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This study aimed to assess the predictive value of tumor regression grade (TRG) and nodal status on survival in esophageal carcinoma with neoadjuvant chemoradiotherapy (nCRT).Tumor pathologic regression and nodal status were assessed. Differences in survival stratified by TRG or nodal status were analyzed using the Kaplan-Meier method and log-rank test. The prognostic value of TRG and nodal status were analyzed using univariate and multivariate Cox proportional hazards methods.From July 2016 to June 2019, 253 patients with esophageal cancer underwent nCRT followed by surgery. Significant differences were presented in survival according to nodal status but not TRG. Multivariate analysis showed that nodal status and not TRG was the only independent predicter for overall survival (HR: 3.550, 95% CI: 2.264-5.566,Lymph node status impacts more importantly than TRG on survival for patients with esophageal cancer undergoing nCRT plus esophagectomy. The modified TRG system may facilitate postoperative treatment decisions and survival surveillance.

Our research aims at the analysis of various stone scoring systems which are referred to as STONE scoring system (SSS) in this study. GUY’s scoring system and RUSS scoring system (RSS) are utilized to predict stone-free status (SFS) after surgery and problems after percutaneous nephrolithotomy (PCNL) for harder stones. The data of 68 patients with renal calculi who received FURL in Ren Ji Hospital from Jan 2020 to Mar 2021 are collected as the study subjects. There were 44 male and 24 female patients, with an average age of 55.6 ± 11.4 years. Reliability analysis of related influencing factors (IF) of stone clearance rate (SCR) and multiple scoring systems after flexible ureteroscopic lithotripsy (FURL) was performed. Relevant factors with statistical significance for postoperative SCR were selected for logistic regression analysis (RA). According to the SSS score, GSS classification, and RUSS score, the SCR after FURL was statistically analyzed. The results showed that the P values corresponding to stone position (lower caliceal), cumulative stone diameter (CSD), urinary tract infection, and external physical vibration lithecbole (EPVL) were less than 0.05. The area under the ROC curve of RUSS score, SSS score, and GSS grading was 0.932, 0.841, and 0.533, respectively. The main IF of SCR after FURL were stone location (lower caliceal), CSD, urinary tract infection, and EPVL. The RUSS score system was the best in the evaluation of SCR after FURL. In the previous research, the score systems such as CROES (CRS), SSS, S-ReS, C, and GSS for the prediction of SFS were compared. In our analysis, we have compared the RUSS scoring system which has proven to be giving better results as compared to SSS and GSS. We also performed the regression analysis and found that the stone location shows the strongest correlation of all the other factors for stone clearing rate.

With the continuous development of wireless sensor networks in the fields of industrial measurement and control, medical monitoring, and intelligent buildings, the demand for network performance is also increasing. Conventional MAC protocols used in wireless sensor networks can no longer meet the low power consumption, interference suppression, high reliability, and high throughput communication requirements of these applications. With the changes in related visual media in education, from wood boards and cards in the age of visual media to slides and projections in the age of audio-visual media, as well as the extensive development of various visual tools, visual teaching systems are all in terms of technology, environment, mode, and meaning. Visual education research in the development of video courses first needs to understand the educational function of the smart classroom, including the related concepts, research progress, and key functions of the smart classroom. At the same time, it is also necessary to clarify the theoretical principles and expression methods of video course development and their effectiveness in professional training. Finally, we can combine the advantages of the two educational institutions to design applied research and apply it to visual education in smart classrooms. This is exactly where the educational philosophy of the university political curriculum of visualized higher education policy plays an important role in running the university political curriculum of higher education policy. In the context of multiculturalism, how to deal with the new problems and new situations of the current ideals and concepts of college students, how to grasp the main problems, and how to solve the problems are a topic worthy of continuous discussion and summary.

We aimed to examine the longitudinal association between frailty and cognitive impairment in the older Chinese population. This prospective cohort study used data from the Chinese Longitudinal Healthy Longevity Study 2011 wave. We calculated the follow-up duration as 3 years from the baseline year. Frailty was measured using the frailty index, and cognitive function was calculated by Mini-Mental State Examination Scale. Participants who were non-frailty and those with normal cognitive function were included in 2011 and followed up in 2014, respectively. Frailty was an independent risk factor for early-onset cognitive impairment. Age, hearing impairment, and a decreased ability to perform daily activities were the main risk factors for cognitive impairment, while affluent economic status was a protective factor. Cognitive impairment was not found to be an independent risk factor for frailty. We concluded that the frailty index is a significant predictor of cognitive impairment among community-dwelling older adults.

The present study was conducted to evaluate the clinical, pathological response, and prognosis characteristics of human epidermal growth factor receptor 2 (HER2)-low breast cancer in the neoadjuvant chemotherapy setting.Patients with HER2-negative breast cancer who received neoadjuvant chemotherapy from January 2017 to December 2019 were retrospectively analyzed. HER2-negative breast cancer was divided into two groups: HER2-zero (defined as immunohistochemistry [IHC] 0) and HER2-low (defined as IHC 1+, or IHC 2+ and fluorescence in-situ hybridization-negative.Overall, 314 patients with HER2-negative breast cancer were analyzed. The proportion of HER2-low patients with hormone receptor (HR)-positive disease was higher than in triple-negative breast cancer (TNBC; 75.3% vs. 63.2%, p = 0.032). In HR-positive breast cancer, HER2-low tumors presented less nodal involvement (p = 0.023) and earlier clinical stage (p = 0.015) compared with HER2-zero tumors; however, in TNBC, HER2-low patients had a later clinical stage (p = 0.028). With the pathological complete response (pCR) defined as ypTis/0ypN0, there was no difference in pCR rates among the entire cohort, HR-positive disease, and TNBC. However, with the pCR defined as ypT0ypN0, the pCR rate in HER2-low breast cancer was significantly lower than HER2-zero breast cancer in the entire cohort (24.3% vs. 36.4%, p = 0.032) and the HR-positive subgroup (18.7% vs. 32.1%, p = 0.035), but not for TNBC. Multivariate analysis demonstrated that HER2 status (low vs. zero) was an independent predictive factor for pCR (p = 0.013) in HR-positive breast cancer. There were no statistically significant differences in 3-year disease-free survival and overall survival between HER2-low and HER2-zero breast cancer among the entire cohort, HR-positive disease, and TNBC.HER2-low breast cancer exhibits specific clinical features and different response to treatment associated with HR status in the neoadjuvant chemotherapy setting.

Fragile X syndrome (FXS) is a leading form of inherited intellectual disability and single-gene cause of autism spectrum disorder (ASD) and is characterized by core deficits in cognitive flexibility, sensory sensitivity, emotion, and social interactions. Motor deficits are a shared feature of FXS and autism. The cerebellum has emerged as one of the target brain areas affected by neurodevelopmental diseases. Alterations in the cerebellar structure, circuits, and function may be the key drivers of impaired fine and gross motor skills in FXS and fragile X-associated tremor/ataxia syndrome (FXTAS). In this review, we briefly examined recent findings in FXS and present a discussion on the literature supporting motor skill deficits in FXS. Subsequently, we focused on neuropathological alterations in the cerebellum in FXS and FXTAS. We highlight studies that have directly examined the function of fragile X mental retardation protein and related epigenetic variations in the cerebellum. Overall, we obtained considerable supporting evidence for the hypothesis that cerebellar dysfunction is evident in FXS and FXTAS; however, compared with studies on other ASD models, studies on motor skills related to fragile X disorders are particularly rare and inconclusive. Hence, future research should address FXS-related motor and behavioral trajectories and examine the underlying mechanisms at both the cell and circuit levels.

