Efficacy and safety of current therapeutic options for COVID-19 - lessons to be learnt from SARS and MERS epidemic: A systematic review and meta-analysis.

The rapidly progressing of coronavirus disease 2019 (COVID-19) pandemic has become a global concern. This meta-analysis aimed at evaluating the efficacy and safety of current option of therapies for severe acute respiratory syndrome (SARS), Middle Eastern respiratory syndrome (MERS) besides COVID-19, in an attempt to identify promising therapy for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients. We searched PubMed, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), and WANFANG DATA for randomized controlled trials (RCTs), prospective cohort, and retrospective cohort studies that evaluated therapies (hydroxychloroquine, lopinavir/ritonavir-based therapy, and ribavirin-based therapy, etc.) for SARS, MERS, and COVID-19. The primary outcomes were mortality, virological eradication and clinical improvement, and secondary outcomes were improvement of symptoms and chest radiography results, incidence of acute respiratory disease syndrome (ARDS), utilization of mechanical ventilation, and adverse events (AEs). Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random-effects models, and the quality of evidence was appraised using GRADEpro. Eighteen articles (5 RCTs, 2 prospective cohort studies, and 11 retrospective cohort studies) involving 4,941 patients were included. Compared with control treatment, anti-coronary virus interventions significantly reduced mortality (RR 0.65, 95% CI 0.44-0.96; I2 = 81.3%), remarkably ameliorate clinical improvement (RR 1.52, 95% CI 1.05-2.19) and radiographical improvement (RR 1.62, 95% CI 1.11-2.36, I2 = 11.0 %), without manifesting clear effect on virological eradication, incidence of ARDS, intubation, and AEs. Subgroup analyses demonstrated that the combination of ribavirin and corticosteroids remarkably decreased mortality (RR 0.43, 95% CI 0.27-0.68). The lopinavir/ritonavir-based combination showed superior virological eradication and radiographical improvement with reduced rate of ARDS. Likewise, hydroxychloroquine improved radiographical result. For safety, ribavirin could induce more bradycardia, anemia and transaminitis. Meanwhile, hydroxychloroquine could increase AEs rate especially diarrhea. Overall, the quality of evidence on most outcomes were very low. In conclusion, although we could not draw a clear conclusion for the recommendation of potential therapies for COVID-19 considering the very low quality of evidence and wide heterogeneity of interventions and indications, our results may help clinicians to comprehensively understand the advantages and drawbacks of each anti-coronavirus agents on efficacy and safety profiles. Lopinavir/ritonavir combinations might observe better virological eradication capability than other anti-coronavirus agents. Conversely, ribavirin might cause more safety concerns especially bradycardia. Thus, large RCTs objectively assessing the efficacy of antiviral therapies for SARS-CoV-2 infections should be conducted with high priority.

Wiskott-Aldrich syndrome protein may be critical for CD8+ T cell function following MCMV infection.

Wiskott-Aldrich syndrome (WAS) patients are characterized by immunodeficiency and viral infections. T cells derived from WAS patients and WAS protein (WASP)-deficient mice have various defects. However, whether WASP plays a role in immune control of cytomegalovirus (CMV) infection remains unclear. We analyzed the distribution of CD8+ T subsets and the pathological damage to various organs and tissues in MCMV infected Was knockout (KO) mice. A relatively high number of MCMV-specific cytotoxic T cells (CTLs) were observed in the spleen of Was KO mice. In MCMV infected Was KO mice, the late differentiated CD8+ T subset (CD27-CD28-) decreased in lungs, compared with those in the spleen and peripheral blood. Additionally, we found that the most severe pathological lesions occurred in the lungs, the main target organ of MCMV infection. By stimulating the spleen-derived CD8+ T lymphocytes of Was KO mice, we found that IL-2 and granzyme B production declined compared with that in wild- type mice. Moreover, the number of apoptotic CD8+ T cells increased in Was KO mice compared with the number in wild-type mice. Therefore, our results demonstrate that WASP may be involved in regulating cytotoxic function and apoptosis in CD8+ T cells following MCMV infection, which is supported by the distribution and memory compartment of MCMV-specific T cells in MCMV infected WAS mice.

