When the Li₂O/Al₂O₃ ratio (wt.%) was increased from 0.89 to 2.4, the main crystalline phase changed from quartz to a lithium disilicate (LD) phase, indicating that a high Li₂O/Al₂O₃ ratio (wt.%) was more favourable for the precipitation of the LD phase. Finally, a glass-ceramic with a flexural strength of 199 ± 5 MPa, a microhardness of 767 ± 20 HV and a visible light transmission rate of 80% at 550 nm was obtained. Owing to its high Li+ content, this glass-ceramic facilitates chemical strengthening to further improve its mechanical properties and expand its range of applications, such as in electronic display devices.

Abstract Background The role of systemic inflammation in promoting cardiovascular diseases has attracted attention, but its correlation with various arrhythmias remains to be clarified. We aimed to comprehensively assess the association between various indicators of systemic inflammation and atrial fibrillation/flutter (AF), ventricular arrhythmia (VA), and bradyarrhythmia in the UK Biobank cohort. Methods After excluding ineligible participants, a total of 478,524 eligible individuals (46.75% male, aged 40–69 years) were enrolled in the study to assess the association between systemic inflammatory indicators and each type of arrhythmia. Results After covariates were fully adjusted, CRP levels were found to have an essentially linear positive correlation with the risk of various arrhythmias; neutrophil count, monocyte count, and NLR showed a non-linear positive correlation; and lymphocyte count, SII, PLR, and LMR showed a U-shaped association. VA showed the strongest association with systemic inflammation indicators, and it was followed sequentially by AF and bradyarrhythmia. Conclusions Multiple systemic inflammatory indicators showed strong associations with the onset of AF, VA, and bradyarrhythmia, of which the latter two have been rarely studied. Active systemic inflammation management might have favorable effects in reducing the arrhythmia burden and further randomized controlled studies are needed.

Background & Aims: Klebsiella pneumoniae (KLP), a Gram-negative bacterium belonging to the family of Enterobacteriaceae, is a common cause of antimicrobial-resistant opportunistic infections in hospitalized patients. KLP can colonize in the human gastrointestinal tract, especially in patients with inflammatory bowel diseases. However, effects of KLP on the onset and development of inflammatory bowel disease remain unclear. Methods: We analyzed the relationship between Mayo indexes of ulcerative colitis and KLP using quantitative reverse-transcription polymerase chain reaction and endoscopy. Using caspase-1/11-/-, NLRP3-/-, NLRC4-/-, interleukin (IL)18-/-, and IL22-/- mice, we showed that KLP could induce colitis through caspase-11–mediated release of mature IL18. Through in vitro gut organoid culture, we determined the mechanism for KLP to induce colitis. Results: We first found that there was a positive relationship between the Mayo indexes of ulcerative colitis and KLP. Then, we isolated a strain of KLP, named Klebsiella pneumoniae J (KLPJ), from the colon tissues of patients with colitis. This strain of bacteria could induce the production of mature IL18 in colon epithelial cells and gut organoids, and also induce colitis and promote dextran sodium sulfate–mediated colitis. Using caspase-1/11-/-, NLRP3-/-, NLRC4-/-, IL18-/-, and IL22-/- mice, we showed that KLPJ-mediated colitis occurred through activation of caspase-11, and was dependent on IL18 and partly on IL22. Our data also showed that lipopolysaccharide from KLPJ could bind with caspase-11 to induce mature IL18 in mouse and human colon organoids. Conclusions: KLPJ from the colon tissues of patients with ulcerative colitis can colonize the colon, activate caspase-11 inflammasomes, and contribute to intestinal inflammation.

