Search

BackgroundType 2 diabetes mellitus (T2DM) is widely acknowledged as a vital warning sign contributing to cognitive dysfunction. However, there is still a lack of consensus on whether hypoglycemic events resulting from poor glycemic control increase the risk of cognitive dysfunction in people with diabetes, and the potential dose–response correlation between hypoglycemic events and cognitive dysfunction remains unexplored. The primary objective of the current study was to assess the contribution of hypoglycemic events to cognitive dysfunction in T2DM patients and the dose–response correlation between the two.MethodsA comprehensive search of nine major databases was executed from inception to May 2023. We screened all observational studies examining the connection between hypoglycemia and cognitive dysfunction. The DerSimonian-Laird method was used to compute the combined risk ratio (RR) and its 95% confidence interval (CI). Additionally, dose–response analysis was employed to investigate the correlation between the frequency of hypoglycemia and the likelihood of cognitive dysfunction.ResultsA total of 30 studies of different levels in 17 articles with 3,961,352 participants were included in this review. The pooled RR for the connection of hypoglycemia and the likelihood of cognitive dysfunction was 1.47 (95% CI: 1.35–1.60). Subgroup analyses showed that the pooled RR for the likelihood of cognitive dysfunction was 1.20 (95% CI: 1.11–1.31) for one episode of hypoglycemia, 1.41 (95% CI: 1.05–1.88) for two episodes of hypoglycemia, and 1.62 (95% CI: 1.20–2.91) for three or more episodes of hypoglycemia. Dose–response analysis showed a linear dose–response relationship between hypoglycemia and the likelihood of cognitive dysfunction (exp (b) = 1.178694, z = 7.12, p

PurposeBased on comparison of different machine learning (ML) models, we developed the model that integrates traditional hand-crafted (HC) features and ResNet50 network-based deep transfer learning (DTL) features from multiparametric MRI to predict Ki-67 status in sinonasal squamous cell carcinoma (SNSCC).MethodsTwo hundred thirty-one SNSCC patients were retrospectively reviewed [training cohort (n = 185), test cohort (n = 46)]. Pathological grade, clinical, and MRI characteristics were analyzed to choose the independent predictor. HC and DTL radiomics features were extracted from fat-saturated T2-weighted imaging, contrast-enhanced T1-weighted imaging, and apparent diffusion coefficient map. Then, HC and DTL features were fused to formulate the deep learning-based radiomics (DLR) features. After feature selection and radiomics signature (RS) building, we compared the predictive ability of RS-HC, RS-DTL, and RS-DLR.ResultsNo independent predictors were found based on pathological, clinical, and MRI characteristics. After feature selection, 42 HC and 10 DTL radiomics features were retained. The support vector machine (SVM), LightGBM, and ExtraTrees (ET) were the best classifier for RS-HC, RS-DTL, and RS-DLR. In the training cohort, the predictive ability of RS-DLR was significantly better than those of RS-DTL and RS-HC (p< 0.050); in the test set, the area under curve (AUC) of RS-DLR (AUC = 0.817) was also the highest, but there was no significant difference of the performance between DLR-RS and HC-RS.ConclusionsBoth the HC and DLR model showed favorable predictive efficacy for Ki-67 expression in patients with SNSCC. Especially, the RS-DLR model represented an opportunity to advance the prediction ability.

BackgroundStudies have reported that metabolic disturbance exhibits in patients with Alzheimer’s disease (AD). Still, the presence of definitive evidence concerning the genetic effect of metabolites on AD risk remains insufficient. A systematic exploration of the genetic association between blood metabolites and AD would contribute to the identification of new targets for AD screening and prevention.MethodsWe conducted an exploratory two-sample Mendelian randomization (MR) study aiming to preliminarily identify the potential metabolites involved in AD development. A genome-wide association study (GWAS) involving 7,824 participants provided information on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of AD, encompassing 21,982 cases and 41,944 controls of Europeans. The primary two-sample MR analysis utilized the inverse variance weighted (IVW) model while supplementary analyses used Weighted median (WM), MR Egger, Simple mode, and Weighted mode, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. For the further identification of metabolites, replication and meta-analysis with FinnGen data, steiger test, linkage disequilibrium score regression, confounding analysis, and were conducted for further evaluation. Multivariable MR was performed to assess the direct effect of metabolites on AD. Besides, an extra replication analysis with EADB data was conducted for final evaluation of the most promising findings.ResultsAfter rigorous genetic variant selection, IVW, complementary analysis, sensitivity analysis, replication and meta-analysis with the FinnGen data, five metabolites (epiandrosterone sulfate, X-12680, pyruvate, docosapentaenoate, and 1-stearoylglycerophosphocholine) were identified as being genetically associated with AD. MVMR analysis disclosed that genetically predicted these four known metabolites can directly influence AD independently of other metabolites. Only epiandrosterone sulfate and X-12680 remained suggestive significant associations with AD after replication analysis with the EADB data.ConclusionBy integrating genomics with metabonomics, this study furnishes evidence substantiating the genetic association of epiandrosterone sulfate and X-12680 with AD. These findings hold significance for the screening, prevention, and treatment strategies for AD.

ObjectiveTo explore the modulations of electroacupuncture in subjective tinnitus (ST) by comparing the difference of functional connectivity (FC) in ST patients and healthy volunteers between the insular (INS) and the whole brain region.MethodsA total of 34 ST patients were selected into electroacupuncture group (EG) and 34 age- and sex-matched normal subjects were recruited into control group (CG). The EG received acupuncture at SI19 (Tinggong), GB11 (Touqiaoyin), TE17 (Yifeng), GV20 (Baihui), GV15 (Yamen), GV14 (Dazhui), SJ13 (Zhongzhu), among which the points of SI19 and GB11 were connected to the electroacupuncture instrument with the density wave of 2/50 Hz, and 3 treatments per week for 10 sessions in total. The severity of tinnitus was evaluated by Tinnitus Handicap Inventory (THI), the hearing status was recorded using pure tone audiometry, and resting-state functional magnetic resonance imaging (rs-fMRI) was performed on the brain before and after treatment, the CG received no intervention yet only rs-fMRI data were collected.ResultsWith the electroacupuncture treatment, the total THI score, average air conduction threshold of patients of EG were significantly lower than before (p

