Salivary Proteome and Intact N-Glycopeptides Analysis Reveal Specific Signatures in Periodontitis.

Periodontitis is a prevalent oral inflammatory disease that can result in tooth loss and is closely linked to type 2 diabetes (T2D). In this study, we analyzed the salivary proteome and intact N-glycopeptides (IGPs) of individuals with mild-moderate, severe, aggressive periodontitis, and periodontitis with T2D, including those treated with antidiabetic drugs, to identify specific signatures associated with the disease. Our results revealed that salivary proteins and glycoproteins were altered in all periodontitis groups (PRIDE ID: 1-20230612-72345), with fucose- and sialic acid-containing N-glycans showing the greatest increase. Additionally, differentially expressed proteins were classified into 9 clusters, including those that were increased in all periodontitis groups and those that were only altered in certain types of periodontitis. Interestingly, treatment with antidiabetic drugs reversed many of the changes observed in the salivary proteome and IGPs in T2D-related periodontitis, suggesting a potential therapeutic approach for managing periodontitis in patients with T2D. Consistent with MS/MS results, the expression of salivary IGHA2 and Fucα1-3/6GlcNAc (AAL) was significantly increased in MP. These findings provide new insights into the pathogenesis of periodontitis and highlight the potential of salivary biomarkers for diagnosis, prognosis, and monitoring of disease progression and treatment response.

TXNIP mediated by EZH2 regulated osteogenic differentiation in hBmscs and MC3T3-E1 cells through the modulation of oxidative stress and PI3K/AKT/Nrf2 pathway.

BACKGROUND: Previous research has identified a significant role of Thioredoxin-interacting protein (TXNIP) in bone loss. The purpose of this investigation was to assess the role and the underlying molecular mechanisms of TXNIP in the osteogenic differentiation of human bone marrow stromal cells (hBMSCs) and pre-osteoblast MC3T3-E1 cells. METHODS: Human bone marrow stem cells (hBMSCs) and MC3T3-E1 cells were used to induce osteogenic differentiation. The expression of genes and proteins was assessed using RT-qPCR and western blot, respectively. ChIP assay was used to validate the interaction between genes. The osteogenic differentiation ability of cells was reflected using ALP staining and detection of ALP activity. The mineralization ability of cells was assessed using ARS staining. DCFCA staining was employed to evaluate the intracellular ROS level. RESULTS: Initially, downregulation of TXNIP and upregulation of EZH2 were observed during osteogenesis in hBMSCs and MC3T3-E1 cells. Additionally, it was discovered that EZH2 negatively regulates TXNIP expression in these cells. Furthermore, experiments indicated that the knockdown of TXNIP stimulated the activation of the PI3K/AKT/Nrf2 signaling pathway in hBMSCs and MC3T3- E1 cells, thus inhibiting the production of reactive oxygen species (ROS). Further functional experiments revealed that overexpression of TXNIP inhibited the osteogenic differentiation in hBMSCs and MC3T3-E1 cells by enhancing ROS produc-tion. On the other hand, knockdown of TXNIP promoted the osteogenic differentiation capacity of hBMSCs and MC3T3-E1 cells through the activation of the PI3K/AKT/Nrf2 pathway. CONCLUSION: In conclusion, this study demonstrated that TXNIP expression, under the regulation of EZH2, plays a crucial role in the osteogenic differentiation of hBMSCs and MC3T3-E1 cells by regulating ROS production and the PI3K/AKT/Nrf2 pathway.

Straight intramedullary MultiLoc nails for displaced proximal humeral fractures: health status, radiographic results, clinical outcome, and complications.

BACKGROUND: The treatment of the displaced proximal humerus fractures (PHF) still facing a lot of unsolved problems. The aim of this study was to evaluate the clinical effect of MultiLoc nails for the treatment of PHF and present outcomes of patients with different Neer's classification and reduction quality. METHODS: Adult patients with PHFs were recruited and treated with MultiLoc nail. Intraoperative data, radiographic and functional outcomes, as well as occurrence of postoperative complications were assessed. RESULTS: 48 patients met inclusion and exclusion criteria and were included in this study. The DASH Score were 32.2 ± 3.1 points at 12 months, and 37.3 ± 2.5 points at the final follow-up. The mean ASES score at 12 months and final follow-up were 74.4 ± 6.2 and 78.8 ± 5.1, respectively. The mean CM Score in all 48 patients reached 68 ± 6.4 points at the final follow-up, relative side related CM Score 75.2 ± 7.7% of contralateral extremity. The incidence rate of complications was 20.8%. Patients with fracture mal-union, adhesive capsulitis were observed but no secondary surgeries were performed. There was no significantly difference of DASH Score 12 months after surgery and at the last follow-up among patients with different Neer's classification or reduction quality. However, functional outcomes such as ASES score and CM score were significantly influenced by severity of fracture and the quality of fracture reduction. CONCLUSIONS: Our study demonstrated that MultiLoc nails is well suited for proximal humeral fractures, with satisfactory health status recovery, good radiographic results, positive clinical outcomes and low rates of complications. The treatment for four part PHF still faces great challenges. Accurate fracture reduction was an important factor for good functional result.

