Key Factors Influencing the Operationalization and Effectiveness of Telemedicine Services in Henan Province, China: Cross-Sectional Analysis.

BACKGROUND: Telemedicine has demonstrated its potential in alleviating the unbalanced distribution of medical resources across different regions. Henan, a province in China with a population of approximately 100 million, is especially affected by a health care divide. The province has taken a proactive step by establishing a regional collaborative platform for telemedicine services provided by top-tier provincial hospitals. OBJECTIVE: We aim to identify the key factors that influence the current operationalization and effectiveness of telemedicine services in Henan province. The insights gained from this study will serve as valuable references for enhancing the efficient operation of telemedicine platforms in low- and middle-income regions. METHODS: We analyzed service reports from the performance management system of telemedicine services in Henan province throughout 2020. Using descriptive statistics and graphical methods, we examined key influencing factors, such as management competency; device configuration; and hospital capability, capacity, and service efficacy, across hospitals at 2 different tiers. In addition, we used generalized linear models and multiple linear regression models to identify key operational factors that significantly affect the service volume and efficacy of 2 major telemedicine services, namely teleconsultation and tele-education. RESULTS: Among the 89 tier 3 hospitals and 97 tier 2 hospitals connected to the collaborative telemedicine platform, 65 (73%) and 55 (57%), respectively, have established standardized management procedures for telemedicine services. As the primary delivery method for telemedicine services, 90% (80/89) of the tier 3 hospitals and 94% (91/97) of the tier 2 hospitals host videoconferencing consultations through professional hardware terminals rather than generic computers. Teleconsultation is the dominant service type, with an average annual service volume per institution of 173 (IQR 37-372) and 60 (IQR 14-271) teleconsultations for tier 3 and tier 2 hospitals, respectively. Key factors influencing the service volume at each hospital include available funding, management competency, the number of connected upper tiers, and the number of professional staff. After receiving teleconsultations from tier 3 (65/89, 73%) and tier 2 (61/97, 63%) hospitals, patients reported significant improvements in their medical conditions. In addition, we observed that service efficacy is positively influenced by management competency, financial incentives, the number of connected upper or lower tiers, and the involvement of participating medical professionals. CONCLUSIONS: Telemedicine has become increasingly popular in Henan province, with a notable focus on teleconsultation and tele-education services. Despite its popularity, many medical institutions, especially tier 2 hospitals, face challenges related to management competency. In addition to enhancing the effectiveness of existing telemedicine services, health care decision-makers in Henan province and other low- and middle-income regions should consider expanding the service categories, such as including remote emergency care and telesurgery, which have promise in addressing crucial health care needs in these regions.

In vitro potency of xeruborbactam in combination with multiple ß-lactam antibiotics in comparison with other ß-lactam/ß-lactamase inhibitor (BLI) combinations against carbapenem-resistant and extended-spectrum ß-lactamase-producing Enterobacterales.

Recently, several ß-lactam (BL)/ß-lactamase inhibitor (BLI) combinations have entered clinical testing or have been marketed for use, but limited direct comparative studies of their in vitro activity exist. Xeruborbactam (XER, also known as QPX7728), which is undergoing clinical development, is a cyclic boronate BLI with potent inhibitory activity against serine (serine ß-lactamase) and metallo-ß-lactamases (MBLs). The objectives of this study were (i) to compare the potency and spectrum of ß-lactamase inhibition by various BLIs in biochemical assays using purified ß-lactamases and in microbiological assays using the panel of laboratory strains expressing diverse serine and metallo-ß-lactamases and (ii) to compare the in vitro potency of XER in combination with multiple ß-lactam antibiotics to that of other BL/BLI combinations in head-to-head testing against recent isolates of carbapenem-resistant Enterobacterales (CRE). Minimal inhibitory concentrations (MICs) of XER combinations were tested with XER at fixed 4 or 8 µg/mL, and MIC testing was conducted in a blinded fashion using Clinical and Laboratory Standards Institute reference methods. Xeruborbactam and taniborbactam (TAN) were the only BLIs that inhibited clinically important MBLs. The spectrum of activity of xeruborbactam included several MBLs identified in Enterobacterales, e.g., and various IMP enzymes and NDM-9 that were not inhibited by taniborbactam. Xeruborbactam potency against the majority of purified ß-lactamases was the highest in comparison with other BLIs. Meropenem-xeruborbactam (MEM-XER, fixed 8 µg/mL) was the most potent combination against MBL-negative CRE with MIC90 values of 0.125 µg/mL. MEM-XER and cefepime-taniborbactam (FEP-TAN) were the only BL/BLIs with activity against MBL-producing CREs; with MEM-XER (MIC90 of 1 µg/mL) being at least 16-fold more potent than FEP-TAN (MIC90 of 16 µg/mL). MEM-XER MIC values were ≤8 µg/mL for >90% of CRE, including both MBL-negative and MBL-positive isolates, with FEP-TAN MIC of >8 µg/mL. Xeruborbactam also significantly enhanced potency of other ß-lactam antibiotics, including cefepime, ceftolozane, ceftriaxone, aztreonam, piperacillin, and ertapenem, against clinical isolates of Enterobacterales that carried various class A, class C, and class D extended-spectrum ß-lactamases and carbapenem-resistant Enterobacterales, including metallo-ß-lactamase-producing isolates. These results strongly support further clinical development of xeruborbactam combinations.

Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF).

Interleukin 17 (IL-17) promotes the expression of chemokines and cytokines via the induction of gene transcription and post-transcriptional stabilization of mRNA. We show here that IL-17 enhanced the stability of chemokine CXCL1 mRNA and other mRNAs through a pathway that involved the adaptor Act1, the adaptors TRAF2 or TRAF5 and the splicing factor SF2 (also known as alternative splicing factor (ASF)). TRAF2 and TRAF5 were necessary for IL-17 to signal the stabilization of CXCL1 mRNA. Furthermore, IL-17 promoted the formation of complexes of TRAF5-TRAF2, Act1 and SF2 (ASF). Overexpression of SF2 (ASF) shortened the half-life of CXCL1 mRNA, whereas depletion of SF2 (ASF) prolonged it. SF2 (ASF) bound chemokine mRNA in unstimulated cells, whereas the SF2 (ASF)-mRNA interaction was much lower after stimulation with IL-17. Our findings define an IL-17-induced signaling pathway that links to the stabilization of selected mRNA species through Act1, TRAF2-TRAF5 and the RNA-binding protein SF2 (ASF).

The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation.

Interleukin 17 (IL-17) is critical in the pathogenesis of inflammatory and autoimmune diseases. Here we report that Act1, the key adaptor for the IL-17 receptor (IL-7R), formed a complex with the inducible kinase IKKi after stimulation with IL-17. Through the use of IKKi-deficient mice, we found that IKKi was required for IL-17-induced expression of genes encoding inflammatory molecules in primary airway epithelial cells, neutrophilia and pulmonary inflammation. IKKi deficiency abolished IL-17-induced formation of the complex of Act1 and the adaptors TRAF2 and TRAF5, activation of mitogen-activated protein kinases (MAPKs) and mRNA stability, whereas the Act1-TRAF6-transcription factor NF-κB axis was retained. IKKi was required for IL-17-induced phosphorylation of Act1 on Ser311, adjacent to a putative TRAF-binding motif. Substitution of the serine at position 311 with alanine impaired the IL-17-mediated Act1-TRAF2-TRAF5 interaction and gene expression. Thus, IKKi is a kinase newly identified as modulating IL-17 signaling through its effect on Act1 phosphorylation and consequent function.

Telemedicine in the Battle with 2019 Novel Coronavirus Disease (COVID-19) in Henan Province, China: A Narrative Study.

Background and Objectives: Based on practical services of the Henan Province Telemedicine Center (HTCC), the purpose of this study is to investigate the design, construction, implementation, and application effect of a specific telemedicine system in response to the coronavirus disease 2019 (COVID-19). Methods: Data on COVID-19 cases from December 31, 2019, through October 17, 2022, were collected from official websites. Data and information of telemedicine services related to COVID-19 in HTCC were collected and analyzed, and relevant graphical representations were plotted. Results: All the 147 COVID-19 designated hospitals in the Henan Province were covered by the specific telemedicine system. The cities near to the Hubei Province in the south of Henan tended to be with more COVID-19 cases, where more COVID-19-related telemedicine services were conducted. For the telemedicine system, function modules, including real-time monitoring, command and dispatch, intractable cases transfer, remote guidance, and data sharing, were designed and realized to deal with COVID-19. Through the system, telemedicine services involved COVID-19 such as epidemic surveillance, emergency rescue, case discussion, diagnosis and treatment, remote ward-round, and distance education were performed. During the period between February 2 and March 3, 2020, 646 COVID-19 patients were served by the telemedicine system, with an improvement rate of 73.2%. Conclusions: Telemedicine can improve the diagnosis and treatment of COVID-19 patients, which play a helpful role in curbing the COVID-19 epidemic. Given the current global COVID-19 pandemic and the potential re-emerge of novel zoonotic pathogens in the future, the use of telemedicine would be imperative to fight against the pandemic.

Intrinsic Antibacterial Activity of Xeruborbactam In Vitro: Assessing Spectrum and Mode of Action.