ObjectiveAlthough intracranial electrical stimulation has emerged as a treatment option for various diseases, its impact on the properties of brain networks remains challenging due to its invasive nature. The combination of intracranial electrical stimulation and whole-brain functional magnetic resonance imaging (fMRI) in patients with refractory epilepsy (RE) makes it possible to study the network properties associated with electrical stimulation. Thus, our study aimed to investigate the brain network characteristics of RE patients with concurrent electrical stimulation and obtain possible clinical biomarkers.MethodsOur study used the GRETNA toolbox, a graph theoretical network analysis toolbox for imaging connectomics, to calculate and analyze the network topological attributes including global measures (small-world parameters and network efficiency) and nodal characteristics. The resting-state fMRI (rs-fMRI) and the fMRI concurrent electrical stimulation (es-fMRI) of RE patients were utilized to make group comparisons with healthy controls to identify the differences in network topology properties. Network properties comparisons before and after electrode implantation in the same patient were used to further analyze stimulus-related changes in network properties. Modular analysis was used to examine connectivity and distribution characteristics in the brain networks of all participants in study.ResultsCompared to healthy controls, the rs-fMRI and the es-fMRI of RE patients exhibited impaired small-world property and reduced network efficiency. Nodal properties, such as nodal clustering coefficient (NCp), betweenness centrality (Bc), and degree centrality (Dc), exhibited differences between RE patients (including rs-fMRI and es-fMRI) and healthy controls. The network connectivity of RE patients (including rs-fMRI and es-fMRI) showed reduced intra-modular connections in subcortical areas and the occipital lobe, as well as decreased inter-modular connections between frontal and subcortical regions, and parieto-occipital regions compared to healthy controls. The brain networks of es-fMRI showed a relatively weaker small-world structure compared to rs-fMRI.ConclusionThe brain networks of RE patients exhibited a reduced small-world property, with a tendency toward random networks. The network connectivity patterns in RE patients exhibited reduced connections between cortical and subcortical regions and enhanced connections among parieto-occipital regions. Electrical stimulation can modulate brain network activity, leading to changes in network connectivity patterns and properties.

Parkinson’s disease (PD) is the second most common neurodegenerative disease globally. Levodopa (L-dopa) has been the cornerstone for treating Parkinson’s since the 1960s. However, complications such as “wearing-off” and dyskinesia inevitably appear with disease progression. With the further development of microbiomics in recent years, It has been recognized that gut microbiota plays a crucial role in Parkinson’s disease pathogenesis. However, Little is known about the impact of gut microbiota in PD treatment, especially in levodopa metabolism. This review examines the possible mechanisms of gut microbiota, such as Helicobacter pylori, Enterobacter faecalis, and Clostridium sporogenes, affecting L-dopa absorption. Furthermore, we review the current status of gut microbiota intervention strategies, providing new insights into the treatment of PD.

ObjectiveWe aimed to construct and validate machine learning models for endotracheal tube (ETT) size prediction in pediatric patients.MethodsData of 990 pediatric patients underwent endotracheal intubation were retrospectively collected between November 2019 and October 2021, and separated into cuffed and uncuffed endotracheal tube subgroups. Six machine learning algorithms, including support vector regression (SVR), logistic regression (LR), random forest (RF), gradient boosting tree (GBR), decision tree (DTR) and extreme gradient boosting tree (XGBR), were selected to construct and validate models using ten-fold cross validation in training set. The optimal models were selected, and the performance were compared with traditional predictive formulas and clinicians. Furthermore, additional data of 71 pediatric patients were collected to perform external validation.ResultsThe optimal 7 uncuffed and 5 cuffed variables were screened out by feature selecting. The RF models had the best performance with minimizing prediction error for both uncuffed ETT size (MAE = 0.275 mm and RMSE = 0.349 mm) and cuffed ETT size (MAE = 0.243 mm and RMSE = 0.310 mm). The RF models were also superior in predicting power than formulas in both uncuffed and cuffed ETT size prediction. In addition, the RF models performed slightly better than senior clinicians, while they significantly outperformed junior clinicians. Based on SVR models, we proposed 3 novel linear formulas for uncuffed and cuffed ETT size respectively.ConclusionWe have developed machine learning models with excellent performance in predicting optimal ETT size in both cuffed and uncuffed endotracheal intubation in pediatric patients, which provides powerful decision support for clinicians to select proper ETT size. Novel formulas proposed based on machine learning models also have relatively better predictive performance. These models and formulas can serve as important clinical references for clinicians, especially for performers with rare experience or in remote areas.

Accurate and reliable estimation of state of health (SOH) for lithium-ion batteries under slight overcharge voltage cycling has great significance for battery management systems. In this study, commercial lithium-ion phosphate batteries are investigated under slight overcharge voltage cycling. The aging mechanism is discussed based on incremental capacity analysis and differential voltage analysis. Moreover, the syncretic health indicator is obtained from the incremental capacity curves based on principal component analysis. Specifically, the capacity retention and Coulombic efficiency are analyzed under slight overcharge voltage cycling. The incremental capacity peaks (i.e., peak B and peak C) are discussed to extract potential health indicators, and a syncretic health indicator is adopted based on principal component analysis. Finally, the Gaussian process regression is established for accuracy SOH estimation with a 95% confidence interval under small data of slight overcharge cycling. In comparison with the traditional methods, the proposed method exhibits higher accuracy with a 95% confidence interval, and the error is limited to 3%.