A Novel Boron Dipyrromethene-Erlotinib Conjugate for Precise Photodynamic Therapy against Liver Cancer.

Photodynamic Therapy (PDT) is recognized for its exceptional effectiveness as a promising cancer treatment method. However, it is noted that overexposure to the dosage and sunlight in traditional PDT can result in damage to healthy tissues, due to the low tumor selectivity of currently available photosensitizers (PSs). To address this challenge, we introduce herein a new strategy where the small molecule-targeted agent, erlotinib, is integrated into a boron dipyrromethene (BODIPY)-based PS to form conjugate 6 to enhance the precision of PDT. This conjugate demonstrates optical absorption, fluorescence emission, and singlet oxygen generation efficiency comparable to the reference compound 7, which lacks erlotinib. In vitro studies reveal that, after internalization, conjugate 6 predominantly accumulates in the lysosomes of HepG2 cells, exhibiting significant photocytotoxicity with an IC50 value of 3.01 µM. A distinct preference for HepG2 cells over HELF cells is observed with conjugate 6 but not with compound 7. In vivo experiments further confirm that conjugate 6 has a specific affinity for tumor tissues, and the combination treatment of conjugate 6 with laser illumination can effectively eradicate H22 tumors in mice with outstanding biosafety. This study presents a novel and potential PS for achieving precise PDT against cancer.

[A multi-center epidemiological study on pneumococcal meningitis in children from 2019 to 2020]. / 2019­2020å¹´160ä¾‹å„¿ç«¥è‚ºç‚Žé“¾çƒèŒè„‘è†œç‚Žä¸´åºŠæµè¡Œç— å­¦å¤šä¸­å¿ƒç ”ç©¶.

OBJECTIVES: To investigate the clinical characteristics and prognosis of pneumococcal meningitis (PM), and drug sensitivity of Streptococcus pneumoniae (SP) isolates in Chinese children. METHODS: A retrospective analysis was conducted on clinical information, laboratory data, and microbiological data of 160 hospitalized children under 15 years old with PM from January 2019 to December 2020 in 33 tertiary hospitals across the country. RESULTS: Among the 160 children with PM, there were 103 males and 57 females. The age ranged from 15 days to 15 years, with 109 cases (68.1%) aged 3 months to under 3 years. SP strains were isolated from 95 cases (59.4%) in cerebrospinal fluid cultures and from 57 cases (35.6%) in blood cultures. The positive rates of SP detection by cerebrospinal fluid metagenomic next-generation sequencing and cerebrospinal fluid SP antigen testing were 40% (35/87) and 27% (21/78), respectively. Fifty-five cases (34.4%) had one or more risk factors for purulent meningitis, 113 cases (70.6%) had one or more extra-cranial infectious foci, and 18 cases (11.3%) had underlying diseases. The most common clinical symptoms were fever (147 cases, 91.9%), followed by lethargy (98 cases, 61.3%) and vomiting (61 cases, 38.1%). Sixty-nine cases (43.1%) experienced intracranial complications during hospitalization, with subdural effusion and/or empyema being the most common complication [43 cases (26.9%)], followed by hydrocephalus in 24 cases (15.0%), brain abscess in 23 cases (14.4%), and cerebral hemorrhage in 8 cases (5.0%). Subdural effusion and/or empyema and hydrocephalus mainly occurred in children under 1 year old, with rates of 91% (39/43) and 83% (20/24), respectively. SP strains exhibited complete sensitivity to vancomycin (100%, 75/75), linezolid (100%, 56/56), and meropenem (100%, 6/6). High sensitivity rates were also observed for levofloxacin (81%, 22/27), moxifloxacin (82%, 14/17), rifampicin (96%, 25/26), and chloramphenicol (91%, 21/23). However, low sensitivity rates were found for penicillin (16%, 11/68) and clindamycin (6%, 1/17), and SP strains were completely resistant to erythromycin (100%, 31/31). The rates of discharge with cure and improvement were 22.5% (36/160) and 66.2% (106/160), respectively, while 18 cases (11.3%) had adverse outcomes. CONCLUSIONS: Pediatric PM is more common in children aged 3 months to under 3 years. Intracranial complications are more frequently observed in children under 1 year old. Fever is the most common clinical manifestation of PM, and subdural effusion/emphysema and hydrocephalus are the most frequent complications. Non-culture detection methods for cerebrospinal fluid can improve pathogen detection rates. Adverse outcomes can be noted in more than 10% of PM cases. SP strains are high sensitivity to vancomycin, linezolid, meropenem, levofloxacin, moxifloxacin, rifampicin, and chloramphenicol.