Xeruborbactam (formerly QPX7728) is a cyclic boronate inhibitor of numerous serine and metallo-beta-lactamases. At concentrations generally higher than those required for beta-lactamase inhibition, xeruborbactam has direct antibacterial activity against some Gram-negative bacteria, with MIC50/MIC90 values of 16/32 µg/mL and 16/64 µg/mL against carbapenem-resistant Enterobacterales and carbapenem-resistant Acinetobacter baumannii, respectively (the MIC50/MIC90 values against Pseudomonas aeruginosa are >64 µg/mL). In Klebsiella pneumoniae, inactivation of OmpK36 alone or in combination with OmpK35 resulted in 2- to 4-fold increases in the xeruborbactam MIC. In A. baumannii and P. aeruginosa, AdeIJK and MexAB-OprM, respectively, affected xeruborbactam's antibacterial potency (the MICs were 4- to 16-fold higher in efflux-proficient strains). In Escherichia coli and K. pneumoniae, the 50% inhibitory concentrations (IC50s) of xeruborbactam's binding to penicillin-binding proteins (PBPs) PBP1a/PBP1b, PBP2, and PBP3 were in the 40 to 70 µM range; in A. baumannii, xeruborbactam bound to PBP1a, PBP2, and PBP3 with IC50s of 1.4 µM, 23 µM, and 140 µM, respectively. Treating K. pneumoniae and P. aeruginosa with xeruborbactam at 1× and 2× MIC resulted in changes of cellular morphology similar to those observed with meropenem; the morphological changes observed after treatment of A. baumannii were consistent with inhibition of multiple PBPs but were unique to xeruborbactam compared to the results for control beta-lactams. No single-step xeruborbactam resistance mutants were obtained after selection at 4× MIC of xeruborbactam using wild-type strains of E. coli, K. pneumoniae, and A. baumannii; mutations selected at 2× MIC in K. pneumoniae did not affect antibiotic potentiation by xeruborbactam through beta-lactamase inhibition. Consistent with inhibition of PBPs, xeruborbactam enhanced the potencies of beta-lactam antibiotics even against strains that lacked beta-lactamase. In a large panel of KPC-producing clinical isolates, the MIC90 values of meropenem tested with xeruborbactam (8 µg/mL) were at least 4-fold lower than those in combination with vaborbactam at 64 µg/mL, the concentration of vaborbactam that is associated with complete inhibition of KPC. The additional enhancement of the potency of beta-lactam antibiotics beyond beta-lactamase inhibition may contribute to the potentiation of beta-lactam antibiotics by xeruborbactam.

The long-term effects of microplastics on soil organomineral complexes and bacterial communities from controlled-release fertilizer residual coating.

Controlled-release fertilizer (CRF) was applied widely in China as an efficient utilization strategy for improving grain yield and reducing the nitrogen contamination. However, it was indeterminate to know the impacts of inevitably imported plastic into the soil on sustainable development. After ten-year fixed-site experiment, the visible residual coating microplastics were separated from the soil to measure their changes, then the long-term effects of CRF application (theoretical microplastic content 0.018-0.151 g kg-1 soil) on soil architecture and bacterial communities were evaluated. Based on soil organomineral complexes (OMC) distribution experiments and soil 16S rRNA sequence analysis, residual coating microplastics had no significant impact on soil architecture and limited effects on soil bacteria, but became the specific microbial habitat. The nitrogen rate and nitrogen release mode affected sand- and silt-grade OMC, and nitrogen rate impacted soil bacteria communities. The residual coating, small inert particles, is safe for soil OMC and bacterial communities in agricultural soil. Due to the effectiveness of CRF on reducing environmental pollution, CRF is considered as a favorable measure to the sustainable agricultural development in Shandong Province, China.

In Vitro Activity of the Ultrabroad-Spectrum Beta-Lactamase Inhibitor QPX7728 in Combination with Multiple Beta-Lactam Antibiotics against Pseudomonas aeruginosa.