MiR-187-3p mimic alleviates ischemia-reperfusion-induced pain hypersensitivity through inhibiting spinal P2X7R and subsequent mature IL-1ß release in mice.

BACKGROUND: Ischemia-reperfusion (IR)-induced pain hypersensitivity shares features of neuroinflammation and neuropathic pain, accompanied by overproduction of interleukin (IL)-1ß. Multiple microRNAs (miRs) are dysregulated during IR; among these miRs, miR-187-3p was recently reported to drive IL-1ß release in retinal disease by activating members of the purinergic receptor family. However, the roles of miR-187-3p in the spinal cord are unclear. Thus, we investigated whether miR-187-3p is involved in the pathogenesis of IR-induced pain hypersensitivity by regulating the P2X7R signal and subsequent IL-1ß release. METHODS: A mouse model was established by 5-min occlusion of the aortic arch. Pain hypersensitivity was assessed by the paw withdrawal threshold (PWT) and paw withdrawal latency (PWL). MiR-187-3p, P2X7R, cleaved caspase-1 and mature IL-1ß expression levels were measured by RT-PCR and Western blotting. The in vivo roles of miR-187-3p, P2X7R and IL-1ß were explored by intrathecal treatment with synthetic miRs, selective agonists and antagonists in separate experiments. Double immunofluorescence staining was performed to delineate the cellular distribution of P2X7R and IL-1ß. RESULTS: IR-induced progressively decreased PWT and PWL values were closely related to decreases in miR-187-3p and increases in P2X7R expression levels over time. The functional miR-187-3p/P2X7R pair was preliminarily predicted by a bioinformatic database and confirmed in vivo by quantitative analysis, as mimic-187 greatly increased miR-187-3p but decreased P2X7R expression levels, whereas inhibitor-187 reversed these changes. In contrast, downregulating P2X7R by mimic-187 or A-438079 treatment comparably increased PWT and PWL values in IR-injured mice, while upregulating P2X7R by inhibitor-187 or BzATP treatment decreased PWT and PWL values in sham-operated mice. Moreover, P2X7R and IL-1ß immunoreactivities in each group were changed in the same patterns. This finding was further supported by results showing that downregulating IL-1ß by A-438079 and IL-1ß-neutralizing antibody similarly decreased P2X7R, cleaved caspase-1 and mature IL-1ß expression levels, whereas BzATP treatment increased these levels. Expectedly, mimic-187 treatment preserved PWT and PWL values, with decreased cleaved caspase-1 and mature IL-1ß expression levels, whereas inhibitor-187 reversed these effects. CONCLUSIONS: The spinal miR-187-3p/P2X7R pair functioned in a mouse IR model. Increasing miR-187-3p protected against pain hypersensitivity and mature IL-1ß overproduction, partially through inhibiting P2X7R activation.

Inhibiting aberrant p53-PUMA feedback loop activation attenuates ischaemia reperfusion-induced neuroapoptosis and neuroinflammation in rats by downregulating caspase 3 and the NF-κB cytokine pathway.

