Patterns of antibiotic use, pathogens, and prediction of mortality in hospitalized neonates and young infants with sepsis: A global neonatal sepsis observational cohort study (NeoOBS).

BACKGROUND: There is limited data on antibiotic treatment in hospitalized neonates in low- and middle-income countries (LMICs). We aimed to describe patterns of antibiotic use, pathogens, and clinical outcomes, and to develop a severity score predicting mortality in neonatal sepsis to inform future clinical trial design. METHODS AND FINDINGS: Hospitalized infants <60 days with clinical sepsis were enrolled during 2018 to 2020 by 19 sites in 11 countries (mainly Asia and Africa). Prospective daily observational data was collected on clinical signs, supportive care, antibiotic treatment, microbiology, and 28-day mortality. Two prediction models were developed for (1) 28-day mortality from baseline variables (baseline NeoSep Severity Score); and (2) daily risk of death on IV antibiotics from daily updated assessments (NeoSep Recovery Score). Multivariable Cox regression models included a randomly selected 85% of infants, with 15% for validation. A total of 3,204 infants were enrolled, with median birth weight of 2,500 g (IQR 1,400 to 3,000) and postnatal age of 5 days (IQR 1 to 15). 206 different empiric antibiotic combinations were started in 3,141 infants, which were structured into 5 groups based on the World Health Organization (WHO) AWaRe classification. Approximately 25.9% (n = 814) of infants started WHO first line regimens (Group 1-Access) and 13.8% (n = 432) started WHO second-line cephalosporins (cefotaxime/ceftriaxone) (Group 2-"Low" Watch). The largest group (34.0%, n = 1,068) started a regimen providing partial extended-spectrum beta-lactamase (ESBL)/pseudomonal coverage (piperacillin-tazobactam, ceftazidime, or fluoroquinolone-based) (Group 3-"Medium" Watch), 18.0% (n = 566) started a carbapenem (Group 4-"High" Watch), and 1.8% (n = 57) a Reserve antibiotic (Group 5, largely colistin-based), and 728/2,880 (25.3%) of initial regimens in Groups 1 to 4 were escalated, mainly to carbapenems, usually for clinical deterioration (n = 480; 65.9%). A total of 564/3,195 infants (17.7%) were blood culture pathogen positive, of whom 62.9% (n = 355) had a gram-negative organism, predominantly Klebsiella pneumoniae (n = 132) or Acinetobacter spp. (n = 72). Both were commonly resistant to WHO-recommended regimens and to carbapenems in 43 (32.6%) and 50 (71.4%) of cases, respectively. MRSA accounted for 33 (61.1%) of 54 Staphylococcus aureus isolates. Overall, 350/3,204 infants died (11.3%; 95% CI 10.2% to 12.5%), 17.7% if blood cultures were positive for pathogens (95% CI 14.7% to 21.1%, n = 99/564). A baseline NeoSep Severity Score had a C-index of 0.76 (0.69 to 0.82) in the validation sample, with mortality of 1.6% (3/189; 95% CI: 0.5% to 4.6%), 11.0% (27/245; 7.7% to 15.6%), and 27.3% (12/44; 16.3% to 41.8%) in low (score 0 to 4), medium (5 to 8), and high (9 to 16) risk groups, respectively, with similar performance across subgroups. A related NeoSep Recovery Score had an area under the receiver operating curve for predicting death the next day between 0.8 and 0.9 over the first week. There was significant variation in outcomes between sites and external validation would strengthen score applicability. CONCLUSION: Antibiotic regimens used in neonatal sepsis commonly diverge from WHO guidelines, and trials of novel empiric regimens are urgently needed in the context of increasing antimicrobial resistance (AMR). The baseline NeoSep Severity Score identifies high mortality risk criteria for trial entry, while the NeoSep Recovery Score can help guide decisions on regimen change. NeoOBS data informed the NeoSep1 antibiotic trial (ISRCTN48721236), which aims to identify novel first- and second-line empiric antibiotic regimens for neonatal sepsis. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT03721302).

Propranolol ameliorates retinopathy of prematurity in mice by downregulating HIF-1α via the PI3K/Akt/ERK pathway.

