Effect of tocilizumab plus corticosteroid on clinical outcome in patients hospitalized with severe fever with thrombocytopenia syndrome: A randomized clinical trial.

BACKGROUND: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging viral hemorrhagic fever with high fatality rates. The blockade of pro-inflammatory cytokines presents a promising therapeutic strategy. METHODS: We conducted a randomized clinical trial at the 154th hospital, Xinyang, Henan Province. Eligible patients with severe SFTS disease were randomly assigned in a 1:2 ratio to receive either a single intravenous infusion of tocilizumab plus usual care; or usual care only. The primary outcome was the clinical status of death/survival at day 14, while secondary outcomes included improvement from baseline in liver and kidney damage and time required for hospital discharge. The efficacy of tocilizumab plus corticosteroid was compared to those receiving corticosteroid alone. The trial is registered with the Chinese Clinical Trial Registry website (ChiCTR2300076317). RESULTS: 63 eligible patients were assigned to the tocilizumab group and 126 to the control group. The addition of tocilizumab to usual care was associated with a reduced death rate (9.5%) compared to those received only usual care (23.0%), with an adjusted hazard ratio (aHR) of 0.37 (95% confidence interval [CI], 0.15 to 0.91, P = 0.029). Combination therapy of tocilizumab and corticosteroids was associated with a significantly reduced fatality (aHR, 0.21; 95% CI, 0.08 to 0.56; P = 0.002) compared to those receiving corticosteroids alone. CONCLUSIONS: A significant benefit of reducing fatality in severe SFTS patients was observed by using tocilizumab. A combined therapy of tocilizumab plus corticosteroids was recommended for the therapy of severe SFTS.

IFITM3 inhibits severe fever with thrombocytopenia syndrome virus entry and interacts with viral Gc protein.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever disease with high fatality rate of 10%-20%. Vaccines or specific therapeutic measures remain lacking. Human interferon inducible transmembrane protein 3 (hIFITM3) is a broad-spectrum antiviral factor targeting viral entry. However, the antiviral activity of hIFITM3 against SFTS virus (SFTSV) and the functional mechanism of IFITM3 remains unclear. Here we demonstrate that endogenous IFITM3 provides protection against SFTSV infection and participates in the anti-SFTSV effect of type Ⅰ and Ⅲ interferons (IFNs). IFITM3 overexpression exhibits anti-SFTSV function by blocking Gn/Gc-mediated viral entry and fusion. Further studies showed that IFITM3 binds SFTSV Gc directly and its intramembrane domain (IMD) is responsible for this interaction and restriction of SFTSV entry. Mutation of two neighboring cysteines on IMD weakens IFITM3-Gc interaction and attenuates the antiviral activity of IFITM3, suggesting that IFITM3-Gc interaction may partly mediate the inhibition of SFTSV entry. Overall, our data demonstrate for the first time that hIFITM3 plays a critical role in the IFNs-mediated anti-SFTSV response, and uncover a novel mechanism of IFITM3 restriction of SFTSV infection, highlighting the potential of clinical intervention on SFTS disease.

Fabrication of levofloxacin-loaded porcine acellular dermal matrix hydrogel and functional assessment in urinary tract infection.

Bacterial cystitis, a commonly occurring urinary tract infection (UTI), is renowned for its extensive prevalence and tendency to recur. Despite the extensive utilization of levofloxacin as a conventional therapeutic approach for bacterial cystitis, its effectiveness is impeded by adverse toxic effects, drug resistance concerns, and its influence on the gut microbiota. This study introduces Lev@PADM, a hydrogel with antibacterial properties that demonstrates efficacy in the treatment of bacterial cystitis. Lev@PADM is produced by combining levofloxacin with decellularized porcine acellular dermal matrix hydrogel and exhibits remarkable biocompatibility. Lev@PADM demonstrates excellent stability as a hydrogel at body temperature, enabling direct administration to the site of infection through intravesical injection. This localized delivery route circumvents the systemic circulation of levofloxacin, resulting in a swift and substantial elevation of the antimicrobial agent's concentration specifically at the site of infection. The in vivo experimental findings provide evidence that Lev@PADM effectively prolongs the duration of levofloxacin's action, impedes the retention and invasion of E.coli in the urinary tract, diminishes the infiltration of innate immune cells into infected tissues, and simultaneously preserves the composition of the intestinal microbiota. These results indicate that, in comparison to the exclusive administration of levofloxacin, Lev@PADM offers notable benefits in terms of preserving the integrity of the bladder epithelial barrier and suppressing the recurrence of urinary tract infections.

