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Summary Background An altered microRNA profile exists in many infectious diseases, including sepsis. CD39 + regulatory T-cells (Tregs) have a remarkable immunosuppressive effect and play an important role in the regulation of immune balance in sepsis. However, the correlation between microRNA changes and the ratio of CD39 + Tregs in sepsis patients has not yet been reported. The altered microRNA expression profile in sepsis patients was analyzed in this study. Moreover, the correlation between microRNAs and disease severity and prognosis was investigated. Furthermore, the correlation between microRNAs and the percentage of peripheral blood CD39 + Tregs was investigated and further verified in an animal model. Methods Sixty sepsis patients and 30 healthy controls were included. The difference in microRNA expression was investigated by microRNA microarray and was further confirmed by real-time quantitative PCR. The correlations between microRNA changes and the Sepsis-related Organ Failure Assessment (SOFA) score, severity of sepsis, and survival were analyzed. The percentage CD39 + Tregs in the peripheral blood of sepsis patients was measured by flow cytometry. The correlation between microRNAs and the percentage CD39 + Tregs was analyzed and further confirmed in a mouse sepsis model. Results Compared to healthy controls, sepsis patients exhibited a significantly elevated microRNA-155 (miR-155) level ( p < 0.05), which was positively related to a higher SOFA score ( r = 0.641, p < 0.05) and a greater severity of sepsis. The area under the receiver operating characteristic curve of miR-155 used for the prediction of 28-day survival was 0.763, with a cut-off point of 2.47. Patients with a miR-155 level >2.47 had a lower 28-day survival ( p < 0.05). The miR-155 level of patients was proportional to the percentage of CD39 + Tregs ( r = 0.637, p < 0.05). After transfection with miR-155 inhibitor, the ratio of CD39 + Tregs in mice with sepsis was significantly reduced ( p < 0.05). Conclusions A higher level of miR-155 indicated a more severe condition and poorer prognosis in sepsis patients. The possible underlying mechanism could be that miR-155 induces an increased percentage of CD39 + Tregs and thus immunosuppression. [ABSTRACT FROM AUTHOR]

Objective: To investigate the role of cholinergic anti-inflammatory pathway in the regulation of peptide transporter 1 (PepT1) expression in small intestinal epithelium of septic rats by Ghrelin., Methods: One hundred adult male Sprague-Dawley (SD) rats were randomly divided into sham operation group, sepsis group, sepsis+vagotomy group, sepsis+Ghrelin group, and sepsis+vagotomy+Ghrelin group, with 20 rats in each group. In the sham operation group, the cecum was separated after laparotomy, without ligation and perforation. In the sepsis group, the rats received cecal ligation puncture (CLP). In the sepsis+vagotomy group, the rats received CLP and vagotomy after laparotomy. In the sepsis+Ghrelin group, 100 μmol/L Ghrelin was intravenously injected after CLP immediately. The rats in the sepsis+vagotomy+Ghrelin group received CLP and vagotomy at the same time, then the Ghrelin was intravenously injected immediately with the same dose as the sepsis+Ghrelin group. Ten rats in each group were taken to observe their survival within 7 days. The remaining 10 rats were sacrificed 20 hours after the operation to obtain venous blood and small intestinal tissue. The condition of the abdominal intestine was observed. The injury of intestinal epithelial cells was observed with transmission electron microscopy. The contents of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) in serum and small intestinal tissue were detected by enzyme-linked immunosorbent assay (ELISA). The brush border membrane vesicle (BBMV) was prepared, the levels of mRNA and protein expression of PepT1 in the small intestinal epithelium were detected by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blotting., Results: All rats in the sham operation group survived at 7 days after operation. The 7-day cumulative survival rate of rats in the sepsis group was significantly lower than that in the sham operation group (20% vs. 100%, P < 0.05). The cumulative survival rate of rats after Ghrelin intervention was improved (compared with sepsis group: 40% vs. 20%, P < 0.05), but the protective effect of Ghrelin was weakened after vagotomy (compared with sepsis+Ghrelin group: 10% vs. 40%, P < 0.05). Compared with the sham operation group, in the sepsis group, the small intestine and cecum were dull red, the intestinal tubules were swollen and filled with gas, the intestinal epithelial cells were seriously injured under transmission electron microscopy, the levels of TNF-α and IL-1β in serum and small intestinal were significantly increased, and the expression levels of PepT1 mRNA and protein in the small intestinal epithelium were significantly decreased. It indicated that the sepsis rat model was successfully prepared. After vagotomy, the intestinal swelling and gas accumulation became worse in septic rats, leading to the death of all rats. Compared with the sepsis group, the abdominal situation in the sepsis+Ghrelin group was improved, the injury of intestinal epithelial cells was alleviated, the serum and small intestinal TNF-α and IL-1β were significantly decreased [serum TNF-α (ng/L): 253.27±23.32 vs. 287.90±19.48, small intestinal TNF-α (ng/L): 95.27±11.47 vs. 153.89±18.15, serum IL-1β (ng/L): 39.16±4.47 vs. 54.26±7.27, small intestinal IL-1β (ng/L): 28.47±4.13 vs. 42.26±2.59, all P < 0.05], and the expressions of PepT1 mRNA and protein in the small intestinal epithelium were significantly increased [PepT1 mRNA (2 -ΔΔCt ): 0.66±0.05 vs. 0.53±0.06, PepT1 protein (PepT1/GAPDH): 0.80±0.04 vs. 0.60±0.05, both P < 0.05]. Compared with the sepsis+Ghrelin group, after vagotomy in the sepsis+vagotomy+Ghrelin group, the effect of Ghrelin on reducing the release of inflammatory factors in sepsis rats was significantly reduced [serum TNF-α (ng/L): 276.58±19.88 vs. 253.27±23.32, small intestinal TNF-α (ng/L): 144.28±12.99 vs. 95.27±11.47, serum IL-1β (ng/L): 48.15±3.21 vs. 39.16±4.47, small intestinal IL-1β (ng/L): 38.75±4.49 vs. 28.47±4.13, all P < 0.05], the up-regulated effect on the expression of PepT1 in small intestinal epithelium was lost [PepT1 mRNA (2 -ΔΔCt ): 0.58±0.03 vs. 0.66±0.05, PepT1 protein (PepT1/GAPDH): 0.70±0.02 vs. 0.80±0.04, both P < 0.05], and the injury of small intestinal epithelial cells was worse., Conclusions: Ghrelin plays a protective role in sepsis by promoting cholinergic neurons to inhibit the release of inflammatory factors, thereby promoting the transcription and translation of PepT1.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a pathogen of global concern due to the fact that therapeutic drugs are limited. Metallo-β-lactamase (MBL)-producing P. aeruginosa has become a critical part of CRPA. Alcaligenes faecalis metallo-β-lactamase (AFM) is a newly identified subclass B1b MBL. In this study, 487 P. aeruginosa strains isolated from patients and the environment in an intensive care unit were screened for AFM alleles. Five AFM-producing strains were identified, including four AFM-2-producing strains (ST262) and one AFM-4-producing strain (ST671). AFM-2-producing strains were isolated from rectal and throat swabs, and AFM-4-producing strains were isolated from the water sink. The bla AFM-2 carrying plasmids belonged to the IncP-2 type, while the bla AFM-4 carrying plasmid pAR19438 was a pSTY-like megaplasmid. Plasmid pAR19438 was acquired bla AFM-4 by the integration of the Tn 1403 -like transposon. All bla AFM genes were embedded in an IS CR29 - bla AFM unit core module flanked by class 1 integrons. The core module of bla AFM-2 was IS CR29 -Δ groL - bla AFM-2 - ble MBL -Δ trpF -ΔIS CR , while the core module of bla AFM-4 was IS CR29 -Δ groL - bla AFM-2 - ble MBL -Δ trpF -IS CR - msrB - msrA - yfcG - corA -ΔIS CR . The flanking sequences of IS CR29 - bla AFM units also differed. The expression of AFM-2 and AFM-4 in DH5α and PAO1 illustrated the same effect for the evaluation of the MICs of β-lactams, except for aztreonam. Identification of AFM-4 underscores that the quick spread and emerging development of mutants of MBLs require continuous surveillance in P. aeruginosa. IMPORTANCE Acquiring metallo-β-lactamase genes is one of the important carbapenem resistance mechanisms of P. aeruginosa. Alcaligenes faecalis metallo-β-lactamase is a newly identified metallo-β-lactamase, the prevalence and genetic context of which need to be explored. In this study, we identified AFM-producing P. aeruginosa strains among clinical isolates and found a new mutant of AFM, AFM-4. The bla AFM-4 carrying plasmid pAR19438 was a pSTY-like megaplasmid, unlike the plasmids encoding other bla AFM alleles. The genetic context of bla AFM-4 was also different. However, AFM-2 and AFM-4 had the same impacts on antibiotic susceptibility. The presence and transmission of AFM alleles in P. aeruginosa pose a challenge to clinical practice.