BackgroundCardiac power-to-left ventricular mass (power/mass) is an index reflecting the muscular hydraulic pump capability of the heart, and the E/e’ ratio is a specific indicator for identifying increased left ventricular filling pressure. Limited data exist regarding the prognostic value of incorporating power/mass and E/e’ ratio in heart failure with preserved ejection fraction (HFpEF).Materials and methodsIn total, 475 patients with HFpEF from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial with complete baseline echocardiography data were included in our analysis. Patients were categorized into four groups according to power/mass and E/e’ ratio. The risk of outcomes was examined using Cox proportional hazards models and competing risk models.ResultsPatients with low power/mass and high E/e’ were more likely to be males (60.5%), with higher waist circumference, and had a higher prevalence of diabetes (52.1%), atrial fibrillation (50.4%), and lower estimated glomerular filtration rate (eGFR). Combined resting power/mass and E/e’ have graded correlations with left ventricular (LV) dysfunction and clinical outcomes in patients with HFpEF. After multivariable adjustments, an integrative approach combining power/mass and E/e’ remained to be a powerful prognostic predictor, with the highest HRs of clinical outcomes observed in patients with low power/mass and high E/e’ (all-cause mortality: HR 3.45; 95% CI: 1.69–7.05; P = 0.001; hospitalization for heart failure: HR 3.27; 95% CI: 1.60–6.67; P = 0.001; and primary endpoint: HR 3.07; 95% CI: 1.73–5.42; P < 0.001).ConclusionIn patients with HFpEF, an echo-derived integrated approach incorporating resting power/mass and E/e’ ratio remained to be a powerful prognosis predictor and may be useful to risk-stratify patients with this heterogeneous syndrome.Clinical Trial Registration[https://clinicaltrials.gov], identifier [NCT00094302].

BackgroundObesity could paradoxically improve prognosis in patients with heart failure (HF), termed the “obesity paradox.” Whether HF etiology could modify the “obesity paradox” is still controversial. In the present study, we aimed to assess the relationship between obesity and death in patients with heart failure with preserved ejection fraction (HFpEF) with non-ischemic versus ischemic etiologies.MethodsWe analyzed 3,360 HFpEF patients from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial. Cox regression models were used to assess the association of obesity assessed by body mass index (BMI) with short-term and long-term death risk.ResultsOverweight and obesity were associated with a lower risk of long-term all-cause death in patients with non-ischemic HFpEF, even in those with class III obesity (adjusted HR: 0.61, 95% CI 0.38–0.97). However, in the ischemic subgroup, as obesity advanced, this paradoxical relationship was gradually attenuated and disappeared in class III obesity (adjusted HR: 0.93, 95% CI 0.56–1.57). Restricted cubic spline analyses confirmed the differential relationship of baseline BMI with risk of long-term death with a BMI higher than 30 kg/m2 in non-ischemic versus ischemic HFpEF. In the short-term follow-up, the beneficial effects of overweight and obesity on survival were consistently observed in all the BMI categories, with the nadirs of all-cause death risk at class III obesity category both in non-ischemic and ischemic subgroups.Conclusion“Obesity paradox” was evident both in non-ischemic and ischemic HFpEF during short-term follow-up, even in those with class III obesity. However, the beneficial effect of class III obesity disappeared during long-term follow-up in ischemic HFpEF.Clinical Trial Registration[https://clinicaltrials.gov], identifier [NCT00094302].

BackgroundMalignant central airway stenosis is a life-threatening condition. However, treatment of malignant airway stenosis remains challenging. There is currently a severe lack of an excellent animal model of malignant airway stenosis to facilitate treatment approaches. This is the first study to establish a rabbit model of malignant airway stenosis for bronchoscopic interventional studies.Materials and methodsNew Zealand White rabbits were used in this study, randomly divided into group A (18 rabbits) and group B (6 rabbits). A VX2 fragment suspension was injected into the submucosal layer of rabbits’ airway by bronchoscopy. Bronchoscopic examinations were performed once a week after VX2 tumor implantation to observe tumor growth and the degree of airway stenosis. Randomly, three rabbits were generally dissected after a weekly bronchoscopic examination in group A. The rabbits that reached grade III airway stenosis underwent stent implantation in group B.ResultsA total of 24 rabbits were successfully implanted with the VX2 fragment suspension in the airway without significant adverse events, and the success rate of the tumor growth was 100%. The degree of airway stenosis reaching grade III took 2 to 3 weeks after implantation of the VX2 tumor. The median survival time of rabbit models without stent implantation and rabbits with stent implantation was 32.5 and 32.0 days, respectively.ConclusionsThe implanting method is safe and effective for the establishment of a rabbit model of malignant airway stenosis. When the tumor grows to 2 to 3 weeks, the rabbit model is available for stent implantation. We recommend the models for more preclinical animal studies on bronchoscopic interventional treatments.

Background:High serum anion gap (AG) on admission is often correlated with poor outcomes in critically ill patients; however, data in patients with non-traumatic subarachnoid hemorrhage (SAH) are lacking. Herein, we aimed to identify the association between serum AG and all-cause mortality in patients with non-traumatic SAH.MethodsA retrospective analysis of data from the Medical Information Mart for Intensive Care (MIMIC-IV) database was performed on critically ill patients with non-traumatic SAH. Serum AG was collected on Intensive Care Unit (ICU) admission, and ICU and hospital all-cause mortality were analyzed. The multivariate Cox proportional hazard regression model and Kaplan-Meier survival curve analysis were used to analyze the correlation of serum AG with ICU and hospital all-cause mortality. Furthermore, interaction and subgroup analyses were evaluated for the consistency of these correlations.ResultsA total of 893 patients with non-traumatic SAH were included in this study. The all-cause mortality in ICU and hospital were 14.8% (132/893), and 18.9% (169/893), respectively. Multivariate analysis after adjusting for potential confounders indicated that high serum AG levels (≥16 mmol/L) were associated with increased risk of ICU and hospital all-cause mortality as compared to that with low serum AG levels (

ObjectivesThis research amid to elucidate the disease stage-specific spatial patterns and the probable sequences of gray matter (GM) deterioration as well as the causal relationship among structural network components in hepatitis B virus-related cirrhosis (HBV-RC) patients.MethodsTotally 30 HBV-RC patients and 38 healthy controls (HC) were recruited for this study. High-resolution T1-weighted magnetic resonance imaging and psychometric hepatic encephalopathy score (PHES) were evaluated in all participants. Voxel-based morphometry (VBM), structural covariance network (SCN), and causal SCN (CaSCN) were applied to identify the disease stage-specific GM abnormalities in morphology and network, as well as their causal relationship.ResultsCompared to HC (0.443 ± 0.073 cm3), the thalamus swelled significantly in the no minimal hepatic encephalopathy (NMHE) stage (0.607 ± 0.154 cm3, p