Metagenomic next-generation sequencing of plasma cell-free DNA improves the early diagnosis of suspected infections.

BACKGROUND: Metagenomic next-generation sequencing (mNGS) could improve the diagnosed efficiency of pathogens in bloodstream infections or sepsis. Little is known about the clinical impact of mNGS test when used for the early diagnosis of suspected infections. Herein, our main objective was to assess the clinical efficacy of utilizing blood samples to perform mNGS for early diagnosis of suspected infections, as well as to evaluate its potential in guiding antimicrobial therapy decisions. METHODS: In this study, 212 adult hospitalized patients who underwent blood mNGS test in the early stage of suspected infections were enrolled. Diagnostic efficacy of mNGS test and blood culture was compared, and the clinical impact of mNGS on clinical care was analyzed. RESULTS: In our study, the total detection rate of blood mNGS was significantly higher than that of culture method (74.4% vs. 12.1%, P < 0.001) in the paired mNGS test and blood culture. Blood stream infection (107, 67.3%) comprised the largest component of all the diseases in our patients, and the detection rate of single blood sample subgroup was similar with that of multiple type of samples subgroup. Among the 187 patients complained with fever, there was no difference in the diagnostic efficacy of mNGS when blood specimens or additional other specimens were used in cases presenting only with fever. While, when patients had other symptoms except fever, the performance of mNGS was superior in cases with specimens of suspected infected sites and blood collected at the same time. Guided by mNGS results, therapeutic regimens for 70.3% cases (149/212) were changed, and the average hospitalized days were significantly shortened in cases with the earlier sampling time of admission. CONCLUSION: In this study, we emphasized the importance of blood mNGS in early infectious patients with mild and non-specific symptoms. Blood mNGS can be used as a supplement to conventional laboratory examination, and should be performed as soon as possible to guide clinicians to perform appropriate anti-infection treatment timely and effectively. Additionally, combining the contemporaneous samples from suspected infection sites could improve disease diagnosis and prognoses. Further research needs to be better validated in large-scale clinical trials to optimize diagnostic protocol, and the cost-utility analysis should be performed.

Exploring the impact of sustainable marketing on consumer behavior in the sports industry.

The general consensus is that climate change poses a significant danger. Scientists and policymakers are increasingly acknowledging that consumer behavior plays a crucial role in this matter. Specifically, the choices people make regarding what they consume, how they consume it, and the quantities they consume have a direct impact on the environment. In this context, this study aims to examine the effects of sustainable marketing strategies and environmental consciousness on consumer behavior. The research collected data from 532 respondents by administering an online questionnaire. The partial least square structural equation modeling (PLS-SEM) using the SmartPLS 4 was used to test the hypotheses, and the findings revealed that sustainable marketing strategies positively influence consumer behavior and environmental consciousness levels of consumers. In addition, environmental consciousness positively mediated the relationship between sustainable marketing strategies and consumer behavior. The study also found that environmental knowledge moderates the relationship between sustainable marketing strategies and environmental consciousness. The theoretical implications of the research suggest that sustainable marketing strategies can be effective in shaping consumer behavior and promoting environmental consciousness. The managerial implications propose that manufacturing firms in the sports industry can benefit from implementing sustainable marketing strategies and promoting environmental consciousness among their consumers.

The Prognosis of Patients Tested Positive for Stenotrophomonas maltophilia from Different Sources.

