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Abstract Background Pulmonary function is very important for the healthy development of children and adolescents. However, fewer studies have been conducted on pulmonary function trends in children and adolescents in remote areas. The aim of this study was to estimate the forced vital capacity (FVC) trend and its relationship with body mass index (BMI) among young people in Xinjiang during 1985–2014 using data from seven successive national surveys. Methods A total of 19,449 Xinjiang children and adolescents aged 7–18 years were extracted from the Chinese National Survey on Students’ Constitution and Health. Height, weight, and FVC were measured repeatedly in each survey. FVC comparisons between adjacent surveys by age and sex were conducted by nonparametric Kruskal-Wallis after Kolmogorov-Smirnov of normality. One-way ANOVA and least significant difference(LSD) method was used to compare differences in FVC levels of Xinjiang children and adolescents with different BMI. The relationship between BMI and FVC was investigated using a nonlinear regression model. Results The FVC levels of Xinjiang children and adolescents peaked in 2000, with overall FVC levels being 8.7% higher in 2000 than in 1985. Since then, a substantial decline occurred, contrasting to 2000, with FVC levels decreasing by 27% in 2014, which was still lower than that in 1985 by 20.73%. The proportion of overnutrition boys increased from 0.2% in 1985 to 22.1% in 2014, and girls from 0.5% in 1985 to 14.5% in 2014. An inverted U-shape association between FVC and BMI values was obtained for Xinjiang children and adolescents. Conclusions Targeted measures should be carried out in schools to control BMI levels to ensure good lung function in children and adolescents in Xinjiang. Future studies should pay more attention to other factors affecting FVC, such as dietary behaviour, physical activity, and racial differences among children and adolescents.

Asphalt mixture is a composite material with a complex multiphase dispersed system, and its macroscopic mechanical behavior is inherently related to the microstructure characteristics. To investigate the low-temperature crack resistance degradation law of polyester fiber asphalt mixture under different dry-wet cycling conditions, six polyester fiber contents (0%, 0.3%, 0.35%, 0.4%, 0.45%, and 0.5%) were dry-blended into SMA-13 asphalt mixture to prepare fiber-reinforced SCB specimens with pre-notches. Semi-circular bending tests were conducted to test the crack resistance performance of the fiber asphalt mixture after 0, 2, 4, 6, and 8 dry-wet cycles. The experimental results show that the crack resistance performance of specimens with different fiber contents decreases with the increase of dry-wet cycling times, and the influence of salt-dry-wet coupling is greater than that of water-dry-wet coupling. Under the same conditions, the crack resistance index (CRI) increases first and then decreases with the increase of polyester fiber content, reaching its maximum at a polyester fiber content of 0.4%. When the fiber is added at 0.5%, the agglomeration of polyester fibers restricts the low-temperature performance of the specimen. In addition, the DIC technology is used to analyze the trend of horizontal strain variation of specimens after different dry-wet cycles. The results indicate that with the increase of the cycle period, the strain concentration area becomes more apparent, and in the destruction stage, the full-field horizontal strain Exx in the crack concentration zone gradually increases, while the crack resistance decreases. Finally, addressing the limitations of traditional BP neural networks in solving nonlinear problems, a particle swarm optimization algorithm is proposed to optimize the BP neural network, and a PSO-BP neural network model is constructed. Through the analysis of evaluation indicators, it is found that the PSO-BP neural network has improved generalization ability compared to the traditional BP neural network model, and overfitting is reduced, making it an effective tool for predicting the low-temperature performance of polyester fiber asphalt mixtures.

BackgroundSingapore, like the rest of Asia, faces persistent challenges to mental health promotion, including stigma around unwellness and seeking treatment and a lack of trained mental health personnel. The COVID-19 pandemic, which created a surge in mental health care needs and simultaneously accelerated the adoption of digital health solutions, revealed a new opportunity to quickly scale innovative solutions in the region. ObjectiveIn June 2020, the Singaporean government launched mindline.sg, an anonymous digital mental health resource website that has grown to include >500 curated local mental health resources, a clinically validated self-assessment tool for depression and anxiety, an artificial intelligence (AI) chatbot from Wysa designed to deliver digital therapeutic exercises, and a tailored version of the website for working adults called mindline at work. The goal of the platform is to empower Singapore residents to take charge of their own mental health and to be able to offer basic support to those around them through the ease and convenience of a barrier-free digital solution. MethodsWebsite use is measured through click-level data analytics captured via Google Analytics and custom application programming interfaces, which in turn drive a customized analytics infrastructure based on the open-source platforms Titanium Database and Metabase. Unique, nonbounced (users that do not immediately navigate away from the site), engaged, and return users are reported. ResultsIn the 2 years following launch (July 1, 2020, through June 30, 2022), the website received >447,000 visitors (approximately 15% of the target population of 3 million), 62.02% (277,727/447,783) of whom explored the site or engaged with resources (referred to as nonbounced visitors); 10.54% (29,271/277,727) of those nonbounced visitors returned. The most popular features on the platform were the dialogue-based therapeutic exercises delivered by the chatbot and the self-assessment tool, which were used by 25.54% (67,626/264,758) and 11.69% (32,469/277,727) of nonbounced visitors. On mindline at work, the rates of nonbounced visitors who engaged extensively (ie, spent ≥40 seconds exploring resources) and who returned were 51.56% (22,474/43,588) and 13.43% (5,853/43,588) over a year, respectively, compared to 30.9% (42,829/138,626) and 9.97% (13,822/138,626), respectively, on the generic mindline.sg site in the same year. ConclusionsThe site has achieved desired reach and has seen a strong growth rate in the number of visitors, which required substantial and sustained digital marketing campaigns and strategic outreach partnerships. The site was careful to preserve anonymity, limiting the detail of analytics. The good levels of overall adoption encourage us to believe that mild to moderate mental health conditions and the social factors that underly them are amenable to digital interventions. While mindline.sg was primarily used in Singapore, we believe that similar solutions with local customization are widely and globally applicable.

X-linked adrenoleukodystrophy (X-ALD) is a rare genetic disorder caused by pathogenic variants in the ABCD1 gene. The symptoms include primary adrenal insufficiency (PAI), progressive spinal cord disease, inflammatory demyelinating cerebral disease, and primary hypogonadism. It is exceptionally rare that pediatric PAI is accompanied by central precocious puberty (CPP). The purpose of this study was to better understand the diversity of clinical manifestations of X-ALD and to identify the ABCD1 gene mutation in a case of a boy with X-ALD accompanied by CPP. We collected clinical, laboratory and imaging data, and used whole-exome sequencing (WES) analysis to evaluate the pathogenicity of the variant. We also predicted the potential deleterious effects of the novel mutation using Mutation Taster and generated three-dimensional protein structures using Swiss-Model and PyMOL Viewer software. The patient presented with PAI accompanied by CPP. Adrenal gland CT revealed adrenal hypoplasia. Gonadotropin-releasing hormone stimulation tests revealed CPP. WES revealed a novel variant (c.1376dup) in the ABCD1 gene, which resulted in a reading frameshift and a premature termination codon (p.Leu461ProfsTer95). Sanger sequencing confirmed that the variant was inherited from his heterozygous mother. Mutation Taster predicted that the variant could be harmful. The overall three-dimensional structures of the mutant wild-type proteins were visually distinct. Our results shed light on additional aspects of X-ALD. The premature activation of the hypothalamic-pituitary-gonadal axis may possibly be related to the pathogenic ABCD1 gene mutation.