BACKGROUND: Ischaemia reperfusion (IR) induces multiple pathophysiological changes. In addition to its classical role in regulating tumourigenesis, the feedback loop formed by p53 and its driven target p53-upregulated modulator of apoptosis (PUMA) was recently demonstrated to be the common node tightly controlling various cellular responses during myocardial IR. However, the roles of the p53-PUMA feedback loop in the spinal cord remain unclear. This study aimed to elucidate the roles of p53-PUMA feedback interactions in the spinal cord after IR, specifically investigating their regulation of caspase 3-mediated apoptosis and nuclear factor (NF)-κB-mediated cytokine release. METHODS: SD rats subjected to 12 min of aortic arch occlusion served as IR models. Neurological assessment as well as p53 and PUMA mRNA and protein expression analyses were performed at 12-h intervals during a 48-h reperfusion period. The cellular distributions of p53 and PUMA were determined via double immunofluorescence staining. The effects of the p53-PUMA feedback loop on modulating hind-limb function; the number of TUNEL-positive cells; and protein levels of caspase 3, NF-κB and cytokines interleukin (IL)-1ß and tumour necrosis factor (TNF)-α, were evaluated by intrathecal treatment with PUMA-specific or scramble siRNA and pifithrin (PFT)-α. Blood-spinal cord barrier (BSCB) breakdown was examined by Evans blue (EB) extravasation and water content analyses. RESULTS: IR induced significant behavioural deficits as demonstrated by deceased Tarlov scores, which displayed trends opposite those of PUMA and p53 protein and mRNA expression. Upregulated PUMA and p53 fluorescent labels were widely distributed in neurons, astrocytes and microglia. Injecting si-PUMA and PFT-α exerted significant anti-apoptosis effects as shown by the reduced number of TUNEL-positive cells, nuclear abnormalities and cleaved caspase 3 levels at 48 h post-IR. Additionally, p53 colocalized with NF-κB within the cell. Similarly, injecting si-PUMA and PFT-α exerted anti-inflammatory effects as shown by the decreased NF-κB translocation and release of IL-1ß and TNF-α. Additionally, injecting si-PUMA and PFT-α preserved the BSCB integrity as determined by decreased EB extravasation and spinal water content. However, injecting si-Con did not induce any of the abovementioned effects. CONCLUSIONS: Inhibition of aberrant p53-PUMA feedback loop activation by intrathecal treatment with si-PUMA and PFT-α prevented IR-induced neuroapoptosis, inflammatory responses and BSCB breakdown by inactivating caspase 3-mediated apoptosis and NF-κB-mediated cytokine release.

MicroRNA-125b mimic inhibits ischemia reperfusion-induced neuroinflammation and aberrant p53 apoptotic signalling activation through targeting TP53INP1.

BACKGROUND: Ischemia reperfusion (IR) injury affects neuronal function through multiple pathogeneses that induce neuroinflammation and cellular apoptosis. The important roles of microRNAs (miRs) in the regulation of spinal cord IR have been recently reported. Among these roles, we investigated whether miR-125b and its downstream targets regulated the p53 signalling network and participated in both inflammation and apoptosis. METHODS: An IR model was established via 12-min occlusion of the aortic arch. The direct interaction between miR-125b and TP53INP1 was demonstrated by Western blotting and luciferase assays. The cellular distributions of TP53INP1 were visualised by double immunofluorescence labelling. The effects of miR-125b on the expression of TP53INP1, p53 and release of proinflammatory cytokines were evaluated by synthetic miRs. Additionally, the detection of hind-limb motor function in vivo and motor neuronal apoptosis in vitro were evaluated to explore the potential mechanisms. RESULTS: IR-induced alterations in hind-limb motor function were closely related to the temporal changes in miR-125b and TP53INP1 expression. The miR-125b/TP53INP1 gene pair was confirmed by luciferase assay. Compared with Sham controls, IR treatment resulted in increased TP53INP1 immunoreactivity that was primarily distributed in neurons. Treatment with miR-125b mimic markedly decreased the protein levels of TP53INP1, p53 and cytokines interleukin (IL)-1ß and tumour necrosis factor (TNF)-α, whereas miR-125b control or inhibitor did not have the above-mentioned effects. Moreover, miR-125b mimic improved motor function in vivo and attenuated neuronal apoptosis in vitro, as demonstrated by the increased average Tarlov scores in lower limbs and lower percentages of neurons in the A4 and A2 quadrants of flow cytometry. Fluorescent staining and quantification further indicated that miR-125b mimic decreased the immunoreactivities of p53 and cleaved caspase 3 in neurons and simultaneously reduced the number of double-labelled cells with TP53INP1. CONCLUSIONS: miR-125b mimic partially protected neurons against neuroinflammation and aberrant p53 network activation-induced apoptosis during IR injury through downregulation of TP53INP1.

Elevated microRNA-129-5p level ameliorates neuroinflammation and blood-spinal cord barrier damage after ischemia-reperfusion by inhibiting HMGB1 and the TLR3-cytokine pathway.