Sweet potato [Ipomoea batatas (L.) Lam] is grown as important cash and food crop worldwide and has been shown to exhibit allelopathic effects on other plants. However, its metabolome has not been studied extensively, particularly with respect to the production of phytotoxic bioactive secondary products. In this study, the chemical composition of petroleum ether extract of sweet potato was characterized, and the morphological and physiological effects of some individual components against four invasive alien weeds Bidens pilosa L., Galinsoga parviflora Cav., Lolium multiflorum Lam., and Phalaris minor Retz. were determined. Twenty-one components were identified by GS-MS, constituting 96.08% of petroleum ether extract in sweet potato. The major components were palmitic acid (PA) (17.48%), ethyl linoleate (EL) (13.19%), linoleic acid (LA) (12.55%), ethyl palmitate (EP) (11.77%), ethyl linolenate (ELL) (8.29%) oleic acid (5.82%), ethyl stearate (4.19%), and 3-methylphenol acetate (3.19%). The five most abundant compounds exhibited strong inhibition activity against the four invasive weeds tested. The highest inhibition rates were seen for LA, followed by PA and EP, respectively. Catalase (CAT), malondialdehyde (MDA), and peroxidase (POD) content of L. multiflorum were increased by the three allelochemicals, i.e., LA, PA and EP, but superoxide dismutase (SOD), chlorophyll-a and chlorophyll-b levels declined. Overall, the combined impact of all five compounds could be quite effective in suppressing the invasive weeds of concern.

ObjectiveTo explore the feasibility of simple high-intensity focused ultrasound (HIFU) ablation for placenta increta.MethodsNinety-five patients after a vaginal delivery were enrolled in this retrospective cohort study, 53 patients were treated with simple HIFU ablation, and 42 patients were treated with HIFU followed by uterine curettage.ResultsAll 95 patients were successfully treated with a single-session HIFU procedure, and in the control group, the necrotic placental tissue was removed with curettage. Vaginal hemorrhage did not occur in either group. The duration of bloody lochia was 25.9 ± 8.6 days in the sHIFU group and 24.2 ± 8.8 days in the control group (P > 0.05). The median serum human chorionic gonadotropin (HCG) level was 3,222 mIU/mL and 2,838 mIU/mL in the sHIFU and control groups, respectively, which decreased and returned to normal within 30 days, and the differences were not significantly on comparing the blood HCG level in the two groups at 7, 15, and 30 days after HIFU (all P > 0.05). Decreased menstrual volume occurred in 85.71% of patients in the control group, which was higher than that in the sHIFU group (23.08%) (χ2 = 6.839, P < 0.001). During 2–8 years of follow-up, six pregnancies occurred in the sHIFU group without any recurrence of placenta increta, three pregnancies occurred in the control group, and one patient developed a repeat placenta increta.ConclusionSimple HIFU treatment is safe and effective for postpartum placenta increta and leaving the placenta in situ. It is a promising option for patients who wish to preserve their fertility and conceive.

Background: The prolongation or shortening of heart rate-corrected QT (QTc) predisposes patients to fatal ventricular arrhythmias and sudden cardiac death (SCD), but the association of dynamic change of QTc interval with mortality in the general population remains unclear.Methods: A total of 11,798 middle-aged subjects from the prospective, population-based cohort were included in this analysis. The QTc interval corrected for heart rate was measured on two occasions around 3 years apart in the Atherosclerosis Risk in Communities (ARIC) study. The ΔQTc interval was calculated by evaluating a change in QTc interval from visit 1 to visit 2.Results: After a median follow-up of 19.5 years, the association between the dynamic change of QTc interval and endpoints of death was U-shaped. The multivariate-adjusted hazard ratios (HRs) comparing subjects above the 95th percentile of Framingham–corrected ΔQTc (ΔQTcF) (≥32 ms) with subjects in the middle quintile (0–8 ms) were 2.69 (95% CI, 1.68–4.30) for SCD, 2.51 (1.68–3.74) for coronary heart disease death, 2.10 (1.50–2.94) for cardiovascular death, and 1.30 (1.11–1.55) for death from any cause. The corresponding HRs comparing subjects with a ΔQTcF below the fifth percentile (

Persistent infection with human papillomavirus (HPV) and immune surveillance failure may be the initiating factors for the carcinogenesis of cervical squamous cell carcinoma (CSCC). HPV infection might affect the innate immune pathway of cervical epithelial cells that constitute the “microenvironment” for tumor cells. Programmed death-ligand 1 (PD-L1) has been reported to be an immunosuppressor that helps cancer cells escape the actions of T cells. In the present study, CXCL10 was substantially upregulated both in cervical tissues of HPV infected patients with cervical intraepithelial neoplasia (CIN) or CSCC, as well as in HPV16 E6/E7 transgenic murine cervix. The HPV-positive (HPV+) cervical cancer cell lines SiHa and Caski secreted increased levels of CXCL10 compared to human foreskin fibroblasts (HFF-1), and its receptor CXCR3 was overexpressed in HFF-1. After co-culture with SiHa or Caski, the JAK-STAT signaling pathway and exosomal PD-L1 expression were both upregulated in HFF-1. Recombinant human CXCL10 induced JAK-STAT and PD-L1, while the CXCL10-CXCR3 and JAK-STAT inhibitors AMG487 or ruxolitinib reduced the expression of PD-L1 in HFF-1 cells. Furthermore, the upregulated expression of PD-L1 was verified in HPV+ but not HPV-negative (HPV-) patients with cervical cancers by analysis of tissue microarray cores in 25 cervical lesion patients (P < 0.05). The results indicate that HPV infection can induce cervical cancer cells to secrete CXCL10, which binds to CXCR3 in the surrounding fibroblast cells,leading to JAK-STAT pathway activation and the subsequent upregulated expression of exosomal PD-L1. These mechanisms may help HPV to escape immune response attack, leading to carcinogenesis.

