Antibacterial And Biofilm Removal Strategies Based On Micro/nanomotors In The Biomedical Field.

Bacterial infection, which can trigger varieties of diseases and tens of thousands of deaths each year, poses  serious threats to human health. Particularly, the new dilemma caused by biofilms is gradually becoming a severe and tough problem in the biomedical field. Thus, the strategies to address these problems are considered an urgent task at present. Micro/nanomotors (MNMs), also named micro/nanoscale robots, are mostly driven by chemical energy or external field, exhibiting strong diffusion and self-propulsion in the liquid media, which has the potential for antibacterial applications. In particular, when MNMs are assembled in swarms, they become robust and efficient for biofilm removal. However, there is a lack of comprehensive review discussing the progress in this aspect. Bearing it in mind and based on our own research experience in this regard, the studies on MNMs driven by different mechanisms orchestrated for antibacterial activity and biofilm removal are timely and concisely summarized and discussed in this work, aiming to show the advantages of MNMs brought to this field. In addition, an outlook was proposed, hoping to provide the fundamental guidance for future development in this area.

Prognostic Value and the Immune Microenvironment-associated Role of SMAD4 in Pancreatic Adenocarcinoma.

BACKGROUND/AIM: SMAD4 is a well-known cancer suppressor gene that regulates cell proliferation, differentiation, autoimmunity, pluripotency, and immune responses in pancreatic adenocarcinoma (PAAD). We herein investigated a novel involvement of SMAD4 within the PAAD microenvironment. MATERIALS AND METHODS: Transcriptome data, derived from The Cancer Genome Atlas and Genotype-Tissue Expression Using TIMER 2.0, CIBERSORT, and ImmuCellAI, were used to identify the immune cell infiltration pattern of PAAD. We then knocked-down SMAD4 in the PANC-1 cell line and acquired RNA-seq data through the Illumina microarray technology. Kyoto Encyclopedia of Genes and Genomes was utilized along with Gene Ontology enrichment analyses, and protein-protein interaction network analysis to screen for genes that were differentially expressed. We constructed a miRNA-mRNA regulatory network and analyzed SMAD4 copy number variation (CNV) data. RESULTS: In PAAD, decreased levels of SMAD4 expression were found to be connected to an unfavorable prognosis. There was a significantly higher infiltration level of DC cells, CD8+ T cells, TgD, Tc, and Tex cells and a lower level of B cells and Th2 in the SMAD4-high group. The expression of SMAD4 and immune cell infiltration including CD8+ T cells, myeloid dendritic cells, neutrophils, and macrophages are significantly positively correlated. DEGs were found enriched in the hypoxia response pathway. The six hypoxia-related genes exhibited a significant correlation with immune cell infiltration and survival rates. SMAD4 CNV levels were associated with MSI, stemness, infiltration of immune cells, and survival rates. CONCLUSION: A statistically significant correlation was found between SMAD4 expression and immune cell infiltration. SMAD4 could mediate hypoxia response in pancreatic cancer. The CNV levels of SMAD4 were associated with prognosis. SMAD4 has potential as a prognostic biomarker and provides a new orientation for the immunotherapy of PAAD.

Focus on the performance enhancement of micro/nanomotor-based biosensors.

Micro/nanomotors (MNMs) emerge as a vital candidate for biosensing due to its nano-size structure, high surface-to-area ratio, directional mobility, biocompatibility, and ease of functionalization, therefore being able to detect objects with high efficiency, precision, and selectivity. The driving mode, nanostructure, materials property, preparation technique, and biosensing applications have been thoroughly discussed in publications. To promote the MNMs-based biosensors from in vitro to in vivo, it is necessary to give a comprehensive discussion from the perspective of sensing performances enhancement. However, until now, there is few reviews dedicated to the systematic discussion on the multiple performance enhancement schemes and the current challenges of MNMs-based biosensors. Bearing it in mind and based on our research experience in this field, we summarized the enhancement methods for biosensing properties such as sensitivity, selectivity, detection time, biocompatibility, simplify system operation, and environmental availability. We hope that this review provides the readers with fundamental understanding on performance enhancement schemes for MNMs-based biosensors.