Purpose: The purpose of this study was to analyze the prognosis of patients tested positive for Stenotrophomonas maltophilia (SMA) from different sources. Methods: A retrospective study was conducted among 651 patients tested positive for SMA from January 2020 to October 2022 in the First Affiliated Hospital of Anhui Medical University. The patients were divided into seven groups by the source of SMA. Univariate and multivariate analyses were used to identify risk factors for mortality in patients tested positive for SMA from different sources. Results: A total of 651 SMA isolates were collected from various sources, including sputum (348 isolates, 53%), bronchoalveolar lavage fluid (52, 8%), abdominal drainage fluid (76, 12%), wound secretion (66, 10%), blood (62, 10%), urine (41, 6%) and cerebrospinal fluid (6, 1%). Compared with other groups, the mortality of the patients in the bronchoalveolar lavage fluid culture group, blood culture group, and abdominal drainage fluid culture group was higher, at 40.38%, 32.26%, and 26.32%, respectively. Multivariate analysis showed that continuous renal replacement therapy was an independent risk factor for mortality in patients with SMA bloodstream infection (P=0.020, OR=6.86), and effective antimicrobial therapy after being positive for S. maltophilia isolates (P=0.002, OR=0.10) was negatively correlated with the death of patients with SMA bloodstream infection. Age ≥65 years (P= 0.043, OR=4.96), kidney disease (P=0.045, OR=4.62) and antifungal agent exposure (P=0.036, OR=5.13) were independent risk factors for mortality in patients with SMA intra-abdominal infection. Antifungal agent exposure (P=0.024, OR=0.51) and glycopeptide exposure (P=0.045, OR=0.53) were independent risk factors for mortality in patients in the sputum culture group. Conclusion: SMA has a high rate of antimicrobial resistance and can cause multisite infection. Pulmonary infections, bloodstream infections and abdominal infections caused by SMA have high mortality, and timely standardized treatment can reduce mortality.

High-Flux Nanofibrous Composite Reverse Osmosis Membrane Containing Interfacial Water Channels for Desalination.

A nanofibrous composite reverse osmosis (RO) membrane with a polyamide barrier layer containing interfacial water channels was fabricated on an electrospun nanofibrous substrate via an interfacial polymerization process. The RO membrane was employed for desalination of brackish water and exhibited enhanced permeation flux as well as rejection ratio. Nanocellulose was prepared by sequential oxidations of 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and sodium periodate systems and surface grafting with different alkyl groups including octyl, decanyl, dodecanyl, tetradecanyl, cetyl, and octadecanyl groups. The chemical structure of the modified nanocellulose was verified subsequently by Fourier transform infrared (FTIR), thermal gravimetric analysis (TGA), and solid NMR measurements. Two monomers, trimesoyl chloride (TMC) and m-phenylenediamine (MPD), were employed to prepare a cross-linked polyamide matrix, i.e., the barrier layer of the RO membrane, which integrated with the alkyl groups-grafted nanocellulose to build up interfacial water channels via interfacial polymerization. The top and cross-sectional morphologies of the composite barrier layer were observed by means of scanning electron microscopy (SEM), atomic force microscopy (AFM), and transmission electron microscopy (TEM) to verify the integration structure of the nanofibrous composite containing water channels. The aggregation and distribution of water molecules in the nanofibrous composite RO membrane verified the existence of water channels, demonstrated by molecular dynamics (MD) simulations. The desalination performance of the nanofibrous composite RO membrane was conducted and compared with that of commercially available RO membranes in the processing of brackish water, where 3 times higher permeation flux and 99.1% rejection ratio against NaCl were accomplished. This indicated that the engineering of interfacial water channels in the barrier layer could substantially increase the permeation flux of the nanofibrous composite membrane while retaining the high rejection ratio as well, i.e., to break through the trade-off between permeation flux and rejection ratio. Antifouling properties, chlorine resistance, and long-term desalination performance were also demonstrated to evaluate the potential applications of the nanofibrous composite RO membrane; remarkable durability and robustness were achieved in addition to 3 times higher permeation flux and a higher rejection ratio against commercial RO membranes in brackish water desalination.

The Analysis of Drug-Resistant Bacteria from Different Regions of Anhui in 2021.