Background: Carbapenem-resistant gram-negative bacteria (CR-GNB) are becoming increasingly important bacterial pathogens in critically ill patients. Several clinicians use Intravenous colistin sulfate to treat infections due to CR-GNB, although the clinical data is limited. The aim of our retrospective observational study was to evaluate the effectiveness and nephrotoxicity of intravenous colistin sulfate in the treatment of CR-GNB infections., Methods: Fifty critically ill intensive care patients with infections due to CR-GNB were retrospectively enrolled between January 2020 and December 2021 in the Zhejiang Provincial People's Hospital. Favorable clinical response rate, bacterial clearance rate, nephrotoxicity, and 28-day mortality were evaluated., Results: The overall favorable clinical response rate was 58%, the bacterial clearance rate was 40%, and the 28-day all-cause mortality was 44%. Temperature, neutrophil count, C-reaction protein (CRP), procalcitonin (PCT), creatinine (Cr), and lactate levels were also significantly decreased (P<0.05). The major adverse reaction is nephrotoxicity, and renal function was evaluated on the day before and after treatment with colistin sulfate. Possible nephrotoxicity was observed in three patients (6%). Backward logistic regression was conducted to determine risk factors for the nephrotoxicity of colistin sulfate, the result showed there were no significant differences in the duration and dose of colistin sulfate., Conclusions: Our results provide evidence for the positive clinical efficacy and safety of colistin sulfate. Appropriate use of colistin sulfate may be viable and safe in the treatment of severe infections caused by CR-GNB., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-4959/coif). The authors have no conflicts of interest to declare., (2022 Annals of Translational Medicine. All rights reserved.)

Odontogenic brain and pulmonary abscesses are extremely rare infectious diseases. It is mainly caused by the upward or downward transmission of local infection or blood-borne spread. In recent years, with the wide application of some novel testing methods in clinical practice, the diagnosis of unexplained infections such as odontogenic abscesses in different organs has gradually become clear. We report a case of a 21-year-old male who was healthy and had not received any oral treatment before onset. He started with acute gastroenteritis-related symptoms, then developed meningitis-related symptoms seven days later with septic shock. No obvious abscess lesions were found on head computed tomography (CT) at admission, and the etiology was not clear by routine examination, which was very easy to misdiagnose as a serious infection caused by intestinal pathogens. But odontogenic pathogens were found both in his blood and cerebrospinal fluid through metagenomic next-generation sequencing (mNGS) analysis. Subsequently, rechecked imaging examination displayed multiple brain and pulmonary abscesses. Finally, it was diagnosed as an odontogenic brain and pulmonary abscess. After an extremely lengthy anti-infection course (13 weeks of intravenous antibiotics plus 2 weeks of oral antibiotics) and surgery, the patient was improved and discharged from the hospital. From this case, we could see that the development of new diagnostic technologies such as mNGS plays an important role in the early and confirmed diagnosis of diseases previously difficult to diagnose such as odontogenic polymicrobial infections and ultimately helps to improve the prognosis of these patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Lai, Cheng, Liang and Lin.)