A sequential scheme including PTT and 2'3'-cGAMP/CQ-LP reveals the antitumor immune function of PTT through the type I interferon pathway.

Photothermal therapy (PTT) is a promising antitumor treatment that is easy to implement, minimally invasive, and precisely controllable, and evokes strong antitumor immunity. We believe that a thorough elucidation of its underlying antitumor immune mechanisms would contribute to the rational design of combination treatments with other antitumor strategies and consequently potentiate clinical use. In this study, PTT using indocyanine green (ICG) induced STING-dependent type I interferon (IFN) production in macrophages (RAW264.7 and bone marrow-derived macrophages (BMDMs)), as proven by the use of a STING inhibitor (C178), and triggered STING-independent type I IFN generation in tumor cells (CT26 and 4T1), which was inhibited by DNase pretreatment. A novel liposome coloaded with the STING agonist 2'3'-cGAMP (cGAMP) and chloroquine (CQ) was constructed to achieve synergistic effect with PTT, in which CQ increased cGAMP entrapment efficiency and prevented STING degradation after IFN signaling activation. The sequential combination treatment caused a significant increase in tumor cell apoptosis, probably due to interferon stimulating gene products 15 and 54 (ISG15 and ISG 54), and achieved a more striking antitumor inhibition effect in the CT26 tumor model than the 4T1 model, likely due to higher STAT1 expression and consequently more intense IFN signal transduction. In the tumor microenvironment, the combination treatment increased infiltrating CD8+T cells (4-fold) and M1-like TAMs (10-fold), and decreased M-MDSCs (over 2-fold) and M2-like TAMs (over 4-fold). Above all, in-depth exploration of the antitumor mechanism of PTT provides guidance for selecting sensitive tumor models and designing reasonable clinical schemes.

Potential of extracellular vesicles for early prediction of severity and potential risk stratification in critical inflammatory diseases.

Some acute inflammatory diseases are often exacerbated during or after hospitalization, leading to some severe manifestations like systemic inflammatory response syndrome, multiple organ failure, and high mortality. Early clinical predictors of disease severity are urgently needed to optimize patient management for better prognosis. The existing clinical scoring system and laboratory tests cannot circumvent the problems of low sensitivity and limited specificity. Extracellular vesicles (EVs) are heterogeneous nanosecretory vesicles containing various biomolecules related to immune regulation, inflammation activation, and inflammation-related complications. This review provides an overview of EVs as inflammatory mediators, inflammatory signaling pathway regulators, promoters of inflammatory exacerbation, and markers of severity and prognosis. Currently, although relevant biomarkers are clinically available or are in the preclinical research stage, searching for new markers and detection methods is still warranted, as the problems of low sensitivity/specificity, cumbersome laboratory operation and high cost still plague clinicians. In-depth study of EVs might open a door in the search for novel predictors.

CCN6 improves hepatic steatosis, inflammation, and fibrosis in non-alcoholic steatohepatitis.

