Widespread Use of High-dose Ceftriaxone Therapy for Uncomplicated Gonorrhea Without Reported Ceftriaxone Treatment Failure: Results From 5 Years of Multicenter Surveillance Data in China.

BACKGROUND: Antimicrobial resistance to Neisseria gonorrhoeae has emerged for each of the antibiotics recommended as first-line therapies following their introduction into clinical practice. To improve rational and effective clinical antibiotic treatment, we analyzed the prescription patterns of antibiotics and their therapeutic effect in the treatment of uncomplicated gonorrhea in China. METHODS: We obtained data from a follow-up multicenter surveillance program. Multinomial logistic regression analyses were conducted to explore the associations between demographic/clinical variables with the levels of sensitivity to ceftriaxone and prescription of high-dose ceftriaxone. RESULTS: In this study, 1686 patients infected with N. gonorrhoeae were recruited in a surveillance network during 1 January 2013 through 31 December 2017 in 7 hospitals distributed in 5 provinces. The prevalence of isolates with decreased susceptibility to ceftriaxone was 9.8% (131/1333), fluctuating between 5.6% and 12.1%. Injectable ceftriaxone was chosen as the first-line treatment among 83.1% of patients, and most of them (72.7% [1018/1401]) received >1000 mg dosage. Patients who were previously infected with gonorrhea or other sexually transmitted infections (adjusted odds ratio [AOR], 1.618 [95% confidence interval {CI}, 1.11-2.358]; AOR, 2.08 [95% CI, 1.41-3.069]) or who already used antibiotics for this infection (AOR, 1.599 [95% CI, 1.041-2.454]) were associated with a higher prescribed ceftriaxone dosage. All of the patients recruited in this study were cured regardless of the isolates' susceptibility to ceftriaxone or the dosage of ceftriaxone they received. CONCLUSIONS: No ceftriaxone treatment failure for uncomplicated gonorrhea was reported in China; however, high-dose ceftriaxone was widely used in China. Its impacts need further study.

Susceptibility of Neisseria gonorrhoeae to azithromycin and ceftriaxone in China: A retrospective study of national surveillance data from 2013 to 2016.

BACKGROUND: Gonorrhea remains one of the most common sexually transmitted diseases worldwide. Successful treatment has been hampered by emerging resistance to each of the antibiotics recommended as first-line therapies. We retrospectively analyzed the susceptibility of gonorrhea to azithromycin and ceftriaxone using data from the China Gonococcal Resistance Surveillance Programme (China-GRSP) in order to provide evidence for updating the treatment recommendations in China. METHODS AND FINDINGS: In this study, we included 3,849 isolates collected from patients with a confirmed positive Neisseria gonorrhoeae (N. gonorrhoeae) culture at clinic visits during the period of 1 January 2013 through 31 December 2016 in 7 provinces. Antimicrobial susceptibility testing of gonorrhea isolates using agar dilution was conducted to determine minimum inhibitory concentration (MIC). Resistance to azithromycin (RTA) was defined as MIC ≥ 1.0 mg/l, and decreased susceptibility to ceftriaxone (DSC) was defined as MIC ≥ 0.125 mg/l. The prevalence of isolates with RTA was 18.6% (710/3,827; 95% CI 17.4%-19.8%). The percentage of patients with DSC fluctuated between 9.7% and 12.2% over this period. The overall prevalence of isolates with both RTA and DSC was 2.3% (87/3,827; 95% CI 1.9%-2.8%) and it increased from 1.9% in 2013 to 3.3% in 2016 (chi-squared test for trend, P = 0.03). Study limitations include the retrospective study design and potential biases in the sample, which may overrepresent men with symptomatic infection, coastal residents, and people reporting as heterosexual. CONCLUSIONS: To our knowledge, this is the first national study on susceptibility of N. gonorrhoeae to azithromycin and ceftriaxone in China. Our findings indicate high rates of RTA and DSC from 2013 to 2016. Although dual therapy with azithromycin and ceftriaxone has been recommended by WHO and many countries to treat gonorrhea, reevaluation of this therapy is needed prior to its introduction in China.

Identification and validation of new fatty acid metabolism-related mechanisms and biomarkers for erectile dysfunction.