Purpose: To analyze the differences in clinical distribution and antimicrobial resistance of pathogens among northern Anhui, central Anhui, and southern Anhui in 2021, and to provide a basis for the rational use of drugs for clinicians in different regions. Methods: Nonrepetitive pathogens isolated from clinical samples of inpatients and outpatients from 59 member units with qualified data in 2021 were obtained from the Anhui Province Antimicrobial Resistance Surveillance System, which was divided into northern Anhui, central Anhui, and southern Anhui by region. Identification and antimicrobial susceptibility analyses were carried out using the Vitek 2 Compact and standard disc diffusion method. The results were determined according to the American Clinical Laboratory Standards Institute in 2021 with data analyzed using WHONET 5.6 and SPSS 17.0. Results: A total of 133,268 pathogenic bacteria were isolated from clinical samples. Staphylococcus aureus (S. aureus) was the most common gram-positive bacterium and Escherichia coli (E. coli) was the most common gram-negative bacterium. Sputum was the main source of clinical specimens. The detection rates of methicillin-resistant S.aureus, methicillin-resistant coagulase-negative Staphylococcus, carbapenem-resistant E. coli, carbapenem-resistant Klebsiella pneumoniae (K. pneumoniae), carbapenem-resistant Acinetobacter baumannii, third-generation cephalosporin-resistant E. coli, and third-generation cephalosporin-resistant K. pneumoniae were higher in northern Anhui than in southern Anhui (P<0.0001). E. coli, K. pneumoniae, and Pseudomonas aeruginosa were sensitive to amikacin. Strains resistant to vancomycin, linezolid, and teicoplanin were not isolated until 2021. Conclusion: There were significant differences in bacterial resistance in different regions of Anhui Province. Antibiotic resistance in northern Anhui was the most serious in 2021. Antimicrobial agents must be used according to the resistance of the bacteria in the local region.

NLR, A Convenient Early-Warning Biomarker of Fatal Outcome in Patients With Severe Fever With Thrombocytopenia Syndrome.

Background: Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease that greatly threatens public health. This study aimed to examine a convenient early-warning biomarker of fatal outcomes in patients with SFTS to reduce mortality. Methods: A retrospective cohort study was performed, and patients with confirmed SFTS were enrolled in the top two hospitals in Anhui Province, China from 1 May 2016 to 31 October 2019. The clinical symptoms, laboratory indicators, and treatment data of patients with SFTS were evaluated. All patients with SFTS were followed up till 28 days from the start of admission. The laboratory indicators that could be used to predict the fatal outcome were identified. Results: A total of 228 patients with SFTS were enrolled, 177 patients were enrolled in the survival group, and 51 patients in the death group. The median age of all 228 patients with SFTS was 63 years. Five laboratory indicators (SFTSV viral load, neutrophil to lymphocyte ratio (NLR), aspartate transaminase (AST)/alanine aminotransferase (ALT), ALT, and blood urea nitrogen (BUN)) were identified as the predicting factors of the fatal outcome of patients with SFTS. The area under the receiver operating characteristic (ROC) curve (AUC) of SFTSV viral load was the highest (0.919), then NLR (0.849), followed by AST/ALT (0.758), AST (0.738), and BUN (0.709). The efficacy of SFTVS viral load and NLR in predicting fatal outcomes was significantly higher than AST/ALT, AST, and BUN. The Kaplan-Meier survival curves show that the case fatality rate was significantly increased in patients whose SFTSV viral load was higher than 500,000 or NLR higher than 2.0. Gamma-globulin treatment showed a significant difference between the survival group and the death group, and the duration of gamma-globulin that had been proposed should not be <3 days. Conclusion: The SFTSV viral load and NLR showed great efficacy in predicting the fatal outcome of patients with SFTS, and NLR is a convenient and efficient early-warning biomarker that helps healthcare workers focus on patients with high risks of fatal outcomes. The efficacy of gamma-globulin provided a new idea for the treatment of SFTS, which needs further analysis in future studies.

A Patient With Failed Liver Transplantation After the Use of PD-1 Blockade Combined With Lenvaxen.