QPX7728 is an ultrabroad-spectrum beta-lactamase inhibitor with potent inhibition of key serine and metallo beta-lactamases. QPX7728 enhances the potency of multiple beta-lactams in beta-lactamase-producing Enterobacterales and Acinetobacter spp. In this study, we evaluated the in vitro activity of QPX7728 (QPX; 8 µg/ml) combined with multiple beta-lactams against clinical isolates of Pseudomonas aeruginosa with various beta-lactam resistance mechanisms. Seven hundred ninety clinical isolates were included in this study; 500 isolates, termed a "representative panel," were selected to be representative of the MIC distribution of meropenem (MEM), ceftazidime-avibactam (CAZ-AVI), and ceftolozane-tazobactam (TOL-TAZ) resistance for clinical isolates according to 2017 SENTRY surveillance data. An additional 290 selected isolates ("challenge panel") that were either nonsusceptible to MEM or were resistant to TOL-TAZ or CAZ-AVI were also tested; 61 strains carried metallo-beta-lactamases (MBLs), 211 strains were defective in the carbapenem porin OprD, and 185 strains had the MexAB-OprM efflux pump overproduced based on a phenotypic test. Against the representative panel, susceptibility for all QPX7728/beta-lactam combinations was >90%. For the challenge panel, QPX-ceftolozane (TOL) was the most active combination (78.6% susceptible) followed by equipotent QPX-piperacillin (PIP) and QPX-cefepime (FEP), restoring susceptibility in 70.3% of strains (CLSI breakpoints for the beta-lactam compound alone). For MBL-negative strains, QPX-TOL and QPX-FEP restored the MIC values to susceptibility rates in ∼90% and ∼80% of strains, respectively, versus 68% to 70% for QPX-MEM and QPX-PIP and 63% to 65% for TOL-TAZ and CAZ-AVI, respectively. For MBL-positive strains, QPX-PIP restored the MIC to susceptibility values for ∼70% of strains versus 2% to 40% for other combinations. Increased efflux and impaired OprD had various effect on QPX7728 combination depending on the partner beta-lactam tested. QPX7728 enhanced the potency of multiple beta-lactams against P. aeruginosa, with varied results according to beta-lactamase production and other intrinsic resistance mechanisms.

FNDC5 induces M2 macrophage polarization and promotes hepatocellular carcinoma cell growth by affecting the PPARγ/NF-κB/NLRP3 pathway.

PURPOSE: The purpose of this study was to investigate the effect of FNDC5 expression levels in hepatocellular carcinoma on the phenotypic changes of macrophages in tumor tissues. METHODS: In this study, we established an in vitro co-culture system of hepatocellular carcinoma cells and macrophages. Then we performed overexpression or knockdown of FNDC5 gene in hepatocellular carcinoma cells to observe the effect of changes in FNDC5 expression level on the phenotypic changes of THP-1 macrophages. And the conclusions obtained in the in vitro assay were further validated by a subcutaneous tumorigenic nude mice model. RESULTS: Our findings suggest that elevated FNDC5 expression in hepatocellular carcinoma cells lead to an increased M2 phenotype and decreased M1 phenotype in macrophages. This effect may be achieved by elevating PPARγ levels in macrophages while decreasing NF-κB and NLRP3 levels. These changes could be reversed by using PPARγ inhibitors. CONCLUSION: We preliminarily demonstrated that FNDC5 in hepatocellular carcinoma cells promotes the polarization of M2 macrophages by affecting the PPARγ/NF-κB/NLRP3 pathway.

Spatio-temporal distribution characteristics of COVID-19 in China: a city-level modeling study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) has become a pandemic. Few studies have been conducted to investigate the spatio-temporal distribution of COVID-19 on nationwide city-level in China. OBJECTIVE: To analyze and visualize the spatiotemporal distribution characteristics and clustering pattern of COVID-19 cases from 362 cities of 31 provinces, municipalities and autonomous regions in mainland China. METHODS: A spatiotemporal statistical analysis of COVID-19 cases was carried out by collecting the confirmed COVID-19 cases in mainland China from January 10, 2020 to October 5, 2020. Methods including statistical charts, hotspot analysis, spatial autocorrelation, and Poisson space-time scan statistic were conducted. RESULTS: The high incidence stage of China's COVID-19 epidemic was from January 17 to February 9, 2020 with daily increase rate greater than 7.5%. The hot spot analysis suggested that the cities including Wuhan, Huangshi, Ezhou, Xiaogan, Jingzhou, Huanggang, Xianning, and Xiantao, were the hot spots with statistical significance. Spatial autocorrelation analysis indicated a moderately correlated pattern of spatial clustering of COVID-19 cases across China in the early phase, with Moran's I statistic reaching maximum value on January 31, at 0.235 (Z = 12.344, P = 0.001), but the spatial correlation gradually decreased later and showed a discrete trend to a random distribution. Considering both space and time, 19 statistically significant clusters were identified. 63.16% of the clusters occurred from January to February. Larger clusters were located in central and southern China. The most likely cluster (RR = 845.01, P < 0.01) included 6 cities in Hubei province with Wuhan as the centre. Overall, the clusters with larger coverage were in the early stage of the epidemic, while it changed to only gather in a specific city in the later period. The pattern and scope of clusters changed and reduced over time in China. CONCLUSIONS: Spatio-temporal cluster detection plays a vital role in the exploration of epidemic evolution and early warning of disease outbreaks and recurrences. This study can provide scientific reference for the allocation of medical resources and monitoring potential rebound of the COVID-19 epidemic in China.