Background: Erectile dysfunction (ED) is a common condition affecting middle-aged and elderly men. Aim: The study sought to investigate differentially expressed fatty acid metabolism-related genes and the molecular mechanisms of ED. Methods: The expression profiles of GSE2457 and GSE31247 were downloaded from the Gene Expression Omnibus database and merged. Differentially expressed genes (DEGs) between ED and normal samples were obtained using the R package limma. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of DEGs were conducted using the R package clusterProfiler. Fatty acid metabolism-related DEGs (FAMDEGs) were further identified and analyzed. Machine learning algorithms, including Lasso (least absolute shrinkage and selection operator), support vector machine, and random forest algorithms, were utilized to identify hub FAMDEGs with the ability to predict ED occurrence. Coexpression analysis and gene set enrichment analysis of hub FAMDEGs were performed. Outcome: Fatty acid metabolism-related functions (such as fatty acid metabolism and degradation) may play a vital role in ED. Results: In total, 5 hub FAMDEGs (Aldh2, Eci2, Acat1, Acadl, and Hadha) were identified and found to be differentially expressed between ED and normal samples. Gene set enrichment analysis identified key pathways associated with these genes. The area under the curve values of the 5 hub FAMDEGs for predicting ED occurrence were all >0.8. Clinical Translation: Our results suggest that these 5 key FAMDEGs may serve as biomarkers for the diagnosis and treatment of ED. Strengths and Limitations: The strengths of our study include the use of multiple datasets and machine learning algorithms to identify key FAMDEGs. However, limitations include the lack of validation in animal models and human tissues, as well as research on the mechanisms of these FAMDEGs. Conclusion: Five hub FAMDEGs were identified as potential biomarkers for ED progression. Our work may prove that fatty acid metabolism-related genes are worth further investigation in ED.

Flexible, sensitive and rapid humidity-responsive sensor based on rubber/aldehyde-modified sodium carboxymethyl starch for human respiratory detection.

Natural polymers with abundant hydrophilic groups are potential candidates for humidity sensor designing. Unfortunately, most of natural polymers lack essential stretchability and high conductivity, which hinder their development in the field of flexible humidity sensor. Cooperation with rubbers and conductive nanometer materials is an effective method to make the best use of natural polymers in flexible humidity sensor. In this paper, a flexible and sensitive sensor with rapid response to humidity change is fabricated based on aldehyde-modified sodium carboxymethyl starch (ACMS), carboxylated styrene-butadiene rubber (XSBR) and Ag nanoflakes through film-forming method. The pre-prepared ACMS owns a better dispersibility in the aqueous phase and serves as reducing agent for formation of Ag nanoflakes. After the film-forming process, the composite film shows a strength of 5.66 MPa and a high stretchability with strain of 367 %. Besides, our sensor shows a rapider response to humidity change than the commercial electronic hygrometer that it takes only 1 s to respond to the humidity change from 25 % RH to 27 % RH. Therefore, the XSBR/ACMS/Ag sensor possesses an impressive sensitive response to slight sweat on human skin and breath, which could find applications in monitoring people's health and distinguish their physical condition.

Loss of histone reader Phf7 leads to immune pathways activation via endogenous retroviruses during spermiogenesis.

Genetic studies have elucidated the critical roles of Phf7 in germline development in animals; however, the exact etiology of Phf7 mutations leading to male infertility and the possibility of mechanism-based therapy are still unclear and warrant further investigation. Using the Phf7 knockout mouse model, we verified that genetic defects were responsible for male infertility by preventing histone-to-protamine exchange, as previously reported. The deficiency of spermatogenesis caused by Phf7 deletion through the endogenous retrovirus-mediated activation of the immune pathway is a common mechanism of infertility. Furthermore, we identified PPARα as a promising target of immunity and inflammation in the testis, where endogenous retroviruses are suppressed, and Phf7 as a crucial regulator of endogenous retrovirus-mediated immune regulation and revealed its role as an epigenetic reader. The loss of Phf7 activates immune pathways, which can be rescued by the PPARα agonist astaxanthin. These results showed that astaxanthin is a potential therapeutic agent for treating male infertility. The findings in our study provide insights into the molecular mechanisms underlying male infertility and suggest potential targets for future research and therapeutic development.

A new strategy for stem cells therapy for erectile dysfunction: Adipose-derived stem cells transfect Neuregulin-1 gene through superparamagnetic iron oxide nanoparticles.