Investigation on the mechanisms of human sperm DNA damage based on the proteomics analysis by SWATH-MS.

BACKGROUND: Spermatozoa have the task of delivering an intact paternal genome to the oocyte and supporting successful embryo development. The detection of sperm DNA fragmentation (SDF) has been emerging as a complementary test to conventional semen analysis for male infertility evaluation, but the mechanism leading to SDF and its impact on assisted reproduction remain unclear. Therefore, the study identified and analyzed the differentially expressed proteins of sperm with high and low SDF. METHODS: Semen samples from men attended the infertility clinic during June 2020 and August 2020 were analyzed, and sperm DNA fragmentation index (DFI) was detected by the sperm chromatin structure assay. Semen samples with low DFI (< 30%, control group) and high DFI (≥ 30%, experimental group) were optimized by density gradient centrifugation (DGC), and the differentially expressed proteins of obtained sperm were identified by the Sequential Window Acquisition of All Theoretical Mass Spectra Mass Spectrometry (SWATH-MS) and performed GO and KEGG analysis. RESULTS: A total of 2186 proteins were identified and 1591 proteins were quantified, of which 252 proteins were identified as differentially expressed proteins, including 124 upregulated and 128 downregulated. These differentially expressed proteins were involved in metabolic pathways, replication/recombination/repair, acrosomal vesicles, kinase regulators, fertilization, tyrosine metabolism, etc. Western blotting results showed that the expression levels of RAD23B and DFFA proteins and the levels of posttranslational ubiquitination and acetylation modifications in the experimental group were significantly higher than those in the control group, which was consistent with the results of proteomics analysis. CONCLUSIONS: Proteomic markers of sperm with high DNA fragmentation can be identified by the SWATH-MS and bioinformatic analysis, and new protein markers and posttranslational modifications related to sperm DNA damage are expected to be intensively explored. Our findings may improve our understanding of the basic molecular mechanism of sperm DNA damage.

Investigation of the mechanisms leading to human sperm DNA damage based on transcriptome analysis by RNA-seq techniques.

RESEARCH QUESTION: What are the molecular mechanisms leading to human sperm DNA damage? DESIGN: Semen samples were collected and the sperm DNA fragmentation index (DFI) was assessed. Differentially expressed RNA in spermatozoa with a high (DFI ≥30%, experimental group) or normal (DFI <30%, control group) DFI were identified by RNA-sequencing (RNA-seq) technology, and Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis was performed. Three differentially expressed RNA related to sperm DNA damage and repair, namely PMS1, TP53BP1 and TLK2, were validated using real-time quantitative (RT-qPCR). RESULTS: A total of 19,970 expressed RNA were detected in the two groups. Compared with the control group, the expression levels of 189 RNA in the experimental group were significantly increased and those of 163 genes decreased. Gene Ontology enrichment analysis showed that these RNA were mainly concentrated in the ATPase-dependent transmembrane transport complex, extracellular exosome, somatic cell DNA recombination, protein binding, cytoplasm and regulation of localization. KEGG pathway analysis showed that these RNA were mainly related to the PI3K-Akt signalling pathway, endocytosis, p53 signalling pathway and cGMP-PKG signalling pathway. The RT-qPCR results showed that the expression levels of PMS1, TP53BP1 and TLK2 in the experimental group were significantly lower than in the control group (P = 0.01, 0.015 and 0.004, respectively), which was identical to the results of RNA sequencing. CONCLUSIONS: Differentially expressed RNA related to sperm DNA damage and repair may be identified by RNA-seq technology, which provides new insights into the understanding of sperm DNA damage and repair, and will help to discover new biomarkers related to sperm DNA damage.

Mesenchymal stem cell-derived extracellular vesicles for treatment of bone loss within periodontitis in pre-clinical animal models: a meta-analysis.

BACKGROUND: Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) represent an effective and promising strategy for periodontitis, although studies remain pre-clinical. Herein, a meta-analysis was conducted to assess the efficacy of MSC-EVs in animal models of periodontitis. METHODS: The PubMed, Web of Science, and Embase electronic databases were searched up to Dec 2022 to retrieve preclinical studies examining the use of MSC-EVs for periodontitis treatment. Meta-analyses and sub-group analyses were performed to assess the effect of MSC-EVs on Bone Volume/Total Volume (BV/TV) or the distance between the cementoenamel junction and alveolar bone crest (CEJ-ABC) in pre-clinical animal models of periodontitis. RESULTS: 11 studies published from Mar 2019 to Oct 2022 met the inclusion criteria. Overall, MSC-EVs contributed to periodontal bone regeneration in the inflammatory bone loss area due to periodontitis, as represented by a weighted mean difference (WMD) of 14.07% (95% CI = 6.73, 21.41%, p < 0.001) for BV/TV and a WMD of -0.12 mm (95% CI= -0.14, -0.11 mm, p < 0.001) for CEJ-ABC. However, sub-analysis suggested that there was no significant difference in CEJ-ABC between studies with bioactive scaffolds and studies without bioactive scaffolds (p = 0.60). CONCLUSIONS: The present study suggests that MSC-EVs may represent an attractive therapy for the treatment of inflammatory bone loss within periodontitis.