Abstract Background Thyroid dysfunction is associated with abnormal glucose-insulin homeostasis, and the triglyceride-glucose (TyG) index has been recommended as a convenient surrogate of insulin resistance (IR). This study aimed to investigate the relationship between TyG and thyroid function in the US population. Methods We analyzed data from the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2012 in a cross-sectional manner. Aside from conventional thyroid parameters, our study evaluated the central sensitivity to thyroid hormones (THs) using the thyroid feedback quantile-based index (TFQI), thyrotropin resistance index (TT4RI), and thyrotropin index (TSHI). To evaluate peripheral sensitivity to THs, we calculated the ratio of free triiodothyronine (FT3) to free thyroxine (FT4) and the sum activity of peripheral deiodinases (SPINA-GD). In the 1848 adults, multivariable linear regression, subgroup, and interaction analyses were employed to estimate the association between TyG and thyroid parameters. The nonlinear relationship was addressed by smooth curve fittings and generalized additive models. Results After adjusting covariates, we demonstrated a significant negative association between TyG and FT4 (β = − 0.57, p

Abstract Refractory or relapsed (R/R) AML is the most challenging form of AML to treat. Due to frequent genetic mutations, therapy alternatives are limited. Here, we identified the role of ritanserin and its target DGKα in AML. Several AML cell lines and primary patient cells were treated with ritanserin and subjected to cell proliferation, apoptosis and gene analyses with CCK-8 assay, Annexin V/PI assay and Western blotting, respectively. We also evaluated the function of the ritanserin target diacylglycerol kinase alpha (DGKα) in AML by bioinformatics. In vitro experiments have revealed that ritanserin inhibits AML progression in a dose- and time-dependent manner, and it shows an anti-AML effect in xenograft mouse models. We further demonstrated that the expression of DGKα was elevated in AML and correlated with poor survival. Mechanistically, ritanserin negatively regulates SphK1 expression through PLD signaling, also inhibiting the Jak-Stat and MAPK signaling pathways via DGKα. These findings suggest that DGKα may be an available therapeutic target and provide effective preclinical evidence of ritanserin as a promising treatment for AML.

Gastric cancer (GC) is a malignant neoplasm originating from the epithelial cells of the gastric mucosa. The pathogenesis of GC is intricately linked to the tumor microenvironment within which the cancer cells reside. Tumor-associated macrophages (TAMs) primarily differentiate from peripheral blood monocytes and can be broadly categorized into M1 and M2 subtypes. M2-type TAMs have been shown to promote tumor growth, tissue remodeling, and angiogenesis. Furthermore, they can actively suppress acquired immunity, leading to a poorer prognosis and reduced tolerance to chemotherapy. Exosomes, which contain a myriad of biologically active molecules including lipids, proteins, mRNA, and noncoding RNAs, have emerged as key mediators of communication between tumor cells and TAMs. The exchange of these molecules via exosomes can markedly influence the tumor microenvironment and consequently impact tumor progression. Recent studies have elucidated a correlation between TAMs and various clinicopathological parameters of GC, such as tumor size, differentiation, infiltration depth, lymph node metastasis, and TNM staging, highlighting the pivotal role of TAMs in GC development and metastasis. In this review, we aim to comprehensively examine the bidirectional communication between GC cells and TAMs, the implications of alterations in the tumor microenvironment on immune escape, invasion, and metastasis in GC, targeted therapeutic approaches for GC, and the efficacy of potential GC drug resistance strategies.

IntroductionTumor-infiltrating myeloid cells (TIMs) are key regulators in tumor progression, but the similarity and distinction of their fundamental properties in pancreatic ductal adenocarcinoma (PDAC) remain elusive.MethodIn this study, we conducted scRNA-seq data analysis of cells from 12 primary tumor (PT) tissues, 4 metastatic (Met) tumor tissues, 3 adjacent normal pancreas tissues (Para), and PBMC samples across 16 PDAC patients, and revealed a heterogeneous TIMs environment in PDAC.ResultSystematic comparisons between tumor and non-tumor samples of myeloid lineages identified 10 necroptosis-associated genes upregulated in PDAC tumors compared to 5 upregulated in paratumor or healthy peripheral blood. A novel RTM (resident tissue macrophages), GLUL-SQSTM1- RTM, was found to act as a positive regulator of immunity. Additionally, HSP90AA1+HSP90AB1+ mast cells exhibited pro-immune characteristics, and JAK3+TLR4+ CD16 monocytes were found to be anti-immune. The findings were validated through clinical outcomes and cytokines analyses. Lastly, intercellular network reconstruction supported the associations between the identified novel clusters, cancer cells, and immune cell populations.ConclusionOur analysis comprehensively characterized major myeloid cell lineages and identified three subsets of myeloid-derived cells associated with necroptosis. These findings not only provide a valuable resource for understanding the multi-dimensional characterization of the tumor microenvironment in PDAC but also offer valuable mechanistic insights that can guide the design of effective immuno-oncology treatment strategies.

To study the effect of aging on the low-temperature crack resistance of fiber asphalt mixes, three kinds of fibers (lignin fiber, polyester fiber, and basalt fiber) were dry blended into AC-13 asphalt mixes to prepare unaged, asphalt aged (that is, the original asphalt material is subjected to aging treatment), short-term aged, and long-term aged fiber reinforced asphalt mixes. Semicircular bending (SCB) tests and scanning electron microscopy tests were used to analyze and study the effects of aging time and fiber type on the low-temperature properties of asphalt mixtures at an ambient temperature of −5 °C. The SCB test results indicated that: with the deepening of aging, the fracture toughness and fracture energy of the fiber asphalt mixture specimens will tend to decrease, and the aging of the original asphalt has a greater impact on the specimens without fiber; there was great variability in the effect of lignin fibers on the crack resistance of the mix, but it could be a good promoter in unaged asphalt mixes; polyester fiber is the material of choice for improving low-temperature crack resistance in long-term aging pavements; the incorporation of basalt fiber greatly enhances the crack resistance of asphalt mixes and is an excellent material for improving aging asphalt mixes. It is clearly seen by the scanning electron microscope test that with the deepening of aging, the adhesion of asphalt and aggregate gradually deteriorates, and even more so, there is the phenomenon of fine aggregate flaking, and the fiber cannot play an excellent role in reinforcement and crack resistance.

Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed cancer types worldwide. Despite significant advances in prevention and diagnosis, CRC is still one of the leading causes of cancer-related mortality globally. RAB27A, the member of RAB27 family of small GTPases, is the critical protein for intracellular secretion and has been reported to promote tumor progression. However, it is controversial for the role of RAB27A in CRC progression, so we explored the exact function of RAB27A in CRC development in this study. Based on the stable colon cancer cell lines of RAB27A knockdown and ectopic expression, we found that RAB27A knockdown inhibited proliferation and clone formation of SW480 colon cancer cells, whereas ectopic expression of RAB27A in RKO colon cancer cells facilitated cell proliferation and clone formation, indicating that RAB27A is critical for colon cancer cell growth. In addition, our data demonstrated that the migration and invasion of colon cancer cells were suppressed by RAB27A knockdown, but promoted by RAB27A ectopic expression. Therefore, RAB27A is identified as an onco-protein in mediating CRC development, which may be a valuable prognostic indicator and potential therapeutic target for CRC.

Abstract Background E2F1 is a transcription factor that regulates cell cycle progression. It is highly expressed in most cancer cells and activates transcription of cell cycle-related kinases. Stathmin1 and transforming acidic coiled-coil-containing protein 3 (TACC3) are factors that enhance the stability of spindle fiber. Methods The E2F1-mediated transcription of transforming acidic coiled-coil-containing protein 3 (TACC3) and stathmin1 was examined using the Cancer Genome Atlas (TCGA) analysis, quantitative polymerase chain reaction (qPCR), immunoblotting, chromatin immunoprecipitation (ChIP), and luciferase reporter. Protein–protein interaction was studied using co-IP. The spindle structure was shown by immunofluorescence. Phenotype experiments were performed through MTS assay, flow cytometry, and tumor xenografts. Clinical colorectal cancer (CRC) specimens were analyzed based on immunohistochemistry. Results The present study showed that E2F1 expression correlates positively with the expression levels of stathmin1 and TACC3 in colorectal cancer (CRC) tissues, and that E2F1 transactivates stathmin1 and TACC3 in CRC cells. Furthermore, protein kinase A (PKA)-mediated phosphorylation of stathmin1 at Ser16 is essential to the phosphorylation of TACC3 at Ser558, facilitating the assembly of TACC3/clathrin/α-tubulin complexes during spindle formation. Overexpression of Ser16-mutated stathmin1, as well as knockdown of stathmin1 or TACC3, lead to ectopic spindle poles including disorganized and multipolar spindles. Overexpression of wild-type but not Ser16-mutated stathmin1 promotes cell proliferation in vitro and tumor growth in vivo. Consistently, a high level of E2F1, stathmin1, or TACC3 not only associates with tumor size, lymph node metastasis, TNM stage, and distant metastasis, but predicts poor survival in CRC patients. Conclusions E2F1 drives the cell cycle of CRC by promoting spindle assembly, in which E2F1-induced stathmin1 and TACC3 enhance the stability of spindle fiber.