Salmonella is one of the most important zoonotic pathogens and a major cause of foodborne illnesses, posing a serious global public health hazard. The emergence of plasmid-mediated mcr genes in Salmonella has greatly reduced the clinical choice of salmonellosis treatment. The aim of this study was to investigate the plasmid characteristics of mcr-positive Salmonella identified from patients in Sichuan, China during 2014 to 2017 by whole genomes sequencing. In this study, a total of 12 mcr-positive isolates (1.15%, ; mcr-1, n=10; mcr-3, n=2) were identified from 1046 Salmonella isolates using PCR. Further characterization of these isolates was performed through antimicrobial susceptibility testing, conjugation assays, whole genome sequencing, and bioinformatics analysis. The mcr-1 gene in these isolates were carried by three types of typical mcr-1-bearing plasmids widely distributed in Enterobacteriaceae (IncX4, IncI2 and IncHI2). Of note, two mcr-1-harboring IncHI2 plasmids were integrated into chromosomes by insertion sequences. Two mcr-3-bearing plasmids were IncC and IncFIB broad-host-range plasmids respectively. Genetic context analysis found that mcr-1 was mainly located in Tn6330 or truncated Tn6300, and mcr-3 shared a common genetic structure tnpA-mcr-3-dgkA-ISKpn40. Overall, we found that mcr gene in clinical Salmonella were commonly carried by broad-host plasmids and have potential to transfer into other bacteria by these plasmids. Continuous surveillance of MDR Salmonella in humans and investigation the underlying transmission mechanisms of ARGs are vital to curb the current severe AMR concern.

ObjectiveThis study aims to translate the Health Professional Communication Skills Scale (HP-CSS) into Chinese and assess its psychometric properties.MethodsA total of 836 healthcare professionals were recruited. The demographic characteristics form and HP-CSS were used for data collection. The psychometric properties of HP-CSS were evaluated by examining item analysis, construct validity, known-group discriminant validity, internal consistency, and split-half reliability.ResultsIn terms of item analysis, the critical ratio (CR) of 18 items was both >3 (CR ranging from 9.937 to 28.816), and the score of each item was positively correlated with the total score (r ranging from 0.357 to 0.778, P < 0.001). The fit indices showed that the original correlated four-factor model of HP-CSS was adequate: χ2 =722.801; df = 126; χ2/df = 5.737; RMSEA = 0.075; CFI = 0.923; NNFI = 0.908; TLI = 0.906; IFI = 0.923. In terms of known-group discriminant validity, the HP-CSS total score was related to gender, occupation, work years, and communication skill training. Cronbach's α coefficient was 0.922, and the split-half reliability was 0.865 for the total scale.ConclusionThe Chinese version of the HP-CSS is a reliable and valid instrument to evaluate communication skills among healthcare professionals in China.

ObjectivesTo assess the disease burden and changing trend of cardiomyopathy in children aged 0–14 years in China from 1990 to 2019.MethodsThis study was based on the Global Burden of Disease Study 2019; the age-specific prevalence rate, mortality rate and disability-adjusted life year (DALY) rate were used for analysis. Estimated annual percentage change (EAPC) in burden rate and its 95% confidence interval were calculated. The data of China were compared with the global average level.ResultsIn 2019, the numbers of prevalence, deaths, and DALYs of cardiomyopathy in children aged 0–14 years in China were 4,493 [95% uncertainty interval (UI): 2687 ~ 6,838], 434 (95%UI: 337 ~ 565) and 37,522 (95%UI: 29,321 ~ 48,891), with declining amplitudes of 16.32, 70.56, and 70.74%, compared with 1990, respectively. In 2019, the prevalence rate of cardiomyopathy in Chinese children aged 0–14 years was 2.00/100,000 (95%UI: 1.2/100,000 ~ 3.04/100,000), higher than 1990 [1.66/100,000 (95%UI:1.00/100,000 ~ 2.53/100,000)]; mortality rate was 0.19/100,000 (95%UI: 0.15/100,000 ~ 0.25/100,000), significantly lower than 1990 [0.46/100,000 (95%UI: 0.25/100,000 ~ 0.95/100,000)]; DALY rate was 16.69/100,000 (95%UI: 13.04/100,000 ~ 21.75/100,000), also significantly lower than 1990 [39.71/100,000 (95%UI: 22.06/100,000 ~ 82.8/100,000)]. All burden rates of cardiomyopathy in Chinese children aged 0–14 years old were all lower than the global averages of 2019; the burden rates of male children were higher than female children. In all calendar years from 1990 to 2019, the mortality and DALY rates of children younger than 1-year-old were significantly higher than in the other age groups of 0–14 years old. From 1990 to 2019, the prevalence rate of cardiomyopathy aged 0–14 years old gradually increased, with EAPC of 0.82 (95%CI: 0.71–0.93); mortality rate and DALY rate decreased [EAPC = −2.32 (95%CI: −2.59 to −2.05)].ConclusionFrom 1990 to 2019, the disease burden of cardiomyopathy in children of China aged 0–14 years was heterogeneous; the burden of male children was higher than females; and the burden of cardiomyopathy in children younger than 1 year old needs more attention.