Objective: This study aims to identify the functional heterogeneity in fully or partially remitted patients with bipolar disorder and explore the correlations between psychosocial functioning and sociodemographic, clinical, neurocognitive and biochemical variables., Methods: One hundred and forty fully or partially remitted patients with bipolar disorder ( BD ) and seventy healthy controls were recruited. The patients were grouped into different profiles based on the Functioning Assessment Short Test ( FAST ) domain scores by hierarchical cluster analysis. The characteristics of subgroups and the correlations between psychosocial functioning and sociodemographic, clinical, neurocognitive and biochemical variables in each cluster were then analyzed., Results: There were three subgroups in fully or partially remitted patients with BD: the lower functioning group (LF ), performed global functioning impairments; the moderate functioning group ( MF ), presented selective impairments in functional domains; and the good functioning subgroup ( GF ), performed almost intact functioning. Among the three subgroups, there were differences in FAST domains, sociodemographic variables, clinical variables, some neurocognitive domains and several biochemical indexes., Conclusions: The study successfully identified three functional subgroups. The characteristics of discrete subgroups and the specific clinical factors, neurocognitive domains and biochemical indexes that are correlated with functional subgroups will allow for making tailored interventions to promote functional recovery and improve the quality of life., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ba, Chen, Lai, Liao, Fang, Lu, Zheng, Zong and Lin.)

Background: Increasing evidences show a clinical significance in the interaction between hypoxia and prostate cancer. However, reliable prognostic signatures based on hypoxia have not been established yet. Methods: We screened hypoxia-related gene modules by weighted gene co-expression network analysis (WGCNA) and established a hypoxia-related prognostic risk score (HPRS) model by univariate Cox and LASSO-Cox analyses. In addition, enriched pathways, genomic mutations, and tumor-infiltrating immune cells in HPRS subgroups were analyzed and compared. HPRS was also estimated to predict immune checkpoint blockade (ICB) therapy response. Results: A hypoxia-related 22-gene prognostic model was established. Furthermore, three independent validation cohorts showed moderate performance in predicting biochemical recurrence-free (BCR-free) survival. HPRS could be a useful tool in selecting patients who can benefit from ICB therapy. The CIBERSORT results in our study demonstrated that hypoxia might act on multiple T cells, activated NK cells, and macrophages M1 in various ways, suggesting that hypoxia might exert its anti-tumor effects by suppressing T cells and NK cells. Conclusion: Hypoxia plays an important role in the progression of prostate cancer. The hypoxia-derived signatures are promising biomarkers to predict biochemical recurrence-free survival and ICB therapy responses in patients with prostate cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Chen, Lin, Ding and Liang.)

Objective: To explore the regulatory functions of ceRNA networks in the nosogenesis of gout and search for potential therapeutic targets., Methods: We searched the GEO database and downloaded the lncRNA microarray chipset GSE160170. This matrix series was analyzed to yield differentially expressed lncRNAs and mRNAs. Then, the correlations between lncRNAs and miRNAs were obtained by comparing the highly conserved miRNA families. The predicted miRNA-regulating mRNAs were matched to the differentially expressed mRNAs from the chipset analyses to obtain miRNA-mRNA interactions. Next, we used the Cytoscape software to model ceRNA networks and the STRING database to determine their protein-protein interactions. The R software was used to algorithmically screen the functional pathways of key PPI modules in the ceRNA networks., Results: A total of 354 lncRNAs (140 downregulated and 214 upregulated) and 693 mRNAs (399 downregulated and 294 upregulated) were differentially expressed between the gout group and the healthy group. The ceRNA network of differentially expressed lncRNAs contained 86 lncRNAs (35 downregulated and 51 upregulated), 29 miRNAs, and 57 mRNAs. The processes identified in the GO enrichment analysis included gene transcription, RNA polymerase II transcription, and the regulation of cell growth and apoptosis. The pathways identified in the KEGG enrichment analysis included IL-17, TNF, and MAPK signaling. Nine lncRNAs (AC104024, AC084082, AC083843, FAM182A, AC022819, FAM215B, AP000525, TTTY10, and ZNF346-IT1), eleven miRNAs (hsa-miR-1297, hsa-miR-17-5p, hsa-miR-429, hsa-miR-139-5p, hsa-miR-449c-5p, hsa-miR-125a-5p, hsa-miR-125b-5p, hsa-miR-23b-3p, hsa-miR-217, hsa-miR-363-3p, and hsa-miR-20b-5p), and nine mRNAs (JUN, CASP2, PMAIP1, FOS, TNFAIP3, MAP3K8, BTG2, NR4A2, and DUSP2) were identified in the exploration of the key modules., Conclusion: Characterization of ceRNA networks could be a promising approach for better understanding the pathogenesis of gout, with the TTTY10/hsa-miR-139-5p/AP-1 axis likely to be of clinical significance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Jianlong Shu et al.)