Phosphorus treatment can reduce Cd accumulation and Cd toxicity in rice, but alterations in the internal regulatory network of rice during this process have rarely been reported. We have removed the effect of cadmium phosphate precipitation from the hydroponic system, treated a pair of different Cd-response rice varieties with different levels of phosphorus and cadmium and examined the changes in physiological indicators and regulatory networks. The results demonstrated that phosphorus treatment significantly reduced Cd accumulation in both types of rice, although the antioxidant systems within the two types of rice produced opposite responses. Overall, 3 mM phosphorus treatment to Cd-N decreased the expression of OsIAA17 and OsACO1 by 32% and 37%, respectively, while increasing the expression of OsNR2 by 83%; these three genes regulate the synthesis of auxin, ethylene, and nitric oxide in rice. IAA and NO levels in rice shoots increased by 24% and 96%, respectively, and these changes contribute to Cd detoxification. The cadmium transporter genes OsHMA2, OsIRT1, and OsABCC1 were significantly down-regulated in Cd-N roots after triple phosphorus treatment. These data suggest that phosphorus treatment can reduce Cd accumulation and enhance Cd resistance in rice by affecting the expression of signaling molecules.

Abstract Background Xinjiang is an economically underdeveloped area in China, but the obesity rate of children and adolescents is increasing year by year. Physical fitness and body mass index (BMI) are very important factors for healthy development, whereas few studies focus on the relationship between them in this region. This study aimed to explore the relationship between physical fitness and BMI of children and adolescents aged 7 to 18 in Xinjiang. Method A total of 17,356 children and adolescents aged 7–18 years were involved. BMI was divided into five levels by percentiles, from very low to very high. Physical fitness was evaluated by five indicators: grip strength, standing long jump, sit-and-reach, 50 m dash, and endurance running. Single-factor analysis of variance was used to compare the Z-scores of the five physical fitness indicators among different BMI levels for the four age groups by gender. A nonlinear quadratic regression model was used to evaluate the relationship between BMI and each indicator in the four age groups. Result There is a significant correlation between the five health-related indicators (grip strength, standing long jump, sit and reach, 50 m dash, endurance run) at two age groups (13-15 yrs., 16-18 yrs) of children and adolescents in Xinjiang, China. The range of the Pearson coefficient is 0.048 ~ 0.744. For the other two age groups (7-9 yrs., 10-12 yrs.,) significant correlations are found only in some indicators, and the Pearson coefficient ranges from 0.002 to 0.589. The relationship between BMI and physical fitness presents an U-shaped or inverted U-shaped curve in most age groups(R2 ranges from − 0.001 to 0.182. Children and adolescents with normal BMI score higher on physical fitness tests, and boys (R2 ranges from − 0.001 to 0.182) are more pronounced than girls (R2 ranges from 0.001 to 0.031). Conclusion Children and adolescents with a BMI above or below the normal ranges have lower physical fitness than those with normal BMI. BMI and physical fitness have an U-shaped or inverted U-shaped curve relationship, and the impact is more evident in boys than girls. Targeted actions such as improving the quality of physical education classes, advocating students to keep a balanced diet and physical exercise should be taken designedly.

Background Changes in cerebral haemodynamics following endovascular therapy (EVT) for large-vessel occlusion stroke may affect the outcomes of patients with acute ischaemic stroke (AIS); however, evidence supporting this belief is limited. This study aims to identify the early haemodynamic predictors of poor outcomes in patients with AIS caused by anterior circulation large-artery occlusion after undergoing EVT and to evaluate the usefulness of these indicators in predicting functional outcomes at 90 days. Methods This retrospective study was conducted at a single academic hospital, using prospectively collected data. We enrolled adult patients with acute anterior circulation stroke who underwent EVT. Transcranial colour-coded sonography (TCCS) examinations of the recanalised and contralateral middle cerebral artery (MCA) were performed within 12 h after undergoing EVT. Haemodynamic indicators were analysed to determine their association with poor functional outcomes (modified Rankin Scale: 3–6) 90 days after stroke. Receiver operating characteristic (ROC) curves were used to evaluate the usefulness of haemodynamic indicators in predicting functional outcomes. Results In total, 108 patients (median age: 66 years; 69.4% males) were enrolled in this study. Complete recanalization was achieved in 93 patients (86.1%); however, 60 patients (55.6%) had a poor 90-day outcome. The peak systolic velocity (PSV) ratio, adjusted PSV ratio, mean flow velocity (MFV) ratio, and adjusted MFV ratio of the MCA were significantly higher in patients with poor prognosis than in patients with good prognosis (p

BackgroundSince the start of the coronavirus 2019 pandemic, people have faced many challenges, including in relation to sleep quality and psychological health. This study aims to analyze the association between sleep quality and psychological symptoms among university students in China, and to provide reference data to facilitate the development of interventions to improve the physical and mental health of university students.MethodsA stratified cluster sampling method was used to investigate the sleep quality and psychological symptoms of 6,363 university students in China. The Chi-square test was used to analyze differences in sleep quality among groups. Logistic regression analysis was used to analyze the association between sleep quality and psychological symptoms.ResultsThe proportions of Chinese university students with good, medium, and poor sleep quality were 25.73, 10.99, and 63.28%, respectively. The overall rate of psychological symptoms was 16.5%. Logistic regression analysis showed that, in general, university students with poor sleep quality had a higher risk of psychological symptoms than those with good sleep quality (OR = 1.53, 95%CI: 1.28, 1.84, p

Summary Colistin is recognized as a last‐resort treatment option against multi‐drug resistant bacteria including carbapenem‐resistant Enterobacteriaceae (CRE). However, the plasmid‐mediated colistin‐resistance gene mcr‐1 has been reported globally resulting in an increase of colistin‐resistant bacteria. A quick and accurate method for determining the pathogen resistance of colistin is therefore crucial in the clinic. Matrix‐assisted laser desorption/ionization time‐of‐flight mass spectrometry (MALDI‐TOF MS) is a potential tool forto be applied for antimicrobial susceptibility testing. We compared the growth of Escherichia coli strains in the presence or absence of colistin. Automated analyses of the spectra were performed with a prototype software tool written with package R. Three mcr‐1‐positive and six mcr‐1‐negative E. coli were used for establishing the model to obtain the optimal incubation time, the breakpoint concentration of colistin and cut‐off of the relative growth (RG) value. The distinction between susceptible and resistant strains was already noticeable after 2 h of incubation. The best separation between the susceptible and resistant strains was achieved at a concentration of 4 µg ml‐1 and a relative growth cut‐off value of 0.6. Application of the model for the analysis of 128 E. coli isolates, a sensitivity of 97.4% and a specificity of 88.2% were achieved compared with colistin MIC results. The rapid MALDI‐TOF MS‐based method approach is simple to set‐up, uses a short incubation time, and had excellent outcomes with respect to sensitivity and specificity for colistin sensitivity testing in Escherichia coli.

Pseudomonas aeruginosa is one of the most common opportunistic pathogens causing severe nosocomial infections for its patterns of multidrug resistance, particularly for carbapenems. Timely epidemiological surveillance could greatly facilitate infection control of P. aeruginosa and many deadly pathogens alike. IR Biotyper (IRBT), is a novel real-time typing tool, based on a Fourier-transform infrared (FTIR) spectroscopy system. It is critical to comprehensively establish and evaluate the feasibility of IRBT in P. aeruginosa strain typing. In the current study, we first established standards and schemes for its routine laboratory application, and we found that Mueller–Hinton agar plates give better discriminatory power than blood agar plates. Data showed that the cut-off value of 0.15 with an additional 0.025 range was optimal. Secondly, 27 clinically isolated carbapenem-resistant P. aeruginosa (CRPA) strains collected from October 2010 to September 2011 were evaluated for typing effectiveness by comparing IRBT to the other commonly used typing methods, such as multi-locus sequence typing (MLST), pulsed-field gel electrophoresis (PFGE) and whole-genome sequencing (WGS)-based typing. When using WGS-based typing as the reference method, the typing method of FTIR spectroscopy (AR = 0.757, SID = 0.749) could better cluster P. aeruginosa strains than MLST and in silico serotyping (AR = 0.544, SID = 0.470). Though PFGE showed the highest discriminatory power, low concordance was observed between PFGE and the other methods. Above all, this study demonstrates the utility of the IRBT as a quick, low-cost, real-time typing tool for the detection of CRPA strains.