Sphingosine-1-phosphate (S1P) is a phospholipid that regulates pleiotropic biological activities and exerts extracellular functions by binding to five specific G-protein-coupled receptors, S1P receptors (S1PR) 1–5. When activated by S1P, S1PR promote the proliferation and invasion of tumor cells by inducing the formation of new blood vessels. We developed and assessed a new monoclonal antibody imaging probe 99mTc-HYNIC-S1PR1mAb, to explore the feasibility of targeting the S1PR1 in vitro and in vivo. S1PR1mAb was prepared and followed by technetium-99m labeling with succinimidyl 6-hydraziniumnicotinate hydrochloride. Cell uptake and blocking studies were performed to investigate the binding specificity of 99mTc-HYNIC-S1PR1mAb in vitro. 99mTc-HYNIC-S1P1mAb was also tested in vivo in mice xenografted with SK-HEP-1 (high-expression of S1PR1) and MCF-7 (low-expression of S1PR1) using single-photon emission-computed tomography (SPECT). Ex vivo gamma counting of tissues from tumor-bearing mice was used to evaluate 99mTc-HYNIC-S1PR1mAb biodistribution. The biodistribution study results showed significantly higher uptake in SK-HEP-1 tumors than in MCF-7 tumors (P < 0.001). Reduced uptake of 99mTc-HYNIC-S1PR1mAb in SK-HEP-1 was observed in tumor-bearing nude mice pretreated with fingolimod, which binds competitively to the receptors, especially S1PR1. 99mTc-HYNIC-S1PR1mAb can be synthesized and specifically targeted to S1PR1 in vitro and in vivo, allowing S1PR1 expression assessment with SPECT imaging.

The El Niño-Southern Oscillation (ENSO) is one of the main drivers of the interannual climate variability of Earth and can cause a wide range of climate anomalies, so multi year ENSO forecasts are a paramount scientific issue. However, most existing works rely on the conventional iterative mechanism and, thus, fail to provide reliable long-term predictions due to error accumulation. Although methods based on deep learning (DL) apply the parallel modeling scheme for different lead times instead of a single iteration model, they leverage the same DL model for prediction, which can not fully mine the variability of different lead times, resulting in a decrease of prediction accuracy. To solve this problem, we propose a novel parallel deep convolutional neural network (CNN) with a heterogeneous architecture. In this study, by adaptively selecting network architectures for different lead times, we realize variability modeling of different tasks (lead times) and thereby improve the reliability of long-term predictions. Furthermore, we propose a relationship between different prediction lead times and neural network architecture from a unique perspective, namely, the receptive field originally proposed in computer vision. According to the spatio-temporal correlated area and sampling scale of lead times, the size of the convolution kernel and the mesh size of sampling are adjusted as the lead time increases. The Coupled Model Intercomparison Project phase 5 (CMIP5) from 1861 to 2004 and the Simple Ocean Data Assimilation (SODA) from 1871 to 1973 were used for model training, and the GODAS from 1982 to 2017 were used for testing the forecast skill of the model. Experimental results demonstrate that the proposed method outperforms the other well-known methods, especially for long-term predictions.

Lapatinib is an FDA-approved EGFR and HER2 tyrosine kinase inhibitor for the treatment of HER2-positive breast cancer patients. However, its therapeutic efficacy is limited by primary or acquired resistance. In the present study, we established breast cancers cells with acquired lapatinib resistance and investigated the antitumor activity of the second-generation HSP90 inhibitor ganetespib in association with lapatinib in lapatinib-sensitive and -resistant cells. The combination treatment showed synergistic inhibition of HER and the downstream PI3K/Akt and Ras/MEK/ERK pathways, in addition to enhancing induction of early apoptotic cell death and G1 arrest in both parent and lapatinib-resistant cells in vitro. The joint administration of ganetespib and lapatinib depleted the aberrant nuclear transcription factor STAT3, a mediator of the cell cycle and apoptosis-related pathways that is probably involved in the lapatinib resistance of HER2-positive breast cancer cells. In conjunctive with the augmented inhibition of tumor growth observed in both SKBR3 and SKBR3-L xenografts compared to monotherapy, our data provide a sound preclinical basis for combination treatment with lapatinib and ganetespib for refractory HER2-positive breast cancer.

Background: We aimed to explore the value of combining real-time three-dimensional echocardiography (RT-3DE) and myocardial contrast echocardiography (MCE) in the left ventricle (LV) evaluating myocardial dysfunction in type 2 diabetes mellitus (T2DM) patients.Patients and Methods: A total of 58 T2DM patients and 32 healthy individuals were selected for this study. T2DM patients were further divided into T2DM without microvascular complications (n = 29) and T2DM with microvascular complications (n = 29) subgroups. All participants underwent RT-3DE and MCE. The standard deviation (SD) and the maximum time difference (Dif) of the time to the minimum systolic volume (Tmsv) of the left ventricle were measured by RT-3DE. MCE was performed to obtain the perfusion measurement of each segment of the ventricular wall, including acoustic intensity (A), flow velocity (β), and A·β.Results: There were significant differences in all Tmsv indices except for Tmsv6-Dif among the three groups (all P < 0.05). After heart rate correction, all Tmsv indices of the T2DM with microvascular complications group were prolonged compared with the control group (all P < 0.05). The parameters of A, β, and A·β for overall segments showed a gradually decreasing trend in three groups, while the differences between the three groups were statistically significant (all P < 0.01). For segmental evaluation of MCE, the value of A, β, and A·β in all segments showed a decreasing trend and significantly differed among the three groups (all P < 0.05).Conclusions: The RT-3DE and MCE can detect subclinical myocardial dysfunction and impaired myocardial microvascular perfusion. Left ventricular dyssynchrony occurred in T2DM patients with or without microvascular complications and was related to left ventricular dysfunction. Myocardial perfusion was reduced in T2DM patients, presenting as diffuse damage, which was aggravated by microvascular complications in other organs.