ObjectivesWe aimed to prospectively investigate the independent and combined relationship between trace elements concentrations [blood (selenium, manganese), serum (copper, zinc), and urine (cobalt, molybdenum, tin, strontium, iodine)] and all-cause mortality.MethodsThis study included 5,412 individuals with demographical, examination, and laboratory data from the National Health and Nutrition Examination Survey. Three statistical models, including Cox proportional hazards models, restricted cubic spline models, and Bayesian kernel machine regression (BKMR) models, were conducted to estimate the longitudinal relationship between trace elements and all-cause mortality.ResultsThere were 356 deaths documented with a median follow-up time of 70 months. In the single-exposure model, the results showed that compared with the lowest quartile, the adjusted hazard ratios (HRs) of mortality for the highest quartile of selenium, manganese, and strontium were 0.47 (95% CI: 0.28–0.79), 1.57 (95% CI: 1.14–2.14), and 0.47 (95% CI: 0.26–0.86), respectively. A nonlinear relationship between zinc, cobalt and mortality was also observed. Furthermore, a significant overall effect of mixtures of trace elements on all-cause mortality was identified, especially when the mixture was at the 60th percentile or lower.ConclusionThe association of multiple trace elements with all-cause mortality was identified in this study. It is recommended that healthcare providers and relevant public health agencies should strengthen the surveillance and management of trace elements. Emphasis should be placed on monitoring the sources of trace elements such as the body, food, and environment. More population studies and animal experiments should be conducted to identify the underlying mechanisms.

BackgroundEven though occupational women have a high incidence of lower urinary tract symptoms (LUTS), which seriously affect their daily work life, few large scale sample studies have provided empirical evidence to support this phenomenon among female nurses in China. Consequently, this article investigated female nurses who was presupposed to have a high prevalence of LUTS, which adversely exposes their health and patient safety to these risks. Additionally, it is considered important to explore the factors associated with LUTS in female nurses for patient care safety and nurse bladder health practice.ObjectivesThe purpose of this study was to assess the incidence of LUTS and symptoms-related risk factors among female nurses, to provide evidence for the prevention and control of LUTS.MethodsAn online survey recruiting 23,066 participants was carried out in a multicenter cross-sectional study in 42 hospitals from December 2020 to November 2022. Stepwise multivariate logistic regression analysis and nomogram were used to identify the factors associated with lower urinary tract symptoms. Besides, SPSS version 26.0, R version 4.2.2, and GraphPad Prism Version 8.3 software packages were used for statistical analysis.ResultsBased on the completion rate of the questionnaire which was 84.1% (n = 19,393), it was found that among 19,393 female nurses, the prevalence of LUTS was 67.71% and this rate was influenced by age, Body Mass Index (BMI), marital status, years of working, menstrual status, mode of delivery, history of breastfeeding, history of miscarriage, history of alcohol and coffee or tea consumption (p