BACKGROUND AND AIMS: CCN6 is a secretory protein with functions of maintaining mitochondrial homeostasis and anti-oxidative stress; and yet, whether it is involved in the pathogenesis of non-alcoholic steatohepatitis (NASH) is still obscure. We investigated the role and mechanism of CCN6 in the development of NASH. METHODS: Human liver tissue samples were collected to detect the expression profile of CCN6. High-fat-high-cholesterol (HFHC) and methionine choline-deficient (MCD) diet were applied to mice to establish NASH animal models. Liver-specific overexpression of CCN6 was induced in mice by tail vein injection of adeno-associated virus (AAV), and then the effect of CCN6 on the course of NASH was observed. Free fatty acid (FFA) was applied to HepG2 cells to construct the cell model of steatosis, and the effect of CCN6 was investigated by knocking down the expression of CCN6 through small interfering RNA (siRNA) transfection. RESULTS: We found that CCN6 expression was significantly downregulated in the liver of NASH. We confirmed that liver-specific overexpression of CCN6 significantly attenuated hepatic steatosis, inflammation response and fibrosis in NASH mice. Based on RNA-seq analysis, we revealed that CCN6 significantly affected the MAPK pathway. Then, by interfering with apoptosis signal-regulating kinase 1 (ASK1), we identified the ASK1/MAPK pathway pairs as the targets of CCN6 action. CONCLUSIONS: CCN6 protects against hepatic steatosis, inflammation response and fibrosis by inhibiting the activation of ASK1 along with its downstream MAPK signalling. CCN6 may be a potential therapeutic target for the treatment of NASH.

Direct immunoactivation by chemotherapeutic drugs in cancer treatment.

The immune system plays a crucial role in recognizing and eliminating pathogenic substances and malignant cells in the body. For cancer treatment, immunotherapy is becoming the standard treatment for many types of cancer and is often combined with chemotherapy. Although chemotherapeutic agents are often reported to have adverse effects, including immunosuppression, they can also play a positive role in immunotherapy by directly stimulating the immune system. This has been demonstrated in preclinical and clinical studies in the past decades. Chemotherapeutics can activate immune cells through different immune receptors and signaling pathways depending on their chemical structure and formulation. In this review, we summarize and discuss the direct immunoactivation effects of chemotherapeutics and possible mechanisms behind these effects. Finally, we prospect chemo-immunotherapeutic combinations for the more effective and safer treatment of cancer.

A Fissure-Aided Registration Approach for Automatic Pulmonary Lobe Segmentation Using Deep Learning.

The segmentation of pulmonary lobes is important in clinical assessment, lesion location, and surgical planning. Automatic lobe segmentation is challenging, mainly due to the incomplete fissures or the morphological variation resulting from lung disease. In this work, we propose a learning-based approach that incorporates information from the local fissures, the whole lung, and priori pulmonary anatomy knowledge to separate the lobes robustly and accurately. The prior pulmonary atlas is registered to the test CT images with the aid of the detected fissures. The result of the lobe segmentation is obtained by mapping the deformation function on the lobes-annotated atlas. The proposed method is evaluated in a custom dataset with COPD. Twenty-four CT scans randomly selected from the custom dataset were segmented manually and are available to the public. The experiments showed that the average dice coefficients were 0.95, 0.90, 0.97, 0.97, and 0.97, respectively, for the right upper, right middle, right lower, left upper, and left lower lobes. Moreover, the comparison of the performance with a former learning-based segmentation approach suggests that the presented method could achieve comparable segmentation accuracy and behave more robustly in cases with morphological specificity.

Construction of a prognostic model of colon cancer patients based on metabolism-related lncRNAs.