BACKGROUND: Ischemia-reperfusion (IR) affects microRNA (miR) expression and causes substantial inflammation. Multiple roles of the tumor suppressor miR-129-5p in cerebral IR have recently been reported, but its functions in the spinal cord are unclear. Here, we investigated the role of miR-129-5p after spinal cord IR, particularly in regulating high-mobility group box-1 (HMGB1) and the Toll-like receptor (TLR)-3 pathway. METHODS: Ischemia was induced via 5-min occlusion of the aortic arch. The relationship between miR-129-5p and HMGB1 was elucidated via RT-PCR, western blotting, and luciferase assays. The cellular distribution of HMGB1 was determined via double immunofluorescence. The effect of miR-129-5p on the expression of HMGB1, TLR3, and downstream cytokines was evaluated using synthetic miRs, rHMGB1, and the TLR3 agonist Poly(I:C). Blood-spinal cord barrier (BSCB) permeability was examined by measuring Evans blue (EB) dye extravasation and the water content. RESULTS: The temporal miR-129-5p and HMGB1 expression profiles and luciferase assay results indicated that miR-129-5p targeted HMGB1. Compared with the Sham group, the IR group had higher HMGB1 immunoreactivity, which was primarily distributed in neurons and microglia. Intrathecal injection of the miR-129-5p mimic significantly decreased the HMGB1, TLR3, interleukin (IL)-1ß and tumor necrosis factor (TNF)-α levels and the double-labeled cell count 48 h post-surgery, whereas rHMGB1 and Poly(I:C) reversed these effects. Injection of miR-129-5p mimic preserved motor function and prevented BSCB leakage based on increased Basso Mouse Scale scores and decreased EB extravasation and water content, whereas injection rHMGB1 and Poly(I:C) aggravated these injuries. CONCLUSIONS: Increasing miR-129-5p levels protect against IR by ameliorating inflammation-induced neuronal and BCSB damage by inhibiting HMGB1 and TLR3-associated cytokines.

miR-320a affects spinal cord edema through negatively regulating aquaporin-1 of blood-spinal cord barrier during bimodal stage after ischemia reperfusion injury in rats.

BACKGROUND: Spinal cord edema is a serious complication and pathophysiological change after ischemia reperfusion (IR) injury. It has been demonstrated closely associated with bimodal disruption of blood-spinal cord barrier (BSCB) in our previous work. Aquaporin (AQP)1 plays important but contradictory roles in water homeostasis. Recently, microRNAs (miRs) effectively regulate numerous target mRNAs during ischemia. However, whether miRs are able to protect against dimodal disruption of BSCB by regulating perivascular AQP1 remains to be elucidated. RESULTS: Spinal water content and EB extravasation were suggested as a bimodal distribution in directly proportion to AQP1, since all maximal changes were detected at 12 and 48 h after reperfusion. Further TEM and double immunofluorescence showed that former disruption of BSCB at 12 h was attributed to cytotoxic edema by up-regulated AQP1 expressions in astrocytes, whereas the latter at 48 h was mixed with vasogenic edema with both endothelial cells and astrocytes involvement. Microarray analysis revealed that at 12 h post-injury, ten miRs were upregulated (>2.0 fold) and seven miRs were downregulated (<0.5 fold) and at 48 h, ten miRs were upregulated and eleven were downregulated compared to Sham-operated controls. Genomic screening and luciferase assays identified that miR-320a was a potential modulator of AQP1 in spinal cord after IR in vitro. In vivo, compared to rats in IR and negative control group, intrathecal infusion of miR-320a mimic attenuated IR-induced lower limb motor function deficits and BSCB dysfunction as decreased EB extravasation and spinal water content through down-regulating AQP1 expressions, whereas pretreated with miR-320a AMO reversed above effects. CONCLUSION: These findings indicate miR-320a directly and functionally affects spinal cord edema through negatively regulating AQP1 of BSCB after IR.

Elevated microRNA-214-3p level ameliorates neuroinflammation after spinal cord ischemia-reperfusion injury by inhibiting Nmb/Cav3.2 pathway.