TYRO3, AXL, and MERTK constitute the TAM family of receptor tyrosine kinases, which play important roles in tumor growth, survival, cell adhesion, as well as innate immunity, phagocytosis, and immune-suppressive activity. Therefore, targeting both AXL and MERTK kinases may directly impact tumor growth and relieve immunosuppression. We describe here the discovery of INCB081776, a potent and selective dual inhibitor of AXL and MERTK that is currently in phase 1 clinical trials. In cellular assays, INCB081776 effectively blocked autophosphorylation of AXL or MERTK with low nanomolar half maximal inhibitory concentration values in tumor cells and Ba/F3 cells transfected with constitutively active AXL or MERTK. INCB081776 inhibited activation of MERTK in primary human macrophages and partially reversed M2 macrophage–mediated suppression of T-cell proliferation, which was associated with increased interferon-γ production. In vivo, the antitumor activity of INCB081776 was enhanced in combination with checkpoint blockade in syngeneic models, and resulted in increased proliferation of intratumoral CD4+ and CD8+ T cells. Finally, antitumor activity of INCB081776 was observed in a subset of sarcoma patient–derived xenograft models, which was linked with inhibition of phospho-AKT. These data support the potential therapeutic utility of INCB081776 as an immunotherapeutic agent capable of both enhancing tumor immune surveillance and blocking tumor cell survival mechanisms.

Objectives: To clarify the clinical characteristics of cured patients with coronavirus disease (COVID-19), and to clarify the re-infection and person-to-person transmission in the cured.Methods: A total of 187 cured COVID-19 patients with antibody test were followed up every 2 weeks in this retrospective observational study. Assessment for general condition, symptoms, epidemiological contact history, polymerase chain reaction (PCR) assay, and antibody tests were performed and recorded. Information from Guangzhou CDC was also screened.Results: There were 33 (17.6%) patients with negative results for IgG and 35 (18.7%) patients with positive results for IgM. The average days of antibody detection from disease onset were 53.0. PCR assay was positive in 10 (5.3%) patients during the follow-up. Neither IgG nor IgM results showed a relationship with PCR test results (all P > 0.05). Neither re-infection nor person-to-person transmission was found in the cured patients. Factors associated with appearance of antibody comprised hospitalization days (OR: 1.06, 95%CI: 1.02–1.11, P = 0.006) and antibiotics treatment (OR: 3.50, 95%CI: 1.40–8.77, P = 0.007).Conclusions: In our study, no evidence of person-to-person transmission was found in cured COVID-19 patients. There seemed to be no re-infection in the cured COVID-19 patients in Guangzhou. These finding suggest that the cured do not cause the spread of disease. Additionally, neither IgG nor IgM can be used to replace the PCR test in cured patients.

As shown in our previous study, SIRT6 promotes an aggressive phenotype and the epithelial-mesenchymal transition (EMT) in papillary thyroid cancer (PTC). In this study, we focused on the regulatory axis including SIRT6, autophagy, and the Warburg effect. We innovatively confirmed that SIRT6 overexpression depleted histone H3 lysine 56 acetylation (H3K56ac) of the negative regulator of reactive oxygen species (NRROS) in vitro, thus increasing reactive oxygen species (ROS) production. The accumulated ROS then activated endoplasmic reticulum stress (ER stress) and subsequently induced autophagy. Furthermore, SIRT6 overexpression inhibited glucose transporter 1 (GLUT1) via autophagy-mediated degradation, ultimately suppressing the Warburg effect. Treatment with the ROS scavenger N-acetyl-L-cysteine (NAC, 5 mM) or the autophagy inhibitor chloroquine (CQ) both rescued the inhibition of the Warburg effect. Additionally, a higher concentration of NAC (15 mM) further inhibited the Warburg effect. These concentration-dependent bilateral effects of NAC on this process were confirmed to be due to the regulation of the AMPK signaling pathway. Finally, we further examined this mechanism in vivo by establishing subcutaneous xenografts in nude mice and analyzed the tumors using 18F radio-labeled fluorodeoxyglucose (18F-FDG) PET/CT. In conclusion, we identified a SIRT6-ROS-ER stress-autophagy-GLUT1-Warburg effect axis in PTC, which may provide a new therapeutic target. In addition, NAC (low concentration) and CQ, previously considered to be tumor inhibitors, were shown to promote tumorigenesis in PTC with high SIRT6 expression by inducing the Warburg effect.

In this paper, the dynamical analysis of Ca2+ oscillations in astrocytes is theoretically investigated by the center manifold theorem and the stability theory of equilibrium point. The global structure of bifurcation and evoked Ca2+ dynamics are presented in a human astrocyte model from a mathematical perspective. Results show that the difference in appearance and disappearance of Ca2+ oscillations is partly due to two subcritical Hopf bifurcation points. In addition, the numerical simulations are performed to further verify the effectiveness of the proposed method.

Alzheimer’s disease (AD) is a common neurodegenerative disease, mainly manifested by cognitive dysfunction. It seriously reduces the quality of life, and there is no ideal treatment strategy in clinical practice. Clinical studies on the treatment of AD with Ginkgo biloba L. leaf extract (EGb) have been reported since 1980s, and many clinical studies have been carried out during the following 30 years. However, the benefits of EGb on the treatment of AD are still controversial. In this review, we collected the clinical trial reports of EGb on cognitive function from Pubmed, Elsevier, Europe PMC, and other database since the 1980s. Through analysis and comparison, we consider that EGb may be able to improve the cognitive function in patients who suffered from mild dementia during long-term administration (more than 24 weeks) and appropriate dosage (240 mg per day). The main evidences and existing problems of the negative and positive experimental results were summarized.

Uveitis is the inflammation of the uvea and is a serious eye disease that can cause blindness for middle-aged and young people. However, the pathogenesis of this disease has not been fully uncovered and thus renders difficulties in designing effective treatments. Completely identifying the genes related to this disease can help improve and accelerate the comprehension of uveitis. In this study, a new computational method was developed to infer potential related genes based on validated ones. We employed a large protein–protein interaction network reported in STRING, in which Laplacian heat diffusion algorithm was applied using validated genes as seed nodes. Except for the validated ones, all genes in the network were filtered by three tests, namely, permutation, association, and function tests, which evaluated the genes based on their specialties and associations to uveitis. Results indicated that 59 inferred genes were accessed, several of which were confirmed to be highly related to uveitis by literature review. In addition, the inferred genes were compared with those reported in a previous study, indicating that our reported genes are necessary supplements.