Background: Many studies have shown that metabolism-related lncRNAs may play an important role in the pathogenesis of colon cancer. In this study, a prognostic model for colon cancer patients was constructed based on metabolism-related lncRNAs. Methods: Both transcriptome data and clinical data of colon cancer patients were downloaded from the TCGA database, and metabolism-related genes were downloaded from the GSEA database. Through differential expression analysis and Pearson correlation analysis, long non-coding RNAs (lncRNAs) related to colon cancer metabolism were obtained. CRC patients were divided into training set and verification set at the ratio of 2:1. Based on the training set, univariate Cox regression analysis was utilized to determine the prognostic differential expression of metabolic-related lncRNAs. The Optimal lncRNAs were obtain by Lasso regression analysis, and a risk model was built to predict the prognosis of CRC patients. Meanwhile, patients were divided into high-risk and low-risk groups and a survival curve was drawn accordingly to determine whether the survival rate differs between the two groups. At the same time, subgroup analysis evaluated the predictive performance of the model. We combined clinical indicators with independent prognostic significance and risk scores to construct a nomogram. C index and the calibration curve, DCA clinical decision curve and ROC curve were obtained as well. The above results were all verified using the validation set. Finally, based on the CIBERSORT analysis method, the correlation between lncRNAs and 22 tumor-infiltrated lymphocytes was explored. Results: By difference analysis, 2491 differential lncRNAs were obtained, of which 226 were metabolic-related lncRNAs. Based on Cox regression analysis and Lasso results, a multi-factor prognostic risk prediction model with 13 lncRNAs was constructed. Survival curve results suggested that patients with high scores and have a poorer prognosis than patients with low scores (P<0.05). The area under the ROC curve (AUC) for the 3-year survival and 5-year survival were 0.768 and 0.735, respectively. Cox regression analysis showed that age, distant metastasis and risk scores can be used as independent prognostic factors. Then, a nomogram including age, distant metastasis and risk scores was built. The C index was 0.743, and the ROC curve was drawn to obtain the AUC of the 3-year survival and the 5-year survival, which were 0.802 and 0.832, respectively. The above results indicated that the nomogram has a good predictive effect. Enrichment analysis of KEGG pathway revealed that differential lncRNAs may be related to chemokines, amino acid and sugar metabolism, NOD-like receptor and Toll-like receptor activation as well as other pathways. Finally, the analysis results based on the CIBERSORT algorithm showed that the lncRNAs used to construct the model had a strong polarized correlation with B cells, CD8+T cells and M0 macrophages. Conclusion: 13 metabolic-related lncRNAs affecting the prognosis of CRC were screened by bioinformatics methods, and a prognostic risk model was constructed, laying a solid foundation for the research of metabolic-related lncRNAs in CRC.

Exosomes derived from human umbilical cord mesenchymal stem cells ameliorate experimental non-alcoholic steatohepatitis via Nrf2/NQO-1 pathway.

BACKGROUND: No approved effective therapy for non-alcoholic steatohepatitis (NASH) is currently available. Exosomes derived from mesenchymal stem cells (MSCs) perform the functions such as inhibiting inflammation, anti-oxidative stress, regulating immunity, but it is not clear whether human umbilical cord mesenchymal stem cells (hUC-MSCs) exosomes protect against NASH through Nrf2/NQO-1 pathway. Therefore, this study was conducted to investigate the effects of hUC-MSCs exosomes on NASH through Nrf2/NQO-1 pathway in vivo and in vitro. METHODS: C57BL/6J male mice were fed with high fat and high cholesterol diet (HFHC) and methionine choline deficiency diet (MCD). Mice were treated with or without hUC-MSCs exosomes by tail intravenous injection. The liver histology, lipid metabolism and oxidative stress were evaluated. HepG2 and AML12 cells were incubated with palmitic acid (PA) and MCD conditioned medium, respectively. Then the therapeutic effect of hUC-MSCs exosomes in steatotic cells was evaluated. To elucidate the signaling pathways, the Nrf2-specific blocker ML385 was applied to intervene in vitro. RESULTS: In NASH models, hUC-MSCs exosomes attenuated steatosis in hepatocytes, altered the abnormal expression of lipid-related genes including SREBP-1c, PPAR-α, Fabp5, CPT1α, ACOX and FAS, suppressed the hepatic inflammatory responses by decreasing the expression of F4/80+ macrophages, CD11c+ macrophages as well as the content of TNF-α and IL-6. hUC-MSCs exosomes also inhibited oxidative stress by reducing the level of MDA, CYP2E1 and ROS, increasing the activity of SOD and GSH in hepatocytes. Notably, hUC-MSCs exosomes enhanced the protein ratio of p-Nrf2/Nrf2 and the protein expression of NQO-1. Moreover, in vitro, the therapeutic effects of hUC-MSCs exosomes on lipid deposition and ROS were reversed by ML385. Also, ML385 reduced the protein expression of p-Nrf2 and NQO-1 in vitro. CONCLUSION: Nrf2/NQO-1 antioxidant signaling pathway may play a key role in the treatment of NASH by hUC-MSCs exosomes.