BACKGROUND: Retinopathy of prematurity (ROP) is the leading cause of blindness in infants, and elevation of HIF-1α through the PI3K/Akt and ERK pathways is implicated in ROP pathogenesis. The mechanism of action of propranolol in ROP remains controversial. We investigated the effect of propranolol on ROP and explored its potential mechanisms of action in an oxygen-induced retinopathy (OIR) mouse model. METHODS: OIR mice were first treated with propranolol intraperitoneally, and the retina integrity was measured by FITC-dextran and hematoxylin-eosin staining. The expression of HIF-1α, VEGF, and key signaling pathway proteins was determined using real-time PCR and western blotting. RESULTS: FITC-dextran staining showed that propranolol treatment reduced damage to retinal morphology in OIR mice. Mice treated with propranolol showed a reduced number of nuclei of vascular endothelial cells penetrating the inner limiting membrane of the retina, confirming the therapeutic effect of propranolol on ROP. Further analysis showed that HIF-1α and PI3K/Akt/ERK pathway protein levels were significantly elevated in OIR mice. In contrast, propranolol treatment downregulated the expression of these proteins, indicating that the PI3K/Akt/ERK/HIF-1α axis is associated with propranolol-induced ROP alleviation. CONCLUSIONS: Propranolol has a therapeutic function against ROP, likely through the downregulation of HIF-1α via the PI3K/Akt/ERK pathway. IMPACT: Propranolol can reduce the formation of abnormal retinal neovascularization in oxygen-induced retinopathy (OIR) models, and reduce leaking, tortuous, and abnormally expanding retinal blood vessels. Propranolol possibly improves OIR by inhibiting the activated ERK and HIF-1α pathways. Furthermore, propranolol may downregulate HIF-1α via the PI3K/Akt/ERK pathway to ameliorate retinopathy of prematurity. This study elucidated that the therapeutic effect of propranolol in OIR mice does not involve the VEGFR-2 pathway.

Lipopolysaccharide downregulates the expression of ZO-1 protein through the Akt pathway.

BACKGROUND: Neonatal bacterial meningitis is a common neonatal disease with high morbidity, and can cause serious sequelae when left untreated. Escherichia coli is the common pathogen, and its endotoxin, lipopolysaccharide (LPS) can damage the endothelial cells, increasing the permeability of the blood-brain barrier (BBB), leading to intracranial inflammation. However, the specific mechanism of bacterial meningitis induced by LPS damaging BBB remains unclear. In this study, the mouse brain microvascular endothelial (bEND.3) cells were used as a research object to investigate whether LPS damage BBB through the PI3K/Akt pathway. METHODS: The bEND.3 cells were stimulated with different concentrations of LPS for 12 h, and the expression of tight junction proteins (ZO-1, claudin-5, occludin) was detected using western blotting. The cells were challenged with the same concentration of LPS (1ug/ml) across different timepoints (0, 2 h, 4 h, 6 h, 12 h, 24 h). Expression of TJ proteins and signal pathway molecules (PI3K, p-PI3K, Akt, p-Akt) were detected. The distribution of ZO-1 in bEND.3 cells were detected by immunofluorescence staining. RESULTS: A negative correlation is observed between ZO-1 and LPS concentration. Moreover, a reduced expression of ZO-1 was most significant under 1 ug/ml of LPS, and the difference was statistically significant (P < 0.05). Additionally, there is a negative correlation between ZO-1 and LPS stimulation time. Meanwhile, the expression of claudin-5 and occludin did not change significantly with the stimulation of LPS concentration and time. The immunofluorescence assay showed that the amount of ZO-1 on the surface of bEND.3 cells stimulated with LPS was significantly lower than that of the control group. After LPS stimulation, p-Akt protein increased at 2 h and peaked at 4 h. The titer of p-PI3K did not change significantly with time. CONCLUSION: LPS can downregulate the expression of ZO-1; however, its effect on claudin-5 and occludin is minimal. Akt signal pathway may be involved in the regulation of ZO-1 expression induced by LPS in bEND.3 cells.

Bounds on mutual information of mixture data for classification tasks.