Hepatocellular carcinoma (HCC) is a common malignant tumor with high extent of invasiveness. Its invasion process is closely related to complex tumor microenvironment and microvascular characteristics. Recently, immune combined targeted therapy has been applied to patients, combination therapy program with better effect needs to be explored. Atezolizumab combined Bevacizumab regimen in phase III clinical trial IMbrave150 was approved by U.S. Federal Drug Administration (FDA) for HCC treatment. This program is mostly used for liver malignant tumors have failed other treatments. Patients in terminal stage, overall curative has an unsatisfactory effect, survival time of patients is limited. Therefore, seeking best plan for combined treatment to improve patient's life quality and survival rate are still one of the most important clinical difficulties. This report describes a 37-year-old male who suffered from HCC repeatedly relapsed after hepatectomy. The patient received transcatheter arterial chemoembolization (TACE), microwave ablation (MWA), targeted therapy, and other combined treatments, all showed poor treatment effects. He received liver transplantation (LT) after receiving PD-1 blockade combined targeted therapy, eventually died due to severe immune rejection. It's first case of an allogeneic liver transplantation patient who received PD-1 blockade and Lenvaxen combined therapy. PD-1 blockade treatment and clinical observations of this case were summarized.

Time Course of Severe Fever With Thrombocytopenia Syndrome Virus and Antibodies in Patients by Long-Term Follow-Up Study, China.

Objectives: The objective was to describe the changes of severe fever with thrombocytopenia syndrome virus (SFTSV) and antibody in the disease course and explore the relationship between antibody titers and patients' prognosis. Methods: The levels of SFTSV, virus-specific immunoglobulin M (IgM), immunoglobulin G (IgG) titers, and cytokines in 37 patients with severe fever with thrombocytopenia syndrome (SFTS) were measured dynamically by real-time PCR and ELISA during the disease course; IgG titers were followed up in 53 cases. The correlation analysis of antibody titers with individual serum cytokines was calculated using the Spearman test. Results: The average time of SFTSV duration in individual serum was 22.45 ± 7.6 days from onset. We found SFTSV turned negative within the 10th day from the onset in two patients. SFTSV-specific IgM seroconversion occurred as early as within 3 days from the onset, increased gradually within the first 2 months, decreased gradually 3 months later, and disappeared after 6 months in all the patients. The average time of SFTSV-specific IgG antibody seroconversion was at 17 days from onset in the patients; the time was later in severe cases than in mild cases (23 ± 1.4 vs. 14.3 ± 1.0 days, p < 0.0001). IgG titers were maintained at the peak levels during the periods from 6 months to 1 year and decreased from the second year gradually. Severe cases had higher IgG levels than mild cases and also had a slower decreasing trend. During follow-up, only one lost IgG antibody 7 years later; no chronic infection and sequela were found among the 53 patients. None of the patients had SFTSV reinfection even if they were bitten by ticks again. The correlation analysis showed a positive relationship between inflammatory factors and IgG antibody levels. Conclusion: IgM antibody has important value in early diagnosis of SFTS. A moderate inflammatory response is beneficial for production and duration of IgG antibodies.

Early-Warning Immune Predictors for Invasive Pulmonary Aspergillosis in Severe Patients With Severe Fever With Thrombocytopenia Syndrome.

Aspergillus-related disease was confirmed to be associated with immune disorders in patients, severe patients with severe fever with thrombocytopenia syndrome (SFTS) infected by novel phlebovirus were confirmed to have severe immune damage including cellular immunosuppression and cytokine storms. Secondary invasive pulmonary aspergillosis (IPA) in severe SFTS patients can increase fatality rate. This study investigated early-warning predictive factors of secondary IPA in severe SFTS patients. Receiver operating characteristic analysis was used to assess the value of immune parameters to predict IPA in SFTS patients. The cut-off values of CD4+ and CD8+ T-cell counts to predict IPA were 68 and 111 cells/mm3, with sensitivities of 82.6% and 72%, and specificities of 56.7% and 83.3%, respectively. Cut-off values of IL-6, TNF-α, IL-8, and IL-10 to predict IPA incidence in critically ill SFTS patients were 99 pg/mL, 63 pg/mL, 120 pg/mL, and 111 pg/mL, with sensitivities of 90.0%, 86.7%, 83.3% and 90.0% and specificities of 80.4%, 71.7%, 82.6% and 65.2%, respectively. Lower CD4+ and CD8+ T-cells counts, higher levels of IL-6, TNF-α, IL-8 and IL-10, higher incidence of pancreatic and renal damage, early antibacterial therapy of carbapenems, and intensive care unit admission were risk factors of IPA in SFTS patients. Multivariate logistic regression analysis indicated counts of CD4+ T-cells <68 cells/mm3 combined with CD8+ T-cells <111 cells/mm3 (odds ratio [OR] 0.218, 95% confidence interval [CI] 0.059-0.803, p=0.022), IL-6 >99 pg/ml combined with IL-10 >111 pg/ml (OR 17.614, 95% CI 2.319-133.769, p=0.006), and brain natriuretic peptide level >500 pg/ml (OR 13.681, 95% CI 1.994-93.871, p=0.008) were independent risk factors for IPA in SFTS patients. The mortality in the IPA group was significantly higher than in the non-IPA group (p=0.001). Early antifungal treatment of IPA patients was significantly associated with improved survival (log-rank, p=0.022). Early diagnosis of IPA and antifungal treatment can improve the prognosis of SFTS patients. Besides, we speculate SFTS may be as a host factor for IPA.