Phosphorylation of MAD2 at Ser195 Promotes Spindle Checkpoint Defects and Sensitizes Cancer Cells to Radiotherapy in ATM Deficient Cells.

The spindle assembly checkpoint (SAC) is a critical monitoring device in mitosis for the maintenance of genomic stability. Specifically, the SAC complex comprises several factors, including Mad1, Mad2, and Bub1. Ataxia-telangiectasia mutated (ATM) kinase, the crucial regulator in DNA damage response (DDR), also plays a critical role in mitosis by regulating Mad1 dimerization and SAC. Here, we further demonstrated that ATM negatively regulates the phosphorylation of Mad2, another critical component of the SAC, which is also involved in DDR. Mechanistically, we found that phosphorylation of Mad2 is aberrantly increased in ATM-deficient cells. Point-mutation analysis further revealed that Serine 195 mainly mediated Mad2 phosphorylation upon ATM ablation. Functionally, the phosphorylation of Mad2 causes decreased DNA damage repair capacity and is related to the resistance to cancer cell radiotherapy. Altogether, this study unveils the key regulatory role of Mad2 phosphorylation in checkpoint defects and DNA damage repair in ATM-deficient cells.

Gut microbiota reflect the crowding stress of space shortage, physical and non-physical contact in Brandt's voles (Lasiopodomys brandtii).

Density-dependence plays a critical role in behavior and population regulation of small mammals, which is likely mediated by hormones and gut microbiota. High density-induced crowding effects often cause a combination of various social stresses including space shortage, physical contact and non-physical contact, but their distinct effects on gut microbiota in animals have not been investigated. In this study, we examined the crowding effects of space shortage and physical or non-physical contact stress on serum corticosterone and gut microbiota of Brandt's voles in both laboratory and field conditions. Our results demonstrated that the space shortage stress showed a more predominant impact on serum corticosterone and gut microbiota of voles than physical or non-physical contact stress; the crowding effects of non-physical contact stress became stronger in high density conditions, while physical contact stress was stronger in a larger group without density effects. High density or group size treatments under both laboratory and semi-natural enclosure conditions significantly increased the relative abundance of key differential taxa, including Bacteroidetes, TM7, S24_7, Streptococcus, and Lactobacillus; while high density or group size treatments decreased the relative abundance of Firmicutes, Staphylococcaceae, Bacteroides, Faecalibacterium, and Adlercreutzia. Our study suggests that high density-induced space shortage and physical contact or non-physical contact stress may play a significant role in behavior and population regulation through altering gut microbiota in small mammals. Our results may also have significant implications in rodent control or health management for livestock.

The Role Transition of Dietary Species Richness in Modulating the Gut Microbial Assembly and Postweaning Performance of a Generalist Herbivore.