In this study, we aimed to identify potential targets modulating the progression of nasopharyngeal carcinoma (NPC) using integrated bioinformatics analysis and functional assays. Differentially expressed genes (DEGs) between NPC and normal tissues samples were obtained from publicly availably microarray datasets (GSE68799, GSE34573, and GSE53819) in the Gene Expression Omnibus (GEO) database. The bioinformatics analysis identified 49 common DEGs from three GEO datasets, which were mainly enriched in cytokine/chemokine pathways and extracellular matrix organization pathway. Further protein-protein interaction network analysis identified 11 hub genes from the 49 DEGs. The 11 hub genes were significantly up-regulated in the NPC tissues when compared to normal tissues by analyzing the Oncomine database. The 8 hub genes including COL5A1, COL7A1, COL22A1, CXCL11, IFI44L, IFIT1, RSAD2, and USP18 were significantly up-regulated in the NPC tissues when compared to normal tissues by using the Oncomine database. Further validation studies showed that IFIT1 was up-regulated in the NPC cells. Knockdown of IFI1T1 suppressed the proliferation, migration, and invasion of NPC cells; while IFIT1 overexpression promoted the proliferation, migration, and invasion of NPC cells. In conclusion, a total of 49 DEGs and 11 hub genes in NPC using the integrated bioinformatics analysis. IFIT1 was up-regulated in the NPC cells lines, and IFIT1 may act as an oncogene by promoting NPC cell proliferation, migration, and invasion., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Immunotherapy based on natural killer (NK) cells is a promising approach for treating a variety of cancers. Unlike T cells, NK cells recognize target cells via a major histocompatibility complex (MHC)-independent mechanism and, without being sensitized, kill the cells directly. Several strategies for obtaining large quantities of NK cells with high purity and high cytotoxicity have been developed. These strategies include the use of cytokine-antibody fusions, feeder cells or membrane particles to stimulate the proliferation of NK cells and enhance their cytotoxicity. Various materials, including peripheral blood mononuclear cells (PBMCs), umbilical cord blood (UCB), induced pluripotent stem cells (iPSCs) and NK cell lines, have been used as sources to generate NK cells for immunotherapy. Moreover, genetic modification technologies to improve the proliferation of NK cells have also been developed to enhance the functions of NK cells. Here, we summarize the recent advances in expansion strategies with or without genetic manipulation of NK cells derived from various cellular sources. We also discuss the closed, automated and GMP-controlled large-scale expansion systems used for NK cells and possible future NK cell-based immunotherapy products., (© 2021. The Author(s), under exclusive licence to CSI and USTC.)

Background: Initial adherence is a predictor of long-term adherence and thus is a crucial metric to explore and support. This study aimed to investigate initial adherence by psychiatric outpatients and relevant personal factors., Methods: The study surveyed psychiatric outpatients using a 30-day timely return visit rate (TRVR) after the first visit to indicate initial adherence. All participants agreed to engage in the self-designed survey and assessments of the Eysenck Personality Questionnaire (EPQ) and Symptoms Checklist-90 (SCL-90). Clients who missed timely return visits received telephone follow-up to determine the main reasons., Results: The overall TRVR was 59.4, and 40.6% of clients missed return visits. Logistic regression analysis revealed risk factors for initial adherence were work, tense family atmosphere, negative attitudes towards medication, higher EPQ psychoticism score, and lower SCL-90 phobic anxiety score. The main reasons given for non-timely return visits were improvement suggesting lack of need for a return visit, various barriers, no improvement, and side effects., Conclusion: Psychiatric outpatients had poor initial adherence related to multiple dimensional factors, including job, family, personality characteristics, mental status, and thoughts about mental illness and treatments., (© 2022. The Author(s).)

Objective: To determine the anti-cataract effects of coconut water (CW) in vivo and in vitro, and to explore the potential pathogenic mechanism., Methods: In this study, 48 male Sprague-Dawley rats were randomly divided into 4 groups: control (CO), diabetic (DM), diabetic treated with CW (DM + CW), and diabetic treated with Glibenclamide (DM + Gli). Except for the CO group, in the other three groups, intraperitoneal injection of STZ (60 mg/kg) was conducted to establish diabetic models. The experiment was conducted for 20 weeks. The slit-lamp examination was undertaken during the period of experiment (20 weeks), and then, all rats were sacrificed. The levels of superoxide dismutase (SOD), malondialdehyde (MDA), and glutathione peroxidase (GSH-Px) in the left lens were measured by using biochemical assays. The right lens was used for pathological analysis. The rat lens epithelial cells (LECs) were cultured in vitro and the subcultured cell were divided into four groups, namely the normal glucose group (5 mmol /L glucose, Group I), the high glucose group (40 mmol/L glucose, Group II), high glucose +5% CW group (Group III), and high glucose +10% CW group (Group IV). LECs were cultured under the conditions as described above for 48 h. Cell proliferation and the morphological changes were observed with interted phase contrast microscope.The level of cell apoptosis was determined by flow cytometry. the level of SOD, MDA and GSH-Px were also detected., Results: The lens opacity index decreased in diabetic rats, and LECs apoptosis ratio also decreased in high glucose environments that received CW. Under treatment with CW, reduced MDA level and elevated activities of SOD and GSH-Px were detected, both in vivo and in vitro experiments. The increased severity of cataract and LECs apoptosis were noted in diabetic rats that received normal water, while CW markedly mitigated the enhanced cataract severity and the reduction of LECs induced by diabetes mellitus., Conclusion: CW is a functional food that can protect the lens from diabetic cataract. The possible underlying mechanism may be partly explained via the decreased oxidative stress in lens. However, further research needs to be conducted to indicate the pathogenic mechanism of anti-diabetic effects of CW., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Colloids in groundwater or geological barriers generally play a key role in the migration of special nuclides. Adsorption characteristics of strontium were investigated on porous media in the presence of colloidal Fe(OH) 3 from the Beishan Site, the only high-level radioactive waste disposal site candidate in China. The effects of colloid amounts, solid contents, and pH were determined and studied by batch texts. The results revealed that the presence of colloidal Fe(OH) 3 in porous media contributed to promotion of the sorption effect, and the influencing factors had a significant impact on the adsorption process. The sorption ability increased with increasing colloid amount when the equilibrium time was approximately 10 h under an optimal solid-liquid ratio of 20 g L -1 . The sorption effect in alkaline conditions was better than that under acidic conditions. The sorption kinetics indicated that the strong chemical interaction and/or surface complexation contributed primarily to strontium sorption. The sorption isotherms and model fitting revealed that the sorption of strontium onto porous media in the presence of colloidal Fe(OH) 3 was a monolayer adsorption, and the presence of colloidal Fe(OH) 3 is an important factor that greatly influences the removal of strontium from aqueous solutions. These findings provide useful information for the treatment of strontium in radioactive waste disposal sites., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Chronic inflammatory responses and leukocyte infiltration are classical pathological features of cerebral small vessel disease (CSVD). To date, limited evidence of a relationship between chronic insomnia and inflammatory responses in patients with CSVD has been uncovered. The purpose of the present study was to investigate the potential relationship between chronic insomnia and pro-inflammatory cytokine levels in patients with atherosclerotic CSVD (A-CSVD)., Methods: In total, 76 A-CSVD patients with or without chronic insomnia (CI) confirmed using magnetic resonance (MR) were prospectively recruited. Overnight polysomnography (PSG) was performed and serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), IL-6, IL-17A, IL-8, and IL-12 assessed. Cytokine levels were compared between CSVD+CI (study group) and CSVD without CI (control group) patients, and the correlations between PSG parameters and cytokine levels were explored in all patients via multiple linear regression analyses., Results: The serum IL-8 level of the study group (12.3±4.4 pg/mL) was significantly higher than that of the control group (7.5±2.2 pg/mL; P<0.05). PSG measurements showed that patients in the study group had significantly higher sleep onset latency (SOL), arousal index (ArI) and wake after sleep onset (WASO) as well as lower total sleep time (TST), sleep efficiency (SE) and stage 3 NREM sleep (N-3) ratio, compared with the control group (P<0.05). Multiple linear regression analyses led to the identification of ArI (β=0.026, P<0.05) and TST (β=-0.054, P<0.05) as significant positive and negative predictors of the IL-8 level, respectively., Conclusion: Chronic insomnia, in particular, sleep fragmentation and short sleep duration, may be involved in promotion of serum IL-8 expression in patients with atherosclerotic CSVD., Competing Interests: The authors have no conflicts of interest to declare., (© 2020 Wang et al.)