Application of Telemedicine Services Based on a Regional Telemedicine Platform in China From 2014 to 2020: Longitudinal Trend Analysis.

BACKGROUND: Telemedicine that combines information technology and health care augments the operational model of traditional medical services and brings new opportunities to the medical field. China promotes telemedicine with great efforts, and its practices in the deployment of telemedicine platforms and delivery of services have become important references for the research and development in this field. OBJECTIVE: Our work described in this paper focuses on a regional telemedicine platform that was built in 2014. We analyzed the system design scheme and remote consultations that were conducted via the system to understand the deployment and service delivery processes of a representative telemedicine platform in China. METHODS: We collected information on remote consultations conducted from 2015 to 2020 via the regional telemedicine platform that employs a centralized architectural system model. We used graphs and statistical methods to describe the changing trends of service volume of remote consultation, geographical and demographic distribution of patients, and waiting time and duration of consultations. The factors that affect consultation duration and patient referral were analyzed by multivariable linear regression models and binary logistic regression models, respectively. The attitudes toward telemedicine of 225 medical practitioners and 225 patients were collected using the snowball sampling method. RESULTS: The regional telemedicine platform covers all levels of medical institutions and hospitals in all 18 cities of Henan Province as well as some interprovince hospitals. From 2015 to 2020, 103,957 remote medical consultations were conducted via the platform with an annual increasing rate of 0.64%. A total of 86.64% (90,069/103,957) of medical institutions (as clients) that applied for remote consultations were tier 1 or 2 and from less-developed regions; 65.65% (68,243/103,945) of patients who applied for remote consultations were aged over 50 years. The numbers of consultations were high for departments focusing in the treatment of chronic diseases such as neurology, respiratory medicine, and oncology. The invited experts were mainly experienced doctors with senior professional titles. Year of consultation, tier of hospital, consultation department, and necessity of patient referral were the main factors affecting the duration of consultations. In surveys, we found that 60.4% (136/225) of medical practitioners and 53.8% (121/225) of patients had high satisfaction and believed that telemedicine is of vital importance for the treatment of illness. CONCLUSIONS: The development of telemedicine in China shows a growing trend and provides great benefits especially to medical institutions located in less developed regions and senior citizens who have less mobility. Cases of remote consultations are mainly for chronic diseases. At present, the importance and necessity of telemedicine are well recognized by both patients and medical practitioners. However, the waiting time needs to be further reduced to improve the efficiency of remote medical services.

In Vitro Activity of the Ultrabroad-Spectrum-Beta-Lactamase Inhibitor QPX7728 against Carbapenem-Resistant Enterobacterales with Varying Intrinsic and Acquired Resistance Mechanisms.

QPX7728 is an investigational ultrabroad-spectrum-beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in isogenic strains of Gram-negative bacteria producing various beta-lactamases. The potency of meropenem alone and in combination with QPX7728 (tested at fixed concentrations of 1 to 16 µg/ml) was tested against 598 clinical isolates of carbapenem-resistant Enterobacterales (CRE). The panel included 363 strains producing serine carbapenemases, 224 strains producing metallo-beta-lactamases (151 NDM, 53 VIM, and 20 IMP), and 50 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 µg/ml). The panel was also enriched in strains that had various defects in the major porins OmpK35/OmpF and OmpK36/OmpC. Increasing concentrations of QPX7728 restored the potency of meropenem against CRE, with the meropenem MIC90 decreasing from >64 µg/ml to 0.5 µg/ml for QPX7728 (8 µg/ml). QPX7728 significantly increased the potency of meropenem against CRE with multiple resistance mechanisms; the reduction in the meropenem MIC90 with QPX7728 (8 µg/ml) ranged from 32- to >256-fold. Compared with other beta-lactamase inhibitor combinations, meropenem-vaborbactam, ceftazidime-avibactam, and imipenem-relebactam, meropenem with QPX7728 was the most potent beta-lactam-BLI combination tested against all groups of CRE with multiple resistance mechanisms. Defects in OmpK36 in KPC-producing strains markedly decreased the potency of meropenem with vaborbactam (128-fold increase in the MIC90), whereas only an 8- to 16-fold change was observed with QPX7728 plus meropenem. More than 90% of various CRE subsets (including those with reduced permeability) were susceptible to ≤8 µg/ml of meropenem with QPX7728 at 8 µg/ml or lower. The combination of QPX7728 with meropenem against CRE has an attractive microbiological profile in CRE with multiple resistance mechanisms.

In Vitro Activity of the Ultra-Broad-Spectrum Beta-Lactamase Inhibitor QPX7728 in Combination with Meropenem against Clinical Isolates of Carbapenem-Resistant Acinetobacter baumannii.