Herbal medicines are commonly used as compound formulas in clinical practice to achieve optimal therapeutic effects. However, the combination mechanisms usually lack solid evidence. In this study, we report synergistic interactions through altering pharmacokinetics in Gegen-Qinlian Decoction (GQD), an anti-diabetic Chinese medicine formula. A multi-component pharmacokinetic study of GQD and the single herbs was conducted by simultaneously monitoring 42 major bioactive compounds (markers) in rats plasma using LC/MS/MS within 30 min. GQD could remarkably improve the plasma concentrations of berberine (BER) and other alkaloids in Huang-Lian by at least 30%, and glycyrrhizic acid (GLY) from Gan-Cao played a major role. A Caco-2 cell monolayer test indicated that GLY improved the permeability of BER by inhibiting P-glycoprotein. Although GLY alone did not show observable effects, the co-administration of GLY (ig, 50 or 80 mg/kg) could improve the anti-diabetic effects of berberine (ig, 50 mg/kg) in db/db mice in a dose-dependent manner. The blood glucose decreased by 46.9%, whereas the insulin level increased by 40.8% compared to the control group. This is one of the most systematic studies on the pharmacokinetics of Chinese medicine formulas, and the results demonstrate the significance of pharmacokinetic study in elucidating the combination mechanisms of compound formulas.

IntroductionBody dysmorphic disorder (BDD) and depression have been reported to be both prevalent among young people worldwide, resulting in serious implications in their quality of life and social functioning. This is worrying especially in men where mental disorders are often overlooked and under-researched. This study aims to determine the proportion of male university students with symptoms suggestive of body dysmorphic disorder and depression, as well as their perception on their body image.MethodsIn this cross-sectional study, 1,308 male students between the aged of 17–26 years in a private university in Malaysia via self-administered online questionnaire comprising the Patient Health Questionnaire (PHQ)-9, the Body Dysmorphic Disorder Questionnaire (BQQD) and the Body Self-Image Questionnaire (BSIQ), in addition to their sociodemographic parameters. Data analyses were performed with Mann Whitney test, chi square test and Fisher's exact test.Results3.3 and 54.2% of the students had symptoms suggestive of BDD and depression respectively, with up to 9.02% of the students reporting having moderate to severe depression. There was a significant association between BDD symptoms and students staying alone, whilst depression was significantly associated with studying in the rural campus. Furthermore, a significant association was demonstrated between presence of BDD and depression symptoms. Most of the students were dissatisfied with their whole body, especially their height.ConclusionThe proportion of BDD and depression symptoms among male students in our university is quite high. Universities and the public health sector should develop better support service targeting male university students.

The fine-tuning of inorganic phosphate (Pi) for enhanced use efficiency has long been a challenging subject in agriculture, particularly in regard to rice as a major crop plant. Among ribonucleases (RNases), the RNase T2 family is broadly distributed across kingdoms, but little has been known on its substrate specificity compared to RNase A and RNase T1 families. Class I and class II of the RNase T2 family are defined as the S-like RNase (RNS) family and have showed the connection to Pi recycling in Arabidopsis. In this study, we first carried out a phylogenetic analysis of eight rice and five Arabidopsis RNS genes and identified mono-specific class I and dicot-specific class I RNS genes, suggesting the possibility of functional diversity between class I RNS family members in monocot and dicot species through evolution. We then compared the in silico expression patterns of all RNS genes in rice and Arabidopsis under normal and Pi-deficient conditions and further confirmed the expression patterns of rice RNS genes via qRT-PCR analysis. Subsequently, we found that most of the OsRNS genes were differentially regulated under Pi-deficient treatment. Association of Pi recycling by RNase activity in rice was confirmed by measuring total RNA concentration and ribonuclease activity of shoot and root samples under Pi-sufficient or Pi-deficient treatment during 21 days. The total RNA concentrations were decreased by < 60% in shoots and < 80% in roots under Pi starvation, respectively, while ribonuclease activity increased correspondingly. We further elucidate the signaling pathway of Pi starvation through upregulation of the OsRNS genes. The 2-kb promoter region of all OsRNS genes with inducible expression patterns under Pi deficiency contains a high frequency of P1BS cis-acting regulatory element (CRE) known as the OsPHR2 binding site, suggesting that the OsRNS family is likely to be controlled by OsPHR2. Finally, the dynamic transcriptional regulation of OsRNS genes by overexpression of OsPHR2, ospho2 mutant, and overexpression of OsPT1 lines involved in Pi signaling pathway suggests the molecular basis of OsRNS family in Pi recycling via RNA decay under Pi starvation.

Lung and brain development is often altered in infants born preterm and exposed to excess oxygen, and this can lead to impaired lung function and neurocognitive abilities later in life. Oxygen-derived reactive oxygen species and the ensuing inflammatory response are believed to be an underlying cause of disease because over-expression of some anti-oxidant enzymes is protective in animal models. For example, neurodevelopment is preserved in mice that ubiquitously express human extracellular superoxide dismutase (EC-SOD) under control of an actin promoter. Similarly, oxygen-dependent changes in lung development are attenuated in transgenic SftpcEC−SOD mice that over-express EC-SOD in pulmonary alveolar epithelial type II cells. But whether anti-oxidants targeted to the lung provide protection to other organs, such as the brain is not known. Here, we use transgenic SftpcEC−SOD mice to investigate whether lung-specific expression of EC-SOD also preserves neurodevelopment following exposure to neonatal hyperoxia. Wild type and SftpcEC−SOD transgenic mice were exposed to room air or 100% oxygen between postnatal days 0–4. At 8 weeks of age, we investigated neurocognitive function as defined by novel object recognition, pathologic changes in hippocampal neurons, and microglial cell activation. Neonatal hyperoxia impaired novel object recognition memory in adult female but not male mice. Behavioral deficits were associated with microglial activation, CA1 neuron nuclear contraction, and fiber sprouting within the hilus of the dentate gyrus (DG). Over-expression of EC-SOD in the lung preserved novel object recognition and reduced the observed changes in neuronal nuclear size and myelin basic protein fiber density. It had no effect on the extent of microglial activation in the hippocampus. These findings demonstrate pulmonary expression of EC-SOD preserves short-term memory in adult female mice exposed to neonatal hyperoxia, thus suggesting anti-oxidants designed to alleviate oxygen-induced lung disease such as in preterm infants may also be neuroprotective.