[Establishment of a risk model for severe adenovirus pneumonia and prospective study of the timing of intravenous immunoglobulin therapy in children]. / å„¿ç«¥é‡ç—‡è ºç— æ¯’æ€§è‚ºç‚Žé£Žé™©æ¨¡åž‹çš„æž„å»ºåŠé™è„‰æ³¨å°„å ç–«çƒè›‹ç™½æ²»ç–—æ—¶æœºçš„å‰çž»æ€§ç ”ç©¶.

OBJECTIVES: To develop a risk prediction model for severe adenovirus pneumonia (AVP) in children, and to explore the appropriate timing for intravenous immunoglobulin (IVIG) therapy for severe AVP. METHODS: Medical data of 1 046 children with AVP were retrospectively analyzed, and a risk prediction model for severe AVP was established using multivariate logistic regression. The model was validated with 102 children with AVP. Then, 75 children aged ≤14 years who were considered at risk of developing severe AVP by the model were prospectively enrolled and divided into three groups (A, B and C) in order of visit, with 25 children in each group. Group A received symptomatic supportive therapy only. With the exception of symptomatic supportive therapy, group B received IVIG treatment at a dose of 1g/(kg·d) for 2 consecutive days, before progressing to severe AVP. With the exception of symptomatic supportive therapy, group C received IVIG treatment at a dose of 1 g/(kg·d) for 2 consecutive days after progressing to severe AVP. Efficacy and related laboratory indicators were compared among the three groups after treatment. RESULTS: Age<18.5 months, underlying diseases, fever duration >6.5 days, hemoglobin level <84.5 g/L, alanine transaminase level >113.5 U/L, and co-infection with bacteria were the six variables that entered into the risk prediction model for severe AVP. The model had an area under the receiver operating characteristic curve of 0.862, sensitivity of 0.878, and specificity of 0.848. The Hosmer-Lemeshow test showed good consistency between the predicted values and the actual observations (P>0.05). After treatment, group B had the shortest fever duration and hospital stay, the lowest hospitalization costs, the highest effective rate of treatment, the lowest incidence of complications, the lowest white blood cell count and interleukin (IL)-1, IL-2, IL-6, IL-8, IL-10 levels, and the highest level of tumor necrosis factor alpha (P<0.05). CONCLUSIONS: The risk model for severe AVP established in this study has good value in predicting the development of severe AVP. IVIG therapy before progression to severe AVP is more effective in treating AVP in children.

Clinical profiles and antimicrobial resistance patterns of invasive Salmonella infections in children in China.

Invasive Salmonella infections result in a significant burden of disease including morbidity, mortality, and financial cost in many countries. Besides typhoid fever, the clinical impact of non-typhoid Salmonella infections is increasingly recognized with the improvement of laboratory detection capacity and techniques. A retrospective multicenter study was conducted to analyze the clinical profiles and antimicrobial resistance patterns of invasive Salmonella infections in hospitalized children in China during 2016-2018. A total of 130 children with invasive Salmonella infections were included with the median age of 12 months (range: 1-144 months). Seventy-nine percent of cases occurred between May and October. Pneumonia was the most common comorbidity in 33 (25.4%) patients. Meningitis and septic arthritis caused by nontyphoidal Salmonella (NTS) infections occurred in 12 (9.2%) patients and 5 (3.8%) patients. Patients < 12 months (OR: 16.04) and with septic shock (OR: 23.4), vomit (OR: 13.33), convulsion (OR: 15.86), C-reactive protein (CRP) ≥ 40 g/L (OR: 5.56), and a higher level of procalcitonin (PCT) (OR: 1.05) on admission were statistically associated to an increased risk of developing meningitis. Compared to 114 patients with NTS infections, 16 patients with typhoid fever presented with higher levels of CRP and PCT (P < 0.05). The rates of resistance to ampicillin, sulfamethoxazole/trimethoprim, ciprofloxacin, and ceftriaxone among Salmonella Typhi and NTS isolates were 50% vs 57.3%, 9.1% vs 24.8%, 0% vs 11.2%, and 0% vs 9.9%, respectively. NTS has been the major cause of invasive Salmonella infections in Chinese children and can result in severe diseases. Antimicrobial resistance among NTS was more common.

Nanoscale Visualization of a Photoinduced Plasmonic Near-Field in a Single Nanowire by Free Electrons.