Few studies have reported the association between the pattern and time point of recurrence in different groups stratified by age in postoperative survival of patients with gastric cancer.The clinicopathological data and recurrence data of 2028 patients with GC who underwent curative surgery from January 2010 to March 2015 were enrolled in this study. Patients were grouped according to age: young group (YG) (≤45 years old) (n = 180) and non-young group (OG) (gt;45 years old) (n = 1848).A total of 2028 patients were enrolled. The young group had better 5-year OS and DFS than the non-young group. In peritoneal recurrence, the cumulative incidence of recurrence in YG was higher than that in OG (P lt; 0.001). In distant recurrence, the cumulative incidence of recurrence YG was always lower than that of OG (P = 0.004). Recurrence hazard function varied over time between the two groups:in the peritoneal metastasis, the recurrence hazard for YG was higher and earlier than that of OG and the YG was observed during five years after surgery with two recurrence peaks in 8.5 months and in 41.5 months. In distant recurrence, the recurrence hazard for OG had an earlier and higher single peak than that of YG (6.0 months).The recurrence characteristics of patients with gastric cancer after curative resection between young group and older group are different. Personalized follow-up strategies should be developed according to the age and time point after operation for the early detection of recurrence and making decision for further treatment.

During the first trimester of pregnancy, there is a large decrease in systemic vascular resistance (SVR) which coincides temporally with increasing extrusion of extracellular vesicles (EVs) from the placenta. We hypothesized that placental EVs may be one of the mechanisms contributing to maternal vasodilation. Macro-, micro-, nano-EVs from human first trimester placenta, or control injections containing EVs derived from fresh culture media, were injected into pregnant mice at day 12.5. After 30 min or 24 h, second order resistance arteries assessed for their reactivity to various vasomodulators. Placental EVs induced an anti-constrictive, pro-vasodilatory effect in maternal resistance arteries compared to control injections after 24 h suggesting that placental EVs may contribute to the maternal vasodilation during pregnancy.

Objective. To explore the mechanism of action of the yin nourishing and heat clearing prescription in treating cough variant asthma (CVA) based on network pharmacology (NP). Methods. The active ingredients and targets of the yin nourishing and heat clearing prescription were screened using the Traditional Chinese Medicine System Pharmacology Analysis Platform (TCMSP); CVA targets were screened by the GeneCards, NCBI gene, and OMIM databases to construct the component-target network and the protein-protein interaction (PPI) network. GO functional enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis of the target genes were performed to construct the component-disease-pathway-target biological network. Moreover, CVA-related core target structures with high values were subjected to molecular docking (MD) with the active components. Results. We found 265 eligible targets in the prescription and 1115 CVA-related genes. The medicine targets were intersected with disease targets, which yielded 148 common targets. After topology analysis, 66 key targets were screened. Upon GO functional annotation, 2408 biological processes, 153 molecular functions, and 162 KEGG pathways were enriched. Molecular docking results suggested that the major active ingredients of the prescription showed high affinity to the key targets, among which AKT1 might be the most important target. Conclusions. Active ingredients might act on AKT1, IL-6, VEGFA, IL-1B, and JUN to suppress eosinophil accumulation, decrease histamine release, suppress airway inflammation, regulate the airway immune microenvironment, increase autophagy in lung tissue, inhibit mucus production, and reduce airway resistance and hyperresponsiveness, thus treating CVA. Our findings provide a reference for further research and clinical applications of the prescription.

Vancomycin is the drug of choice in the treatment of MRSA infections. In a published vancomycin population pharmacokinetic study on neonates in Singapore healthcare institutions, it was found that vancomycin clearance was predicted by weight, postmenstrual age, and serum creatinine. The aim of this study was to externally validate the vancomycin population pharmacokinetic model to develop a new dosage regimen in neonates, and to compare this regimen with the existing institutional and NeoFaxA retrospective chart review of neonates who received vancomycin therapy and therapeutic drug monitoring was conducted. The median prediction error percentage was calculated to assess bias, while the median absolute prediction error percentage and the root mean squared error percentage were calculated to assess precision. The new dosage regimen was developed using Monte Carlo simulation.A total of 20 neonates were included in the external validation dataset. Eighteen of them were premature, with a median gestational age of 27.7 (25.9-31.5) weeks and postmenstrual age of 30.5 (27.3-34.3) weeks at the point of vancomycin initiation. No apparent systematic bias was found in the predictions of the model. The external validation performed in the current study found the model to be generally unbiased. Our new vancomycin dosage regimen was able to achieve target trough concentrations and area under the curve (AUCThe pharmacokinetic model built in the previous study can be used to conduct reliable population simulations of our Asian neonatal population in Singapore. The new dosage regimen was able to achieve target trough concentrations and AUC

BACKGROUND: Middle cerebral artery (MCA) occlusion is extremely common, especially unilateral artery, which can result in a significant incidence of cerebral infarction. OBJECTIVE: To assess the value of whole-brain computed tomography perfusion (CTP) imaging combined with dynamic CT angiography (dCTA) in the evaluation of pial collateral circulation in patients with MCA occlusion. METHODS: Whole-brain CTP and dCTA images were acquired in 58 patients with unilateral MCA occlusion. All patients were divided into three groups according to the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology (ASITN/SIR) collateral score (by CTA). The CTP parameters were analysed, including relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), relative mean transit time (rMTT), and relative time to peak (rTTP). Patients were followed up with the modified Rankin scale (mRS). All cases in this study were confirmed by DSA. RESULTS: The CTP parameters of the MCA blood supply area on the affected side of patients with different degrees of stenosis were significantly different from those on the unaffected side. There are significant differences in the CTP parameters and openings of the Willis circle in patients with different degrees of stenosis. Significant differences were found in the number of patients with good prognosis. CONCLUSIONS: Whole-brain CT perfusion combined with dynamic CTA can structurally and functionally evaluate the establishment of pial collateral circulation and its effect on cerebral hemodynamic changes.

Objectives Dry weight assessment (DWA) is an important part of dialysis and fluid management in patients receiving renal replacement therapy. With the development of bioimpedance analysis (BIA), the development of the direct segmental multi-frequency BIA (DSM–BIA) has provided a more convenient measure for DWA of dialysis patients, but its accuracy remains unclear. This study was designed to evaluate the application of DSM–BIA in DWA of continuous ambulatory peritoneal dialysis (CAPD) patients. Design This is a cross-sectional study. Using the conventional BIA as a reference, we examined the accuracy of the DSM–BIA technique for assessing dry weight in CAPD patients and analyzed the potential factors influencing their fluid volume status. Setting and participants A total of 31 patients with end-stage renal disease receiving CAPD and 310 healthy volunteers were recruited for this study. Methods The intraclass correlation coefficients (ICC) and Bland–Altman plots were used to assess the consistency between DSM–BIA and the conventional BIA for DWA. Univariate and multivariate linear regression analyses were used to explore the influencing factors associated with the edema index. Results DSM–BIA and the conventional BIA technology were consistent in DWA in CAPD patients (ICC female 0.972, ICC male 0.882, ICC total 0.960). Similarly, Bland–Altman plots showed good agreements between the two methods in DWA for both genders. Univariate and multivariate linear regression analysis showed both eGFR level (P = 0.04) and serum NT-pro BNP concentration (P = 0.007) were positively correlated with the ratio of extracellular water to total body water (ECW/TCW). Conclusions DSM–BIA in DWA has good accuracy in clinical applications and has potential application value for fluid volume management in CAPD patients.