We explored the effect of the presence or absence of humic acid (HA) on the sorption behaviour of Sr onto soil. We examined three different experimental cases for Sr sorption: (1) sorption in the presence of only colloidal HA, (2) sorption in the presence of only soil and (3) sorption in the presence of both colloidal HA and soil (HS). A batch technique was used to study the influencing factors, including the amount of colloidal HA, solid content, pH, initial concentration of Sr and contact time. The experiments showed that the influencing factors significantly affected the sorption process. For example, in the case of soil and HS, the sorption percentage increased rapidly with increasing solid content at m/V < 20 g/L, changing from 8.35% and 37.54% to 49.09% and 77.03%, respectively. Moreover, scanning electron microscopy and Fourier transform infrared spectroscopy were used to characterize samples. The kinetics and isotherms of Sr were best described by the pseudo-second-order and Langmuir models, which indicated that the process was controlled by chemisorption and uniform monolayer sorption with constant energy on the outer surface. These findings provide valuable information for predicting strontium migration in radioactive waste disposal sites.

The objective of this study was to explore the controlling factors on the migration and transformation of nitrogenous wastes in groundwater using long-term observations from a contaminated site on the southwestern edge of the Tengger Desert in northwestern China. Contamination was caused by wastewater discharge rich in ammonia. Two long-term groundwater monitoring wells (Wells 1# and 2#) were constructed, and 24 water samples were collected. Five key indicators were tested: ammonia, nitrate, nitrite, dissolved oxygen, and manganese. A numerical method was used to simulate the migration process and to determine the migration stage of the main pollutant plume in groundwater. The results showed that at Well 1# the nitrogenous waste migration process had essentially been completed, while at Well 2# ammonia levels were still rising and gradually transitioning to a stable stage. The differences for Well 1# and Well 2# were primarily caused by differences in groundwater flow. The change in ammonia concentration was mainly controlled by the migration of the pollution plume under nitrification in groundwater. The nitrification rate was likely affected by changes in dissolved oxygen and potentially manganese., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To investigate differential diagnosis between intrahepatic cholangiocarcinoma (ICC) and arterial phase enhanced hepatic inflammatory lesions in patients without liver cirrhosis using contrast-enhanced ultrasound (CEUS)., Methods: ICC and hepatic inflammatory lesions cases with CEUS and pathological diagnosis between Sep 2013 and Oct 2016 were investigated retrospectively. Imaging features of conventional ultrasound and CEUS were analyzed. The parameters of time intensity curve (TIC), including the arrival time, peak intensity (PI) in the lesions, the starting time for washout, and the intensity difference at 3 min (ΔI 3 ) after contrast agent infection between the lesion and the liver parenchyma, were compared between ICC and hepatic inflammatory lesions., Results: Twenty-five ICC and fifteen inflammatory patients were included in this study. Seventeen ICC (68.0%) and two inflammatory cases (13.3%) showed bile duct dilatation on conventional ultrasound. Using CEUS, three ICC cases (12.0%) were misdiagnosed as inflammatory lesions and three inflammatory lesions (20.0%) as ICC; two ICC (8.0%) and one inflammatory case (6.7%) could not be made definite diagnosis. Washout started at 34.5±3.5 s and 61.5±12.9 s for ICC and inflammatory lesions respectively (P<0.001). The intensity difference between lesion and liver parenchyma at 3 min after contrast agent injection was 10.8±3.1 dB in ICC and 4.2±2.3 dB in inflammatory group (P<0.001). The sensitivity and specificity differentiating ICC and inflammatory lesions were 76% and 87% if the cut-off value of the intensity difference was 7.7 dB., Conclusions: Combined with TIC analysis, and particularly with the characteristic of the early-starting and obvious washout in ICC, CEUS can be useful in differential diagnosis between hepatic inflammatory lesions and ICC.