Swift electrons can undergo inelastic interactions not only with electrons but also with near-fields, which may result in an energy loss or gain. Developments in photon-induced near-field electron microscopy (PINEM) enable direct imaging of the plasmon near-field distribution with nanometer resolution. Here, we report an analysis of the surface plasmonic near-field structure based on PINEM observations of silver nanowires. Single-photon order-selected electron images revealed the wavelike and banded structure of electric equipotential regions for a confined near-field integral associated with typical absorption of photon quanta (nℏω). Multimodal plasmon oscillations and second-harmonic generation were simultaneously observed, and the polarization dependence of plasmon wavelength and symmetry properties were analyzed. Based on advanced imaging techniques, our work has implications for future studies of the localized-field structures at interfaces and visualization of novel phenomena in nanostructures, nanosensors, and plasmonic devices.

PINK1 mediated mitophagy attenuates early apoptosis of gingival epithelial cells induced by high glucose.

BACKGROUND: Oxidative stress mediated by hyperglycemia damages cell-reparative processes such as mitophagy. Down-regulation of mitophagy is considered to be a susceptible factor for diabetes mellitus (DM) and its complications. However, the role of mitophagy in DM-associated periodontitis has not been fully elucidated. Apoptosis of human gingival epithelial cells (hGECs) is one of the representative events of DM-associated periodontitis. Thus, this study aimed to investigate PTEN-induced putative kinase 1 (PINK1)-mediated mitophagy activated in the process of high glucose (HG)-induced hGECs apoptosis. METHODS: For dose-response studies, hGECs were incubated in different concentrations of glucose (5.5, 15, 25, and 50 mmol/L) for 48 h. Then, hGECs were challenged with 25 mmol/L glucose for 12 h and 48 h, respectively. Apoptosis was detected by TdT-mediated dUTP nick end labeling (TUNEL), caspase 9 and mitochondrial membrane potential (MMP). Subsequently, autophagy was evaluated by estimating P62, LC3 II mRNA levels, LC3 fluorescent puncta and LC3-II/I ratio. Meanwhile, the involvement of PINK1-mediated mitophagy was assessed by qRT-PCR, western blotting and immunofluorescence. Finally, hGECs were transfected with shPINK1 and analyzed by MMP, caspase 9 and annexin V-FITC apoptosis. RESULTS: The number of TUNEL-positive cells and caspase 9 protein were significantly increased in cells challenged with HG (25 mmol/L) for 48 h (HG 48 h). MMP was impaired both at HG 12 h and HG 48 h, but the degree of depolarization was more serious at HG 48 h. The autophagy improved as the amount of LC3 II increased and p62 decreased in HG 12 h. During this process, HG 12 h treatment induced PINK1-mediated mitophagy. PINK1 silencing with HG 12 h resulted in MMP depolarization and cell apoptosis. CONCLUSIONS: These results suggested that loss of the PINK1 gene may cause mitochondrial dysfunction and increase sensitivity to HG-induced apoptosis of hGECs at the early stage. PINK1 mediated mitophagy attenuates early apoptosis of gingival epithelial cells induced by high glucose.

Exosome-mediated circ_0001846 participates in IL-1ß-induced chondrocyte cell damage by miR-149-5p-dependent regulation of WNT5B.

AIMS: Osteoarthritis (OA) is the leading cause of physical disability in middle-aged and elderly people globally. Previous studies have revealed that circular RNA (circRNA) is involved in the pathogenesis of OA. In this study, we studied the role of circ_0001846 in interleukin-1ß (IL-1ß)-induced OA progression. METHODS: Twenty-one patients with OA and 17 volunteers were recruited for the collection of articular cartilage tissues. The expression of circ_0001846, microRNA-149-5p (miR-149-5p) and Wingless-type MMTV integration site family, member 5B (WNT5B) was detected by quantitative real-time polymerase chain reaction. The protein expression was determined by western blot analysis. Cell viability, apoptosis, invasion and migration were demonstrated by cell counting kit-8, flow cytometry analysis, transwell invasion and wound-healing assays, respectively. The levels of IL-6 and tumor necrosis factor-α were detected by Enzyme-linked immunosorbent assay. The interaction between miR-149-5p and circ_0001846 or WNT5B was predicted by starbase online database, and proved by dual-luciferase reporter and RIP assays. RESULTS: Circ_0001846 and WNT5B expression were upregulated, while miR-149-5p expression was downregulated in articular cartilage tissues from patients with OA and IL-1ß-treated CHON-001 cells compared with normal articular cartilage tissues or untreated CHON-001 cells. Circ_0001846 expression was increased in IL-1ß-treated CHON-001 cell exosomes. Circ_0001846 knockdown reversed IL-1ß-mediated cell proliferation, apoptosis, migration, invasion, inflammation and extracellular matrix (ECM) degradation in CHON-001 cells. Additionally, circ_0001846 participated in IL-1ß-induced chondrocyte cell damage by sponging miR-149-5p. MiR-149-5p mediated IL-1ß-induced chondrocyte cell dysfunction by targeting WNT5B. Furthermore, circ_0001846 secretion was mediated by exosomes in IL-1ß-treated CHON-001 cells. CONCLUSION: Exosome-mediated transfer of circ_0001846 modulated IL-1ß-induced chondrocyte cell damage by miR-149-5p/WNT5B axis, providing a novel avenue for the therapy of OA.