IntroductionCarbapenemase-producing Enterobacteriales (CPE) are a major health threat worldwide, and therefore the development of rapid detection methods is needed. Here, we established a method to distinguish metallo-β-lactamase and serine carbapenemases using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) with ethylenediaminetetraacetic acid (EDTA) and phenylboronic acid (PB).MethodsTo assess the specificity and sensitivity of the method, 110 carbapenemase-producing and 72 carbapenemase-negative Enterobacteriales isolates were collected, among which 51 strains produced only metallo-β-lactamase, 55 strains only serine carbapenemases, and four strains both metallo-β-lactamase and serine carbapenemases. In the proposed MALDI-TOF MS method, imipenem (IPM) and the bacterial strains to be tested were mixed, EDTA and/or PB was added, and the mixture was incubated for 4 h. The carbapenemase type was confirmed by the IPM waveform spectrum before and after incubation.ResultsBased on the presence, absence, and recovery of the IPM-cyano-4-hydroxy-cinnamic acid-specific waveform peak near 479 m/z, the detection sensitivity and specificity of the method were 98.2 and 100%, respectively.DiscussionAlthough CPE detection by MALDI-TOF MS has been studied previously, our method distinguishes between metallo-β-lactamase and serine carbapenemases, which will be very helpful for the clinical selection of antibiotics.

Introduction: Flat dosing regimen has recently been approved for programmed death receptor-1 (PD-1) inhibitors including toripalimab, nivolumab and pembrolizumab. The objective of this study is to provide pharmacological evidence for a flat dosing regimen of toripalimab by assessing the efficacy and safety profile of a 240 mg Q3W flat dose relative to the currently approved 3 mg/kg Q2W.Methods: A population pharmacokinetic (PopPK) model was established based on 1,014 evaluable patients in 13 clinical studies. The exposure-objective response rate (ORR, n = 234) and exposure-safety (n = 152) analyses were performed by logistic regression. Three safety endpoints including grade ≥ 3 adverse events (AEs), treatment-related grade ≥ 3 AEs, and AEs leading to study drug discontinuation were evaluated. Progression-free survival (PFS, n = 234) was evaluated using a Cox proportional hazard model with the Kaplan-Meier survival curve.Results: The PK profiles of toripalimab are best described by a two-compartment model with time-varying clearance characterized by a sigmoidal maximum effect (Emax) function. Simulations for the first dose and steady-state exposures for the 240 mg Q3W dosing regimen were comparable to those for the 3 mg/kg Q2W dosing regimen with 95% exposure coverage ranging from 88% to 96%. The exposure-safety analysis showed that the probability of an adverse event occurring did not increase with increases in toripalimab exposure. A flat exposure-response relationship for ORR was identified. The Kaplan–Meier survival curve showed that exposure was a predictor for PFS; however, no difference in treatment benefit was demonstrated across exposure quantiles using a Cox proportional hazard model.Discussion: This study revealed that toripalimab exposure of 240 mg Q3W dosing regimen was comparable to 3 mg/kg Q2W dosing regimen. The safety and efficacy E-R results of 240 mg Q3W is flat. Hence, the 240 mg Q3W dosing regimen is determined to be a preferred therapeutic dosage for toripalimab due to the convenience of flat dose.

ABSTRACT This study reports an extensively drug resistant Pseudomonas aeruginosa strain PA166-2 which was of chicken origin and carrying blaIMP-45, tet(X6) and tmexCD3-toprJ3 on a single plasmid. The strain was characterized by antimicrobial susceptibility testing, resistance gene screening, conjugation assay, whole-genome sequencing, and bioinformatics analysis. Strain PA166-2 was resistant to tigecycline and carbapenems. It belonged to ST313 and carried a plasmid pPA166-2-MDR, which belongs to the incompatibility group IncpRBL16. pPA166-2-MDR harbored a 78 Kb multidrug resistance (MDR) region carrying an array of antimicrobial resistance genes, including blaIMP-45, tet(X6), and tmexCD3-toprJ3. The gene blaIMP-45 was inserted into the backbone of plasmid pPA166-2-MDR within a class 1 integron, In786. tmexCD3-toprJ3 in plasmid pPA166-2-MDR was inserted in umuC, constituting the genetic context of ISCfr1-tnfxB3-tmexC3-tmexD3-toprJ3-△umuC. The genetic context of tet(X6) in this plasmid was identical to that of other reported plasmid-borne tet(X) variants, namely, tet(X6)-abh-guaA-ISVsa3. To the best of our knowledge, this is the first report of the cooccurrence of blaIMP-45, tet(X6), and tmexCD3-toprJ3 in one plasmid in Pseudomonas sp. The emergence of plasmid-mediated tigecycline resistance genes tmexCD3-toprJ3 and tet(X6), as well as carbapenemase genes from chickens expanded the global transmission of vital resistance genes. Findings from us and from others indicate that plasmids of the incompatibility group IncpRBL16 may serve as a reservoir for carbapenem and tigecycline resistance determinants. IMPORTANCE Pseudomonas aeruginosa is an opportunistic pathogen that causes infections that are difficult to treat. This study reported, for the first time, the occurrence of last-resort antibiotic resistance determinants blaIMP-45, tet(X6), and tmexCD3-toprJ3 on a single plasmid in P. aeruginosa from chickens. The P. aeruginosa strain belonged to ST313 and was resistant to last-line antibiotics, namely, carbapenems and tigecycline. The plasmid carrying the last-line resistance genes belonged to the incompatibility group IncpRBL16, which was reported to contain different profiles of accessory modules and thus carried diverse collections of resistance genes. The emergence of plasmid-mediated tigecycline resistance genes tmexCD3-toprJ3 and tet(X6), as well as carbapenemase genes, from chickens expanded the global transmission of vital resistance genes. The results in this study highlighted that IncpRBL16 plasmids may serve as a reservoir for the dissemination of resistance genes. Control measures should be implemented to prevent the further dissemination of such strains.

BackgroundTryptophan 2,3-dioxygenase (TDO2) is one of the emerging immune checkpoints. Meanwhile, TDO2 is also a key enzyme in the tryptophan (Trp)–kynurenine (Kyn) signaling pathway. Many studies have evaluated that TDO2 is highly expressed in various malignant tumor patients and plays a prognostic role. However, the sample size of a single prognostic study was small, and the results were still controversial.MethodsWe used Stata software and referenced the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement to conduct a meta-analysis on TDO2 and its clinical features and prognosis. We searched the PubMed, Cochrane Library, and Web of Science databases to find publications concerning TDO2 expression in malignant tumor patients up to June 2021. We used the Newcastle–Ottawa Scale (NOS) to evaluate the bias risk of the included literature. Risk ratios (RRs) and hazard ratios (HRs) were used for clinical outcomes, specifically overall survival (OS) and progression-free survival (PFS). In addition, we used data from The Cancer Genome Atlas (TCGA) to verify our conclusions.ResultsNine studies including 667 patients with malignant tumors were identified. Our results suggested that overexpression of TDO2 was statistically correlated with poor OS and poor PFS (HR = 2.58, 95% CI = 1.52–4.40, p = 0.0005; HR = 2.38, 95% CI = 0.99–5.73, p = 0.05). In terms of clinicopathological characteristics, the overexpression level of TDO2 was statistically correlated with TNM (tumor–node–metastasis) stage (RR = 0.65, 95% CI = 0.48–0.89, p = 0.002) and regional lymph node metastasis (RR = 0.76, 95% CI = 0.59–0.99, p = 0.04). Subgroup analysis revealed the potential sources of heterogeneity. In addition, bioinformatics studies suggested that the level of TDO2 was high in malignant tumors and higher in cancer tissue than in matched paracarcinoma tissue. Gene enrichment analysis showed that TDO2 was closely related to immune response.ConclusionOverall, TDO2 may be a biomarker for the survival and prognosis of patients with malignant tumors and a potential therapeutic target in the future.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=260442, identifier (CRD42021260442)