Effects of Tigecycline Combined with Azithromycin Against Biofilms of Multidrug-Resistant Stenotrophomonas maltophilia Isolates from a Patient in China.

PURPOSE: Our aim was to investigate in vitro biofilm formation by S. maltophilia and the effects of antibacterial agents used to prevent biofilm formation. METHODS: Two trimethoprim/sulfamethoxazole-resistant S. maltophilia strains were isolated from the pleural effusion of a patient with cancer. The minimum inhibitory concentrations (MICs) of amikacin, azithromycin, cefoperazone/sulbactam, and tigecycline were determined. The checkerboard method was used to determine the fractional inhibitory concentration indices (FICIs). A crystal violet biofilm assay and confocal laser scanning microscopy (CLSM) were used to observe biofilm formation. In vitro effects of azithromycin combined with tigecycline on biofilms of S. maltophilia strains were tested. RESULTS: The two S. maltophilia isolates were confirmed to produce strong biofilms. Crystal violet biofilm assay and CLSM analysis of S. maltophilia biofilm were in the initial adhesive stage after 2 h incubation. Biofilm was in the exponential phase of growth at 12 h and reached maximal growth at 36-48 h. Compared with tigecycline or azithromycin alone, the combination of tigecycline and azithromycin increased the inhibiting effect S. maltophilia biofilm biomass after incubation for 12 h. Compared with the control group, in almost all strains treated with tigecycline and azithromycin, the biofilm was significantly suppressed significance (P<0.001). We found that 2x MIC azithromycin combined with 1x MIC tigecycline had the best inhibiting effect against the biofilm, the biofilm inhibition rates of three strains were all over 60%, the biofilm thickness was inhibited from 36.00 ± 4.00 µm to 8.00 µm, from 40.00 µm to 6.67± 2.31 µm, and from 32.00 µm to 13.33 ± 2.31 µm in SMA1, SMA2 and ATCC17666, respectively. CONCLUSION: Azithromycin combined with tigecycline inhibited biofilm formation by S. maltophilia. Our study provides an experimental basis for a possible optimal treatment strategy for S. maltophilia biofilm-related infections.

Microbiota-Derived Short-Chain Fatty Acids Promote LAMTOR2-Mediated Immune Responses in Macrophages.

ABSRTACTKlebsiella pneumoniae is a common cause of human-pneumonia-derived sepsis with high morbidity and mortality. The microbiota promotes and maintains host immune homeostasis. The mechanisms by which the gut microbiota affects the host defenses in the respiratory system systematically, however, remain poorly understood. Here, we show that gut microbiota depletion increases susceptibility to extracellular K. pneumoniae infections in terms of increased bacterial burdens in lung and decreased survival rates. Oral supplementation with gut microbiota-derived short-chain fatty acids (SCFAs), subsequently activating G protein-coupled receptor 43 (GPCR43), enhances a macrophage's capacity to phagocytose invading K. pneumoniae Furthermore, SCFAs and GPR43 increase macrophage bacterial clearance by upregulating LAMTOR2, which is further identified as an antibacterial effector and elucidated to facilitate phagosome-lysosome fusion and extracellular signal-regulated kinase (ERK) phosphorylation. Lastly, conditional ablation of Lamtor2 in macrophages decreases their antimicrobial activity, even though mice were pretreated with exogenous SCFA supplementation.IMPORTANCE These observations highlight that SCFAs promote macrophage elimination of K. pneumoniae via a LAMTOR2-dependent signal pathway and suggest that it is possible to intervene in K. pneumoniae pneumonia by targeting the gut microbiota.