Microbiological profiles and antimicrobial resistance patterns of pediatric bloodstream pathogens in China, 2016-2018.

OBJECTIVES: This study aimed to investigate the microbiological profiles and antimicrobial resistance patterns of bloodstream pathogens in Chinese children. METHODS: This retrospective study was conducted at 13 tertiary hospitals in China during 2016-2018. The first bloodstream isolates of the same species from one pediatric patient < 18 years were included to this study for analysis. Antimicrobial susceptibility testing was determined based on minimum inhibitory concentrations or Kirby-Bauer disk diffusion methods according to the 2018 Clinical and Laboratory Standards Institute guidelines. RESULTS: Overall, 9345 nonduplicate bloodstream isolates were collected. Top 10 pathogens included Coagulase-negative staphylococcus (CoNS) (44.4%), Escherichia coli (10.2%), Klebsiella pneumoniae (5.9%), Staphylococcus aureus (5.0%), Streptococcus pneumoniae (4.9%), Pseudomonas aeruginosa(2.8%), Enterococcus faecium (2.7%), Stenotrophomonas maltophilia (2.4%), Salmonella spp. (2.3%), and Streptococcus agalactiae (2.0%). The commonest pathogens apart from CoNS in age group 0-28 days, 29 days-2 months, 3-11 months, 1-5 years, and ≥ 5 years were Escherichia coli (17.2%), Escherichia coli (14.0%), Escherichia coli (7.9%), Streptococcus pneumoniae (10.7%) ,and Staphylococcus aureus (13.6%), respectively. The overall prevalence of extended-spectrum ß-lactamases-producing Enterobacteriaceae, carbapenem-resistant Klebsiella pneumoniae, carbapenem-resistant Acinetobacter baumannii, and carbapenem-resistant Pseudomonas aeruginosa were 41.4, 28.4, 31.7, and 5.6%, respectively. The overall prevalence of methicillin-resistant Staphylococcus aureus, penicillin-resistant Streptococcus pneumoniae and vancomycin-resistant Enterococcus was 38.1, 28.3, and 0.7%, respectively. CONCLUSIONS: The major bacterial pathogens have differences in different age groups, ward types, and regions in Chinese children, and the commonest causing microorganism was the Escherichia coli, especially in neonates and infants. High prevalence of important resistant phenotypes is of a serious concern.

Antibiotics prescription for targeted therapy of pediatric invasive pneumococcal diseases in China: a multicenter retrospective study.

BACKGROUND: Streptococcus pneumoniae (S. pneumoniae) is a major cause of bacterial meningitis, septicemia and pneumonia in children. Inappropriate choice of antibiotic can have important adverse consequences for both the individual and the community. Here, we focused on penicillin/cefotaxime non-susceptibility of S. pneumoniae and evaluated appropriateness of targeted antibiotic therapy for children with IPD (invasive pneumococcal diseases) in China. METHODS: A multicenter retrospective study was conducted in 14 hospitals from 13 provinces in China. Antibiotics prescription, clinical features and resistance patterns of IPD cases from January 2012 to December 2017 were collected. Appropriateness of targeted antibiotics therapy was assessed. RESULTS: 806 IPD cases were collected. The non-susceptibility rates of S. pneumoniae to penicillin and cefotaxime were 40.9% and 20.7% respectively in 492 non-meningitis cases, whereas those were 73.2% and 43.0% respectively in 314 meningitis cases. Carbapenems were used in 21.3% of non-meningitis cases and 42.0% of meningitis cases for targeted therapy. For 390 non-meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were used in 17.9% and 8.7% of cases respectively for targeted therapy. For 179 meningitis cases with isolates susceptible to cefotaxime, vancomycin and linezolid were prescribed in 55.3% and 15.6% of cases respectively. Overall, inappropriate targeted therapies were identified in 361 (44.8%) of 806 IPD cases, including 232 (28.8%) cases with inappropriate use of carbapenems, 169 (21.0%) cases with inappropriate use of vancomycin and 62 (7.7%) cases with inappropriate use of linezolid. CONCLUSIONS: Antibiotic regimens for IPD definite therapy were often excessive with extensive prescription of carbapenems, vancomycin or linezolid in China. Antimicrobial stewardship programs should be implemented to improve antimicrobial use.

Single-cell transcriptome profiling reveals the mechanism of abnormal proliferation of epithelial cells in congenital cystic adenomatoid malformation.