Background: Diagnostic tools for hepatocellular carcinoma (HCC) are critical for patient treatment and prognosis. Thus, this study explored the diagnostic value of the exosomal microRNA panel for HCC.Methods: Expression profiles of microRNAs in exosomes and plasma of HCC and control groups were assessed using microRNA microarray analysis. Reverse transcription-quantitative PCR was applied to evaluate the expression of candidate microRNAs in blood samples from 50 HCC patients, 50 hepatic cirrhosis patients, and 50 healthy subjects. The area calculated the diagnostic accuracy of the microRNAs and microRNA panel under the receiver operating characteristic curve (AUC).Results: MicroRNA microarray analysis revealed that there were more differentially expressed microRNAs in the exosome HCC group than plasma HCC group. Among the 43 differentially expressed microRNAs contained in both exosomes and plasma, we finally decided to testify the expression and diagnostic significance of microRNA-26a, microRNA-29c, and microRNA-199a. The results indicated that expression of the microRNA-26a, microRNA-29c, and microRNA-199a in both exosomes and plasma was significantly lower in HCC patients compared with hepatic cirrhosis and healthy group. Interestingly, exosomal microRNAs were substantially more accurate in diagnosing HCC than microRNAs and alpha-fetoprotein in plasma. Moreover, the exosomal microRNA panel containing microRNA-26a, microRNA-29c, and microRNA-199a showed high accuracy in discriminating HCC from healthy (AUC = 0.994; sensitivity 100%; specificity 96%) and hepatic cirrhosis group (AUC = 0.965; sensitivity 92%; specificity 90%).Conclusion: This study revealed that the exosomal microRNA panel has high accuracy in diagnosing HCC and has important clinical significance.

As the heart of aircraft, the aero-engine is not only the main power source for aircraft flight but also an essential guarantee for the safe flight of aircraft. Therefore, it is of great significance to find effective methods for remaining useful life (RUL) prediction for aero-engines in order to avoid accidents and reduce maintenance costs. With the development of deep learning, data-driven approaches show great potential in dealing with the above problem. Although many attempts have been made, few works consider the error of the point prediction result caused by uncertainties. In this paper, we propose a novel RUL probability prediction approach for aero-engines with prediction uncertainties fully considered. Before forecasting, a principal component analysis (PCA) is first utilized to cut down the dimension of sensor data and extract the correlation between multivariate data to reduce the network computation. Then, a multi-layer bidirectional gate recurrent unit (BiGRU) is constructed to predict the RUL of the aero-engine, while prediction uncertainties are quantized by the improved variational Bayesian inference (IVBI) with a Gaussian mixture distribution. The proposed method can give not only the point prediction of RUL but also the confidence interval of the prediction result, which is very helpful for real-world applications. Finally, the experimental study illustrates that the proposed method is feasible and superior to several other comparative models.

Summary Klebsiella pneumoniae has emerged as one of the most important pathogens that frequently encounter in community‐acquired or hospital‐acquired infections. Timely epidemiological surveillance could greatly facilitate infection control of K. pneumoniae and many deadly pathogens alike. In this study, we evaluated the performance of the IR Biotyper, a Fourier transform infrared (FTIR) spectroscopy system for K. pneumoniae isolates typing through (i) optimizing the culture scheme and defining the cutoff value (COV) range and (ii) comparing with commonly used typing tools such as multi‐locus sequence typing (MLST), pulsed‐field gel electrophoresis (PFGE) and whole‐genome sequencing (WGS). We found that a non‐selective and non‐chromogenic medium with 24 ± 2 h incubation gives the best discriminatory power for the IR Biotyper (IRBT). COV evaluation indicated that the IRBT is a robust typing method with good reproducibility. Besides, we observed that the modified H2O‐EtOH suspensions preparation method could enhance the quality of the spectrum, especially for those hypermucoviscous strains. For the method comparison study, our data demonstrated that FTIR spectroscopy could accurately cluster K. pneumoniae strains. The typing results of the IRBT were almost entirely in concordance with those from PFGE and WGS. Together with the advantages such as low costs and short turnaround time (less than 3h), the IRBT is a promising tool for strain typing that could make real‐time outbreak investigation a reality.

Abstract Background Glucocorticoid treatment is used in children with Graves’ disease (GD) only in cases of exophthalmos. The purpose of this study was to observe the effects of glucocorticoid pulse therapy on thyroid function and thyroid antibodies in children with GD. Methods Twenty children who were treated by intravenous methylprednisolone pulse therapy (MPT) followed by oral prednisolone administration and antithyroid drugs were included in the pulse group. Twenty children who were treated with antithyroid drugs alone were included in the control group. Serum concentrations of free triiodothyronine (FT3), free thyroxine (FT4), thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb), and thyrotropin receptor antibodies (TRAb) were recorded at baseline and 10 days, 30 days, and 60 days after treatment. Results Significant differences in FT3, FT4, TSH, TPOAb, TGAb, and TRAb levels were found in the pulse group and the control group from baseline to follow-up time points (all p 0.05). No significant differences were observed in FT3, FT4, TSH, TPOAb, and TGAb levels between the pulse group and the control group (all p > 0.05). Conclusions The results suggested that the effect of intravenous MPT followed by oral prednisolone on TRAb level was temporary in children with GD. Glucocorticoid pulse therapy was not beneficial for the sustained recovery of thyroid function.

The proton exchange membrane fuel cell (PEMFC) is a promising power source, but the short lifespan and high maintenance cost restrict its development and widespread application. Performance degradation prediction is an effective technique to extend the lifespan and reduce the maintenance cost of PEMFC. This paper proposed a novel hybrid method for the performance degradation prediction of PEMFC. Firstly, considering the randomness of PEMFC degradation, a Wiener process model is established to describe the degradation of the aging factor. Secondly, the unscented Kalman filter algorithm is used to estimate the degradation state of the aging factor from monitoring voltage. Then, in order to predict the degradation state of PEMFC, the transformer structure is used to capture the data characteristics and fluctuations of the aging factor. To quantify the uncertainty of the predicted results, we also add the Monte Carlo dropout technology to the transformer to obtain the confidence interval of the predicted result. Finally, the effectiveness and superiority of the proposed method are verified on the experimental datasets.

Porphyromonas gingivalis is an important oral pathogen that causes periodontal disease and is difficult to culture under conventional conditions. Therefore, a reliable technique for detecting this pathogenic bacterium is required. Here, isothermal recombinase polymerase amplification (RPA), a new nucleic acid amplification method, was combined with a visualization method based on nanoparticle-based lateral flow strips (LFS) for the rapid detection of P. gingivalis. The species-specific 16S rRNA sequence of P. gingivalis was used as the target for RPA, and a set of specific primer–probe combinations were designed and screened to amplify the target sequences. As a thermostatic amplification method, the RPA reaction, under optimized conditions, takes only 30 min to complete at a constant temperature (37°C). The amplification reaction products can be detected visually by LFS without any need for special equipment. The RPA-LFS method established for the detection of P. gingivalis was shown to be highly specific in distinguishing P. gingivalis from other pathogenic organisms by using 20 clinical isolates of P. gingivalis and 23 common pathogenic microorganisms. Susceptibility measurements and probit regression analysis were performed with gradient dilutions of P. gingivalis genomic DNA. The method was obtained to be highly sensitive, with a detection limit of 9.27 CFU per reaction at 95% probability. By analyzing the gingival sulcus fluid specimens from 130 patients with chronic periodontitis, the results showed that the RPA-LFS method detected 118 positive cases and 12 negative cases of P. gingivalis, and the results obtained were consistent with those of a conventional PCR assay. The RPA–LFS method is an efficient, rapid, and convenient diagnostic method that simplifies the tedious process of detecting P. gingivalis.