To quantify the optimum performance for classification tasks, the Shannon mutual information is a natural information-theoretic metric, as it is directly related to the probability of error. The data produced by many imaging systems can be modeled by mixture distributions. The mutual information between mixture data and the class label does not have an analytical expression nor any efficient computational algorithms. We introduce a variational upper bound, a lower bound, and three approximations, all employing pair-wise divergences between mixture components. We compare the new bounds and approximations with Monte Carlo stochastic sampling and bounds derived from entropy bounds. To conclude, we evaluate the performance of the bounds and approximations through numerical simulations.

Molecular characteristics of the new emerging global clone ST1193 among clinical isolates of Escherichia coli from neonatal invasive infections in China.

Sequence type 1193 (ST1193) constitutes an emerging fluoroquinolone-resistant Escherichia coli clone in several countries. However, reports of such isolates in neonatal invasive diseases are limited. Here, we assessed the antimicrobial resistance and molecular characteristics of E. coli ST1193 isolates causing neonatal bloodstream infections and meningitis in China. A total of 56 E. coli isolates were collected from neonatal blood and cerebrospinal fluid between September 2009 and June 2015. Antimicrobial susceptibility was evaluated using E-test methods. Polymerase chain reaction amplification was used to detect antibiotic resistance genes including blaTEM, blaSHV, and blaCTX-M groups. Molecular typing was performed via multi-locus sequence typing. Among 56 E. coli isolates, 17 (17/56, 30.4%) were extended-spectrum ß-lactamase (ESBL) producers, and 37(37/56, 66.1%) were multidrug-resistant. The most frequent sequence types were ST1193 (12/56), followed by ST95 and ST62. ST1193 isolates exhibited a 91.7% resistance rate to ciprofloxacin, amoxicillin, and sulfonamides, and 83.3% resistance rate to tetracycline. A total of 4 (33.3%) among the 12 ST1193 isolates were ESBL producers, of which three carried both blaCTX-M-15 and blaTEM genes with the remaining isolate harboring blaCTX-M-27 and blaTEM genes. Additionally, 1 of the 3 ST1193 isolates obtained from cerebrospinal fluid was an ESBL producer that carried both blaCTX-M-15 and blaTEM genes. This study revealed for the first time the molecular characteristics of E. coli ST1193 causing neonatal invasive diseases in China. Notably, we found that ST1193 isolates were multidrug-resistant. Further multicenter studies are needed to assess the molecular epidemiology of ST1193 in China to control its spread.

Systematic Review and Meta-Analyses of Incidence for Group B Streptococcus Disease in Infants and Antimicrobial Resistance, China.

We performed a systematic review and meta-analysis of the incidence, case-fatality rate (CFR), isolate antimicrobial resistance patterns, and serotype and sequence type distributions for invasive group B Streptococcus (GBS) disease in infants <1-89 days of age in China. We searched the PubMed/Medline, Embase, Wanfang, and China National Knowledge Infrastructure databases for research published during January 1, 2000-March 16, 2018, and identified 64 studies. Quality of included studies was assessed by using Cochrane tools. Incidence and CFR were estimated by using random-effects meta-analyses. Overall incidence was 0.55 (95% CI 0.35-0.74) cases/1,000 live births, and the CFR was 5% (95% CI 3%-6%). Incidence of GBS in young infants in China was higher than the estimated global incidence (0.49 cases/1,000 live births) and higher than previous estimates for Asia (0.3 cases/1,000 live births). Our findings suggest that implementation of additional GBS prevention efforts in China, including maternal vaccination, could be beneficial.

Abundance of the nasopharyngeal microbiome effects pertussis diagnosis and explains the sensitivity difference between bacterial culture and real-time PCR.