When facing a food shortage, generalist herbivores can respond by expanding their dietary species richness (DSR) to maximize energy collection, regardless of whether forages are preferred or not. Higher DSR usually indicates higher nutrient adequacy and better health. However, the high-DSR diet containing a large proportion of preferred species or a large proportion of less-preferred species means different things to an animal. It is still unknown how different shift patterns in DSR would affect distinctly the performance of animals via altering gut microbiota. We examined the gut microbial composition, diversity, community assembly processes, and performance of a generalist herbivore, Lasiopodomys brandtii, in a feeding experiment with increased levels of simulated DSR shifting from preferred plant species to less preferred ones. We found the survival rate and body growth of Brandt's voles showed a dome-shaped association with DSR: species performance increased initially with the increase of preferred plant species but declined with the increase of less-preferred food items. Several microbial taxa and functions closely related to the metabolism of amino acids and short-chain fatty acids also showed a dome-shaped association with DSR, which is consistent with the observation of performance change. However, the alpha diversities of gut microbiota increased linearly with DSR. The null model and phylogenetic analysis suggested that stochastic processes dominate at low DSR diets, whereas deterministic processes prevail at high DSR diets. These results suggest that the role of DSR in regulating animal performance by gut microbiota depends on the number of preferred forage items. IMPORTANCE The plant species diversity varies greatly under the influence of both climate change and human disturbance, which may negatively affect the productivity as well as the variability of organisms (e.g., small herbivores) at the next trophic level. It is still unknown how gut microbiota of small herbivores respond to such changes in dietary species richness. Our manipulative food experiment revealed that dietary species richness can affect the composition, functions, and community assembly of gut microbiota of Brandt's vole in a nonlinear way. Given the fast-growing interest in therapeutic diets to treat dysbiosis and to improve health conditions, our study highlights the need to consider not just the variety of consumed food but also the principles of rational nutrition.

Timing outweighs magnitude of rainfall in shaping population dynamics of a small mammal species in steppe grassland.

Climate change-induced shifts in species phenology differ widely across trophic levels, which may lead to consumer-resource mismatches with cascading population and ecosystem consequences. Here, we examined the effects of different rainfall patterns (i.e., timing and amount) on the phenological asynchrony of population of a generalist herbivore and their food sources in semiarid steppe grassland in Inner Mongolia. We conducted a 10-y (2010 to 2019) rainfall manipulation experiment in 12 0.48-ha field enclosures and found that moderate rainfall increases during the early rather than late growing season advanced the timing of peak reproduction and drove marked increases in population size through increasing the biomass of preferred plant species. By contrast, greatly increased rainfall produced no further increases in vole population growth due to the potential negative effect of the flooding of burrows. The increases in vole population size were more coupled with increased reproduction of overwintered voles and increased body mass of young-of-year than with better survival. Our results provide experimental evidence for the fitness consequences of phenological mismatches at the population level and highlight the importance of rainfall timing on the population dynamics of small herbivores in the steppe grassland environment.

Gut Microbial Dysbiosis in the Irritable Bowel Syndrome: A Systematic Review and Meta-Analysis of Case-Control Studies.

BACKGROUND: Irritable bowel syndrome (IBS) is the most common functional digestive condition in the industrialized world. The gut microbiota plays a key role in disease pathogenesis. OBJECTIVE: A systematic review and meta-analysis on case-control studies was conducted to determine whether there is gut microbial dysbiosis in participants with IBS in comparison with healthy controls and, if so, whether the dysbiosis pattern differs among IBS subtypes and geographic regions. METHODS: This review was conducted and reported according to the MOOSE (Meta-Analysis of Observational Studies in Epidemiology) 2000 and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2009 guidelines. Research articles published up to May 9, 2018 were identified through MEDLINE (PubMed), Cochrane Central Register of Controlled Trials (Cochrane Library), ClinicalTrials.gov, EMBASE, and Web of Science. Study quality was assessed using the Newcastle-Ottawa Scale. Case-control studies of participants with IBS who had undergone quantitative gut microbial stool analysis were included. The primary exposure measure of interest is log10 bacterial counts per gram of stool. Meta-analyses were performed to estimate the mean difference (MD) in gut microbiota between participants with IBS and healthy controls using the random-effects model with inverse variance in Revman 5.3 and R 3.5.1. Publication bias was assessed with funnel plots and Egger's test. Between-study heterogeneity was analyzed using Higgins I2 statistic with 95% CIs. RESULTS: There were 6,333 unique articles identified; 52 qualified for full-text screening. Of these, 23 studies were included for analysis (n=1,340 participants from North America, Europe, and Asia). Overall, the studies were moderate in quality. Comparing participants with IBS to healthy controls, lower fecal Lactobacillus (MD= -0.57 log10 colony-forming unit [CFU]/g; P<0.01) and Bifidobacterium (MD= -1.04 log10CFU/g; P<0.01), higher Escherichia coli (MD=0.60 log10CFU/g; P<0.01), and marginally higher Enterobacter (MD=0.74 log10CFU/g; P=0.05). No difference was found between participants with IBS and healthy controls in fecal Bacteroides and Enterococcus (P=0.18 and 0.68, respectively). Publication bias was not observed except in Bifidobacterium (P=0.015). Subgroup analyses on participants with diarrhea-predominant and constipation-predominant IBS showed consistent results with the primary results. A subgroup analysis of Chinese studies was consistent with the primary results, except for fecal Bacteroides, which was increased in participants with IBS vs healthy controls (MD=0.29; 95% CI 0.13 to 0.46; P<0.01). Although substantial heterogeneity was detected (I2>75%) in most comparisons, the direction of the effect estimates is relatively consistent across studies. CONCLUSIONS: IBS is characterized by gut microbial dysbiosis. Prospective, large-scale studies are needed to delineate how gut microbial profiles can be used to guide targeted therapies in this challenging patient population.