QPX7728 is a recently discovered ultra-broad-spectrum beta-lactamase inhibitor (BLI) with potent inhibition of key serine and metallo-beta-lactamases. QPX7728 enhances the potency of many beta-lactams, including carbapenems, in beta-lactamase-producing Gram-negative bacteria, including Acinetobacter spp. The potency of meropenem alone and in combination with QPX7728 (1 to 16 µg/ml) was tested against 275 clinical isolates of Acinetobacter baumannii (carbapenem-resistant A. baumannii [CRAB]) collected worldwide that were highly resistant to carbapenems (MIC50 and MIC90 for meropenem, 64 and >64 µg/ml). Addition of QPX7728 resulted in a marked concentration-dependent increase in meropenem potency, with the MIC90 of meropenem alone decreasing from >64 µg/ml to 8 and 4 µg/ml when tested with fixed concentrations of QPX7728 at 4 and 8 µg/ml, respectively. In order to identify the mechanisms that modulate the meropenem-QPX7728 MIC, the whole-genome sequences were determined for 135 isolates with a wide distribution of meropenem-QPX7728 MICs. This panel of strains included 116 strains producing OXA carbapenemases (71 OXA-23, 16 OXA-72, 16 OXA-24, 9 OXA-58, and 4 OXA-239), 5 strains producing NDM-1, one KPC-producing strain, and 13 strains that did not carry any known carbapenemases but were resistant to meropenem (MIC ≥ 4 µg/ml). Our analysis indicated that mutated PBP3 (with mutations localized in the vicinity of the substrate/inhibitor binding site) is the main factor that contributes to the reduction of meropenem-QPX7728 potency. Still, >90% of isolates that carried PBP3 mutations remained susceptible to ≤8 µg/ml of meropenem when tested with a fixed 4 to 8 µg/ml of QPX7728. In the absence of PBP3 mutations, the MICs of meropenem tested in combination with 4 to 8 µg/ml of QPX7728 did not exceed 8 µg/ml. In the presence of both PBP3 and efflux mutations, 84.6% of isolates were susceptible to ≤8 µg/ml of meropenem with 4 or 8 µg/ml of QPX7728. The combination of QPX7728 with meropenem against CRAB isolates with multiple resistance mechanisms has an attractive microbiological profile.

Spectrum of Beta-Lactamase Inhibition by the Cyclic Boronate QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases: Enhancement of Activity of Multiple Antibiotics against Isogenic Strains Expressing Single Beta-Lactamases.

QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor, with potent inhibition of key serine and metallo-beta-lactamases being observed in biochemical assays. Microbiological studies using characterized strains were used to provide a comprehensive characterization of the spectrum of beta-lactamase inhibition by QPX7728. The MICs of multiple antibiotics administered intravenously only (ceftazidime, piperacillin, cefepime, ceftolozane, and meropenem) and orally bioavailable antibiotics (ceftibuten, cefpodoxime, tebipenem) alone and in combination with QPX7728 (4 µg/ml), as well as comparator agents, were determined against panels of laboratory strains of Pseudomonas aeruginosa and Klebsiella pneumoniae expressing over 55 diverse serine and metallo-beta-lactamases. QPX7728 significantly enhanced the potency of antibiotics against strains expressing class A extended-spectrum beta-lactamases (CTX-M, SHV, TEM, VEB, PER) and carbapenemases (KPC, SME, NMC-A, BKC-1), consistent with the beta-lactamase inhibition demonstrated in biochemical assays. It also inhibited both plasmidic (CMY, FOX, MIR, DHA) and chromosomally encoded (P99, PDC, ADC) class C beta-lactamases and class D enzymes, including carbapenemases, such as OXA-48 from Enterobacteriaceae and OXA enzymes from Acinetobacter baumannii (OXA-23/24/72/58). QPX7728 is also a potent inhibitor of many class B metallo-beta-lactamases (NDM, VIM, CcrA, IMP, and GIM but not SPM or L1). Addition of QPX7728 (4 µg/ml) reduced the MICs for a majority of the strains to the level observed for the control with the vector alone, indicative of complete beta-lactamase inhibition. The ultrabroad-spectrum beta-lactamase inhibition profile makes QPX7728 a viable candidate for further development.

Impact of Intrinsic Resistance Mechanisms on Potency of QPX7728, a New Ultrabroad-Spectrum Beta-Lactamase Inhibitor of Serine and Metallo-Beta-Lactamases in Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii.