Hepatocellular carcinoma (HCC), one of the most common malignant cancers with a low 5-year survival rate, is the third leading cause of cancer-related deaths worldwide. The finding of novel agents and strategies for the treatment of HCC is an urgent need. Sesquiterpene lactones (SLs) have attracted extensive attention because of their potent antitumor activity. In this study, a new series of SL derivatives (3–18) were synthesized using epimers 1 and 2 as parent molecules, isolated from Sphagneticola trilobata, and evaluated for their anti-HCC activity. Furthermore, the structures of 4, 6, and 14 were confirmed by X-ray single-crystal diffraction analyses. The cytotoxic activities of 3–18 on two HCC cell lines, including HepG2 and Huh7, were evaluated using the CCK-8 assay. Among them, compound 10 exhibited the best activity against the HepG2 and Huh7 cell lines. Further studies showed that 10 induced cell apoptosis, arrested the cell cycle at the S phase, and induced the inhibition of cell proliferation and migration in HepG2 and Huh7. In addition, absorption, distribution, metabolism, and excretion (ADME) properties prediction showed that 10 may possess the properties to be a drug candidate. Thus, 10 may be a promising lead compound for the treatment of HCC.

Abstract. Background:. Response to immune checkpoint inhibitors (ICIs) is affected by multiple factors. This study aimed to explore whether sites of metastasis are associated with clinical outcomes of ICIs in advanced non-small-cell lung cancer (NSCLC) patients. Methods:. The data of NSCLC patients with high programmed death-ligand 1 expression and good performance status receiving first-line ICIs monotherapy from Guangdong Provincial People's Hospital between May 2019 and July 2020 were retrospectively analyzed. Metastatic sites included liver, bone, brain, adrenal gland, pleura, and contralateral lung. Progression-free survival (PFS) and overall survival (OS) were compared between different metastatic sites and metastatic burden by the Kaplan-Meier method. Organ-specific disease control rate (OSDCR) of different individual metastatic sites was evaluated. Results:. Forty NSCLC patients meeting the criteria were identified. The presence of liver metastasis was significantly associated with shorter PFS (3.1 vs. 15.5 months, P = 0.0005) and OS (11.1 months vs. not reached, P = 0.0016). Besides, patients with bone metastasis tend to get shorter PFS (4.2 vs. 15.5 months, P = 0.0532) rather than OS (P = 0.6086). Moreover, the application of local treatment could numerically prolong PFS in patients with brain metastasis (15.5 vs. 4.3 months, P = 0.1894). More metastatic organs involved were associated with inferior PFS (P = 0.0052) but not OS (P = 0.0791). The presence of liver metastasis or bone metastasis was associated with more metastatic organs (Phi[ϕ]: 0.516, P = 0.001). The highest OSDCR was observed in lung (15/17), and the lowest in the liver (1/4). Conclusions:. Metastases in different anatomical locations may be associated with different clinical outcomes and local tumor response to ICIs in NSCLC. ICIs monotherapy shows limited efficacy in patients with liver and bone metastasis, thus patients with this type of metastasis might require more aggressive combination strategies.

Abstract Background Uterine cancer is one of the most common female cancers worldwide, with huge heterogeneity in morbidity and mortality. Although a high body‐mass index (BMI) has been linked to uterine cancer, systematic reports about the influence of high BMI and its temporal trends are scarce. Methods The annual morbidity, mortality, and disability‐adjusted life years (DALYs) of uterine cancer in 204 countries or territories were retrieved from the GBD 2019 study. To reflect trends in disease burden, we also calculated the estimated annual percentage change (EAPC) based on the age‐standardized rates of uterine cancer from 1990 to 2019. Results The global incident cases of uterine cancer increased 2.3 times from 187,190 in 1990 to 435,040 in 2019. Although the age‐standardized incidence rate (ASIR) of uterine cancer increased worldwide from 8.67/100,000 in 1990 to 9.99/100,000 in 2019, the age‐standardized death rate (ASDR) and DALY rate decreased during the same period. High socio‐demographic index (SDI) countries tended to have a higher ASIR than developing regions, and their increasing trend in ASIR was also more pronounced. The disease was rare before 40 years old, but its risk rose sharply among women aged 50–70. A high BMI was linked to more than one‐third of deaths from uterine cancer in 2019. Conclusions The incidence in developed areas was significantly higher than in developing areas and also increased much more rapidly. Elderly females, especially those with a high BMI, have a higher risk of uterine cancer. Therefore, more health resources may be needed to curb the rising burden in specific populations.