Initial medical and surgical management of inflammatory bowel disease in the biologic era: A comparison between the United States and China.

BACKGROUND AND AIMS: We compared the initial medical and surgical management of Crohn's disease (CD) and ulcerative colitis (UC) between the United States and China, with aims to better characterize the global variation in the treatment patterns of inflammatory bowel disease (IBD). METHODS: Participants from the United States and China completed a questionnaire on demographic and clinical characteristics, medications (biologics, immunomodulators, aminosalicylates, steroids), and IBD-related surgical history. Patients diagnosed in 2006 and later were eligible. Analysis was restricted to treatment patterns within 1 year of diagnosis. Multivariable logistic regressions examined differences by country. RESULTS: We recruited 202 CD (US: 49%, China: 51%) and 133 UC (US: 63%, China: 37%) participants. Median age at survey was 31 years (range: 18-76) and at diagnosis was 28 years (range: 12-70). Biologics were commonly used in the United States for CD (66%) and UC (28%) and less commonly in China for CD (19%) and UC (0%). On regression, US CD participants were more likely to receive biologics (odds ratio [OR] 23.82 [95% confidence interval [CI] 8.98-63.14]), aminosalicylates (OR 4.93 [2.00-12.15]), and steroids (OR 4.36 [1.87-10.16]). US UC participants were more likely to receive immunomodulators (OR 3.45 [1.09-10.90]) and steroids (OR 3.31 [1.55-7.06]). There existed minimal differences regarding undergoing surgery for CD (US: 16%, China: 16%) and UC (US: 5%, China: 2%). A proportion (US: 12%, China: 19%) underwent IBD-related surgery prior to diagnosis (median: 5 years; range: 1-39). CONCLUSION: US, relative to Chinese, participants were more likely to report early biologic use. There were no differences between countries in undergoing early surgery. Evaluating global practice variation is integral to optimizing early pharmacological therapy and timing of surgery for patients with IBD.

Multi-Fidelity Local Surrogate Model for Computationally Efficient Microwave Component Design Optimization.

In order to minimize the number of evaluations of high-fidelity ("fine") model in the optimization process, to increase the optimization speed, and to improve optimal solution accuracy, a robust and computational-efficient multi-fidelity local surrogate-model optimization method is proposed. Based on the principle of response surface approximation, the proposed method exploits the multi-fidelity coarse models and polynomial interpolation to construct a series of local surrogate models. In the optimization process, local region modeling and optimization are performed iteratively. A judgment factor is introduced to provide information for local region size update. The last local surrogate model is refined by space mapping techniques to obtain the optimal design with high accuracy. The operation and efficiency of the approach are demonstrated through design of a bandpass filter and a compact ultra-wide-band (UWB) multiple-in multiple-out (MIMO) antenna. The response of the optimized design of the fine model meet the design specification. The proposed method not only has better convergence compared to an existing local surrogate method, but also reduces the computational cost substantially.