Challenges with emotion dysregulation, self-injurious behavior (SIB), and aggression are common in autistic individuals. Prior research on the relationships between these behaviors is limited mainly to cross-sectional correlations of parent-report data. Understanding how emotion dysregulation, SIB, and aggression present and relate to one another in real-time could add to our understanding of the context and function of these behaviors. The present study examined the real-time occurrence and temporal relationships between these behaviors in 53 psychiatrically hospitalized autistic youth. Over 500 hours of behavioral observation occurred during everyday activities in the hospital. Start and stop times for instances of overt emotion dysregulation, SIB, and aggression were coded live using a custom mobile phone app. Results indicated large individual variability in the frequency and duration of these behaviors and their co-occurrence. Both SIB and aggression co-occurred with overt emotion dysregulation at above-chance levels, suggesting a role for emotional distress in the occurrence of these behaviors. However, there was substantial variability within and between individuals in co-occurrence, and SIB and aggression often (and for some individuals, almost always) occurred without overt emotion dysregulation. Relatedly, cross-recurrence quantitative analysis revealed that SIB and aggression preceded emotion dysregulation more often than emotion dysregulation preceded SIB and aggression. Future research, perhaps using ambulatory psychophysiological measures, is needed to understand whether emotion dysregulation may sometimes be present but not easily observed during SIB and aggression. LAY SUMMARY: This study provides insight into how overt emotion dysregulation (i.e., visible distress), aggression, and self-injury unfold in real-time for autistic individuals. Participants were 53 autistic youth staying in a psychiatric hospital. Research staff observed participants in everyday activities on the hospital unit and noted instances of aggression, self-injurious behavior, and emotion dysregulation. Results suggest that aggression and self-injury sometimes occur with visible signs of distress but also often occur without visible distress. In addition, observable distress was more common in the moments after these behaviors than in the moments before.

Non-obstructive azoospermia (NOA) is one of the most severe forms of male infertility, but its diagnosis biomarkers with high sensitivity and specificity are largely unknown. Transcription factors (TFs) play essential roles in many pathological processes in different diseases. Herein, we aimed to identify the TFs showing high diagnosis ability for NOA through machine learning algorithms. The transcriptome data of the testicular tissue from 11 control and 47 NOA subjects were set as the training dataset; meanwhile, 1665 TFs were retrieved from the HumanTFDB. Through the feature extraction methods, including genomic difference analysis, Lasso, Boruta, SVM-RFE, and logistic regression, ETV2, TBX2, and ZNF689 were ultimately screened and then were included in the random forest (RF) diagnosis model. The RF model displayed high predictive power in the training (F-measure = 1) and two external validation (n = 31, F-measure = 0.902; n = 20, F-measure = 0.941) cohorts. The seminal plasma and testicular biopsy samples of 20 control and 20 NOA patients were collected from the local hospital, and the expression levels of ETV2, TBX2, and ZNF689 were measured via RT-qPCR and immunohistochemistry. The RF model could also distinguish the NOA samples in the local cohort (F-measure = 0.741). Single-cell RNA sequencing analysis, which was based on the 432 testicular cell samples from an NOA patient, showed that ETV2, TBX2, and ZNF689 were all significantly associated with spermatogenesis. In all, a 3-TF random forest diagnosis model was successfully established, providing novel insights into the latent mechanisms of NOA.

Rapid glycolysis of tumor cells produces excessive lactate to trigger acidification of the tumor microenvironment (TME), leading to the formation of immunosuppressive TME and tumor-associated macrophage (TAM) dysfunction. Therefore, reprogramming TAMs by depleting lactate with nanodrugs is expected to serve as an effective means of tumor-targeted immunotherapy. Herein, we report the use of lactic acid dehydrogenase (LDH)-mimicking SnSe nanosheets (SnSe NSs) loaded with a carbonic anhydrase IX (CAIX) inhibitor to reconstruct an acidic and immunosuppressive TME. As expected, this nanosystem could reprogram the TAM to achieve M1 macrophage activation and could also restore the potent tumor-killing activity of macrophages while switching their metabolic mode from mitochondrial oxidative phosphorylation to glycolysis. In addition, the repolarizing effect of SnSe NSs on macrophages was validated in a coculture model of bone marrow-derived macrophages, in three patient-derived malignant pleural effusion and in vivo mouse model. This study proposes a feasible therapeutic strategy for depleting lactate and thus ameliorating acidic TME employing Se-containing nanosheets, which could further amply the effects of TAM-based antitumor immunotherapy.

Circular RNAs (circRNAs) have been verified as vital regulators in various diseases, including membranous nephropathy (MN). Therefore, the role of circ_CDYL in podocyte apoptosis and MN was investigated. The real-time quantitative polymerase chain reaction was performed to measure the expression of circ_CDYL, microRNA-149-5p (miR-149-5p), and tumor necrosis factor superfamily member 11 (TNFSF11) in podocytes. In addition, angiotensin II (Ang II) was used to induce apoptosis of podocytes. The apoptosis-related protein expression was quantified by western blot assay. The apoptosis of podocytes was evaluated by flow cytometry assay. The interaction relationship between miR-149-5p and circ_CDYL or TNFSF11 was confirmed by dual-luciferase reporter assay. Circ_CDYL was significantly overexpressed in MN patients and Ang II-induced podocytes compared with control groups. Importantly, loss-of-functional experiments indicated that knockdown of circ_CDYL protected podocytes from Ang II-induced apoptosis. MiR-149-5p was verified as target of circ_CDYL and negatively correlated with circ_CDYL expression in MN patients. Knockdown of circ_CDYL-mediated effects on Ang II-induced podocyte cells were abolished by silencing miR-149-5p. Besides, the upregulation of miR-149-5p could suppress apoptosis in Ang II-induced podocyte cells by targeting TNFSF11. Under Ang II stimulation, the upregulation of TNFSF11 could increase the expression of TNFSF11 and induce apoptosis in circ_CDYL-silencing podocytes. Our results confirmed that circ_CDYL specifically targeted miR-149-5p/TNFSF11 pathway to regulate Ang II-induced apoptosis in podocytes, which might be useful diagnostic biomarkers in MN.

Due to respiratory motion, precise tracking of lung nodule movement is a persistent challenge for guiding percutaneous lung biopsy during image-guided intervention. We developed an automated image-guided system incorporating effective and robust tracking algorithms to address this challenge. Accurate lung motion prediction and personalized image-guided intervention are the key technological contributions of this work.A patient-specific respiratory motion model is developed to predict pulmonary movements of individual patients. It is based on the relation between the artificial 4D CT and corresponding positions tracked by position sensors attached on the chest using an electromagnetic (EM) tracking system. The 4D CT image of the thorax during breathing is calculated through deformable registration of two 3D CT scans acquired at inspiratory and expiratory breath-hold. The robustness and accuracy of the image-guided intervention system were assessed on a static thorax phantom under different clinical parametric combinations.Real 4D CT images of ten patients were used to evaluate the accuracy of the respiratory motion model. The mean error of the model in different breathing phases was 1.59 ± 0.66 mm. Using a static thorax phantom, we achieved an average targeting accuracy of 3.18 ± 1.2 mm across 50 independent tests with different intervention parameters. The positive results demonstrate the robustness and accuracy of our system for personalized lung cancer intervention.The proposed system integrates a patient-specific respiratory motion compensation model to reduce the effect of respiratory motion during percutaneous lung biopsy and help interventional radiologists target the lesion efficiently. Our preclinical studies indicate that the image-guided system has the ability to accurately predict and track lung nodules of individual patients and has the potential for use in the diagnosis and treatment of early stage lung cancer.

Purpose We developed an augmentation technique for PCL reconstruction with independent internal brace reinforcement and evaluated the functional outcome after PCL reconstruction employing autologous hamstrings augmented with an internal brace system for patients with isolated or combined grade 3 posterior instability who were treated with this technique. Methods From January 2016 to January 2018, patients with isolated or combined grade 3 PCL tears who underwent single-bundle PCL reconstruction using autologous hamstrings augmented with independent internal braces were studied. The function of the operated knee was evaluated according to the International Knee Documentation Committee (IKDC) score, Lysholm score, and Tegner activity score. The patients were asked the level of returned to their previous sport. Posterior knee laxity was examined with a KT-1000 arthrometer, and data on range of motion (ROM), re-operation, and other complications were collected. Results A total of 33 consecutive patients who received single-bundle PCL reconstruction using autologous hamstrings augmented with independent internal braces with a minimum two years follow-up were included in this study. Two patients had undergone this procedure during the study period and were not included in this study (one had combined bone fractures, and one patient had previous meniscus surgery). Thirty-one patients were available for final analysis. The mean follow-up was 45.35 ± 10.88 months (range 29–66 months). The average IKDC subjective knee evaluation scores from 51.65 ± 12.35 to 84.52 ± 6.42, the Lysholm score from 53.90 ± 11.86 to 85.68 ± 4.99, and the Tegner score from 2.81 ± 0.79 to 6.71 ± 1.83 (P P Conclusion Single-bundle PCL reconstruction with internal brace augmentation for PCL injury exhibited satisfactory posterior stability and clinical outcomes in patients with isolated or combined grade 3 PCL injuries at a minimum two year follow-up.