Virulence-Related Gene Distribution Among Shigella Isolates in Anhui, China: The Association with Antimicrobial Resistance.

OBJECTIVE: The aim of this study was to investigate the antimicrobial resistance profiles and distribution of virulence-related genes (VRGs) among Shigella isolates in Anhui, China, and to identify the correlation between the VRGs and antimicrobial resistance. MATERIALS AND METHODS: A total of 525 non-duplicate Shigella isolates (449 S. flexneri, 68 S. sonnei, 3 S. boydii, and 5 S. dysenteriae) were collected in Anhui Province, China between September 2011 and September 2015. The antimicrobial resistance of the strains was determined by the agar dilution method according to CLSI guidelines. The presence of 16 VRGs, including ipaH, ipaA-D, ial, virB, virF, set, sen, icsA, icsB, sigA, sat, pic, and sepA, was evaluated using PCR amplification and sequencing. RESULTS: Shigella flexneri was the most abundant (85.5%), followed by S. sonnei (13.0%). The proportion of males with S. flexneri was higher than that of females (57% vs 43%; P<0.0001). The most common resistance pattern was the combination of ampicillin, nalidixic acid, and tetracycline for S. flexneri (90.2%) and S. sonnei (94.1%). Resistance to ciprofloxacin and levofloxacin was more common among S. flexneri than among S. sonnei (49.7% vs.19.1%, P<0.0001; 30.5% vs 10.3%, P=0.001, respectively). All the isolates were positive for the ipaH gene, while the set, sat, pic, and sepA genes were not detected among the S. sonnei isolates. Except for sigA and sen, resistance to chloramphenicol and ciprofloxacin was more common among VRG-positive S. flexneri than among VRG-negative S. flexneri (P<0.05). Furthermore, resistance to ceftriaxone and ceftazidime was more frequently detected among sat- and set-positive S. flexneri than among sat- and set-negative S. flexneri (P<0.05). However, gentamicin resistance was more prevalent among VRG-negative (ial, virF, set, sat, pic, and sepA) S. flexneri than among VRG-positive S. flexneri (P<0.05). CONCLUSION: Shigella flexneri remains the predominant species in Anhui, China, and the resistance to fluoroquinolones was more widespread among S. flexneri than among S. sonnei. Shigella flexneri strains harboring specific VRGs were associated with antimicrobial resistance. To the best of our knowledge, this is the first report of the correlation between the VRGs and antimicrobial resistance in Anhui, China.

[Differences in immune damage between patients with severe fever with thrombocytopenia syndrome and patients with tsutsugamushi disease].