Gleason Score (GS) 3 + 4 prostate cancer (PCa) is heterogeneous in clinical course and molecular features. Risk stratification of indolent and aggressive PCa with GS 3 + 4 is critical, especially those with bone metastasis (BM) potential. Microarray-based microRNA(miRNA) profiling with eight PCa cases with or without BM was used to screen the candidate miRNAs associated with BM. Transwell and MTS assays were used to characterize the function of miRNAs and target gene LASP1. RT-qPCR and immunohistochemistry assays were utilized to illustrate the clinical significance of miRNAs and target gene in a cohort of 309 Chinese PCa cases. In the current study, we identified that miR-1-3p, miR-143–3p and miR-145–5p are associated with BM of GS 3 + 4 PCa. Through functional experiments, we show that miR-1-3p/143–3p/145–5p promotes proliferation and migration of PCa in vitro. LASP1 was predicted as the common target of these three miRNAs which was further confirmed by a luciferase assay. Overexpression of LASP1 was correlated with higher GS, higher pathological stage, and the presence of metastasis by immunohistochemistry. siRNA knockdown of LASP1 significantly suppressed proliferation and migration, whereas overexpression of LASP1 promoted it. Bioinformatics analysis revealed the involvement of Wnt signaling pathway in LASP1 mediated function. LASP1 may activate Wnt signaling by interacting with β-catenin. In all, we suggest that miR-1-3p/143–3p/145–5p are associated with BM of Gleason 3 + 4 PCa. LASP1 is the common target of these miRNAs and may active Wnt signaling by interacting with β-catenin.

BackgroundObservational studies have reported that educational attainment has been related to the risk of esophageal cancer (EC) and its precancerous lesions. However, the causal relationship remains controversial. We aimed to apply the Mendelian randomization (MR) design to determine the causal associations between genetically predicted educational attainment and EC, Barrett's esophagus (BE), and gastroesophageal reflux disease (GERD), and to explore whether modifiable risk factors play a mediating role.MethodsUsing summary statistics from genome-wide association studies (GWASs) based on European ancestry individuals of several years in education (EduYears, primary analysis, n = 293,723), college completion (College, secondary analysis, n = 95,427), EC (n = 420,531), BE (n = 361,194), and GERD (n = 420,531), genetic associations between two education phenotypes and EC, BE, and GERD were tested by two-sample MR analyses. Then, two-step MR mediation analyses were used to assess the proportion of the aforementioned association that might be mediated by body mass index (BMI), major depressive disorder (MDD), smoking, drinking, carbohydrates, fat, and protein intake.ResultsGenetically predicted EduYears was negatively associated with the risk of EC, BE, and GERD {odds ratio (OR), 0.64 [95% confidence interval (CI) 0.44–0.94], 0.86 (95% CI, 0.75–0.99), and 0.62 (95%CI, 0.58–0.67)}. EduYears was negatively associated with BMI, MDD, and smoking (range of OR: 0.76–0.84). There were positive associations between BMI, smoking with EC, BE, and GERD, as well as between MDD with GERD (range of OR: 1.08–1.50). For individual mediating effect, BMI and smoking mediated 15.75 and 14.15% of the EduYears-EC association and 15.46 and 16.85% of the EduYears-BE association. BMI, MDD, and smoking mediated 5.23, 4.98, and 4.49% of the EduYears-GERD association. For combined mediation, the aforementioned mediators explained 26.62, 28.38, and 11.48% of the effect of EduYears on EC, BE, and GERD. The mediating effects of drinking and dietary composition were not significant in the effect of education on EC, BE, and GERD.ConclusionOur study supports that genetically predicted higher educational attainment has a protective effect on EC, BE, and GERD, and is partly mediated by reducing adiposity, smoking, and depression.