Efficacy and Safety of Ledipasvir/Sofosbuvir with and without Ribavirin in Patients with Chronic Hepatitis C Virus Genotype 1 Infection: a meta-analysis.

BACKGROUND: The addition of ribavirin (RBV) to the combination treatment of Ledipasvir (LDV) and Sofosbuvir (SOF) remains controversial in the treatment of hepatitis C virus (HCV) infection. We performed a meta-analysis to assess the efficacy and safety of the LDV-SOF with and without RBV in treating HCV genotype 1 patients. METHOD: The electronical databases of PubMed Medline, EMBASE database, Cochrane Central Register of Controlled Trials (CENTRAL) and ClinicalTrials.gov website with registered trials were searched. Eligible studies were randomized controlled trials (RCTs) and prospective cohort studies that assessed the efficacy and safety of LDV-SOF with or without RBV in patients with HCV genotype 1 (GT 1). Two reviewers independently screened studies, extracted data and assessed methodology quality. Review Manager 5.3 software was used to analyze the data. RESULTS: Seven studies involving 2,626 patients with HCV GT 1 - some of whom had cirrhosis - were included in this meta-analysis. The addition of RBV to LDV- SOF regimen neither significantly improved sustained viral response at 12 weeks (SVR12) after the last dose of treatment (RR=1.00, 95%CI 0.99-1.01, p=0.99) nor decreased virologic breakthrough (RR=1.01, 95%CI 0.14-7.19, p=0.99) and relapse (RR=1.36, 95% CI 0.81-2.29, p=0.24). There was no significant difference in the incidence of discontinuation (RR=0.61, 95%CI 0.25-1.53, p=0.30) between LDV- SOF therapy and LDV- SOF plus RBV. LDV- SOF plus RBV therapy had significantly higher rate of the overall adverse events (RR=0.88, 95%CI=0.84- 0.92, p<0.00001). LDV - SOF therapy had higher incidence of serious adverse events (RR=1.60, 95%CI=1.00-2.56, p=0.05) than LDV-SOF plus RBV. CONCLUSION: This meta-analysis suggests that LDV-SOF based therapy is a safe and effective treatment for patients with GT 1 HCV. The addition of RBV to LDV-SOF may increase toxicity without achieving improved efficacy. However, due to the relatively small sample sizes and moderate risk of bias of included studies, large-scale and high-quality clinical research is still needed to confirm the results.

Usage of a Reward System for Dealing with Pediatric Dental Fear.

BACKGROUND: Pediatric dental fear, if left unchecked, can persist for a lifetime and adversely impact the physical and psychological health of a patient. In this study, a feasible nonmedical method for relieving pediatric dental fear was investigated. METHODS: A randomized, single-blind, controlled trial model was applied. The juvenile patients experiencing dental fear, whose parents or guardian had signed an informed consent form, were randomly divided into two groups. Group A (n = 50) was the control group, while Group B (n = 50) was the reward group. Participants in Group A accepted routine treatment. Participants in Group B were told that they would obtain a gift as a rewarda for their good behavior if they were compliant during their dental treatments. The Chinese version of the Children's Fear Survey Schedule-Dental Subscale (CFSS-DS) was used to evaluate the level of dental fear of each patient both before and after each treatment. A contrast analysis and a correlation analysis of the results were used to assess the efficacy of the reward mechanism. RESULTS: All participants in Group B, were obedient during the dental treatment, and they also successfully chose the present they wanted at the end of their dental treatment. Children at different ages showed different reward preferences. Significant difference in the fear scores of the participants in Group B before the treatment and after receiving the reward was found (independent samples t-test, t = 14.72, P < 0.001). In Group A, 86% children's fear score did not undergo a noticeable change. CONCLUSIONS: A reward system is proved feasible to relieve pediatric dental fear, and the form of reward should meet the demand of patients.