BACKGROUND: Neuromedin B (Nmb) plays a pivotal role in the transmission of neuroinflammation, particularly during spinal cord ischemia-reperfusion injury (SCII). However, the detailed molecular mechanisms underlying this process remain elusive. METHODS: The SCII model was established by clamping the abdominal aorta of male Sprague-Dawley (SD) rats for 60 min. The protein expression levels of Nmb, Cav3.2, and IL-1ß were detected by Western blotting, while miR-214-3p expression was quantified by qRT-PCR. The targeted regulation between miR-214-3p and Nmb was investigated using a dual-luciferase reporter gene assay. The cellular localization of Nmb and Cav3.2 with cell-specific markers was visualized by immunofluorescence staining. The specific roles of miR-214-3p on the Nmb/Cav3.2 interactions in SCII-injured rats were explored by intrathecal injection of Cav3.2-siRNA, PD168368 (a specific NmbR inhibitor) and synthetic miR-214-3p agomir and antagomir in separate experiments. Additionally, hind-limb motor function was evaluated using the modified Tarlov scores. RESULTS: Compared to the Sham group, the protein expression levels of Nmb, Cav3.2, and the proinflammatory factor Interleukin(IL)-1ß were significantly elevated at 24 h post-SCII. Intrathecal injection of PD168368 and Cav3.2-siRNA significantly suppressed the expression of Cav3.2 and IL-1ß compared to the SCII group. The miRDB database and dual-luciferase reporter gene assay identified Nmb as a direct target of miR-214-3p. As expected, in vivo overexpression of miR-214-3p by agomir-214-3p pretreatment significantly inhibited the increases in Nmb, Cav3.2 and IL-1ß expression and improved lower limb motor function in SCII-injured rats, while antagomiR-214-3p pretreatment reversed these effects. CONCLUSIONS: Nmb protein levels positively correlated with Cav3.2 expression in SCII rats. Upregulating miR-214-3p ameliorated hind-limb motor function and protected against neuroinflammation via inhibiting the aberrant Nmb/Cav3.2 interactions and downstream IL-1ß release. These findings provide novel therapeutic targets for clinical prevention and treatment of SCII.

A graphene-based electrochemical sensor for rapid determination of phenols in water.

A glassy carbon electrode (GCE) coated with a graphene/polymer film was fabricated for rapid determination of phenols in aqueous solutions. The electrochemical behavior of different phenols at the graphene/polymer-coated GCE was also investigated. In PBS buffer solution with a pH of 6.5, hydroquinone exhibits a well-defined reduction peak at the modified GCE. Based on this, an electrochemical method for the direct determination of phenols is proposed. Investigating different parameters revealed the optimized detection conditions for the electrode are a scan rate of 50 mV/s, dosage of graphene-polyaniline of 8 µL, dosage of tyrosinase of 3 µL, and pH of 6.5. Under the optimal conditions, the reduction peak current varies linearly with the concentration of phenols, with a linear regression equation of I (10(-6)A) = -4.887 × 10(-4)C (mol/L)-5.331 × 10(-6) with a correlation coefficient of 0.9963 and limit of detection (S/N = 3) of 2.00 × 10(-4) mol/L. The electrochemical sensor is also used to detect phenols in actual samples, where it shows great promise for rapid, simple and quantitative detection of phenols.

Fra-1 induces apoptosis and neuroinflammation by targeting S100A8 to modulate TLR4 pathways in spinal cord ischemia/reperfusion injury.

Spinal cord ischemia/reperfusion injury (SCII) is a severe complication driven by apoptosis and neuroinflammation. An increase in the expression of c-Fos, a member of the AP-1 family, is known as a neuronal activation marker in SCII. The AP-1 family is composed of Jun, Fos, and is associated with the regulation of cytokines expression and apoptosis. Fra-1 is a member of the Fos family, however, the contribution of Fra-1 to SCII is still unclear. In our study, Fra-1 was highly upregulated especially in neurons and microglia and promoted apoptosis by changing the expression of Bax/Bcl-2 after SCII. Furthermore, we found that Fra-1 directly regulated the transcription expression of S100A8. We demonstrated that knockdown of Fra-1 alleviated S100A8 mediated neuronal apoptosis and inflammatory factor release, thus improved motor function after SCII. Interestingly, we showed that administration of TAK-242, the TLR4 inhibitor, to the ischemia/reperfusion (I/R) injury induced rats suppressed the activation of the ERK and NF-κB pathways, and further reduced Fra-1 expression. In conclusion, we found that Fra-1-targeted S100A8 was expressed the upstream of Fra-1, and the Fra-1/S100A8 interaction formed a feedback loop in the signaling pathways activated by SCII.