QPX7728 is an ultrabroad-spectrum boronic acid beta-lactamase inhibitor that demonstrates inhibition of key serine and metallo-beta-lactamases at a nanomolar concentration range in biochemical assays with purified enzymes. The broad-spectrum inhibitory activity of QPX7728 observed in biochemical experiments translates into enhancement of the potency of many beta-lactams against strains of target pathogens producing beta-lactamases. The impacts of bacterial efflux and permeability on inhibitory potency were determined using isogenic panels of KPC-3-producing isogenic strains of Klebsiella pneumoniae and Pseudomonas aeruginosa and OXA-23-producing strains of Acinetobacter baumannii with various combinations of efflux and porin mutations. QPX7728 was minimally affected by multidrug resistance efflux pumps either in Enterobacteriaceae or in nonfermenters, such as P. aeruginosa or A. baumannii Against P. aeruginosa, the potency of QPX7728 was further enhanced when the outer membrane was permeabilized. The potency of QPX7728 against P. aeruginosa was not affected by inactivation of the carbapenem porin OprD. While changes in OmpK36 (but not OmpK35) reduced the potency of QPX7728 (8- to 16-fold), QPX7728 (4 µg/ml) nevertheless completely reversed the KPC-mediated meropenem resistance in strains with porin mutations, consistent with the lesser effect of these mutations on the potency of QPX7728 compared to that of other agents. The ultrabroad-spectrum beta-lactamase inhibition profile, combined with enhancement of the activity of multiple beta-lactam antibiotics with various sensitivities to the intrinsic resistance mechanisms of efflux and permeability, indicates that QPX7728 is a useful inhibitor for use with multiple beta-lactam antibiotics.

Impact of the Internet on Medical Decisions of Chinese Adults: Longitudinal Data Analysis.

BACKGROUND: The internet has caused the explosive growth of medical information and has greatly improved the availability of medical knowledge. This makes the internet one of the main ways for residents to obtain medical information and knowledge before seeking medical treatment. However, little has been researched on how the internet affects medical decisions. OBJECTIVE: The purpose of this study was to explore the associations between internet behaviors and medical decisions among Chinese adults aged 18 or over, including whether to go to the hospital and which level of medical institution to choose. METHODS: With the adult residents (≥18 years old) in 12 regions including urban and rural areas taken as the research objects, the differences in medical choices of adults with various characteristics were analyzed, and generalized linear mixed models were adopted to analyze the longitudinal data of the China Health Nutrition Survey from 2006 to 2015. RESULTS: Adult groups with different ages, genders, education levels, regions, places of residence, severities of illness and injury, years of suffering from hypertension, and history of chronic diseases showed diverse medical decisions, and the differences were statistically significant (P<.05). After controlling for these potential confounding factors and taking self-care as the reference, the probability of Chinese adults who participated in online browsing activities selecting hospital care was 0.82 (95% CI 0.69-0.98; P=.03) times that of residents who did not participate in online browsing activities. In terms of medical institution choices, adults who participated in online browsing activities were 1.86 (95% CI 1.35-2.58; P<.001) times more likely to opt for municipal medical treatment than primary care. However, the effect of online browsing on the selection probability of county-level hospitals was not significant compared with primary hospitals (P=.59). Robust analysis verified that accessing the internet had a similar effect on Chinese adults' medical decisions. CONCLUSIONS: Chinese adults who use the internet are a little less likely to go to the hospital than self-care. The internet has broken down the barriers to obtain knowledge of common diseases and thus has a slight substitution effect of self-care on hospital care. Internet use may increase the probability of adults going to municipal hospitals. The rising tendency of visiting high-level medical institutions may be consequently exacerbated due to knowledge monopoly of severe and complicated diseases that is difficult to eliminate, and the increase in inconsistent and incomplete medical information online will blur the residents' cognitive boundary of common diseases and severe diseases. Exploring the substantive impact of the internet on medical decision making is of great significance for further rational planning and utilization of the internet, in order to guide patients to appropriate medical institution.

Design and Application of a Telemedicine System Jointly Driven by Videoconferencing and Data Exchange: Practical Experience from Henan Province, China.

Background and Objectives: There are a few problems restraining the effective operation of telemedicine in China. On the basis of practices of the Henan Province Telemedicine Center of China (HTCC), the purpose of this study was to design a telemedicine system jointly driven by videoconferencing and data exchange to address the issues limiting the further development and implementation of telemedicine. Methods: Based on service-oriented architecture, the organizational design of the telemedicine system was gradually refined from top to bottom to complete its hierarchical layout. Technologies including multiprotocol stack adaptation, self-adaptive multilink network transmission, information exchange of heterogeneous medical systems, and open application system architecture were also used to construct the system. Results: The telemedicine system realizes the integration of videoconferencing, data acquisition and exchange of heterogeneous medical information systems, and the actual applications and expansion of telemedicine services. The HTCC currently covers more than 500 telemedicine centers, workstations, and service points, forming a five-level "province-city-county-township-village" telemedicine network linkage. The HTCC handles nearly 30,000 teleconsultation cases per year, helping patients save about ¥120 million Chinese Yuan RMB (approximately US $17.5 million). Conclusions: The proposed telemedicine system achieves satisfactory operation effects, along with social and economic benefits. It has the potential to increase the coverage of medical resources in remote regions, and it can play a role in solving other problems facing telemedicine development in China. The findings also inform measures for further improvement in telemedicine's implementation effects, service quality, and application scope in China and globally.