PurposeOur purpose was to assess job stress and burnout among anesthesiologists in the tertiary class A hospitals in Northwest China, analyze the possible causes and adverse consequences of increased job stress and burnout of anesthesiologists in this region, and put forward suggestions in combination with the current national policies.MethodsWe sent 500 electronic questionnaires to all anesthesiologists practicing in the tertiary class A hospitals in Northwest China from 1960 to 2017 on April 2020. A total of 336 (67.2%) questionnaires were returned and could be used for analysis. Burnout and job stress were assessed by using the modified Maslach Burnout Inventory—Human Services Survey and Chinese Perceived Stress Scale, respectively.ResultsFirst, as for emotional exhaustion, the situations of anesthesiologists with different working years and workloads are different with statistical significance (P < 0.05). Second, as for depersonalization, the situations of anesthesiologists with different ages, professional titles, working years, physical health status, and workload are different (P < 0.05). Third, as for personal accomplishment, the situations of anesthesiologists with different physical health status are different (P < 0.05). Finally, the regression results showed that the longer the fatigue working years and the worse the physical health of anesthesiologists in Northwest China, the more likely these two factors were to cause burnout (P < 0.05), as for job stress, there was a negative correlation between job stress and physical health status (P < 0.05).ConclusionBurnout and high job pressure are common among anesthesiologists in tertiary class A hospitals in Northwest China. We should focus on the allocation of labor intensity, pay attention to the physical and mental health of employees, establish targeted incentive mechanism, and improve the system of promotion and income rises for grassroots doctors. This may be not only conducive to the quality of medical care for patients but also conducive to the development of anesthesiology in China.Trial registrationIdentifier: ChiCTR2000031316.

The pyrite and marcasite polymorphs of FeS2 have attracted considerable interests for their potential applications in optoelectronic devices because of their appropriate electronic and optical properties. Controversies regarding their fundamental band gaps remain in both experimental and theoretical materials research of FeS2. In this work, we present a systematic theoretical investigation into the electronic band structures of the two polymorphs by using many-body perturbation theory with the GW approximation implemented in the full-potential linearized augmented plane waves (FP-LAPW) framework. By comparing the quasi-particle (QP) band structures computed with the conventional LAPW basis and the one extended by high-energy local orbitals (HLOs), denoted as LAPW + HLOs, we find that one-shot or partially self-consistent GW (G0W0 and GW0, respectively) on top of the Perdew-Burke-Ernzerhof (PBE) generalized gradient approximation with a converged LAPW + HLOs basis is able to remedy the artifact reported in the previous GW calculations, and leads to overall good agreement with experiment for the fundamental band gaps of the two polymorphs. Density of states calculated from G0W0@PBE with the converged LAPW + HLOs basis agrees well with the energy distribution curves from photo-electron spectroscopy for pyrite. We have also investigated the performances of several hybrid functionals, which were previously shown to be able to predict band gaps of many insulating systems with accuracy close or comparable to GW. It is shown that the hybrid functionals considered in general fail badly to describe the band structures of FeS2 polymorphs. This work indicates that accurate prediction of electronic band structure of FeS2 poses a stringent test on state-of-the-art first-principles approaches, and the G0W0 method based on semi-local approximation performs well for this difficult system if it is practiced with well-converged numerical accuracy.

Due to the surge in type 2 diabetes mellitus (T2DM), treatments for chronic metabolic dysregulations with fewer side-effects are sought. Lycii Cortex (LyC), a traditional Chinese Medicine (TCM) herb has a long history of being widely prescribed to treat T2DM as alternative medicine; however, the bioactive molecules and working mechanism remained unknown. Previous studies revealed kukoamine B (KB) as a major and featured compound for LyC with bioactivities for anti-oxidation and acute inflammation, which may be related to anti-diabetes properties. This study aims to understand the efficacy and the mode of action of KB in the diabetic (db/db) mouse model using a metabolomics approach. Parallel comparison was conducted using the first-line anti-diabetic drugs, metformin and rosligtazone, as positive controls. The db/db mice were treated with KB (50 mg kg−1 day−1) for 9 weeks. Bodyweight and fasting blood glucose were monitored every 5 and 7 days, respectively. Metabolomics and high-throughput molecular approaches, including lipidomics, targeted metabolomics (Biocrates p180), and cytokine profiling were applied to measure the alteration of serum metabolites and inflammatory biomarkers between different treatments vs. control (db/db mice treated with vehicle). After 9 weeks of treatment, KB lowered blood glucose, without the adverse effects of bodyweight gain and hepatomegaly shown after rosiglitazone treatment. Lipidomics analysis revealed that KB reduced levels of circulating triglycerides, cholesterol, phosphatidylethanolamine, and increased levels of phosphatidylcholines. KB also increased acylcarnitines, and reduced systemic inflammation (cytokine array). Pathway analysis suggested that KB may regulate nuclear transcription factors (e.g., NF-κB and/or PPAR) to reduce inflammation and facilitate a shift toward metabolic and inflammatory homeostasis. Comparison of KB with first-line drugs suggests that rosiglitazone may over-regulate lipid metabolism and anti-inflammatory responses, which may be associated with adverse side effects, while metformin had less impact on lipid and anti-inflammation profiles. Our research from holistic and systemic views supports the conclusion that KB is the bioactive compound of LyC for managing T2DM, and suggests KB as a nutraceutical or a pharmaceutical candidate for T2D treatment. In addition, our research provides insights related to metformin and rosiglitazone action, beyond lowering blood glucose.