MicroRNA-101a-3p mimic ameliorates spinal cord ischemia/reperfusion injury.

miR-101a-3p is expressed in a variety of organs and tissues and plays a regulatory role in many diseases, but its role in spinal cord ischemia/reperfusion injury remains unclear. In this study, we established a rat model of spinal cord ischemia/reperfusion injury by clamping the aortic arch for 14 minutes followed by reperfusion for 24 hours. Results showed that miR-101a-3p expression in L4-L6 spinal cord was greatly decreased, whereas MYCN expression was greatly increased. Dual-luciferase reporter assay results showed that miR-101a-3p targeted MYCN. MYCN immunoreactivity, which was primarily colocalized with neurons in L4-L6 spinal tissue, greatly increased after spinal cord ischemia/reperfusion injury. However, intrathecal injection of an miR-101a-3p mimic within 24 hours before injury decreased MYCN, p53, caspase-9 and interleukin-1ß expression, reduced p53 immunoreactivity, reduced the number of MYCN/NeuN-positive cells and the number of necrotic cells in L4-L6 spinal tissue, and increased Tarlov scores. These findings suggest that the miR-101a-3p mimic improved spinal ischemia/reperfusion injury-induced nerve cell apoptosis and inflammation by inhibiting MYCN and the p53 signaling pathway. Therefore, miR-101a-3p mimic therapy may be a potential treatment option for spinal ischemia/reperfusion injury.

The roles of microRNAs in spinal cord ischemia-reperfusion injury.

Spinal cord ischemia/reperfusion injury is a devastating medical disorder with poor prognosis that is associated with several pathophysiological conditions. However, multiple stimuli can trigger SCII, so the underlying mechanism of this pathology has not yet been fully established. MicroRNAs (miRNAs) are a class of non-coding RNAs that mediate a variety of nervous system diseases and regulate numerous physiological functions, including apoptosis, autophagy, inflammation, and blood-spinal cord barrier damage. miRNA expression profiles are known to be altered after spinal cord ischemia/reperfusion injury. Therefore, gaining a better understanding of the significant roles that miRNAs play in spinal cord ischemia/reperfusion injury could help develop potential preventive and therapeutic strategies for spinal cord ischemia/reperfusion injury. This review summarizes the current state of our knowledge about the relationship between miRNAs and spinal cord ischemia/reperfusion injury, as well as potential miRNAs that could be targeted to treat spinal cord ischemia/reperfusion injury.

Antimicrobial Stewardship in Surgery: A Literature Bibliometric Analysis.

Background: Antimicrobial resistance and the dwindling antibiotic development pipeline have resulted in a looming post-antibiotic era. Research related to antimicrobial stewardship (AMS) has grown rapidly in the past decade, especially in the field of surgery. We conducted a bibliometric analysis of these publications. In addition, we aimed to identify research hotspots and infer future research trends. Methods: We screened global publications on AMS in the surgical field over ten years (between 2011 and 2020) from the Web of Science core collection database. The keywords "antimicrobial or antibiotic", "stewardship", "management", "management strategies", "programme", "surgery" and "surgical" were used to search for related papers. VOS viewer, R software, and other machine learning and visualization tools were used to conduct the bibliometric analysis of the publications. Results: We identified 674 publications on AMS in surgical fields; "antimicrobial stewardship" (with total link strength of 1,096) was the most frequent keyword, and had strong links to "antimicrobial resistance" and "guidelines". The top 100 most cited papers had a mean citation count of 47.21 (range: 17-1155) citations, which were cited by survey research studies, clinical trials, and observational studies. The highest-ranking and most cited journal was Clinical Infectious Diseases with eight publications. Jason G. Newland from Washington University wrote seven papers and was cited 1,282 times. The University of Washington published 17 papers and was cited 1,258 times, with the largest number of publications by author and organization. The USA published 198 papers and cooperated with 21 countries, mainly partnering with Italy, the UK, and Canada. Published articles mainly focused on the current clinical situation regarding surgical AMS management, antibiotic prescription, and antibiotic resistance. Conclusions: Publications on surgical AMS management have increased in recent decades, with the USA being the most prolific. Epidemiological investigations of surgical-related infections, antibiotic prescriptions, and antibiotic resistance are fast-developing research trends. However, further improvements are still needed according to the recommendations gained from the bibliometric analysis.