Quantitative real time PCR (qPCR)is used for pertussis diagnosis. The positive rate of qPCR is generally much higher than that of bacterial culture, which may cause confusion. The current study utilized the 16S ribosomal RNA (16S rRNA) sequencing to assess the correlation between conventional culture and qPCR and to explore the value of 16S rRNA in diagnosing pertussis. Nasopharyngeal swabs, collected from 102 children meeting clinical diagnostic criteria for pertussis, were subjected to Bordetella pertussis culture and qPCR. Bioinformatic microbiota analysis was based on 16S rRNA V3-V4 gene sequencing. Among 102 samples, 14 (13.7%) were culture-positive for Bordetella pertussis, while 61 (59.8%) were qPCR positive. Genus Bordetella was identified in 68 (66.7%) samples via 16S rRNA sequencing. When the relative abundance of Bordetella genus exceeded 0.70%, both qPCR and culture results were positive. Samples with a relative abundance of less than 0.20% exhibited positive qPCR and negative culture results. Samples with a low Bordetella abundance are the key factors underlying poor correlation between culture and qPCR results in laboratory tests.

Systematic review of carbapenem-resistant Enterobacteriaceae causing neonatal sepsis in China.

BACKGROUND: Carbapenems are ß-lactam antibiotics which are used to treat severe infections caused by multidrug resistant Enterobacteriacea. The recent emergence and rapid spread of Enterobacteriaceae resistant to carbapenems is a global concern. We undertook a systematic review of the antibiotic susceptibility and genotypic characteristics of carbapenem-resistant Enterobacteriaceae in Chinese neonates. METHODS: Systematic literature reviews were conducted (PubMed/Medline, Embase, Wanfang medical online databases, China National Knowledge Infrastructure (CNKI) database) regarding sepsis caused by carbapenem-resistant Enterobacteriaceae in Chinese neonates aged 0-30 days. RESULTS: 17 studies were identified. Eleven patients in the six studies reported the source of infection. Ten patients (10/11, 90.9%) were hospital-acquired infections. Genotypic data were available for 21 isolates in 11 studies (20 K. pneumoniae, 1 E. coli). NDM-1 was the most frequently reported carbapenem-resistant genotype (81.0%, 17/21). Carbapenem-resistant Klebsiella pneumoniae and Escherichia coli were resistant to many antibiotic classes with the exception of colistin and fosfomycin. Sequence type 105 (ST105) was the most commonly reported K. pneumoniae ST type (30.8%; 4/13), which was from the same hospital in Western China. ST17 and ST20 were the second and third most common K. pneumoniae ST type, 23.1% (3/13) and 15.4% (2/13) respectively. The three strains of ST17 are all from the same hospital in central China. The two strains of ST20, although not from the same hospital, belong to the eastern part of China. CONCLUSIONS: Klebsiella pneumoniae with the NDM-1 genotype was the leading cause of neonatal carbapenem resistant sepsis in China. Hospital acquired infection is the main source of carbapenem resistant sepsis. There is currently no licenced antibiotic regimen available to treat such an infection in China. Improved surveillance, controlling nosocomial infection and the rational use of antibiotics are the key factors to prevent and reduce its spread.

Text mining for identifying topics in the literatures about adolescent substance use and depression.

BACKGROUND: Both adolescent substance use and adolescent depression are major public health problems, and have the tendency to co-occur. Thousands of articles on adolescent substance use or depression have been published. It is labor intensive and time consuming to extract huge amounts of information from the cumulated collections. Topic modeling offers a computational tool to find relevant topics by capturing meaningful structure among collections of documents. METHODS: In this study, a total of 17,723 abstracts from PubMed published from 2000 to 2014 on adolescent substance use and depression were downloaded as objects, and Latent Dirichlet allocation (LDA) was applied to perform text mining on the dataset. Word clouds were used to visually display the content of topics and demonstrate the distribution of vocabularies over each topic. RESULTS: The LDA topics recaptured the search keywords in PubMed, and further discovered relevant issues, such as intervention program, association links between adolescent substance use and adolescent depression, such as sexual experience and violence, and risk factors of adolescent substance use, such as family factors and peer networks. Using trend analysis to explore the dynamics of proportion of topics, we found that brain research was assessed as a hot issue by the coefficient of the trend test. CONCLUSIONS: Topic modeling has the ability to segregate a large collection of articles into distinct themes, and it could be used as a tool to understand the literature, not only by recapturing known facts but also by discovering other relevant topics.

A heuristic approach to determine an appropriate number of topics in topic modeling.