PURPOSE: Our previous studies showed that nanotechnology improves derived adipose-derived stem cells (ADSCs) therapy for erectile dysfunction (ED). In this study, the Neuregulin-1(NRG1) gene was transfected into ADSCs with superparamagnetic iron oxide nanoparticles (SPION) further to improve the therapeutic effect of ADSCs on ED. MATERIALS AND METHODS: ADSCs were isolated from epididymal adipose tissue of Sprague-Dawley rats. The optimal concentration of PEI-SPION (SPION modified with polyethyleneimine) was selected to construct the gene complex. After electrostatic binding of PEI-SPION and DNA, a PEI layer was wrapped to make the PEI-SPION-NRG1-PEI gene transfection complex. Different groups were set up for transfection tests. Lipo2000 transfection reagent was used as the control. PEI-SPION-NRG1-PEI in the experimental group was transfected under an external magnetic field. RESULTS: When the concentration of PEI-SPION was 10 µg/mL, it had little cytotoxicity, and cell activity was not significantly affected. PEI-SPION-NRG1-PEI forms positively charged nanocomposites with a particle size of 72.6±14.9 nm when N/P ≥8. The PEI-SPION-NRG1-PEI gene complex can significantly improve the transfection efficiency of ADSCs, reaching 26.74%±4.62%, under the action of the external magnetic field. PCR and Western blot showed that the expression level of the NRG1 gene increased significantly, which proved that the transfection was effective. CONCLUSIONS: PEI-SPION can be used as a vector for NRG1 gene transfection into ADSCs. PEI-SPION-NRG1-PEI packaging has the highest transfection efficiency under the external magnetic field than the other groups. These findings may provide a new strategy for ADSCs therapy for ED.

A High-Performance, Sensitive, Wearable Multifunctional Sensor Based on Rubber/CNT for Human Motion and Skin Temperature Detection.

Recently, flexible wearable electronic devices have attracted immense interest as an alternative for conventional rigid metallic conductors in personal healthcare monitoring, human motion detection, and sensory skins, owing to their intrinsic characteristics. However, the practical applications of most wearable sensors are generally limited by their poor stretchability and sensitivity, unsatisfactory strength, lower conductivity, and single sensory function. Here a hydrogen bond cross-linked network based on carboxylic styrene butadiene rubber (XSBR) and hydrophilic sericin (SS) non-covalently modified carbon nanotubes (CNTs) is rationally designed and then fabricated into multi-functional sensors. The resultant versatile sensors are able to detect both weak and large deformations, which owns a low detection limit of 1% strain, high stretchability up to 217%, superior strength of 12.58 MPa, high sensitivity with a gauge factor up to 25.98, high conductivity of 0.071 S m-1 , and lower percolation threshold of 0.504 wt%. Moreover, the prepared sensors also possess an impressively thermal response (0.01636 °C-1 ) and realize the application in the measurement of human body temperature. The multifunctional and scalable XSBR/SSCNT sensor with the integrated tracking capabilities of real-time and in situ physiological signals, providing a promising route to develop wearable artificial intelligence in human health and sporting applications.

Strengthened self-healable natural rubber composites based on carboxylated cellulose nanofibers participated in ionic supramolecular network.

Cellulose, as a green reinforcing agent for rubber, has excellent improvement on the tensile strength but usually accompany with a deterioration of extensibility and self-healing property. Herein, we report an efficient method to prepare robust and self-healable natural rubber/zinc dimethacrylate/carboxylated cellulose nanofibers (NR/ZDMA/CNC) composites which are constructed by a CNC participated ionic supramolecular network. Ionic supramolecular network in NR is generated by the polymerization of ZDMA during a controlled peroxide-initiated vulcanization of NR. Interestingly, NR with massive ion clusters has strong affinity with CNC, which facilitates the uniform dispersion of CNC and the compatibility between CNC and NR. Meanwhile, CNC participates into the supramolecular network via non-covalent interaction with NR chains equipped with ionic crosslinks. This greatly reduces the adverse effect of CNC on the dynamic characteristics of supramolecular network. As a result, the tensile strength of NR/ZDMA composite with 20 phr CNC could reach 4.13 MPa, while its self-healing efficiency still maintains at >80 %. Thus, NR composites with non-covalent interaction between CNC and supramolecular network display improved strength, maintained extensibility, and excellent self-healing capability. This study thus demonstrates a feasible approach to reduce the negative effect of reinforcing fillers on a self-healing rubber based on supramolecular networks.

Strengthened, Antibacterial, and Conductive Flexible Film for Humidity and Strain Sensors.