Chronic kidney disease (CKD) is a global public health problem and one of the leading causes of all-cause mortality. However, the pathogenic mechanisms and intervention methods for CKD progression are not fully understood.Plasma from patients with uraemia and from healthy controls (n = 30 per group) was analysed with LC-MS/MS-based non-targeted metabolomics to identify potential markers of uraemia. These potential markers were validated in the same cohort and a second cohort (n = 195) by quantitative analysis of the markers, using LC-MS/MS. The most promising marker was identified by correlation analysis and further validated using HK-2 cells and mouse models.Trimethylamine N-oxide (TMAO) was identified as a promising marker among the 18 potential markers found in the first cohort, and it was optimally correlated with renal function of CKD patients in the second cohort. Treatment of HK-2 cells with TMAO decreased cell viability and up-regulated expression of α-smooth muscle actin. In mice, a TMAO-containing diet decreased kidney mass and increased protein expression of α-smooth muscle actin. Also, control of TMAO production by inhibiting its biosynthetic pathway with 3,3-dimethyl-1-butanol or disrupting gut microbiota function with an antibiotic cocktail, attenuated renal injury in a murine model of CKD.Our data show that decreased TMAO production could be a new strategy to attenuate the progression of renal injury in CKD.

Xiao-Qi Chen,* Yun-Xia Zhao,* Chuan-Lei Zhang, Xin-Ting Wang, Xin Zhang, Xi Chen, Chang-Wei Yuan, Qing Zhao, Xin-Ju Chen Department of Gastroenterology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, Zhengzhou, Henan, 450000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xin-Ju Chen, Department of Gastroenterology, The First Affiliated Hospital of Henan University of Traditional Chinese Medicine, No. 19, Renmin Road, Jinshui District, Zhengzhou, Henan, 450000, People’s Republic of China, Tel +86-13700867158, Email chxj888@163.comPurpose: Anlotinib, a novel multi-target tyrosine kinase inhibitor, has shown encouraging antitumor effects in advanced hepatocellular carcinoma (HCC). This study evaluated the effectiveness and safety of anlotinib with or without programmed death-1 (PD-1) blockades for patients with advanced primary HCC in a real-world setting in China.Patients and Methods: Between July 2019 and May 2021, 27 patients with advanced primary HCC who received at least 2 cycles of anlotinib were included in this retrospective study. Primary endpoint was objective response rate (ORR). Secondary endpoints were disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety.Results: Of the 27 patients, ORR and DCR were 25.93% and 74.07%, respectively. The median follow-up time was 6.27 months (range: 1.30– 17.40) with a median PFS and OS of 3.29 months (95% CI: 1.31– 15.47) and 6.21 months (95% CI: 2.23– 15.87), respectively. A total of 14 patients received anlotinib and PD-1 blockade combination therapy, and 13 received anlotinib monotherapy. No significant differences were observed in ORR (28.57 vs 23.08%), DCR (71.43 vs 76.92%), PFS (3.38 [95% CI: 2.66– 13.14] vs 11.86 months [95% CI: 4.27– 15.93]) and OS (4.90 [95% CI: 2.56– 13.60] vs 11.04 months [95% CI: 1.31– 17.18]) between the two groups (all p> 0.05). Treatment-related AEs were reported in 88.89% of patients. Grade 3 AE was bleeding, which occurred in 3 patients (11.11%).Conclusion: Anlotinib yielded a promising efficacy and manageable safety in patients with advanced primary HCC irrespective of whether patients received PD-1 blockades, indicating that anlotinib might be a promising treatment option for this patient population.Keywords: anlotinib, objective response rate, PD-1 blockades, primary hepatocellular carcinoma

PURPOSE/BACKGROUND: Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics. METHODS/PROCEDURES: We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants–antipsychotics in the U.S. Food and Drug Administration (FDA) Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants–antipsychotics through January 13, 2020. FINDINGS/RESULTS: We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants–antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n=23, 64%), followed by amphetamine products (n=9, 25%), and atomoxetine (n=4, 11%). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n=20, 56%). Most of the cases were reported in males (n=31, 86%) aged 6–12 years (n=27, 75%). Approximately 53% of the cases reported a time-to-onset within 24 hours of the drug change. Acute dystonic reactions (n=27, 75%) were the most frequently reported movement disorder. IMPLICATIONS/CONCLUSIONS: As outlined in changes to the U.S. prescribing information for all methylphenidate and risperidone products, healthcare professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder.

A major threat to rice production is the disease epidemics caused by insect-borne viruses that emerge and re-emerge with undefined origins. It is well known that some human viruses have zoonotic origins from wild animals. However, it remains unknown whether native plants host uncharacterized endemic viruses with spillover potential to rice (Oryza sativa) as emerging pathogens. Here, we discovered rice tiller inhibition virus (RTIV), a novel RNA virus species, from colonies of Asian wild rice (O. rufipogon) in a genetic reserve by metagenomic sequencing. We identified the specific aphid vector that is able to transmit RTIV and found that RTIV would cause low-tillering disease in rice cultivar after transmission. We further demonstrated that an infectious molecular clone of RTIV initiated systemic infection and causes low-tillering disease in an elite rice variety after Agrobacterium-mediated inoculation or stable plant transformation, and RTIV can also be transmitted from transgenic rice plant through its aphid vector to cause disease. Finally, global transcriptome analysis indicated that RTIV may disturb defense and tillering pathway to cause low tillering disease in rice cultivar. Thus, our results show that new rice viral pathogens can emerge from native habitats, and RTIV, a rare aphid-transmitted rice viral pathogen from native wild rice, can threaten the production of rice cultivar after spillover.

Multiple myeloma (MM) is a malignant plasma cancer which remains difficult to be cured. Recently, numerous research studies have appeared, exploring MM from molecular level. However, there is no study about the impact of metabotropic glutamate receptors (mGluRs), especially mGluR5, on MM progression. Thus, the present research was dedicated to the exploration of the influence of mGluR5 on MM.In this research, we used quantitative real-time polymerase chain reaction (qRT-PCR) to check the gene expression in MM, western blot assay to check the protein expression of the gene, MTT assay to quantify the cell viability, and flow cytometry (FCM) apoptosis method to evaluate cell apoptosis in order to acquire the results. The purpose was to assess the role of mGluR5 in MM cells.The qRT-PCR was used and it was found that mGluR5 was overexpressed in MM cell lines and MM tissues compared to normal ones. To better observe the function of mGluR5 in MM, cell viability and apoptosis were checked using MTT and FCM apoptosis assays after the treatment with agonists and antagonists.Agonist-induced mGluR5 upregulation could promote MM cell viability and inhibit apoptosis. The same results were obtained through MTT and FCM apoptosis assays after upregulation and downregulation of mGluR5 by transfection. To further investigate the inner mechanism, the effect of mGluR5 on Ras-MAPK pathway was checked using western blot. It was found that the upregulation of mGluR5 could activate the Ras-MAPK pathway.The mGluR5 might be involved in promoting cell proliferation and inhibiting cell apoptosis in MM. It can be an essential biomarker in the screening for MM and a potential part of future MM therapies.