BACKGROUND: Topic modelling is an active research field in machine learning. While mainly used to build models from unstructured textual data, it offers an effective means of data mining where samples represent documents, and different biological endpoints or omics data represent words. Latent Dirichlet Allocation (LDA) is the most commonly used topic modelling method across a wide number of technical fields. However, model development can be arduous and tedious, and requires burdensome and systematic sensitivity studies in order to find the best set of model parameters. Often, time-consuming subjective evaluations are needed to compare models. Currently, research has yielded no easy way to choose the proper number of topics in a model beyond a major iterative approach. METHODS AND RESULTS: Based on analysis of variation of statistical perplexity during topic modelling, a heuristic approach is proposed in this study to estimate the most appropriate number of topics. Specifically, the rate of perplexity change (RPC) as a function of numbers of topics is proposed as a suitable selector. We test the stability and effectiveness of the proposed method for three markedly different types of grounded-truth datasets: Salmonella next generation sequencing, pharmacological side effects, and textual abstracts on computational biology and bioinformatics (TCBB) from PubMed. CONCLUSION: The proposed RPC-based method is demonstrated to choose the best number of topics in three numerical experiments of widely different data types, and for databases of very different sizes. The work required was markedly less arduous than if full systematic sensitivity studies had been carried out with number of topics as a parameter. We understand that additional investigation is needed to substantiate the method's theoretical basis, and to establish its generalizability in terms of dataset characteristics.

[Clinical characteristics of whooping cough in neonates and antimicrobial resistance of the pathogenic bacteria].

OBJECTIVE: To study the clinical characteristics of whooping cough in neonates and the antimicrobial resistance of the bacterial isolates. METHODS: Clinical information of 7 neonates with whooping cough confirmed by bacterial culture was collected. The antimirobial resistance of the isolates was tested using E-test and disk diffusion methods. RESULTS: The children′s mothers or other family members had cough for more than 10 days in 6 neonates, in which four neonates contacted with 3 or more family members with cough. All the neonates had rhinobyon and slight cough at the beginning of the disease. Five cases presented typical spasmodic cough after 4-7 days of the onset. Five cases displayed cyanosis, four cases occurred apnea, three cases suffered breath holding, and only two cases had fever. Nares flaring and three depression signs were found in the physical examination. No bacteriostatic ring around the erythromycin disks were found for five bacterial isolates. The minimal inhibitory concentration (MIC) for erythromycin, azithromycin, clarithromycin and clindamycin were all >256 mg/L against the five isolates. CONCLUSIONS: Whooping cough should be considered for neonates with respiratory symptoms and a history of close contact with respiratory infection patients. Macrolide-resistant Bordetella pertussis is common in children with whooping cough.

Incidence of Group B Streptococcus Disease in Infants in China: An Updated Systematic Review and Meta-analysis.

New studies of Group B Streptococcus (GBS) in infants <3 months of age in China have been published since our previous systematic review and meta-analysis. Using the same methodology, we updated these estimates and determined a total incidence of 0.41 (95% CI, 0.32-0.51) cases/1000 live births, lower than previously (0.55/1000). New intrapartum antibiotic prophylaxis policies may have played an important role in this reduction.

Differences in the effects of Bordetella pertussis and respiratory syncytial virus infection on the composition of nasopharyngeal flora in neonates.

Introduction: Bordetella pertussis and respiratory syncytial virus (RSV) are important pathogens causing cough in neonates. Few studies have investigated the differences in the effects of these two specific infections on respiratory flora. The aim of this study was to explore whether infections with Bordetella pertussis and RSV have different effects on respiratory floral composition in neonates. Methods: Nasopharyngeal respiratory flora was assessed by 16S ribosomal RNA amplification and V3-V4 region sequencing. Shannon and Simpson indices were calculated to determine the α diversity and principal coordinate analysis was performed to determine the ß diversity. Results: In total, 111 hospitalized neonates were divided into the pertussis (n = 29), RSV (n = 57), and control groups (n = 25) according to the pathogens detected. The relative abundance of Bordetella was significantly higher in the pertussis group (median: 19.18%, interquartile range: 72.57%). In contrast, this species was not detected in the other two groups. In the RSV group, the relative abundance of Streptococcus (median: 77.15%, interquartile range: 45.84%) was significantly higher than those in the pertussis and control groups (both P < 0.001). The α diversity of the RSV group was significantly lower than that of the control group (P < 0.001). Moreover, no statistically significant differences in the Shannon and Simpson indices were observed between the pertussis and control groups (P = 0.101 and P = 0.202, respectively). Principal coordinate analysis revealed a large overlap between the pertussis and control groups and a significant distance between the RSV and control groups without any overlap. Discussion: Thus, the effects of infections with the two species, B. pertussis and RSV, impacted the diversity of nasopharyngeal flora differently. The principles underlying the difference in the effects of different pathogens on microbial flora require further investigation.