Abstract Background To assess the spatiotemporal variation in female breast cancer attributable to low physical activity (LPA) at a global scale from 1990 to 2019, which is essential to promote physical activity, as well as prevent and control breast cancer. Methods The number of deaths and disability-adjusted life years (DALYs), and the corresponding age-standardized rates (ASMR and ASDR) of LPA-related breast cancer in 204 countries and territories from 1990 to 2019 were retrieved from the Global Burden of Disease Study 2019 to measure the related breast cancer burden by age and region. The estimated annual percentage change (EAPC) was calculated to quantify the secular trend in breast cancer burden rates. Results From 1990 to 2019, globally, both breast cancer deaths and DALYs attributable to LPA nearly doubled, although the corresponding ASMR and ASDR decreased slightly, with EAPC of -0.46 (95% confidence interval: -0.52, -0.40) and -0.44 (95% confidence interval: -0.49, -0.39), respectively. The LPA-related breast cancer burden varied considerably across the world, with the highest-burden rates in Oceania, Tropical Latin America and Caribbean, and the fastest growth in North Africa and Middle East. The ASMR and ASDR showed a logarithmic association with the Socio-demographic Index, and a temporally upward trend in most of 204 countries regardless of the Socio-demographic Index or the ASMR in 1990. Conclusions Despite a decline in LPA-related breast cancer burden achieved in many countries during the last 3 decades like Bermuda, Myanmar, USA and China, an increase still occurred in most of 204 countries and territories, such as Solomon Islands, Equatorial Guinea, Japan and India. The findings can bring greater awareness to the importance of promoting physical activity for the local government to control the attributable breast cancer burden.

This study aimed to estimate the latest magnitudes and temporal trends of melanoma burden at the national, regional, and global levels. The data on melanoma incidence, deaths, and disability-adjusted life-years (DALYs) in 204 countries and territories between 1990 and 2019 came from the Global Burden of Disease 2019 Study. Estimated annual percentage change (EAPC) was calculated to depict the temporal trends and Spearman rank correlation was used to analyze the influential factors of EAPC. From 1990 to 2019, the incident cases of melanoma increased by 170% to 289,950, death increased by 90% to 62,840, and DALYs increased by 67% to 1,707,800 globally. The age-standardized incidence rate (ASIR) of melanoma increased globally by an average of 1.13 [95% confidence interval (CI): 0.93–1.32], while the age-standardized rates of death and DALYs both declined with the EAPC of −0.27 (95% CI: −0.36 to −0.19) and −0.49 (95% CI: −0.57 to −0.41). In 2019, the highest burden of melanoma was observed in Australasia, followed by high-income North America and Europe regions, which all presented an incremental growth in ASIR. The positive association between the EAPC in ASIR and socio-demographic index (SDI) in 2019 (ρ = 0.600, P

Abstract Background IL-35–producing Bregs and Treg cells critically regulate chronic illnesses worldwide via mechanisms related to disrupting the gut microbiota composition. However, whether the gut microbiota regulates these IL-35+ cells remains elusive. We herein investigated the regulatory effects of the gut microbiota on IL-35+ cells by using genetically modified mouse models of obesity. Results We first found that gut Reg4 promoted resistance to high-fat diet-induced obesity. Using 16S rRNA sequencing combined with LC-MS (liquid chromatography–mass spectrometry)/MS, we demonstrated that gut Reg4 associated with bacteria such as Lactobacillus promoted the generation of IL-35+ B cells through 3-idoleacetic acid (IAA) in the presence of LPS. HuREG4 IECtg mice fed a high-fat diet exhibited marked IL-35+ cell accumulation in not only their adipose tissues but also their colons, whereas decreased IL-35+ cell accumulation was observed in the adipose and colon tissues of Reg4 knockout (KO) mice. We also found that Reg4 mediated HFD-induced obesity resistance via IL-35. Lower levels of IAA were also detected in the peripheral blood of individuals with obesity compared with nonobese subjects. Mechanistically, IAA together with LPS mediated IL-35+ B cells through PXR and TLR4. KO of PXR or TLR4 impaired the generation of IL-35+ B cells. Conclusion Together, IAA and LPS induce the generation of IL-35+ B cells through PXR and TLR4. Video Abstract