Global trends and hotspots in research of carbapenem-resistant Enterobacteriaceae (CRE): a bibliometric analysis from 2010 to 2020.

BACKGROUND: Infectious disease caused by carbapenem-resistant Enterobacteriaceae (CRE) has become one of the most serious challenges due to its high morbidity and mortality and research on it has aroused great concern worldwide in the last decade. Thus, a bibliometric analysis of relevant publications is needed to identify the situation of current investigations and prioritize the future research areas. METHODS: The current study retrieved articles related to CRE published between 2010 and 2020 from the Web of Science core collection database. The search strategy syntax included "carbapenem-resistant Enterobacteriaceae", "carbapenem-resistant Klebsiella pneumoniae", "carbapenemase producing Enterobacteriaceae" and "carbapenemase producing Klebsiella pneumoniae" which were searched in both Medical Subject Headings (MeSH) and titles. A bibliometric analysis was conducted using VOSviewer, Bibliographic Item Co-Occurrence Matrix Builder, gCLUTO and other machine learning tools. Key words, subject terms, contributions as well as collaborations were assessed. Moreover, hot off the press and future research trends were demonstrated. RESULTS: A total of 1,671 publications on CRE were finally included in the bibliometric analysis and 5 related theme clusters were identified which mainly focused on epidemiology, resistance mechanisms, antibiotics treatment and infection control. A total of 142 keywords occurred more than 5 times and the most frequent keyword was "carbapenem-resistant Enterobacteriaceae" with 247 occurrences and a total link strength of 559. The output on CRE has gradually increased during the last decade, and the USA has made the greatest contribution due to the 533 research papers. Agents that act against CRE, especially ceftazidime-avibactam (occurrences, 85; average publication year, 2018.26), and the early detection of CRE by genome sequencing techniques (occurrences, 97; average publication year, 2017.94) were emerging hot topics which would probably attract future research interest. CONCLUSIONS: The bibliometric analysis revealed that development of antibacterial agents, early etiological detection and genome sequencing techniques were the hotspots and would probably direct the future research directions which would also facilitate a better understanding of the epidemiology of drug-resistant bacteria and implementing the antibiotic stewardship program.

Efficacy and safety of tigecycline for complicated urinary tract infection: a systematic review.

BACKGROUND: Facing the global threat of emerging resistance to antibiotics, tigecycline, a novel glycylcycline antibiotic, is developed to against multidrug-resistant pathogens, but not recommended for the treatment of complicated urinary tract infection (cUTI). We performed a summary of the literatures to characterize and evaluate the efficacy and safety of tigecycline in patients with cUTI. METHODS: We searched PubMed, EMBASE, Cochrane and Clinical Trials using appropriate syntax to retrieve potential articles up to Jan 2020. General information, pathogen, medication regimen, comorbidities of patients from eligible literatures were recorded. Univariate logistic regression analysis was used to detect the potential factors associated with clinical cure. RESULTS: Nineteen articles comprising 31 cases were included. The subpopulation with transplantation (25.8% of the patients) was the most common comorbidity, and cUTIs were mainly caused by Klebsiella pneumoniae (K. pneumoniae) (48.28%) in our research. Tigecycline 100 mg per day as monotherapy was most common. Clinical cure was reported as majority (77.4%), and microbiological eradication cases accounted for the most (65.2%) among the clinical cure cases. Univariate analysis showed that K. pneumoniae caused cUTI and tigecycline as a single treatment have significant meaning to clinical outcomes (P=0.044 and P=0.034, respectively). CONCLUSIONS: Clinical and microbiological outcomes of tigecycline treatment revealed high rate of successful response. Tigecycline monotherapy may have a role in the treatment of cUTI except that caused by the pathogen K. pneumoniae. Further randomized controlled trials was still needed to evaluate tigecycline monotherapy for cUTI.

MiR-126-3p-Enriched Extracellular Vesicles from Hypoxia-Preconditioned VSC 4.1 Neurons Attenuate Ischaemia-Reperfusion-Induced Pain Hypersensitivity by Regulating the PIK3R2-Mediated Pathway.