The COVID-19 pandemic has exacerbated disparities in access to healthcare and mental health, often forcing healthcare social workers into ethical and moral dilemmas as they endeavor to provide equitable, humanistic care to their patients and caregivers. The purpose of this mixed method study was to explore how COVID-19-related personal and professional grief and losses impacted healthcare social worker's distress and resilience. Participants were recruited through healthcare social work professional organizations from September-November 2020. Participants (

Model complexity has a close relationship with the generalization ability and the interpretability of the learned models. Simple models are more likely to generalize well and easy to interpret. However, too much emphasis on minimizing complexity can prevent the discovery of more complex yet more accurate solutions. Genetic programming (GP) has a trend of generating overcomplex models that are difficult to interpret while not being able to generalize well. This work proposes a novel complexity measure based on the Rademacher complexity for GP for symbolic regression. The complexity of an evolved model is measured by the maximum correlation between the model and the Rademacher variables on the selected training instances. Taking minimizing the training error and the Rademacher complexity of the models as the two objectives, the proposed GP method has shown to be much superior to the standard GP on generalization performance. Compared with GP equipped with two state-of-the-art complexity measures, the proposed method still has a notable advance on generating a better front consisting of individuals with lower generalization errors and being simpler in the behavioral complexity. Further analyses reveal that compared with the state-of-the-art methods, the proposed GP method evolves models that are much closer to the target models in the model structure, and have better interpretability. © 2020 IEEE. Personal use of this material is permitted. Permission from IEEE must be obtained for all other uses, in any current or future media, including reprinting/republishing this material for advertising or promotional purposes, creating new collective works, for resale or redistribution to servers or lists, or reuse of any copyrighted component of this work in other works

Therapies based on immune checkpoint inhibitors (ICIs) are transforming the treatment landscape of urologic oncology. Nevertheless, an exhaustive overview of the toxicity spectrum of these novel therapies has yet to be provided.To comprehensively investigate the incidence and profile of ICI therapy-related adverse events (AEs) across urologic cancers.We searched for all clinical trials investigating the role of ICI therapy published between January 2010 and September 2021. Studies involving urologic cancers with reported overall incidence or tabulated data of treatment-related AEs (trAEs) or immune-related AEs (irAEs) were included. A systematic review and meta-analysis was performed after protocol registration in PROSPERO (CRD42021276435).We identified 2638 records, of which 92 studies (including 22942 participants) met the inclusion criteria. The pooled overall incidence was 81.6% (95% confidence interval [CI] 78.0-84.7) for any-grade trAEs and 29.3% (95% CI 24.9-34.1) for grade ≥3 trAEs. The pooled overall incidence was 34.3% (95% CI 28.5-40.7) for any-grade irAEs and 10.2% (95%CI 8.2-12.7) for grade ≥3 irAEs. On a multivariable analysis, cancer type, therapy combination, clinical settings (perioperative vs advanced/metastatic), and drug exposure were independently associated with the occurrence of trAEs or irAEs. The overall rate of treatment-related mortality was 0.94% (140 of 14 899 participants), with pneumonitis (9.3%), pneumonia (7.9%), and respiratory failure (7.1%) being the most common causes. Immune-related mortality occurred in 0.26% (28 of 10 723) patients, with pneumonitis (35.7%), hepatic failure (10.7%), and hepatitis (7.1%) being most common.Our study provides a comprehensive overview of ICI-associated AEs in urologic cancer patients. The spectrum and incidence of AEs vary across cancer types, ICI types, clinical settings, and therapy combinations. These findings provide important guidance to clinicians in counseling and management of patients with urologic cancers.A high proportion of patients experience immune checkpoint inhibitor-associated toxicity. Physician and patient education is critical for early recognition and proper management.

SARS-CoV-2 has evolved into a panel of variants of concern (VOCs) and constituted a sustained threat to global health. The wildtype (WT) SARS-CoV-2 isolates fail to infect mice, while the Beta variant, one of the VOCs, has acquired the capability to infect standard laboratory mice, raising a spreading risk of SARS-CoV-2 from humans to mice. However, the infectivity and pathogenicity of other VOCs in mice remain not fully understood. In this study, we systematically investigated the infectivity and pathogenicity of three VOCs, Alpha, Beta, and Delta, in mice in comparison with two well-understood SARS-CoV-2 mouse-adapted strains, MASCp6 and MASCp36, sharing key mutations in the receptor-binding domain (RBD) with Alpha or Beta, respectively. Our results showed that the Beta variant had the strongest infectivity and pathogenicity among the three VOCs, while the Delta variant only caused limited replication and mild pathogenic changes in the mouse lung, which is much weaker than what the Alpha variant did. Meanwhile, Alpha showed comparable infectivity in lungs in comparison with MASCp6, and Beta only showed slightly lower infectivity in lungs when compared with MASCp36. These results indicated that all three VOCs have acquired the capability to infect mice, highlighting the ongoing spillover risk of SARS-CoV-2 from humans to mice during the continued evolution of SARS-CoV-2, and that the key amino acid mutations in the RBD of mouse-adapted strains may be referenced as an early-warning indicator for predicting the spillover risk of newly emerging SARS-CoV-2 variants.

Alpha fetoprotein (AFP) is an important biomarker for diagnosis of hepatocellular carcinoma (HCC). Whereas, it is always a challenge to detect trace AFP in serum. In this work, a ratiometric fluorescence enzyme immunoassay (RFEIA) was developed using nanobody-alkaline phosphatase (Nb-AP) heptamer and MnFe layered double hydroxides nanoflakes (MnFe LDH) for ultrasensitive detection of AFP. The Nb-AP heptamer (Nb-C4bpα-AP) was constructed by fusion expression of Nb, AP, and α-chain of C4 binding protein (C4bpα), where the C4bpα contributed to multimerization through self-assembly. The dual functional Nb-C4bpα-AP can recognize AFP, dephosphorylate ascorbic acid-2-phosphate (AAP) into ascorbic acid (AA), and thus tune the MnFe LDH-mediated ratiometric fluorescence, which was generated from the oxidization of MnFe LDH on o-phenylenediamine (OPD) and the catalyzation of MnFe LDH on the cyclization reaction between AA and OPD. By integration of Nb-C4bpα-AP, MnFe LDH, AAP, and OPD, the RFEIA showed a limit of detection of 0.013 ng/mL with good selectivity, accuracy and precision. Furthermore, results of clinical serum samples tested by the RFEIA were well confirmed by the automated chemiluminescence immunoassay analyzer. Thus, this work demonstrated that the Nb-C4bpα-AP is a robust immunoreagent and the developed RFEIA could be a very promising tool for diagnosis of HCC.

Cleidocranial dysplasia (CCD) represents a rare autosomal dominant skeletal dysplasia caused by mutations that induce haploinsufficiency in RUNX2, the important transcription factor of osteoblasts related to bone/cartilage development and maintenance. Clavicular hypoplasia, which involves aberrant tooth/craniofacial bone/skeletal formation, is a feature of classic CCD. RUNX2 mutations can be found in approximately 60-70% of patients with CCD, and around ∼10% of these mutations are microdeletions. The present paper describes the radiological and clinical characteristics of a 5-year-old girl who showed representative CCD features, including extra teeth, aplasia of clavicles, sloping shoulders, marked calvarial hypomineralization, and osteoporosis.We obtained genomic DNA of her family members and performed whole-genome sequencing (WGS) for samples collected from the proband. Quantitative fluorescent PCR (QF-PCR) and specific PCR plus electrophoresis were then performed as validation assays for all participants. In vitro analysis was performed. Luciferase assay for Runx2 transcription activity and evaluation of mRNA levels of Runx2 downstream osteogenic markers were conducted.WGS identified a 11.38-kb microdeletion in RUNX2 comprising 8-9 exons, which was validated by QF-PCR and specific PCR plus electrophoresis. In vitro experiments confirmed the pathogenicity of this variation.The present study identified a 11.38-kb microdeletion in RUNX2 that causes CCD. The deletion in the PST domain of RUNX2 reduces its transcription activity and reduces osteogenic marker levels, eventually decreasing the differentiation of osteoblasts. These findings clarify the role of the CCD-related mechanism in the development of CCD and suggest that it is important to consider copy number variation for the suspected familial patients early.