Purpose: The CD8 + CD28 + /CD8 + CD28 - T lymphocyte balance is vital for human ulcerative colitis (UC) but has not been defined in experimental colitis. This investigation will try to identify the changes that occur in the CD8 + CD28 + /CD8 + CD28 - T lymphocyte balance during the progression of trinitrobenzenesulfonic acid (TNBS)-induced colitis in rats., Methods: The frequencies of blood CD8 + CD28 + and CD8 + CD28 - T lymphocytes were detected in the rats belonging to the normal, model, and treated groups on five days using flow cytometry. The treated rats were administered with mesalazine and were euthanized after a 14-day treatment, as were the normal and model rats. The sensitivity and specificity of the CD8 + CD28 + /CD8 + CD28 - T lymphocyte balance in diagnosing early colitis were analyzed by receiver operating characteristics (ROC) curves. The frequencies of CD8 + CD28 + and CD8 + CD28 - T lymphocytes in the colon tissue were tested via immunofluorescence. ELISA was used to measure the levels of the cytokines. Immunohistochemistry and Western blotting were used to detect the colonic expression of JAK3, STAT6, NFATc2, and GATA3., Results: We found that the ratio of CD8 + CD28 + /CD8 + CD28 - T lymphocytes decreased, as did the level of interleukin-7, but not IL-12p40, IL-13, or IL-15, in the blood; however, the ratio increased along with JAK3, STAT6, NFATc2, and GATA3 in the colon of the rats with colitis. The changes were effectively reversed through the administration of mesalazine for 13 days. Surprisingly, the balance in the blood could sensitively distinguish rats with early colitis from normal rats., Conclusion: These data show that increase in CD8 + CD28 + T cells in blood and decrease in CD8 + CD28 - T cells in colon are associated with experimental colitis.

Objective: To evaluate the clinical value of contrast-enhanced ultrasound (CEUS) in transthoracic biopsy of anterior-medial mediastinal lesions., Methods: A total of 123 patients with anterior or middle mediastinum lesions required ultrasound guided transthoracic biopsy for pathological diagnosis. Among them, 72 patients received CEUS examinations before biopsy. After CEUS, 8 patients were excluded from biopsy and the rest 64 patients underwent biopsy (CEUS group). During the same period, 51 patients received biopsy without CEUS examination (US group). The ultrasonography characteristics, the number of biopsy puncture attempts, diagnostic accuracy rate and the incidence of complications were recorded and compared between the two groups., Results: A large portion of necrosis area or superficial large vessels was found in 8 patients, so the biopsy was cancelled. The internal necrosis was demonstrated in 43.8% of the lesions in CEUS group and in 11.8% of US group (P>0.001). For thymic carcinoma, CEUS increased the detection rate of internal necrosis and pericardial effusion than conventional ultrasound (62.5% vs . 18.8%, P=0.012; 56.3% vs . 12.5%, P=0.023). The average number of punctures in CEUS group and US group was 2.36±0.70 and 2.21±0.51 times, respectively (P>0.05). The diagnostic accuracy rate of biopsy in CEUS group (96.9%, 62/64) was significantly higher than that in US group (84.3%, 43/51) (P=0.022). In US group, 2 patients suffered from mediastinal bleeding (3.9%), while no major complications occurred in CEUS group., Conclusions: CEUS examination provided important information before transthoracic mediastinum biopsy and improved diagnostic accuracy rate in biopsy of anterior and middle mediastinum lesions than conventional ultrasound.

Paired box protein 5 (PAX5) plays a lineage determination role in B-cell development. However, high expression of PAX5 has been also found in various malignant diseases, including B-lymphoproliferative disorders (B-LPDs), but its functions and mechanisms in these diseases are still unclear. Here, we show that PAX5 induces drug resistance through association and activation of receptor-interacting serine/threonine-protein kinase 2 (RIP2; also known as RIPK2), and subsequent activation of NF-κB signaling and anti-apoptosis gene expression in B-lymphoproliferative cells. Furthermore, PAX5 is able to interact with RIP1 and RIP3, modulating both RIP1-mediated TNFR and RIP2-mediated NOD1 and NOD2 pathways. Our findings describe a new function of PAX5 in regulating RIP1 and RIP2 activation, which is at least involved in chemotherapeutic drug resistance in B-LPDs., (© 2016. Published by The Company of Biologists Ltd.)

Objective: To investigate the impact of early initiation of continuous renal replacement therapy (CRRT) based on "Kidney Disease: Improving Global Outcomes (KDIGO)" classification on the prognosis of critically ill patients with acute kidney injury (AKI)., Methods: A retrospective analysis of clinical data of patients diagnosed as AKI in Department of Critical Care Medicine of Zhejiang Provincial People's Hospital from January 2011 to January 2015 was conducted. All patients included should be 18 years old or older, having stayed in intensive care unit (ICU) for more than 48 hours, and received CRRT. All subjects were divided into three groups according to their renal function before CRRT according to the KDIGO-AKI guideline: AKI-stage 1 group, AKI-stage 2 group and AKI-stage 3 group. The general condition, original disease, severity of disease, duration of mechanical ventilation, the length of ICU or hospital stay, 28-day survival rate and in-hospital mortality rate were compared among these three groups. Additionally, risk factors for the 28-day survival rate and hospital mortality of critically ill patients with AKI were screened by logistic regression analysis., Results: A total of 258 critically ill patients with AKI were enrolled, with 64 cases in AKI-stage 1 group, 62 cases in AKI-stage 2 group, and 132 cases in AKI-stage 3 group. 116 patients survived with 28-day survival rate of 44.96%. 154 patients died with hospital mortality 59.69%. The precipitating factors of AKI in all three groups (stage 1, stage 2, and stage 3) were similar, with sepsis, heart failure and poisoning (drugs or poison) being the main triggers for AKI, accounting for 35.66%, 19.38% and 13.18%, respectively. There were significant differences in the rate of vasoactive agent usage (31.25%, 41.94%, 50.00%, χ2 = 6.241, P = 0.044), acute physiology and chronic health evaluation Ⅱ (APACHE Ⅱ) score (20.87±7.37, 17.19±7.02, 22.58±7.95, F = 5.292, P = 0.006) and sequential organ failure assessment (SOFA) score (8.41±3.46, 6.22±2.43, 9.58±3.71, F = 10.328, P = 0.000), while there was no significant difference in gender, age, primary disease, time from ICU admission to the beginning of CRRT, mean arterial pressure (MAP), lactate level or 24-hour lactate clearance rate (LCR), mechanical ventilation time, the length of ICU or hospital stay, 28-day survival rate or hospital mortality among these three groups (all P > 0.05). According to the logistic regression analysis, time from ICU admission to start of CRRT and lactate level were the independent risk factors for 28-day survival rate or hospital mortality of critically ill patients with AKI [odds ratio (OR) for 28-day survival rate was 0.850 and 0.774, 95% confidence interval (95%CI) was 0.752-0.960 and 0.638-0.940, P value was 0.009 and 0.010, respectively; OR for hospital mortality was 0.884 and 0.756, 95%CI was 0.781-1.000 and 0.610-0.939, P value was 0.049 and 0.011, respectively]., Conclusion: Early initiation of CRRT based on KDIGO-AKI classification could not improve the prognosis of critically ill patients with AKI, the optimal timing of RRT for such patients remains to be further explored.