Recent evidence suggests that hypoxia preconditioning can alter the microRNA (miRNA) profile of extracellular vesicles (EVs) and has better neuroprotective effects when enriched miRs are delivered to recipients. However, the roles of exosomal miRNAs in regulating ischaemia-reperfusion (IR)-induced pain hypersensitivity are largely unknown. Thus, we isolated EVs from normoxia-conditioned neurons (Nor-VSC EVs) and Hypo-VSC EVs by ultracentrifugation. After the initial screening by a microarray analysis and quantitative RT-PCR (qRT-PCR), miR-126-3p, which was detected as the most altered miR in the Hypo-VSC EVs, was further confirmed by applying GW4869 to inhibit exosomal secretion. Moreover, transfection with a miR-126 mimic obviously increased miR-126-3p expression in Nor-VSC EVs, whereas a miR-126 inhibitor prevented the increase in miR-126-3p in Hypo-VSC EVs. A rat model of pain was established by performing 8-min occlusion of the aorta. Following IR, compared with the Nor-VSC EVs- or antagomir-126-injected rats, the Hypo-VSC EVs-injected rats displayed improved pain hypersensitivity demonstrated as higher PWT and PWL values. Mechanistically, PIK3R2 is a target of miR-126-3p and might be a modulator of the phosphoinositide 3-kinase (PI3K)/Akt pathway as the PIK3R2 and PI3K immunoreactivities in each group were changed in opposite directions. Compared with the controls, higher protein levels of PI3K and phosphorylated Akt but lower levels of phosphorylated nuclear factor-κ B (NF-κB), tumour necrosis factor (TNF)-α and interleukin (IL)-1ß were detected in the spinal cords of the Hypo-VSC EVs-injected rats, and these effects were impaired by an injection of Hypo-VSC EVs combined with antagomir-126. Collectively, the miR-126-3p-enriched Hypo-VSC EVs attenuated IR-induced pain hypersensitivity by restoring miR-126-3p expression in the injured spinal cord and subsequently modulating PIK3R2-mediated PI3K/Akt and NF-κB signalling pathways.

Reduction in antimicrobial use associated with a multifaceted antimicrobial stewardship programme in a tertiary teaching hospital in Shanghai: a segmented regression analysis.

BACKGROUND: Rational use of antibiotics received great attention in China, therefore the multifaceted antimicrobial stewardship (MAMS) is urgently required in hospital management. We conducted this study to assess the impact of a MAMS programme on antimicrobial use in a tertiary teaching hospital in Shanghai. METHODS: This retrospective observational study was conducted at a tertiary teaching hospital in Shanghai. The MAMS programme involved multifaceted interventions consisting of a quality premium with financial incentives, antibiotic restriction, audit and feedback, and education. Data were extracted from the electronic medical records of inpatients to analyse monthly and annual antibiotic consumption and the percentage of antibiotic prescriptions during 2017-2020. Segmented regression analysis of the interrupted time series was used to contrast antimicrobial use during 2019-2020, with non-MAMS data from the 2017-2018 period as the historical control. RESULTS: With MAMS implementation, antibiotic consumption decreased from 63.3 (59.3, 67.2) defined daily doses (DDDs) per 100 patient-days (PD) to 43.3 (39.0, 49.8) DDDs/100 PD (P<0.001), and the percentage of antibiotic prescriptions decreased from 44.8% (44.1%, 45.4%) to 43.3% (42.2%, 44.3%) (P<0.001). Segmented regression models suggested a reduction in antibiotic consumption (coefficient = -12.537, P<0.001) and indicated a downward trend in the percentage of antibiotic prescriptions (coefficient =-0.165, P=0.049). Neither antibiotic consumption nor the percentage of antibiotic prescriptions was influenced by the coronavirus disease 2019 (COVID-19) pandemic. CONCLUSIONS: This study suggests that MAMS plays an important role in reducing antibiotic use and is not affected by special circumstances such as the COVID-19 pandemic. This novel intervention, consisting of a quality premium and multidisciplinary cooperation, should be prioritized by policy and decision makers, where rational management of antimicrobial use is urgently needed.