Influenza A viruses possess a high antigenic shift, and the approved anti-influenza drugs are extremely limited, which makes the development of novel anti-influenza drugs for the clinical treatment and prevention of influenza outbreaks imperative. Herein, we report a series of novel aryl benzoyl hydrazide analogs as potent anti-influenza agents. Particularly, analogs

Monoclonal antibodies represent important weapons in our arsenal to against the COVID-19 pandemic. However, this potential is severely limited by the time-consuming process of developing effective antibodies and the relative high cost of manufacturing. Herein, we present a rapid and cost-effective lipid nanoparticle (LNP) encapsulated-mRNA platform for in vivo delivery of SARS-CoV-2 neutralization antibodies. Two mRNAs encoding the light and heavy chains of a potent SARS-CoV-2 neutralizing antibody HB27, which is currently being evaluated in clinical trials, were encapsulated into clinical grade LNP formulations (named as mRNA-HB27-LNP). In vivo characterization demonstrated that intravenous administration of mRNA-HB27-LNP in mice resulted in a longer circulating half-life compared with the original HB27 antibody in protein format. More importantly, a single prophylactic administration of mRNA-HB27-LNP provided protection against SARS-CoV-2 challenge in mice at 1, 7 and even 63 days post administration. In a close contact transmission model, prophylactic administration of mRNA-HB27-LNP prevented SARS-CoV-2 infection between hamsters in a dose-dependent manner. Overall, our results demonstrate a superior long-term protection against SARS-CoV-2 conferred by a single administration of this unique mRNA antibody, highlighting the potential of this universal platform for antibody-based disease prevention and therapy against COVID-19 as well as a variety of other infectious diseases.

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD), are characterized by the progressive degeneration of neurons. Although the etiology and pathogenesis of neurodegenerative diseases have been studied intensively, the mechanism is still in its infancy. In general, most neurodegenerative diseases share common molecular mechanisms, and multiple risks interact and promote the pathologic process of neurogenerative diseases. At present, most of the approved drugs only alleviate the clinical symptoms but fail to cure neurodegenerative diseases. Numerous studies indicate that dietary plant polyphenols are safe and exhibit potent neuroprotective effects in various neurodegenerative diseases. However, low bioavailability is the biggest obstacle for polyphenol that largely limits its adoption from evidence into clinical practice. In this review, we summarized the widely recognized mechanisms associated with neurodegenerative diseases, such as misfolded proteins, mitochondrial dysfunction, oxidative damage, and neuroinflammatory responses. In addition, we summarized the research advances about the neuroprotective effect of the most widely reported dietary plant polyphenols. Moreover, we discussed the current clinical study and application of polyphenols and the factors that result in low bioavailability, such as poor stability and low permeability across the blood-brain barrier (BBB). In the future, the improvement of absorption and stability, modification of structure and formulation, and the combination therapy will provide more opportunities from the laboratory into the clinic for polyphenols. Lastly, we hope that the present review will encourage further researches on natural dietary polyphenols in the treatment of neurodegenerative diseases.

Results from recently completed clinical studies suggest the dopamine D1 receptor positive allosteric modulator (PAM) mevidalen (

A boron-dipyrromethene (BODIPY)-based fluorescent probe, BDP-CN, was synthesized in this work. It had a fluorescence emission maximum at 512 nm and a high quantum yield (48%). As evidenced by agarose gel electrophoresis and liquid chromatography-mass spectrometry, it could realize the fluorescent labeling of human serum albumin (HSA) through a thiol-cyanimide addition. Interestingly, f-HSA, defined as HSA labeled by BDP-CN, had an even higher quantum yield (77%). In addition, BDP-CN would not affect the secondary structure of HSA. Based on the successful formation of f-HSA, it was further applied to study the interactions with nanoparticles. The fluorescence quenching of f-HSA by dihydrolipoic acid-coated gold nanoclusters (DHLA-AuNCs) obeyed a dynamic mechanism, consistent with the intrinsic fluorescence quenching of HSA by DHLA-AuNCs. The association constant

Background: Early cardiovascular impairment in obstructive sleep apnea (OSA) patients is often overlooked, leading to irreversible outcome. Left ventricular (LV) global longitudinal strain (GLS) derived from automated function imaging (AFI) echocardiography provides a fast tool to assess global longitudinal function. We therefore aimed to compare the feasibility and reproducibility of AFI with mitral annulus plane systolic excursion (MAPSE) as obesity is common in OSA. Methods: A comprehensive echocardiographic examination was done in 186 consecutive patients having polysomnography for suspected OSA in this prospective study. MAPSE was measured by using M-mode. AFI was derived by offline analysis of three long-axis views that semi-automatically detects LV endocardial boundary, which is adjusted manually as necessary. Variability of AFI and MAPSE were compared among the different subgroups and further tested in BMI subgroups. Results: Despite a relatively high obesity rate (42.9%), AFI was feasible in 94% (175/186) patients and MAPSE could be recorded in all patients. Although more segments were measured with AFI it showed excellent correlation (r=0.882) superior to MAPSE (r=0.819) between the expert and beginner. Intra- and inter- observer variability of AFI were comparable with MAPSE in Bland-Altman analysis, 5.5% and 6.5% for AFI, 6.2% and 8.8% for MAPSE, respectively. In repeated measurements, AFI showed higher intra-class correlation (ICC=0.95) than MAPSE (ICC=0.87). Furthermore, analysis showed that AFI was feasible even in more obese patients (BMI≥28kg/m2). Conclusions: Even in obese patients with OSA, AFI-GLS is feasible and more reliable for less expert operators than MAPSE for detecting LV longitudinal dysfunction.

We launched a retrospective cohort study to explore the interactions among serum uric acid (UA), urine UA, and stone types.Clinical characteristics of urolithiasis patients in Beijing Tsinghua Changgung Hospital from October 2015 to August 2017 were retrospectively collected. Participants were categorized according to the quartiles of SUA and UUA respectively. Logistic regression model was built to identify the relationship between stone composition and UA level. Cubic spline was fitted to explore the correlation between 24-h urine UA and serum UA.718 hospitalized patients (51.1 ± 14.3 years, male 63.4%) with urinary calculi were included. Higher serum UA is associated with male, alcohol use, multiple serum and urine electrolytes (e.g. potassium, chloride, calcium, phosphorus), and lower estimated glomerular filtration rate. The risk of UA stone and carbonate apatite stone was associated with serum UA while the risk of calcium oxalate (CaOx) stone and ammonium magnesium hexahydrate (AMH) was dependent on urine UA. In the unadjusted model (Model 1), higher risks of UA stones were observed in the third quartile (OR 3.26, 95% CIs 1.63-6.53, P = 0.001) and the fourth quartile (OR 3.55, 95% CIs 1.78-7.08, P 0.001) of serum UA compared with the first quartile. The risks of carbonate apatite stone were lowered in the third (OR 0.48, 95% CIs 0.31-0.73, P = 0.001) and fourth quartile (OR 0.40, 95% CIs 0.42-0.98, P = 0.042) of serum UA. The risk of CaOx stone was increased in the fourth quartile (OR 2.14, 95% CIs 1.15-3.99, P = 0.017) while the risk of AMH stone was decreased in the third (OR 0.46, 95% CIs 0.22-0.94, P = 0.034) and fourth quartile (OR 0.35, 95% CIs 0.16-0.78, P = 0.009) of urine UA. The elevated risks of UA stones in high levels of serum UA were demonstrated in the adjusted model (Model 2). An M-shaped association was found between serum UA and urine UA in our population.Serum UA and urine UA might cast different impact on urinary calculus composition. Proper control of the parameters should be considered based on different predisposing factors in individual patients.