OBJECTIVES: Congenital cystic adenomatoid malformation (CCAM) is the most common congenital pulmonary anomaly with unknown etiology. Here, single-cell RNA sequencing (scRNA-seq) was used to map its cellular landscape and identify the underlying cellular and molecular events related to CCAM. METHODS: This study involved a 4.25 year old patient with grade Ⅱ-Ⅲ CCAM at the Children's Hospital of Fudan University. Samples of lesioned and non-lesioned areas were collected during surgery for scRNA-seq. RESULTS: In total, 19,904 cells were obtained with median UMI counts of 7032 per cell and 1995 median genes per cell. In terms of lesioned and non-lesioned areas, epithelial cells accounted for 27.23% and 17.85%, respectively, while mesenchymal cells accounted for 2.67% and 16.06%, respectively (P < 0.0001). Further clustering of epithelial cells revealed that the fractions of alveolar type 1 cells (AT1, N: 23.65%; L: 49.81%), AT2(N: 2.02%; L: 5.26%), club-1(N: 9.02%; L: 17.57%), club-3(N: 1.18%; L: 4.15%), and basal cells (N: 0.34%; L: 2.93%) were increased in lesioned samples (P < 0.0001). Pseudotime trajectory analysis showed tracks of club-1/basal cells→AT2→club-3→AT1 and club-1,2/basal→AT2. Mast cells (N: 0.63%; L: 2.48%) were also increased in lesioned samples and interactions of CD44 with HBEGF and FGFR2 were detected between mast and epithelial cells. CONCLUSIONS: AT1, AT2, club, and basal cells were increased in CCAM patients, and newly defined club-1/3 and basal cells might be the origin of proliferating AT1 and AT2 cells. Increased mast cells might promote epithelial cell proliferation through interactions of CD44 with HBEGF and FGFR2.

Efficacy and safety of mycophenolate mofetil in the treatment for IgA nephropathy: a meta-analysis of randomized controlled trials.

AIM: IgA nephropathy is virtually known as the most common glomerulopathy to end-stage renal failure in the world. Mycophenolate mofetil is a selective immunosuppressant widely used in organ transplantation, yet its tolerance and effectiveness in IgAN is controversial. METHODS: This is a systematic review and random-effects meta-analysis, searching PubMed, Embase, Te Cochrane Library, Science Citation Index, Ovid evidence-based medicine, Chinese Biomedical Literature and Chinese Science and Technology Periodicals. Screen out randomized controlled trials on patients with biopsy-proven IgA nephropathy and analysis mycophenolate mofetil treatment regimens used for therapy of IgA nephropathy. Complete remission and partial remission, doubling of creatinine level, proteinuria, incidence of end-stage kidney disease, infection, Cushing syndrome, diabetes, hepatic dysfunction or gastrointestinal symptoms, neurologic or visual ambiguity, acne, and alopecia were observed. RESULTS: Nine relevant trials were conducted with 587 patients enrolled. In Mycophenolate mofetil or plus medium/low-dose steroid comparing full-dose steroid alone or placebo, there was no significant difference. The risk of Cushing syndrome and diabetes had been significantly lowered with Mycophenolate mofetil-treated patients, while the risk of infection had been increased. CONCLUSIONS: Mycophenolate mofetil therapy did not differ in reducing proteinuria and Scr in patients with IgAN who had persistent proteinuria, while having fewer Cushing syndrome and diabetes risk and more infection risk. However, larger randomized studies are needed to reveal these results.

Pediatric Antibiotic Prescribing in China According to the 2019 World Health Organization Access, Watch, and Reserve (AWaRe) Antibiotic Categories.

OBJECTIVES: To assess clinical indication-specific antibiotic prescribing in pediatric practice in China based on the World Health Organization (WHO) Access, Watch, and Reserve (AWaRe) metrics and to detect potential problem areas. STUDY DESIGN: Pediatric prescription records on the 16th of each month during 2018 were sampled for all encounters at outpatient and emergency departments of 16 tertiary care hospitals via hospital information systems. Antibiotic prescribing patterns were analyzed across and within diagnostic conditions according to WHO AWaRe metrics and Anatomical Therapeutic Chemical (ATC) classification. RESULTS: A total of 260 001 pediatric encounters were assessed, and antibiotics were prescribed in 94 453 (36.3%). In 35 167 encounters (37.2%), at least 1 intravenous antibiotic was administered. WHO Watch group antibiotics accounted for 82.2% (n = 84 176) of all antibiotic therapies. Azithromycin (n = 15 791; 15.4%) was the most commonly prescribed antibiotic, and third-generation cephalosporins (n = 44 387; 43.3%) were the most commonly prescribed antibiotic class. In at least 66 098 encounters (70.0%), antibiotics were prescribed for respiratory tract conditions, mainly for bronchitis/bronchiolitis (n = 25 815; 27.3%), upper respiratory tract infection (n = 25 184; 26.7%), and pneumonia (n = 13 392; 14.2%). CONCLUSIONS: Overuse and misuse of WHO Watch group antibiotics for respiratory tract conditions and viral infectious diseases is common in pediatric outpatients in China. Pediatric antimicrobial stewardship should be strengthened using WHO AWaRe metrics.