Objective: To explore the value of ultrasound-guided percutaneous radiofrequency ablation (RFA) in designing the indication, treatment protocol and operational skills for patients with primary hepatocellular carcinoma (HCC) near the liver surface., Methods: Sixty-one HCC patients with 69 lesions, confirmed by clinical examination and pathology, underwent percutaneous radiofrequency ablation. The study included 40 cases of liver function Child-Pugh grade A and 21 cases of grade B. The average size of tumors was (3.8 ± 1.2) cm, tumor diameter ≥ 4 cm accounted for 39.1% (27/69 lesions), and the average age was 58.2 years (range, 35-76 years). Taking comprehensive measures, such as intraperitoneal injection of saline adjacent to the tumor before RFA, increasing the puncture sites on the surface of tumor to avoid overlapping of the central portion of tumor, repeated ablation of the needle track to reduce needle tract metastasis, avoid vertical puncture, and other additional measures, to improve the inactivation of tumors adjacent to the liver surface. Enhanced CT/MRI was performed to evaluate the curative effect at 1, 3, 6 and 24 months after the treatment., Results: The inactivation rate of tumor was 98.6% (68/69 lesions) and local recurrence rate was 5.8%(4/69) after RFA. The tumor-related marker AFP was 1 000-1 500 ng/ml before and reduced to (98.5 ± 42.5) ng/ml after radiofrequency ablation, among them returned to normal in 13 cases (21.3%). Since the ablation area was rather small, the level of serum alanine aminotransferase was elevated only to (148.5 ± 38.5) U/ml at one week after RFA and returned to normal at (1.8 ± 0.6) week after RFA. No patient experienced severe liver dysfunction. The local HCC recurrent rate after RFA was 5.8%(4/69 lesions) and intrahepatic heterotopic recurrence rate was 24.6% (15/61). The 20-61 months follow-up showed that the 1-, 2- and 3-year survival rate was 83.6%, 57.3% and 44.2%, respectively., Conclusions: Ultrasound-guided percutaneous radiofrequency ablation provides an effective minimally invasive treatment for primary HCC near the liver surface. Taking some additional measures such as intraperitoneal injection of saline, increase of percutaneous puncture sites, and avoiding vertical needle puncture, may reduce complications and improve the therapeutic outcome. RFA is one of effective and minimally invasive treatment and causing less liver damage for primary HCC near the liver surface.

Background: The acute respiratory distress syndrome (ARDS) is a common devastating syndrome in intensive care unit in critically ill patients. Continuous renal replacement therapy (CRRT) has been shown beneficial effects on oxygenation and survival in patients with ARDS. However, it is still controversial about the timing of initiation of CRRT., Methods: Fifty-three patients with ARDS admitted to intensive care unit in Zhejiang Provincial People's Hospital, China from 2009 to 2013 were enrolled in the study. The authors compared ventilation parameter, including PaO2/FIO2, A-a gradient, positive end-expiratory pressure, plateau pressure, dynamic compliance and hemodynamic parameters, including central venous pressure, mean arterial pressure, cardiac index, extravascular lung water index, fluid balance between early initiation (within 12 hours after ARDS onset) and late initiation of CRRT (48 hours after ARDS onset) groups. The authors further investigated transforming growth factor (TGF)-β1 level changes in serum and bronchoalveolar lavage fluid (BALF) by enzyme-linked immunosorbent assay during 7 days of follow-up., Results: Significant improvement of oxygenation and shorter duration of mechanical ventilation were observed in early CRRT group during 7-day follow-up. In addition, TGF-β1 concentrations in serum and BALF were significantly decreased in patients with early initiation of CRRT compared to those with late initiation of CRRT on day 2 and day 7. Furthermore, patients who died of ARDS had higher levels of TGF-β1 in BALF than survivors., Conclusions: Our findings showed that early initiation of CRRT is associated with favorable clinical outcomes in ARDS patients, which might be due to the reduced serum and BALF TGF-β1 levels through CRRT. However, large multi-center studies are needed to make further recommendations as to the optimal use of CRRT in ARDS patient populations.