Antibiotic susceptibility of Escherichia coli isolated from neonates admitted to neonatal intensive care units across China from 2015 to 2020.

Background: Escherichia coli is one of the most common pathogens causing neonatal infections. Recently, the incidence and drug resistance of E. coli have increased, posing a major threat to neonatal health. The aim of this study was to describe and analyze the antibiotic resistance and multilocus sequence typing (MLST) characteristics of E. coli derived from infants admitted to neonatal intensive care units (NICUs) across China. Methods: In this study, 370 strains of E. coli from neonates were collected. E. coli isolated from these specimens were subjected to antimicrobial susceptibility testing (by broth microdilution method) and MLST. Results: The overall resistance rate was 82.68%, with the highest rate of methicillin/sulfamethoxazole (55.68%) followed by cefotaxime (46.22%). Multiple resistance rate was 36.74%, 132 strains (35.68%) had extended-spectrum ß-lactamase (ESBL) phenotype and 5 strains (1.35%) had insensitivity to the tested carbapenem antibiotics. The resistance of E. coli isolated from different pathogenicity and different sites of infections varied, strains derived from sputum were significantly more resistant to ß-lactams and tetracyclines. Currently, the prevalence spectrum in NICUs was dominated by ST1193, ST95, ST73, ST69 and ST131 across China. And the multidrug resistance of ST410 was the most severe. ST410 had the highest resistance rate to cefotaxime (86.67%), and its most common multidrug resistance pattern was ß-lactams + aminoglycosides + quinolones + tetracyclines + sulfonamides. Conclusions: Substantial proportions of neonatal E. coli isolates were severely resistant to commonly administered antibiotics. MLST results can suggest the prevalent characteristics of antibiotic resistance in E. coli with different ST types.

CUL4B orchestrates mesenchymal stem cell commitment by epigenetically repressing KLF4 and C/EBPδ.

Dysregulated lineage commitment of mesenchymal stem cells (MSCs) contributes to impaired bone formation and an imbalance between adipogenesis and osteogenesis during skeletal aging and osteoporosis. The intrinsic cellular mechanism that regulates MSC commitment remains unclear. Here, we identified Cullin 4B (CUL4B) as a critical regulator of MSC commitment. CUL4B is expressed in bone marrow MSCs (BMSCs) and downregulated with aging in mice and humans. Conditional knockout of Cul4b in MSCs resulted in impaired postnatal skeletal development with low bone mass and reduced bone formation. Moreover, depletion of CUL4B in MSCs aggravated bone loss and marrow adipose accumulation during natural aging or after ovariectomy. In addition, CUL4B deficiency in MSCs reduced bone strength. Mechanistically, CUL4B promoted osteogenesis and inhibited adipogenesis of MSCs by repressing KLF4 and C/EBPδ expression, respectively. The CUL4B complex directly bound to Klf4 and Cebpd and epigenetically repressed their transcription. Collectively, this study reveals CUL4B-mediated epigenetic regulation of the osteogenic or adipogenic commitment of MSCs, which has therapeutic implications in osteoporosis.

atBioNet--an integrated network analysis tool for genomics and biomarker discovery.