Left bundle branch area pacing (LBBAP) has developed in an effort to improve cardiac resynchronization therapy (CRT). We aimed to compare the long-term clinical outcomes between LBBAP and biventricular pacing (BIVP) in patients with heart failure (HF) and complete left bundle branch block (CLBBB). Consecutive patients with HF and CLBBB requiring CRT received either LBBAP or BIVP were recruited at the Second Affiliated Hospital of Nanchang University from February 2018 to May 2019. We assessed their implant parameters, electrocardiogram (ECG), clinical outcomes at implant and during follow-up at 1, 3, 6, 12, and 24 months. Forty-one patients recruited including 21 for LBBAP and 20 for BIVP. Mean follow-up duration was 23.71 ± 4.44 months. LBBAP produced lower pacing thresholds, shorter procedure time and fluoroscopy duration compared to BIVP. The QRS duration was significantly narrower after LBBAP than BIVP (129.29 ± 31.46 vs. 156.85 ± 26.37 ms, p = 0.005). Notably, both LBBAP and BIVP significantly improved LVEF, LVEDD, NYHA class, and BNP compared with baseline. However, LBBAP significantly lowered BNP compared with BIVP (416.69 ± 411.39 vs. 96.07 ± 788.71 pg/ml, p = 0.007) from baseline to 24-month follow-up. Moreover, patients who received LBBAP exhibited lower number of hospitalizations than those in the BIVP group (p = 0.019). In addition, we found that patients with moderately prolonged left ventricular activation time (LVAT) and QRS notching in limb leads in baseline ECG respond better to LBBAP for CLBBB correction. LBBAP might be a relative safe and effective resynchronization therapy and as a supplement to BIVP for patients with HF and CLBBB.

Severe cases of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with elevated blood glucose levels and metabolic complications. However, the molecular mechanisms for how SARS-CoV-2 infection alters glycometabolic control are incompletely understood. Here, we connect the circulating protein GP73 with enhanced hepatic gluconeogenesis during SARS-CoV-2 infection. We first demonstrate that GP73 secretion is induced in multiple tissues upon fasting and that GP73 stimulates hepatic gluconeogenesis through the cAMP/PKA signaling pathway. We further show that GP73 secretion is increased in cultured cells infected with SARS-CoV-2, after overexpression of SARS-CoV-2 nucleocapsid and spike proteins and in lungs and livers of mice infected with a mouse-adapted SARS-CoV-2 strain. GP73 blockade with an antibody inhibits excessive glucogenesis stimulated by SARS-CoV-2 in vitro and lowers elevated fasting blood glucose levels in infected mice. In patients with COVID-19, plasma GP73 levels are elevated and positively correlate with blood glucose levels. Our data suggest that GP73 is a glucogenic hormone that likely contributes to SARS-CoV-2-induced abnormalities in systemic glucose metabolism.

The SARS-CoV-2 pandemic has become a severe global public health event, and the development of protective and therapeutic strategies is urgently needed. Downregulation of angiotensin converting enzyme 2 (ACE2; one of the important SARS-CoV-2 entry receptors) and aberrant inflammatory responses (cytokine storm) are the main targets to inhibit and control COVID-19 invasion. Silver nanomaterials have well-known pharmaceutical properties, including antiviral, antibacterial, and anticancer properties. Here, based on a self-established metal evaporation-condensation-size graded collection system, smaller silver particles reaching the Ångstrom scale (AgÅPs) were fabricated and coated with fructose to obtain a stabilized AgÅP solution (F-AgÅPs). F-AgÅPs potently inactivated SARS-CoV-2 and prevented viral infection. Considering the application of anti-SARS-CoV-2, a sterilized F-AgÅP solution was produced

Background Postoperative renal function impairment represents a main limitation for delivering adjuvant chemotherapy after radical nephroureterectomy (RNU). Objective To create a model predicting renal function decline after minimally invasive RNU. Design, setting, and participants A total of 490 patients with nonmetastatic UTUC who underwent minimally invasive RNU were identified from a collaborative database including 17 institutions worldwide (February 2006 to March 2020). Renal function insufficiency for cisplatin-based regimen was defined as estimated glomerular filtration rate (eGFR) 50 ml/min/1.73 m2 (n = 361) were geographically divided into a training set (n = 226) and an independent external validation set (n = 135) for further analysis. Outcome measurements and statistical analysis Using transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD) guidelines, a nomogram to predict postoperative eGFR Results and limitations The model that incorporated age, body mass index, preoperative eGFR, and hydroureteronephrosis was developed with an area under the curve of 0.771, which was confirmed to be 0.773 in the external validation set. The calibration curve demonstrated good agreement. Besides, the model was converted into a risk score with a cutoff value of 0.583, and the difference between the low- and high-risk groups both in overall death risk (hazard ratio [HR]: 4.59, p Conclusions A nomogram incorporating immediately available clinical variables can accurately predict renal insufficiency for cisplatin-based adjuvant chemotherapy after minimally invasive RNU and may serve as a tool facilitating patient selection. Patient summary We have developed a model for the prediction of renal function loss after radical nephroureterectomy to facilitate patient selection for perioperative chemotherapy.

Tinea capitis is still common in developing countries, such as China. Its pathogen spectrum varies across regions and changes over time.This study aimed to clarify the current epidemiological characteristics and pathogen spectrum of tinea capitis in China.A multicentre, prospective descriptive study involving 29 tertiary hospitals in China was conducted. From August 2019 to July 2020, 611 patients with tinea capitis were enrolled. Data concerning demography, risk factors and fungal tests were collected. When necessary, the pathogens were further identified by morphology or molecular sequencing in the central laboratory.Among all enrolled patients, 74·1% of the cases were in patients aged 2-8 years. The children with tinea capitis were mainly boys (56·2%) and were more likely than adults to have a history of animal contact (57·4% vs. 35·3%, P = 0·012) and zoophilic dermatophyte infection (73·5% vs. 47%). The adults were mainly female (83%) and were more likely than children to have anthropophilic agent infection (53% vs. 23·9%). The most common pathogen was zoophilic Microsporum canis (354, 65·2%), followed by anthropophilic Trichophyton violaceum (74, 13·6%). In contrast to the eastern, western and northeastern regions, where zoophilic M. canis predominated, anthropophilic T. violaceum predominated in central China (69%, P 0·001), where the patients had the most tinea at other sites (20%) and dermatophytosis contact (26%) but the least animal contact (39%). Microsporum ferrugineum was the most common anthropophilic agent in the western area, especially in Xinjiang province.Boys aged approximately 5 years were the most commonly affected group. Dermatologists are advised to pay more attention to the different transmission routes and pathogen spectra in different age groups from different regions.

An imbalance between the goal-directed and habitual learning systems has been proposed to underlie compulsivity in obsessive-compulsive disorder (OCD). In addition, the overall balance between these systems may be influenced by stress hormones. We examined the multimodal networks underlying these dual learning systems. Both functional and structural measures indicated reduced connectivity within the goal-directed subnetwork (FC: P = 0.042; SC–FN: P = 0.014) and reduced connectivity between the goal-directed and habitual subnetworks (FC: P = 0.014; SC–FA: P = 0.052), but no differences within the habitual subnetwork in patients with OCD compared with controls. Path modeling indicated that anatomical connectivity in the goal-directed subnetwork influenced compulsive symptoms (R2 = 0.41), whereas functional connectivity within the habit subnetwork and between goal-directed and habitual subnetworks influenced obsessive symptoms (R2 = 0.63). In addition, the relationship between anatomical connectivity in the goal-directed subnetwork and compulsion was moderated by the stress hormone ACTH (adrenocorticotropic hormone), such that at low levels of ACTH greater connectivity resulted in lower compulsion, but at high levels of ACTH this relationship was reversed. These results provide new insights into the neural correlates of the imbalance between dual learning systems, and their relationship with symptom dimensions in patients with OCD. It may further support the reconceptualization of OCD as “compulsive–obsessive disorder,” with a greater focus on the transdiagnostic dimension of compulsivity.