With the development of artificial intelligence, people are not satisfied with the traditional conductive materials and tend to focus on stretchable and flexible electronic systems. Flexible conductive rubbers have great potential applications in wearable strain sensors. However, the rapid propagation of bacteria during the use of wearable sensors may be an ineluctable threat to humans' health. Herein, a conductive rubber film is fabricated based on carboxylic styrene-butadiene rubber (XSBR), citric acid (CA), and silver nitrate (AgNO3) via a convenient approach, where Ag nanoparticles (Ag NPs) are in situ reduced without sintering at elevated temperatures. The resultant films exhibit many desirable and impressive features, such as strengthened mechanical properties, flexibility, and conductivity. More importantly, the Ag NP flexible conductive films exhibit excellent antibacterial activity against Escherichia coli (Gram-negative bacteria) and Staphylococcus aureus (Gram-positive bacteria), which have potential applications as flexible antibacterial materials to monitor movements of the human body in real time. Also, because of the hygroscopicity of CA, the resistance of our conductive film is sensitive to various humidities, which can be applied in the humidity sensor.

Disk-Diffusion Testing Is an Inappropriate Screening Tool for Cephalosporin-Resistant Gonorrhoea Strains in Clinical Practice in China.

PURPOSE: Injectable ceftriaxone and oral cefixime are the last agents effective against Neisseria gonorrhoeae. In vitro antimicrobial-susceptibility testing (AST) is done to identify the most efficacious antibiotic needed to combat the infection in that particular individual. The objective of this study was to evaluate whether Kirby-Bauer (KB) disk-diffusion tests can detect N. gonorrhoeae isolates that have decreased susceptibility to ceftriaxone and cefixime for appropriate clinical management. METHODS: A total of 1,633 consecutive clinical isolates of N. gonorrhoeae were collected from January 1, 2013 to December 31, 2017 from seven dermatology clinics located in five provinces in China. Consistency between KB disk-diffusion tests and the agar-dilution method, as well as sensitivity of the KB test for detecting N. gonorrhoeae isolates with decreased susceptibility to ceftriaxone and cefixime, were determined using 1,306 clinical isolates that had been recovered to complete agar-dilution AST. RESULTS: The prevalence of isolates with decreased susceptibility to ceftriaxone and cefixime was 12.1% (198 of 1,633) and 12.7% (208 of 1,633), respectively, using KB disk-diffusion tests. The prevalence of isolates with decreased susceptibility was 9.9% (129 of 1,306) for ceftriaxone and 9.9% (129 of 1,305) for cefixime using agar-dilution AST. The categorical agreement of these two methods was 80.9% for both ceftriaxone and cefixime. Compared to agar-dilution AST, the sensitivity of the KB test for detecting N. gonorrhoeae isolates with decreased susceptibility was 22.5% (29 of 129) for ceftriaxone and 29.5% (38 of 129) for cefixime, and its specificity 87.3% (1,028 of 1,177) for ceftriaxone and 86.7% (1,018 of 1,176) for cefixime. CONCLUSION: Although KB tests are easy to carry out in clinical practice, their ability to detect cephalosporin-resistant gonorrhoea strains is limited. This method is not an appropriate selection for screening cephalosporin-resistant gonorrhoea strains in clinical practice in China.

Framework for determining optimal strategy for sustainable remediation of contaminated sediment: A case study in Northern Taiwan.

Contaminated sediment may pose a serious threat to human health and ecosystems. However, sediment remediation is typically an expensive and time-consuming process. Therefore, an effective decision-making process for the remediation of contaminated sediment is essential for identifying the optimal approach. Since a single assessment for sediment remediation may be insufficient, combining different analytical approaches is highly recommended. The objective of this study was to develop a comprehensive assessment framework based on the concept of green and sustainable remediation that considers various environmental, economic, and social aspects for the management of contaminated sediment. We propose a framework based on human health risk assessment (HHRA) and cost-benefit analysis (CBA) and apply the multicriteria decision analysis (MCDA) technique to implement integrated and sustainable strategies for sediment management. We used the framework to determine the best alternative for managing heavy-metal-contaminated sediment in a river in Northern Taiwan. The results of the pre-remediation HHRA indicated an unacceptably high cancer risk to children, while the CBA revealed that a remediation project was economically feasible. Moreover, the results of the MCDA revealed that a strategy involving in-situ capping with anthracite-based activated carbon would be relatively inexpensive and result in low risk to human health. In addition, this strategy would have a higher environmental impact and greater public acceptance as compared to a method involving the dredging and washing of soil. Thus, in this case study, in-situ capping using anthracite-based activated carbon was identified as the preferable remediation alternative from multiple perspectives. The proposed framework should allow decision-makers to choose the optimal integrated management strategy for similar river sites with contaminated sediment.