Emergence of tigecycline-resistance tet(X) genes is of concern. Here, the authors determine tet(X) prevalence in more than 6,000 clinical Gram-negative bacterial isolates collected between 1994 to 2019 in hospitals in China and suggest that Flavobacteriaceae could be the potential ancestral source of the tigecycline resistance genes.

ABSTRACTCarbapenem-resistant Klebsiella pneumoniae (CRKP) is emerging as a worldwide public health concern; however, the long-term molecular epidemiological surveillance of clinical CRKP in China is limited. We conducted a retrospective observational study (2008–2018) to assess the prevalence, susceptibility, risk factors and molecular epidemiology of clinical CRKP isolates. We found the prevalence of CRKP increased from 2.5%, 2008 to 15.8%, 2018. CRKP were significantly more frequent among hospitalized patients from ICU, and it was significantly more likely to be isolated from the capital city (Hangzhou) and the patients aged ≥60 years. Additionally, seasons and specimen types were associated with CRKP infections. The main CRKP sequence type (ST) was ST11, and blaKPC-2 was the most prevalent gene variant. Together these data reveal an increasing incidence and resistance trends among CRKP, especially the ST11-blaKPC-2-CRKP, in Zhejiang, during 2008–2018. Our findings are important for hospitals to limit its dissemination and optimize antibiotic administration.

We presented a 67-year-old nonsmoking female lung adenocarcinoma patient with novel epidermal growth factor receptor (EGFR) A289G/F287_G288insHA cis mutations who responded positively to sintilimab combined with regorafenib and albumin paclitaxel, and sequential treatment of icotinib. Gene mutations in patients were detected by next-generation sequencing (NGS) technology, and changes in gene mutations before and after treatments were observed by ctDNA monitoring. We observed the efficacy of the patient through chest computed tomography (CT) imaging and carcinoembryonic antigen (CEA) level and found that the patient benefited from immunotherapy in combination with antiangiogenesis and chemotherapy for more than 1 year, CEA levels initially fell sharply and then rebounded during the treatment period. After changing to EGFR-TKI therapy, the CEA level of the patient does not only decreased sharply at the initial stage of treatment but also rebounded and increased at the later stage of treatment. The patient was tested for genetic mutations after 4 months of sequential EGFR-TKI therapy and was found to have lost all previous EGFR mutations, which may be the cause of resistance to targeted drug icotinib. We believe that our findings have enriched the EGFR mutation spectrum in NSCLC and highlighted the possible choice for patients harboring this mutation by immunotherapy combined with chemotherapy and antivascular therapy, and EGFR-TKI-targeted therapy.

Previous studies indicated that G-protein coupled receptor 174 (GPR174) is involved in the dysregulated immune response of sepsis, however, the clinical value and effects of GPR174 in septic patients are still unknown. This study is aimed to evaluate the potential value of GPR174 as a prognostic biomarker for sepsis and explore the pathological function of GPR174 in cecal ligation and puncture (CLP)-induced septic mice. In this prospective longitudinal study, the expressions of peripheral GPR174 mRNA were measured in 101 septic patients, 104 non-septic ICU controls, and 46 healthy volunteers at Day 1, 7 after ICU (Intensive Care Unit) admission, respectively. Then, the clinical values of GPR174 for the diagnosis, severity assessment, and prognosis of sepsis were analyzed. Moreover, the expressions of GPR174 mRNA in CLP-induced septic mice were detected, and Gpr174-knockout (KO) mice were used to explore its effects on inflammation. The results showed that the levels of GPR174 mRNA were significantly decreased in septic patients compared with non-septic ICU and healthy controls. In addition, the expressions of GPR174 mRNA were correlated with the lymphocyte (Lym) counts, C-reactive protein (CRP), and APACHE II and SOFA scores. The levels of GPR174 mRNA at Day 7 had a high AUC in predicting the death of sepsis (0.83). Further, we divided the septic patients into the higher and lower GPR174 mRNA expression groups by the ROC cut-off point, and the lower group was significantly associated with poor survival rate (P = 0.00139). Similarly, the expressions of peripheral Gpr174 mRNA in CLP-induced septic mice were also significantly decreased, and recovered after 72 h. Intriguingly, Gpr174-deficient could successfully improve the outcome with less multi-organ damage, which was mainly due to an increased level of IL-10, and decreased levels of IL-1β and TNF-α. Further, RNA-seq showed that Gpr174 deficiency significantly induced a phenotypic shift toward multiple immune response pathways in septic mice. In summary, our results indicated that the expressions of GPR174 mRNA were associated with the severity of sepsis, suggesting that GPR174 could be a potential prognosis biomarker for sepsis. In addition, GPR174 plays an important role in the development of sepsis by regulating the inflammatory response.

ABSTRACT Pseudomonas aeruginosa may become multidrug-resistant (MDR) due to multiple inherited and acquired resistance mechanisms. The human gastrointestinal tract is known as a reservoir of P. aeruginosa and its resistance genes. In this study, we collected 76 intestinal carbapenem-resistant P. aeruginosa (CRPA) strains from clinical inpatients admitted to our hospital from 2014 to 2019, together with their medical data. We aim to analyze the clinical risk factors associated with CRPA infection and its molecular features. We found that the prevalence of CRPA in P. aeruginosa strains was 41.3% (95% confidence interval [CI], 34.1 to 48.8%). We also identified four variables associated with intestinal CRPA positivity, prior antibiotic exposure to aminoglycosides or carbapenems, underlying diabetes mellitus, and extraintestinal P. aeruginosa isolation. blaKPC-2 is the only detected carbapenemase gene, accounting for 21.1% of CRPA strains. The genetic environment showed that the blaKPC-2 gene was flanked immediately by ISKpn8 and ISKpn6 and several other mobile elements further upstream or downstream. Four sequence types (STs) were identified, with ST463 as the dominant sequence type. In conclusion, screening for P. aeruginosa colonization upon hospital admission could reduce the risk of P. aeruginosa infection and spread of CRPA in the hospital. IMPORTANCE Pseudomonas aeruginosa may become multidrug-resistant (MDR) due to multiple inherited and acquired resistance mechanisms. The human gastrointestinal tract is known as a reservoir of P. aeruginosa and its resistance genes. Risk factor analysis and molecular epidemiology are critical for preventing their potential dissemination. Here, we identified four risk factors associated with intestinal CRPA—prior antibiotic exposure to aminoglycosides or carbapenems, underlying diabetes mellitus, and extraintestinal P. aeruginosa isolation. Further, we found similar genetic environments with several mobile elements surrounding the blaKPC gene, a carbapenemase gene only detected in intestinal CRPA strains in this study. These findings are of significant public health importance, as the information will facilitate the control of the emergence and spread of CRPA.

Objectives: To develop an effective enrichment method for tet(X) detection, we performed PCR and Sanger sequencing to screen and confirm the presence of tet(X) gene. Methods: Species were identified by MALDI-TOF MS analysis. The minimum inhibitory concentrations (MICs) of common antibiotics were determined by broth microdilution and interpreted according to the CLSI guidelines and EUCAST breakpoints. Results: We obtained 29 (2.26%, 29/1284) tet(X4)-positive Escherichia coli, and 96.6% of those (28 isolates) exhibited resistance to tigecycline. Conclusion: This specific screening strategy for functional tet(X) mediating tigecycline resistance will be useful to facilitate development and advancement of our knowledge of tet(X).