BACKGROUND: Large amounts of mammalian protein-protein interaction (PPI) data have been generated and are available for public use. From a systems biology perspective, Proteins/genes interactions encode the key mechanisms distinguishing disease and health, and such mechanisms can be uncovered through network analysis. An effective network analysis tool should integrate different content-specific PPI databases into a comprehensive network format with a user-friendly platform to identify key functional modules/pathways and the underlying mechanisms of disease and toxicity. RESULTS: atBioNet integrates seven publicly available PPI databases into a network-specific knowledge base. Knowledge expansion is achieved by expanding a user supplied proteins/genes list with interactions from its integrated PPI network. The statistically significant functional modules are determined by applying a fast network-clustering algorithm (SCAN: a Structural Clustering Algorithm for Networks). The functional modules can be visualized either separately or together in the context of the whole network. Integration of pathway information enables enrichment analysis and assessment of the biological function of modules. Three case studies are presented using publicly available disease gene signatures as a basis to discover new biomarkers for acute leukemia, systemic lupus erythematosus, and breast cancer. The results demonstrated that atBioNet can not only identify functional modules and pathways related to the studied diseases, but this information can also be used to hypothesize novel biomarkers for future analysis. CONCLUSION: atBioNet is a free web-based network analysis tool that provides a systematic insight into proteins/genes interactions through examining significant functional modules. The identified functional modules are useful for determining underlying mechanisms of disease and biomarker discovery. It can be accessed at: http://www.fda.gov/ScienceResearch/BioinformaticsTools/ucm285284.htm.

Invertibility of multi-energy X-ray transform.

PURPOSE: The goal is to provide a sufficient condition for the invertibility of a multi-energy (ME) X-ray transform. The energy-dependent X-ray attenuation profiles can be represented by a set of coefficients using the Alvarez-Macovski (AM) method. An ME X-ray transform is a mapping from N AM coefficients to N noise-free energy-weighted measurements, where N ≥ 2 . METHODS: We apply a general invertibility theorem to prove the equivalence of global and local invertibility for an ME X-ray transform. We explore the global invertibility through testing whether the Jacobian of the mapping J ( A ) has zero values over the support of the mapping. The Jacobian of an arbitrary ME X-ray transform is an integration over all spectral measurements. A sufficient condition for J ( A ) ≠ 0 for all A is that the integrand of J ( A ) is ≥ 0 (or ≤ 0 ) everywhere. Note that the trivial case of the integrand equals 0 everywhere is ignored. Using symmetry, we simplified the integrand of the Jacobian to three factors that are determined by the total attenuation, the basis functions, and the energy-weighting functions, respectively. The factor related to the total attenuation is always positive; hence, the invertibility of the X-ray transform can be determined by testing the signs of the other two factors. Furthermore, we use the Cramér-Rao lower bound (CRLB) to characterize the noise-induced estimation uncertainty and provide a maximum-likelihood (ML) estimator. RESULTS: The factor related to the basis functions is always negative when the photoelectric/Compton/Rayleigh basis functions are used and K-edge materials are not considered. The sign of the energy-weighting factor depends on the system source spectra and the detector response functions. For four special types of X-ray detectors, the sign of this factor stays the same over the integration range. Therefore, when these four types of detectors are used for imaging non-K-edge materials, the ME X-ray transform is globally invertible. The same framework can be used to study an arbitrary ME X-ray imaging system, for example, when K-edge materials are present. Furthermore, the ML estimator we presented is an unbiased, efficient estimator and can be used for a wide range of scenes. CONCLUSIONS: We have provided a framework to study the invertibility of an arbitrary ME X-ray transform and proved the global invertibility for four types of systems.

Antimicrobial Resistance Analysis of Clinical Escherichia coli Isolates in Neonatal Ward.