A high throughput method for total alcohol determination in fermentation broths.

BACKGROUND: The potassium dichromate oxidation method used in determination of alcohols in fermentation has two major disadvantages. This method cannot be used to determine alcohols in raw fermentation broth samples, which often contain various reducing sugars. The method is not environment friendly due to the carcinogenicity of Cr (VI) used. RESULTS: A new method for determination of reducing sugars and total alcohols in raw fermentation broths was developed. The fermentation broth was pretreated to remove proteins, polysaccharides, glycerol and organic acids. The colorimetric change from both total alcohols and reducing sugars by potassium permanganate oxidation was measured. The portion of colorimetric change from oxidation of reducing sugars was determined by DNS test and subtracted. The remaining portion of colorimetric change was then used to calculate the total alcohol concentration in the sample. CONCLUSIONS: Using this method, total alcohol concentration can be easily and accurately determined in both distilled samples and raw fermentation broth samples. It is fast and environmental friendly.

Recombinant streptavidin fusion proteins as signal reporters in rapid test of human hepatitis C virus infection.

BACKGROUND: Early diagnosis of hepatitis C virus (HCV) infection is very important for the treatment of the disease. Development of sensitive and specific rapid detection assays is of great significance for the diagnosis. Here, we describe a promising method of using gold-labeled streptavidin fusion proteins as novel signal reporter in a rapid detection assay for HCV infection. METHODS: Recombinant genes encoding streptavidin fused with Escherichia coli maltose-binding protein (MBP) or with a portion of bacterial translational initiation factor 2 were cloned in expression vectors pMAL-5CX and pET28 and transformed in proper Escherichia coli host strains. The genes were induced and streptavidin fusion proteins, named M-STV and IF-STV, respectively, were purified by affinity chromatography to over 90% purity. The biotin-binding activity of M-STV and IF-STV was tested by enzyme-linked immunosorbent assay (ELISA). M-STV was labeled with colloidal gold nanoparticles and used as a signal reporter to develop a lateral flow-based rapid test for detecting anti-HCV antibodies in human blood samples. RESULTS: M-STV showed slightly higher biotin-binding activity and similar binding specificity as compared to commercial streptavidin. The gold-labeled M-STV bound specifically to biotin moieties immobilized on the rapid test strips in a dose-responsive manner and was successfully used in detecting HCV antibodies in serum samples of patients infected with HCV. The rapid test displayed higher detection sensitivity than gold-labeled commercial NeutrAvidin. CONCLUSION: Our results indicate that gold-labeled M-STV is a promising agent in rapid tests of HCV infection and possibly other viral infections.

Alkannin Inhibited Hepatic Inflammation in Diabetic Db/Db Mice.

BACKGROUND/AIMS: The current study was designed to investigate the protective role of alkannin (ALK) on liver injury in diabetic C57BL/KsJ-db/db mice and explore its potential mechanisms. METHODS: An oral glucose tolerance test (OGTT) was performed. The levels of insulin, alanine aminotransferase (ALT), aspartate aminotransaminase (AST), total cholesterol (TC) and triglyceride (TG) were determined by commercial kits. The pro-inflammatory cytokines interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α were determined by ELISA. The levels of the ROCK/NF-κB pathway were determined by Western blotting. RESULTS: The contents of pro-inflammatory cytokines interleukin (IL)-1ß, IL-6 and tumour necrosis factor (TNF)-α were inhibited by ALK, metformin or fasudil in diabetic db/db mice. Further, Western blotting analysis showed that the expression of Rho, ROCK1, ROCK2, p-NF-κBp65, and p-IκBα was significantly reversed by ALK treatment. In human hepatic HepG2 cells, the hepatoprotective effects of ALK were further characterized. With response to palmitic acid-challenge, increased amounts of insulin, ALT, AST, TG, and TC were observed, whereas ALK pretreatment significantly inhibited their leakage in HepG2 cells without appreciable cytotoxic effects. The inflammation condition was recovered with ALK treatment as shown by changes of IL-1ß, IL-6 and TNF-α. Further, Western blotting analysis also suggested that ALK improves hepatic inflammation in a Rho-kinase pathway. CONCLUSION: The present study successfully investigated the role of Rho-kinase signalling in diabetic liver injury. ALK exhibited hepatoprotective effects in diabetic db/db mice, and it might act through improving hepatic inflammation through the Rho-kinase pathway.