Bloodstream infections (BSI) are associated with high morbidity and mortality and remain a leading cause of death. Blood culture (BC) including the identification and the antimicrobial susceptibility testing of the causative microorganisms should be performed as soon as possible. In this study, we developed an in-house rapid antimicrobial susceptibility testing (rAST) protocol for positive BC. First, the rAST was performed in the simulated positive BC of standard strains (Escherichia coli ATCC 25922, Staphylococcus aureus ATCC 25923, and Pseudomonas aeruginosa ATCC 27853) at three different times to assess the reproducibility and operability by dispensing four drops of BC broth onto a Mueller–Hinton agar plate after a positive signal. Furthermore, the rAST was performed in clinical positive BCs. The results of rAST at 4, 6, 8, and 18 h of incubation were compared with results of the standard 16- to 20-h disk diffusion method, and the preliminary breakpoints of the rAST method were established according to the inhibition diameter of sensitive strains and resistant strains. Finally, the rAST was performed in the simulated positive BC of clinical strains to evaluate the availability of the preliminary breakpoints. The rAST results of standard strains were distributed evenly at three different times. Among the 202 clinical strains used to establish the preliminary breakpoints, the number of zone diameters that could be read and interpreted (60, 87, 98, and 100%) increased with incubation time (4, 6, 8, and 18 h), and the categorical agreement was acceptable, with total error rates of 3.0, 2.3, 2.1, and 1.3% at 4, 6, 8, and 18 h of incubation, respectively. In conclusion, the in-house rAST protocol for positive BC can be implemented in routine laboratories. It provides reliable antimicrobial susceptibility testing results for BSI pathogens after 4–6 h of incubation.

Health care-associated infections, also known as nosocomial infections, are the most frequent adverse events in health care delivery worldwide, causing high rates of morbidity and mortality and high health care costs. Pseudomonas aeruginosa

Abstract Background Secondary infection has a higher incidence in septic patients and affects clinical outcomes. This study aims to investigate the clinical characteristics, risk factors, immune status and prognosis of secondary infection of sepsis. Methods A four-year retrospective study was carried out in Zhongshan Hospital, Fudan University, enrolling septic patients admitted between January, 2014 and January, 2018. Clinical data were acquired from medical records. CD14+ monocyte human leukocyte antigen-D related (HLA-DR) expression and serum cytokines levels were measured by flow cytometry and enzyme-linked immunosorbent assay (ELISA) respectively. Results A total of 297 septic patients were enrolled, 92 of whom developed 150 cases of secondary infections. Respiratory tract was the most common site of secondary infection (n = 84, 56%) and Acinetobacter baumanii the most commonly isolated pathogen (n = 40, 31%). Urinary and deep venous catheterization increased the risk of secondary infection. Lower HLA-DR expression and elevated IL-10 level were found in secondary infection group. The expected prolonged in-hospital stay owing to secondary infection was 4.63 ± 1.87 days. Secondary infection was also associated with higher in-hospital, 30-day and 90-day mortality. Kaplan-Meier survival analysis and Log-rank test revealed that secondary infection group had worse survival between day 15 and day 90. Conclusions Urinary and deep venous catheterization increased the risk of secondary infection, in which underlying immunosuppression might also play a role. Secondary infection affected the prognosis of septic patients and prolonged in-hospital length of stay.

Abstract Background Gram-positive bacteria are dangerous and challenging agents of infection due to their increasing resistance to antibiotics. We aim to analyse the epidemiology and risk factors of methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) in Zhejiang China. Methods Gram-positive bacteria (including S. aureus, Enterococcus faecalis and Enterococcus faecium) were collected from eighty-six hospitals of eleven cities in Zhejiang China from 2015 to 2017. The detection rates of MRSA and VRE infection were calculated for the non-duplicated isolate according to year, region, hospital level, patient age, specimen type and patient category. Meanwhile, the detected resistances of MRSA, E. faecalis and E. faecium to different antibiotics from 2015 to 2017 were compared. The risk factors and the differences in MRSA and VRE detection rates were compared using odds ratio (OR) with 95% confidence interval (95% CI) and Chi-square test respectively. Results From 2015 to 2017, the detection rates of MRSA and VRE decreased gradually. The cities with the highest MRSA and VRE detection rates tended to be adjacent; for example, the neighbouring cities Hangzhou and Quzhou had simultaneously high rates of MRSA and VRE infection. Patients from IIIA hospital who were older than 75 years and in the intensive care unit (ICU) were most at risk. No vancomycin-resistant isolate was found in MRSA. Resistance of E. faecalis and E. faecium to vancomycin and linezolid decreased slightly and then maintained a low level. Conclusions The detection rates of MRSA and VRE stayed at moderate and low levels during the three year period of this study, while local dissemination was found in MRSA and VRE isolates. Sustained surveillance is necessary to prevent the spread or clonal dissemination of drug-resistant strains in Zhejiang China.

Abstract Background This article intends to explore the association between interleukin-6 gene (IL-6) -174 G/C single nucleotide polymorphism (SNP) and the risk and mortality of sepsis by conducting this updated meta-analysis with trial sequential analysis. Methods References were made to PubMed, Web of Science, China National Knowledge Infrastructure for studies available by September 2018. Each publication was screened for its eligibility and data accessible. Statistical analysis was conducted on Stata 14.1 and TSA software 0.9.5.10 Beta Results Twenty studies (including 3282 cases and 4926 controls) and eight studies (including 610 cases and 1856 controls) were respectively enrolled in the analysis on the association between IL-6-174 G/C polymorphism and the risk and mortality of sepsis. The results did not present any association between IL-6-174 G/C polymorphism and the risk and mortality of sepsis. An exception was that IL-6-174 G/C polymorphism was correlated with worse outcome in non-adults in recessive model, co-dominant model (CC vs. GG) and allelic model, while trial sequential analysis revealed it could be a false positive result nevertheless. Conclusions IL-6-174 G/C polymorphism is not associated with the risk and mortality of sepsis. Trial sequential analysis showed that a large sample size was needed to get a more reliable result of the association between IL-6-174 G/C polymorphism and sepsis in non-adults.

This paper investigates the problem of fault detection, isolation, and estimation for a networked system with actuator and sensor faults. To deal with the bandwidth constraint, an event-triggered scheduling mechanism is utilized to determine whether the sensor observation shall be transmitted to the fault filter according to the importance of information. In this study, two independent Markovian jump chains are introduced to describe the temporal occurrence of sensor fault and the random switching between the normal condition and the faulty ones of the actuator, respectively. To alleviate the compromise between the model number of fault models and computational complexity in the existing interacting multiple models (IMM) approaches, a novel event-triggered fault detection and diagnosis algorithm is proposed based on the augmented IMM framework, where the fault location to be detected is added into the model set and the fault amplitude to be estimated is augmented into the system state. Finally, a Monte Carlo simulation involving tracking a two-dimension moving target is provided to illustrate the effectiveness and efficiency of the proposed method.

This paper addressed the optimal policy selection problem of attacker and sensor in cyber-physical systems (CPSs) under denial of service (DoS) attacks. Since the sensor and the attacker have opposite goals, a two-player zero-sum game is introduced to describe the game between the sensor and the attacker, and the Nash equilibrium strategies are studied to obtain the optimal actions. In order to effectively evaluate and quantify the gains, a reinforcement learning algorithm is proposed to dynamically adjust the corresponding strategies. Furthermore, security state estimation is introduced to evaluate the impact of offensive and defensive strategies on CPSs. In the algorithm, the ε-greedy policy is improved to make optimal choices based on sufficient learning, achieving a balance of exploration and exploitation. It is worth noting that the channel reliability factor is considered in order to study CPSs with multiple reasons for packet loss. The reinforcement learning algorithm is designed in two scenarios: reliable channel (that is, the reason for packet loss is only DoS attacks) and unreliable channel (the reason for packet loss is not entirely from DoS attacks). The simulation results of the two scenarios show that the proposed reinforcement learning algorithm can quickly converge to the Nash equilibrium policies of both sides, proving the availability and effectiveness of the algorithm.