Background: Escherichia coli (E. coli) column for one of the most common pathogens causing neonatal infections. The emergence of antibiotic-resistant bacteria is a major cause of treatment failure in infected newborns. The purpose of this study was to describe antibiotic and multidrug resistance of E. coli strains isolated from neonates with infection throughout the years 2009-2011. Methods: The antimicrobial susceptibility testing of E. coli strains to selected antibiotics was assessed using the E-test technique on the Mueller-Hinton agar. The antimicrobial tests included ceftazidime, cefuroxime, cefatriaxone, amoxicillin, amoxicillin-clavulanic acid, cefoperazone- sulbactam, meropenem, gentamicin, ciprofloxacin, and sulfonamides. Results: A total of 100 E. coli strains were isolated from sputum (n = 78), blood (n = 10), cerebrospinal fluid (n = 5), and umbilical discharge (n = 7) samples of hospitalized neonates at the Beijing Children's Hospital. The highest rate of E. coli resistance was found in amoxicillin (85%), followed by cefuroxime (65%), and cefatriaxone (60%), respectively. A total of 6 and 5% of all isolates were only resistant to amoxicillin/clavulanic acid and cefoperazone -sulbactam. The rates of resistance to ceftazidime, gentamicin, ciprofloxacin, and sulfonamides were 31, 20, 33, and 47%, respectively. All isolates were susceptible to meropenem. Approximately 26% of all E. coli isolates were multidrug-resistant. The detection rate of ESBL-Producing E. coli was 55%. Conclusions: Multi-drug-resistant E. coli has become an important and complex problem in clinical treatment, and it is thus essential to monitor E. coli resistance in neonates.

One-Week Effects of Antibiotic Treatment on Gut Microbiota of Late Neonates With Pneumonia or Meningitis.

Background: The neonatal period is a critical period for the establishment of the intestinal microbial community. Antibiotics can change the composition of gut microbiota. Methods: Fecal samples were collected from 14 patients with pneumonia and 14 patients with meningitis before and after antibiotic treatment, and fecal samples from five healthy neonates at the 14th and 21st days after birth were collected as well. DNA of fecal samples was extracted, and PCR amplification was performed targeting the V3-V4 variable region of 16S rDNA. After detection by high-throughput sequencing, OTU (operational taxonomic unit) clustering, species annotation, and α diversity analysis were calculated and analyzed statistically. Results: In the healthy control group, the abundance of Bifidobacterium increased significantly from 16.75 to 40.42%, becoming the most dominant bacteria. The results of α diversity analysis suggested that the Sobs indexes of the gut microbiota in the pneumonia and meningitis groups were significantly lower than that in the healthy control group (p < 0.05). PCoA analysis showed that the gut microbiota of pneumonia and meningitis groups clustered distinctly with the control group (Adonis p = 0.001, R 2 = 0.565), and there was no significant change in the diversity of gut microbiota before and after the use of antibiotics. Conclusions: The gut microbiota of neonates with infectious diseases were mainly related to the disease conditions. The initial state of neonatal gut microbiome determines its state after 1-week antibiotic treatment. Antibiotic application with 7 days had little effect on the community richness and some effect on the composition of gut microbiota of neonates with pneumonia or meningitis.

Truncated Pneumolysin from Streptococcus pneumoniae as a TLR4-Antagonizing New Drug for Chronic Inflammatory Conditions.

Microbial proteins have recently been found to have more benefits in clinical disease treatment because of their better-developed strategy and properties than traditional medicine. In this study, we investigated the effectiveness of a truncated peptide synthesized from the C-terminal sequence of pneumolysin, i.e., C70PLY4, in Streptococcus pneumoniae, in treating chronic inflammatory conditions. It has been shown that C70PLY4 significantly blocks the transendothelial migration of neutrophils and attenuates the formation of atherosclerotic plaque and the secretion of soluble forms of the intercellular adhesion molecule-1 (ICAM-1), the vascular cell adhesion molecule 1 (VCAM-1), and E-selectin in high-fat-diet/streptozotocin-induced inflammatory rats. The mechanism and the docking simulation analysis further indicated that C70PLY4 might serve as a Toll-like receptor 4 (TLR4) antagonist by competing for the binding site of MD2, an indispensable protein for lipopolysaccharide (LPS)-TLR4 interaction signaling, on the TLR4 structure. Moreover, compared to the full-length PLY, C70PLY4 seems to have no cytotoxicity in human vascular endothelial cells. Our study elucidated a possible therapeutic efficacy of C70PLY4 in reducing chronic inflammatory conditions and clarified the underlying mechanism. Thus, our findings identify a new drug candidate that, by blocking TLR4 activity, could be an effective treatment for patients with chronic inflammatory diseases.