ABSTRACT Mobile colistin resistance (mcr) genes are present mainly in plasmids and can disseminate clonally or horizontally via either plasmids or insertion sequences in different genomic locations among the Enterobacteriaceae. A nationwide large-scale study on mcr prevalence and transmission in nontyphoidal Salmonella isolates is still lacking. Here, we identified 140 mcr-positive Salmonella isolates out of 7,106 isolates from 29 provinces in China from 2011 to 2020. We aligned short reads to putative plasmids from long-read hybrid assemblies and predicted the plasmid backbones of non-long-read sequencing isolates to elucidate mcr transmission patterns. The mcr-1 and mcr-3 genes are transmitted on similar high-risk clones (sequence type 34 [ST34]) but through plasmids of various replicon types. Furthermore, the ban on colistin use in food animals can lead to a decrease in the mcr-positive Salmonella prevalence among diarrheal patients, related mainly to IncHI2A_IncHI2 plasmids. We provide a framework for plasmid data incorporation into genomic surveillance systems, contributing to a better understanding of mcr spread and transmission. IMPORTANCE Nontyphoidal Salmonella is one of four major causative agents of diarrheal diseases globally, with most cases of salmonellosis being mild. Antimicrobial treatments are required for cases of life-threatening infections, and colistin is one of the last-line antibiotics for the treatment of multidrug-resistant Salmonella infections. However, the efficacy of colistin has been compromised by the emergence of various mcr genes. To elucidate the transmission of mcr genes in Salmonella isolates, our study analyzed 7,106 Salmonella strains from 29 provinces in China from 2011 to 2020. The results showed that mcr genes are transmitted on similar high-risk clones (ST34) but through plasmids of various replicon types. In addition, our data illustrated that the ban on the use of colistin in food animals led to a significant decrease in mcr-positive isolates. Our findings offer an essential step toward a more comprehensive understanding of the spread and transmission of mcr genes.

PURPOSETo map the magnitudes and temporal trends of chronic myeloid leukemia (CML) along with its attributable risk factors, providing the essential foundation for targeted public policies at the national, regional, and global levels.MATERIALS AND METHODSWe retrieved annual data on CML burden in 204 countries and regions from the Global Burden of Disease Study 2019 in 1990-2019. The estimated annual percentage change (EAPC) was calculated to quantify the temporal trends of CML burden by region, sex, and age group.RESULTSGlobally, the age-standardized incidence rate of CML declined weakly over the past few years (EAPC: −1.04), but the number of incident cases increased by 54.1% to 65.8 × 103 in 2019. By contrast, a dramatic drop in death and disability-adjusted life years (DALYs) rate (EAPCs: −2.55; −2.69) led to a reduction in deaths and DALYs, especially in high-income regions. In 2019, the highest age-standardized death rate was observed in Ethiopia (1.89 per 100,000). The death rate of CML was pronounced among the population age above 70 years. DALYs of CML worldwide were primarily attributable to smoking (12.2%), high body mass index (5.0%), occupational exposure to benzene (0.9%), and occupational exposure to formaldehyde (0.3%) in 2019.CONCLUSIONAlthough the mortality rate of CML has decreased significantly, the management of patients with CML cannot be neglected, especially in elders and developing regions.