Background: Carriage of carbapenem-resistant Enterobacteriaceae (CRE) in humans may contribute to the dissemination of CRE and impact on communities and healthcare facilities. Carbapenem-resistant Escherichia coli (CREC) is one of the major type of CRE in the human gut. Here, we describe a cross-sectional study to investigate the prevalence of CREC, and in particular the mcr-1 carrying CREC, in health volunteers in China. Methods: During September to December 2016, 3859 non-duplicated stool specimens were collected from healthy volunteers who received regular physical examinees in healthcare centers located in 19 provinces across China. Enrichment culture supplemented meropenem was used to isolate CREC. Carbapenemase producing determinants and the mcr-1 gene were determined by PCR amplification and sequencing. Isolates were further analyzed by antibiotic susceptibility test, genotyping, and whole genome analysis. Findings: A total of 92 non-duplicated CREC were isolated from 3859 stool specimens, among which 43 CREC are carbapenemase positive. In addition, the co-existence of blaNDM and mcr-1 was found in 14 CREC, which also showed resistance to the majority of all antimicrobial agents analyzed. The genetic background of these CREC isolates are highly diversified based on molecular typing. Furthermore, whole genome sequence indicated that NDM-5 is the predominant determinant conferring carbapenem resistance in CREC, and that NDM-5 carrying plasmids (IncX3) are very similar. Interpretation: The incidence of CREC carriage in healthy people in China was small; however, the co-existence of CREC with mcr-1 is disconcerting. Therefore, pre-screening prior to admission and monitoring of patients on high-dependency wards is highly recommended to control and prevent the dissemination of CRE in hospitals. Outstanding Question: The high prevalence of CREC in the healthy people should not be underestimated, as it may increase the risk of infection. This knowledge could have impact on the pre-screening and monitoring of CRE before patient administration. Keywords: CREC, NDM, MCR-1, Gut, Carriage, Healthy people

Pseudomonas aeruginosa is one of the most common opportunistic pathogens, which causes severe nosocomial infections because of its well-known multidrug-resistance and hypervirulence. It is critical to curate routinely the epidemic P. aeruginosa clones encountered in the clinic. The aim of the present study was to investigate the connection between virulence factors and antimicrobial resistance profiles in epidemic clones. Herein, we found that ST463 (O4), ST1212 (O11), and ST244 (O5) were prevalent in 30 isolates derived from non-cystic fibrosis patients, based on multilocus sequence type (MLST) and serotype analysis. All isolates were multidrug-resistant (MDR) and each was resistance to at least three classes of antibiotics in antimicrobial susceptibility tests, which was consistent with the presence of the abundant resistance genes, such as blaOXA–50, blaPAO, aph(3′), catB7, fosA, crpP, and blaKPC–2. Notably, all blaKPC–2 genes were located between ISKpn6-like and ISKpn8-like mobile genetic elements. In addition, classical exotoxins encoded by exoU, exoS, and pldA were present in 43.44% (13/40), 83.33% (25/30), and 70% (21/30) of the isolates, respectively. The expression of phz operons encoding the typical toxin, pyocyanin, was observed in 60% of isolates (18/30) and was quantified using triple quadrupole liquid chromatograph mass (LC/MS) assays. Interestingly, compared with other MLST types, all ST463 isolates harbored exoU, exoS and pldA, and produced pyocyanin ranging from 0.2 to 3.2 μg/mL. Finally, we evaluated the potential toxicity of these isolates using hemolysis tests and Galleria mellonella larvae infection models. The results showed that ST463 isolates were more virulent than other isolates. In conclusion, pyocyanin-producing ST463 P. aeruginosa, carrying diverse virulence genes, is a potential high-risk clone.

Background. The incidence of diabetes mellitus (DM) was increasing in recent years, and it is important to screen those nondiabetic populations through health examination to detect the potential risk factors for DM. We aimed to find the predictive effect of health examination on DM. Methods. We used the public database from Rich Healthcare Group of China to evaluate the potential predictive effect of health examination in the onset of DM. The colinear regression was used for estimating the relationship between the dynamics of the health examination index and the incident year of DM. The time-dependent ROC was used to calculate the best cutoff in predicting DM in the follow-up year. The Kaplan-Meier method and Cox regression were used to evaluate the HR of related health examination. Results. A total of 211,833 participant medical records were included in our study, with 4,172 participants diagnosing as DM in the following years (among 2-7 years). All the initial health examination was significantly different in participants’ final diagnosing as DM to those without DM. We found a negative correlation between the incidence of years of DM and the average initial FPG (r=−0.1862, P5.21 mmol/L) had a 2.73-fold chance to develop as DM in follow-up (95%CI=2.65–2.81, P

KTaO3 and KNbO3, two typical perovskite ferroelectric crystal materials with identical cubic structure at high temperature, undergoes totally different phase transition path. The underlying mechanism is explored by comparing their phonon anharmonic behavior based on first-principle calculation. The results of Grüneisen parameters indicate larger phonon anharmonicity of KNbO3 than that of KTaO3, which leads to structural unstable of KNbO3. Different with previous studies of soft mode theory, apparent phonon anharmonicity of both crystals are stemmed not from the center, but the corner and boundary of the first Brillouin zone. In order to essentially understand the difference in the anharmonic behavior of phonons, the chemical bond strength of these two perovskite materials was analyzed by ELF. The results show that due to the stronger covalent properties of Ta-O bond, it will cause weak phonon anharmonicity, and ultimately lead to high phonon relaxation time and low Grüneisen parameters of KTaO3. The weakly ionic Nb-O bond give rise to the obvious phonon anharmonic behavior and lattice instability of KNbO3, resulting in a series of temperature-dependent phase transitions.

In this research, we report on a high-performance near-infrared (near-IR) photodetector based on single-walled carbon nanotube-germanium (SWCNT-Ge) heterojunction by assembling SWCNT films onto n-type Ge substrate with ozone treatment. The ozone doping enhances the conductivity of carbon nanotube films and the formed interfacial oxide layer (GeOx) suppresses the leakage current and carriers’ recombination. The responsivity and detectivity in the near-IR region are estimated to be 362 mA W−1 and 7.22 × 1011 cm Hz1/2 W−1, respectively, which are three times the value of the untreated device. Moreover, a rapid response time of ~11 μs is obtained simultaneously. These results suggest that the simple SWCNT-Ge structure and ozone treatment method might be utilized to fabricate high-performance and low-cost near-IR photodetectors.

Background: Anal canal condyloma acuminatum (CA) is a refractory disease with a high recurrence rate caused by human papillomavirus (HPV). Multiple clinical trials demonstrate that anti-HPV biological dressing is safe and effective in treating HPV infection, which has been used in treating high-risk HPV-positive and cervical intraepithelial neoplasia I (CIN I) patients. Yet, there is still a lack of clinical data for the treatment of anal canal CA. Aims and Objectives: To evaluate the clinical efficacy and application value of anti-HPV biological dressing in anal canal CA. Materials and Methods: Taken currently recommended treatment 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) as a positive control, 128 patients were included with 64 in each group, and a prospective, randomized, positive controlled, non-inferiority clinical trial was conducted. After removing visible skin lesions with conventional microwave, the treatment group was given anti-HPV biological dressing, while the control group received the conventional ALA-PDT treatment. Patients were followed up on the 1st, 12th and 24th weeks after the treatment. The cure rate, recurrence rate, HPV-negative conversion rate, and adverse events were recorded. Results: In the 1st, 12th and 24th weeks after treatment, the cure rate, recurrence rate and HPV-negative conversion rate of the treatment group and the control group showed no statistically significant difference. In the treatment group, 56 patients developed transient mild itching and all were relieved spontaneously, while in the control group, most of the patients experienced obvious pain and some patients needed symptomatic treatment. No severe systemic adverse events were observed. Conclusion: Compared with ALA-PDT, topical application of anti-HPV biological dressing has comparable promising outcomes in the treatment of anal canal CA, with fewer side effects and simpler operation making it suitable for clinical applications.

This paper is concerned with the state fusion estimation problem for a class of stochastic hybrid systems with asynchronous multi-sensors and multiple packet dropouts. The stochastic packet dropouts over communication channels from sensors to the fusion center are formulated as independent Bernoulli sequences. As one of the most cost-effective estimation approach for hybrid systems, the interactive multiple model framework is adopted, where an input mixing step is introduced at the beginning of each filtering cycle. The asynchronous sensor measurements collected at the fusion center are first aligned to the fusion time, and then fused to update the mode-matched filters based on the quasi-recursive form of linear minimum mean square error estimation, where correlations induced by the synchronization process are carefully calculated and the stochastic packet dropouts are taken into account. Finally, the overall estimate is obtained by further fusing the mode-matched estimates with their updated posterior mode probabilities accordingly. The feasibility and effectiveness of the proposed algorithm is illustrated by a numerical simulation.