Osteoarthritis (OA) is a cartilage degenerative disease commonly observed in the elderly population and significantly impacts the normal life of OA patients. It has been reported that the development of pathological cell senescence in chondrocytes is involved in the pathogenesis of OA. Celecoxib is a common non-steroidal anti-inflammatory drug, and it has been recently reported to exert therapeutic effects on OA. However, its underlying mechanism is still unclear. The present study intends to explore its mechanism and provide fundamental evidence for the application of Celecoxib in the treatment of clinical OA. Tumor necrosis factor-α (TNF-α) was utilized to establish an in vitro model of chondrocytes senescence. The elevated reactive oxygen species (ROS) generation, increased cell cycle arrest in G0/G1 phase, reduced telomerase activity, and upregulated senescence-associatedβ-galactosidase (SA-β-Gal) staining were all observed in TNF-α-treated chondrocytes, which were then dramatically reversed by 10 and 20 μM Celecoxib. In addition, the upregulated DNA damage biomarkers, p-ATM, and p-CHK2, observed in TNF-α-treated chondrocytes were significantly downregulated by 10 and 20 μM Celecoxib. Lastly, the expression level of p21 and p53 was greatly elevated in chondrocytes by stimulation with TNF-α which was then pronouncedly repressed by treatment with Celecoxib. Taken together, our data reveal that Celecoxib ameliorated TNF-α-induced cellular senescence in human chondrocytes.

Meta-analyses suggest an association between autism spectrum disorder (ASD) and obesity, but the factors underlying this association remain unclear. This study investigated the association between ASD and obesity stratified on intellectual disability (ID). In addition, in order to gain insight into possible shared etiological factors, the potential role of shared familial liability was examined.We studied a cohort of 3,141,696 individuals by linking several Swedish nationwide registers. We identified 35,461 individuals with ASD and 61,784 individuals with obesity. Logistic regression models were used to estimate the association between ASD and obesity separately by ID and sex and by adjusting for parental education, psychiatric comorbidity, and psychotropic medication. Potential shared familial etiologic factors were examined by comparing the risk of obesity in full siblings, maternal and paternal half-siblings, and full- and half-cousins of individuals with ASD to the risk of obesity in relatives of individuals without ASD.Individuals with ASD + ID (OR = 3.76 [95% CI, 3.38-4.19]) and ASD-ID (OR = 3.40 [95% CI, 3.23-3.58]) had an increased risk for obesity compared with individuals without ASD. The associations remained statistically significant when adjusting for parental education, psychiatric comorbidity, and medication. Sex-stratified analyses indicated a higher relative risk for males compared with females, with statistically significant interaction effects for ASD-ID, but not for ASD+ID in the fully adjusted model. First-degree relatives of individuals with ASD+ID and ASD-ID had an increased risk of obesity compared with first-degree relatives of individuals without ASD. The obesity risk was similar in second-degree relatives of individuals with ASD+ID but was lower for and ASD-ID. Full cousins of individuals with ASD+ID had a higher risk compared with half-cousins of individuals with ASD+ID). A similar difference in the obesity risk between full cousins and half-cousins was observed for ASD-ID.Individuals with ASD and their relatives are at increased risk for obesity. The risk might be somewhat higher for males than females. This warrants further studies examining potential common pleiotropic genetic factors and shared family-wide environmental factors for ASD and obesity. Such research might aid in identifying specific risks and underlying mechanisms in common between ASD and obesity.

Circadian dysregulation involves malignant tumor initiation and progression, but the understanding of circadian rhythm's roles in bladder cancer (BCa) remains insufficient. The circadian rhythm-related genes were collected and clustered based on the Cancer Genome Atlas (TCGA), and the clustering was significantly associated with the prognosis and risk clinicopathological features. Through genomic difference analysis and gene pairing, a circadian rhythm-related signature was successfully established. Kaplan-Meier survival analysis and time-dependent receiver operating curves displayed that the prognosis model was a reliable prognosis biomarker both in the training cohort (n = 396, P = 2.687e-10) and external validation cohort (n = 224, P = 1.45e-02). The patients with high risk have high immune infiltration and high expression of immune checkpoint genes, which partly account for the poor prognosis. TIDE algorithm and the validation in IMvigor210 cohort indicated that the risk signature was a promising marker for the immunotherapeutic response. The risk model could also predict the therapeutic response of cisplatin, which was validated in the Genomics of Drug Sensitivity in Cancer database (P = 0.0049), TCGA (P = 0.038), and T24 BCa cells treated with cisplatin. The functional enrichment showed the risk model was significantly correlated with some malignant phenotypes, such as angiogenesis, epithelial-mesenchymal transition, and KRAS signaling pathway. Totally, we proposed a novel circadian rhythm-related signature for prognosis evaluation, which also helped to predict the immune infiltration and cisplatin sensitivity in BCa.

The morbidity and mortality of cardiovascular diseases (CVDs) are increasing worldwide and seriously threaten human life and health. Fibroblast growth factor 21 (FGF21), a metabolic regulator, regulates glucose and lipid metabolism and may exert beneficial effects on the cardiovascular system. In recent years, FGF21 has been found to act directly on the cardiovascular system and may be used as an early biomarker of CVDs. The present review highlights the recent progress in understanding the relationship between FGF21 and CVDs including coronary heart disease, myocardial ischemia, cardiomyopathy, and heart failure and also explores the related mechanism of the cardioprotective effect of FGF21. FGF21 plays an important role in the prediction, treatment, and improvement of prognosis in CVDs. This cardioprotective effect of FGF21 may be achieved by preventing endothelial dysfunction and lipid accumulating, inhibiting cardiomyocyte apoptosis and regulating the associated oxidative stress, inflammation and autophagy. In conclusion, FGF21 is a promising target for the treatment of CVDs, however, its clinical application requires further clarification of the precise role of FGF21 in CVDs.

G-quadruplex is an essential element in gene transcription that serves as a promising drug target. Guanine-vacancy-bearing G-quadruplex (GVBQ) is a newly identified G-quadruplex that has distinct structural features from the canonical G-quadruplex. Potential GVBQ-forming motifs are widely distributed in gene promoter regions. However, whether GVBQ can form in genomic DNA and be an effective target for manipulating gene expression is unknown. Using photo-crosslinking, dimethyl sulfate footprinting, exonuclease digestion and in vitro transcription, we demonstrated the formation of a GVBQ in the G-rich nuclease hypersensitivity element within the human PDGFR-β gene promoter region in both single-stranded and double-stranded DNA. The formation of GVBQ in dsDNA could be induced by negative supercoiling created by downstream transcription. We also found that the PDGFR-β GVBQ was specifically recognized and stabilized by a new synthetic porphyrin guanine conjugate (mPG). Targeting the PDGFR-β GVBQ in human cancer cells using the mPG could specifically alter PDGFR-β gene expression. Our work illustrates that targeting GVBQ with mPG in human cells can regulate the expression level of a specific gene, thus indicating a novel strategy for drug development.

Neutrophilic asthma (NA) is a severe type of steroid resistant asthma, and so far the immune mechanisms underlying NA are not clear. In this article, we performed a comprehensive assessment of Th-cell subsets and cytokines in severe NA patients. A total of 13 healthy individuals and 31 severe asthma patients were enrolled in this study. Refractory asthma patients were defined as those with eosinophilic asthma (EA, accounted for 32% of asthmatic patients) or NA (68%) according to sputum neutrophil/eosinophil counts or blood eosinophils. Th-cell subsets in peripheral blood mononuclear cells (PBMCs) were analyzed by flow cytometry, and cytokines were detected by cytometric bead array (CBA). The results showed significant differences were observed in Th-cell phenotypes, where the number of Th1 cells were reduced and the numbers of Th2 cells were increased in NA and EA groups, respectively, when compared with healthy controls. Th17 cells were not strongly associated with severe neutrophilic asthma. The frequencies of mucosal-associated invariant T (MAIT) cells were strikingly reduced in severe asthma patients, especially in the NA group. This NA group also showed increased levels of IL-17A, IL-17F, TNF-α, and IL-6 in serum and increased levels of IL-17A, IL-17F, IFN-γ, TNF-α, IL-1β, IL-5, IL-6, and IL-8 in sputum. In addition, sputum IL-6 was positively correlated with TNF-α, IFN-γ, IL-17A, and IL-8. Our results uncovered a controversial role for Th17 cells, which were reduced in severe asthma patients. Severe neutrophilic asthma was associated with a striking deficiency of MAIT cells and high pro-inflammatory cytokine levels.