Switchable broadband terahertz spatial modulators based on patterned graphene and vanadium dioxide.

We numerically demonstrate a switchable broadband terahertz spatial modulator composed of ginkgo-leaf-patterned graphene and transition material vanadium dioxide (VO2). The phase transition property of VO2 is used to switch the spatial modulator from absorption mode to transmission mode, and the graphene behaves as dynamically adjustable material for a large scale of absorption and transmittance modulation. When VO2 is in the metallic state and the Fermi energy of graphene is set as 0.8 eV, the proposed modulator behaves as a broadband absorber with the absorbance over 85% from 1.33 to 2.83 THz. By adjusting the graphene Fermi level from 0 to 0.8 eV, the peak absorbance can be continuously tuned from 24.3% to near 100% under the absorption mode, and the transmittance at 2.5 THz can be continuously tuned from 87% to 35.5% under the transmission mode. To further increase the bandwidth, a three-layer-patterned-graphene is introduced into a new modulator design, which achieves a wide bandwidth of 3.13 THz for the absorbance over 85%. By the combination of the tunability of graphene and VO2, the proposed modulators not only can flexibly switch between dual-functional modulation modes of absorption and transmission but also possess deep modulation depth. Benefitting from the excellent modulation performance, the proposed switchable dual-functional spatial modulators may offer significant potential applications in various terahertz smart optoelectronic devices.

The therapeutic role of baicalein in combating experimental periodontitis with diabetes via Nrf2 antioxidant signaling pathway.

BACKGROUND AND OBJECTIVE: Oxidative stress has been suggested as an important pathogenic factor contributing to chronic periodontitis with diabetes mellitus (CPDM). Previous studies have revealed the potential therapeutic properties of baicalein (BCI) in oxidative stress-related diseases; however, the antioxidant effects of BCI on therapy for individual with CPDM remain largely unexplored. Nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in cellular defence against oxidative stress. In this study, we aim to determine whether BCI prevents diabetes-related periodontal tissue destruction by regulating Nrf2 signaling pathway. MATERIAL AND METHODS: Human gingival epithelial cells (hGECs) were challenged with high glucose (HG, 25 mmol/L) and/or lipopolysaccharide (LPS, 20 µg/mL). Reactive oxygen species (ROS) were detected by fluorescence-activated cell sorting. The changes of antioxidant-related genes, including Nrf2, catalase (Cat), glutamate-cysteine ligase catalytic subunit (Gclc), superoxide dismutase 1 (Sod1), and superoxide dismutase 2 (Sod2), were quantified by real-time PCR. The localization of phospho-Nrf2 (pNrf2, S40) in the nucleus was detected by immunofluorescence staining and laser scanning confocal microscope (LSCM). PNrf2 and total form of Nrf2 were determined using western blot. The above indicators together with mitochondrial membrane potential (MMP) were further investigated in hGECs pre-treated with different concentrations of BCI (0.01, 0.1, or 0.5 µg/mL) before stimulated with HG plus LPS (GP). Finally, the role of BCI in activating Nrf2 signaling pathway and relieving the alveolar bone absorption was examined in the CPDM model of Sprague Dawley rats. CPDM rats were oral gavaged with BCI (50, 100, or 200 mg/kg daily). The pNrf2 was detected by immunohistochemistry, and the alveolar bone absorption was examined by microcomputed tomography. RESULTS: Our results showed that ROS were significantly increased in both groups of HG and LPS, with the strongest generation in the GP group. In terms of ROS-related gene expression, we found that the mRNA levels of Nrf2, Cat, Gclc, Sod1, and Sod2 were significantly decreased in HG and LPS groups. In consistent with the strongest induction of ROS in GP group, the gene expression in GP group was further decreased as compared to those of HG and LPS groups. Also, the expression of pNrf2 exhibited the same trend with the expression of those antioxidant genes. However, the generation of ROS and the loss of mitochondrial membrane potential induced by GP were abolished by pre-treatment with different concentrations of BCI (0.01, 0.1, or 0.5 µg/mL). Interestingly, we observed that BCI promoted the nucleus translocation of pNrf2, as well as the gene expression levels of pNrf2 and its target genes (Cat, Gclc, Sod1, and Sod2). Finally, in the CPDM animal model, we found that BCI (at concentrations: 50, 100, and 200 mg/kg) markedly increased the number of pNrf2-positive cells in periodontal tissue and mitigated the alveolar bone loss. CONCLUSIONS: Our data revealed a potential role for clinic application of BCI under CPDM conditions, suggesting a new therapeutic drug for CPDM patients.