Objective: To investigate the incidence of hypomagnesemia and the effect of serum magnesium levels on the prognosis of critically ill patients in intensive care unit (ICU)., Methods: A single-center prospective observation was conducted. The adult patients admitted to ICU of Zhejiang Provincial People's Hospital from January 2012 to January 2014 were enrolled, and they were expected to stay in hospital for more than 48 hours. All the patients who had been diagnosed with hypomagnesemia before ICU admission, or those who had received magnesium supplement therapy were excluded. All patients were monitored for serum magnesium levels within 24 hours after ICU admission, and they were divided into three groups: normomagnesemic group (serum magnesium levels 0.7-1.2 mmol/L), hypomagnesemic group (serum magnesium levels < 0.7 mmol/L), and hypermagnesemic group (serum magnesium levels > 1.2 mmol/L). Various parameters were recorded for every patient, including general information, disease composition, laboratory indexes, duration of mechanical ventilation, ICU stay days and final outcome. The acute physiology and chronic health evaluation II (APACHEII) score and sequential organ failure assessment (SOFA) score during the first 24 hours after ICU admission were calculated. The risk factors for the death in critically ill patients were postulated by logistic regression analysis., Results: A total of 374 critically ill patients were enrolled, with 242 patients (64.71%) in normomagnesemic group, 102 (27.27%) in hypomagnesemic group, and 30 (8.02%) in hypermagnesemic group. As to the disease composition, although the patients in normomagnesemic group and hypomagnesemic group were mainly consisted of patients with nervous system diseases (33.06%, 31.37%) or pneumonia (25.62%, 25.49%), the proportion of patients with major abdominal and thoracic surgery (15.69% vs. 5.78%, χ (2) = 8.837, P = 0.003) or severe sepsis (7.84% vs. 1.65%, χ (2) = 9.935, P = 0.007) was significantly greater in the hypomagnesemic group compared with that of normomagnesemic group, and most hypermagnesemic patients were complicated by renal dysfunction in different degrees. Compared with the normomagnesemic group, the hypomagnesemic group was found to have higher SOFA scores (6.86±3.12 vs. 5.46±2.75, t = -2.930, P = 0.004), longer stay in ICU (days: 15.98±13.29 vs. 12.43±7.14, t = -2.318, P = 0.034) and higher mortality [54.90% (56/102) vs. 33.88% (82/242), χ (2) = 6.587, P = 0.010], but no statistically significant differences were found in gender composition, age, levels of other electrolytes (natrium, potassium, calcium, phosphorus), and APACHEII score. As shown by the result of the logistic regression analysis, APACHEII score [odds ratio (OR) = 1.129, 95% confidence interval (95%CI) = 1.064-1.197, P = 0.000] and serum magnesium level (OR = 2.163, 95%CI = 1.015-4.610, P = 0.046) were independent risk factors for death in critically ill patients., Conclusions: Serum magnesium levels are closely related to mortality rate in patients in ICU, so more attention should be paid to the occurrence of hypomagnesemia in critically ill patients.

Objective: To compare the enhancement features of dysplastic nodules with a focus of hepatocellular carcinoma (DN-HCC) versus HCC and regenerative nodules (RN) in cirrhotic patients., Methods: One hundred and ninety-three cirrhotic patients were enrolled in this study; they had 215 focal liver lesions, 1.0-3.5 cm in size, which were examined using contrast-enhanced ultrasound (CEUS) with SonoVue(®) and diagnosed as HCC, RN or DN-HCC by biopsy. Samples were obtained using 18-gauge needles in the different enhanced areas. The enhancement features of DN-HCC, HCC and RN were evaluated., Results: There were 86 HCC lesions, 102 RN lesions, and 27 DN-HCC lesions diagnosed by biopsy. Of 86 HCC lesions, 87.2% (75/86) showed complete enhancement during the arterial phase, and 12.8% (11/86) had inhomogeneous enhancement, with no enhancement in the central area during the arterial phase; 100% (86/86) exhibited washout during the late phase. Of 102 RN lesions, 95.1% (97/102) had delayed or simultaneous enhancement during the arterial phase, and 4.9% (5/102) displayed slight enhancement during the arterial phase; 26.5% (27/102) exhibited washout and 73.5% (75/102) exhibited no washout during the late phase. In 27 DN-HCC lesions, only part of the lesions enhanced during the arterial phase and washed out during the late phase; the other areas had delayed or simultaneous enhancement during the arterial phase, and 29.6% (8/27) exhibited slight washout in the late phase. In 86 HCCs, the pathological feature was HCC in the enhanced area of 75 lesions, hepatocellular fatty degeneration in the slightly enhanced area of 7 lesions, and hepatocellular necrosis in the unenhanced area and HCC in the enhanced area of 4 lesions. In 102 RNs, the pathological diagnosis was hepatocyte proliferation with or without fatty degeneration. In 27 DN-HCCs, the pathological feature was HCC in the enhanced area and hepatocyte regeneration in the unenhanced area., Conclusions: CEUS is useful for the diagnosis of focal liver lesions in cirrhotic patients. CEUS can help determine the progression from RN to DN-HCC to HCC by analyzing the hemodynamics. CEUS can promote the diagnostic accuracy of a biopsy by providing more accurate information on the site of the biopsy.

Objective: To retrospectively investigate the role of contrast-enhanced ultrasonography (CEUS) in percutaneous radiofrequency ablation (RFA) in patients with liver metastases and evaluate the therapeutic efficacy of RFA assisted by CEUS., Methods: From May 2004 to September 2010, 136 patients with 219 liver metastatic lesions received CEUS examination 1 h before RFA (CEUS group), and other 126 patients with 216 lesions without CEUS examination in the earlier period were served as a historical control group. The mean tumor size was 3.2 cm and the mean tumor number was 1.6 in the CEUS group, while 3.4 cm and 1.7 in the control group, respectively (P>0.05). The clinical characteristics, recurrence results and survival outcomes were compared between two groups., Results: In the CEUS group, two isoechoic tumors were not demonstrated on unenhanced ultrasonography (US), and 63 (47%) of 134 tumors examined with CEUS were 0.3 cm larger than with unenhanced US. Furthermore, in 18.4% of 136 patients, additional 1-3 tumors were detected on CEUS. The CEUS group showed higher early tumor necrosis and lower intrahepatic recurrence than the control group. The 3-year overall survival (OS) rate and the 3-year local recurrence-free survival (LRFS) rate in the CEUS group were 50.1% and 38.3%, in contrast to 25.3% and 19.3% in the control group, respectively (P=0.002 and P<0.001)., Conclusions: CEUS provides important information for RFA treatment in patients with liver metastases and better therapeutic effect could be attained.

There is often interest in predicting an individual's latent health status based on high-dimensional biomarkers that vary over time. Motivated by time-course gene expression array data that we have collected in two influenza challenge studies performed with healthy human volunteers, we develop a novel time-aligned Bayesian dynamic factor analysis methodology. The time course trajectories in the gene expressions are related to a relatively low-dimensional vector of latent factors, which vary dynamically starting at the latent initiation time of infection. Using a nonparametric cure rate model for the latent initiation times, we allow selection of the genes in the viral response pathway, variability among individuals in infection times, and a subset of individuals who are not infected. As we demonstrate using held-out data, this statistical framework allows accurate predictions of infected individuals in advance of the development of clinical symptoms, without labeled data and even when the number of biomarkers vastly exceeds the number of individuals under study. Biological interpretation of several of the inferred pathways (factors) is provided.