A Whole-genome Sequencing Analysis of Neisseria gonorrhoeae Isolates in China: An Observational Study.

BACKGROUND: Tracking the spread of the Neisseria gonorrhoeae strains with decreased susceptibility or resistance to cephalosporins is a major priority for global surveillance programmes. Whole-genome sequencing (WGS) has been widely used by increasing countries in North America, Europe, and Pacific to determine the decreased susceptible or resistance determinants of Neisseria gonorrhoeae, track the spread of these determinants throughout the gonococcal population at national or regional level. However, no studies to date have examined the genomic epidemiology of gonorrhea in Asia where the antimicrobial resistant strains of Neisseria gonorrhoeae appears to have emerged before disseminating the strains globally. METHODS: We obtained clinical isolates and data from the China Gonococcal Resistance Surveillance Programme (China-GRSP) from 2012 to 2013. We sequenced the genomes of 435 clinical isolates of Neisseria gonorrhoeae, including 112 (25.6%) isolates with decreased susceptibility to ceftriaxone (Cfx-DS). We assessed the association between antimicrobial resistance genotype and phenotype. We also compared our data with the whole genome data of the isolates from the USA and the UK in the GenBank. FINDINGS: The most prevalent MLST STs in our gonococcal population were MLST ST7827 (n = 74), followed by ST7365 (n = 58), ST1600 (n = 38), ST7367 (n = 35), and ST7363 (n = 29). MLST ST1901 which was reported as the predominant ST in the US was not found in our population. A total of 2512 strains, including additional 2077 published NG strains, were further included for phylogenetic analysis. It generated two distinct lineages - lineage 1 and lineage 2. Analysis of MLST ST1901 in the database indicate that most of MLST ST1901 isolates in the lineage2.6 were Cfx-DS isolates while all isolates in the lineage 2.1 were sensitive to ceftriaxone (77/110 vs. 0/13; p < 0.001). ST1901/lineage 2.6 is a ceftriaxone resistant clone which cannot distinguished by MLST genotyping. In the isolates from our study, the MICs of ceftriaxone for ST7363/lineage 2.6 isolates ranged from 0.008-0.125 mg/L (mean ±â€¯SD; 0.054 ±â€¯0.043 mg/L) while those for ST7363/lineage 2.8 isolates ranged from 0.032-0.250 mg/L (0.134 ±â€¯0.085 mg/L). All ST7363/lineage 2.8 isolates contained penA mosaic alleles. INTERPRETATION: To our knowledge, current study is the first WGS-based analysis of gonococcal population at national level in Asia. China harbors the different predominant clones associated with decreased susceptibility to ceftriaxone from those clones circulated in other regions. The findings from the study can be not only used as baseline data for future studies in China but also contributable to our understanding on spread of N. gonorrhoeae and its resistant strains at regional and global levels. FUNDING: The Chinese Academy Medical Sciences (CAMS) Initiative for Innovative Medicine.

Subcutaneous liraglutide ameliorates methylglyoxal-induced Alzheimer-like tau pathology and cognitive impairment by modulating tau hyperphosphorylation and glycogen synthase kinase-3ß.

Memory deterioration and synapse damage with accumulation of ß-amyloid and hyperphosphorylated tau are hallmark lesions of Alzheimer's disease (AD). Methylglyoxal (MG), a key intermediate of glucose metabolism, is elevated in AD brains and modifies Aß42, increasing misfolding and leading to the accumulation of senile plaques. Liraglutide, an analog of glucagon-like peptide-1 (GLP-1), is neurotrophic and neuroprotective. However, whether liraglutide can protect against AD-like memory-related deficits and tau hyperphosphorylation caused by MG in vivo is not known. Here, we report that MG induces tau hyperphosphorylation and causes ultrastructural hippocampal damage and cognitive impairment in C57BL/6J mice. Liraglutide reduced these effects via activation of the protein kinase B and glycogen synthase kinase-3ß pathways. Our data reveal that liraglutide may alleviate AD-like cognitive impairment by decreasing the phosphorylation of tau.