OBJECTIVE: To analyze the difference of immune damage between patients with severe fever with thrombocytopenia syndrome (SFTS) and patients with tsutsugamushi disease. METHODS: A prospective case-control study was conducted. Thirty-one patients with SFTS and 16 patients with tsutsugamushi disease admitted to the First Affiliated Hospital of Anhui Medical University from October 2014 to June 2017 were enrolled, and another 10 healthy people were enrolled as control. The counts of CD4+ and CD8+ T lymphocytes, and the proportion of CD3+ T lymphocytes, natural kill cells (NK cells), B lymphocytes and plasma cells were detected by flow cytometry. Thirty-four inflammatory mediators were determined by a multiplex Luminex® system synchronously. The differences of lymphocytes and cytokines between the two groups were compared. RESULTS: The proportion of CD3+ T lymphocytes, the counts of CD4+ and CD8+ T lymphocytes in SFTS patients were significantly lower than those in patients with tsutsugamushi disease (t values were 4.860, 9.411 and 5.030, respectively, all P < 0.01), and the proportion of NK cells and B lymphocytes were significantly higher than those in patients with tsutsugamushi disease (t values were 2.344 and 5.896, respectively, both P < 0.05). The proportion of plasma cells in peripheral blood of SFTS patients was (7.7±1.2)%, the highest proportion of plasma cells in severe SFTS patients was up to 30%, and all patients showed λ monoclonal cell group in plasma cells. No plasma cells were detected in tsutsugamushi disease patients. The abnormal expressions of interleukin-1 receptor antibody (IL-1RA), interleukin (IL-6, IL-15, IL-10, IL-8), tumor necrosis factor-α (TNF-α), γ-interferon (IFN-γ), granulocyte colony-stimulating factor (G-CSF), eosinophil chemotactic factor (Eotaxin), IFN-γ-inducible protein-10 (IP-10), monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein (MIP-1α, MIP-1ß), platelet-derived growth factor (PDGF-AA, PDGF-AB/BB), activated regulatory normal T cells and secretion factors (RANTES) were found in patients with SFTS and tsutsugamushi disease. The levels of IL-1RA, IL-6, IL-15, IL-10, TNF-α, IFN-γ, G-CSF, Eotaxin, IL-8, IP-10, MCP-1 and MIP-1α in SFTS patients were significantly higher than those in patients with tsutsugamushi disease (Z values were 2.312, 2.447, 3.660, 5.444, 1.965, 2.402, 2.402, 2.997, 3.525, 2.481, 3.817, and 2.211, respectively, all P < 0.05), while PDGF-AA, PDGF-AB/BB and RANTES were significantly lower than those in patients with tsutsugamushi disease (Z values were 3.728, 2.514, 2.649, respectively, all P < 0.05). Correlation analysis showed that RANTES, PDGF-AA and PDGF-AB/BB levels were significantly positively correlated with the level of platelet in patients with SFTS and tsutsugamushi disease (SFTS: r values were 0.223, 0.365, 0.330; tsutsugamushi disease: r values were 0.263, 0.632, 0.407, respectively, all P < 0.05). In SFTS patients, compared with the survival group (n = 21), the CD3+ and CD4+ T lymphocytes in the death group (n = 10) significantly decreased, while the plasma cells significantly increased (t values were 3.980, 3.314 and 26.692, respectively, all P < 0.01); IL-1RA, IL-6, IL-15, IL-10, TNF-α, IFN-γ, G-CSF, Eotaxin, IL-8, IP-10, MCP-1, MIP-1α and MIP-1ß significantly increased, while PDGF-AA, PDGF-AB/BB and RANTES significantly decreased (Z values were 3.930, 4.014, 2.832, 3.592, 2.958, 3.508, 2.578, 3.254, 4.270, 3.465, 2.663, 3.085, 3.107, 3.639, 3.043 and 3.825, respectively, all P < 0.05). CONCLUSIONS: The immune function was impaired more seriously in SFTS patients than that in tsutsugamushi disease patients. Excessive humoral immunity and apoptosis of T lymphocytes are closely related to the death in SFTS patients. The detection of CD4 cells, plasma cells and proinflammatory and anti-inflammatory cytokines (e.g. IL-6, IL-10) had great clinical significance for the differentiation and illness evaluation in disease with SFTS or tsutsugamushi disease.

Minocycline and Fluconazole Have a Synergistic Effect Against Cryptococcus neoformans Both in vitro and in vivo.

In recent decades, the incidence of Cryptococcus neoformans infection, which causes cryptococcosis, has consistently increased. Fluconazole (FLU) is frequently used in the treatment of this disease, mainly in the immunocompromised population, and long-term therapy usually produces drug resistance. Research on antifungal sensitizers has gained attention as a possible means of overcoming this drug resistance. Minocycline (MINO) has an inhibitory effect in vitro on FLU-resistant Candida albicans, and the combination of MINO and FLU has a synergistic effect on FLU-resistant C. albicans. A synergistic effect of MINO/FLU has been reported against C. neoformans, but this effect has not been evaluated on FLU-resistant isolates. This study aimed to investigate the interaction of MINO and FLU against FLU-resistant C. neoformans both in vitro and in vivo. We found that the combination of MINO and FLU had a synergistic effect on FLU-resistant C. neoformans in vitro. For all FLU-resistant strains, the minimum inhibitory concentration (MIC) of FLU decreased significantly when used in combination with MINO, dropping from >128 µg/ml down to 4-8 µg/ml. Additionally, MINO and FLU had a synergistic effect on both susceptible and resistant C. neoformans biofilms, in which the MIC of FLU decreased from >256 µg/ml down to 4-16 µg/ml. Compared with FLU alone, the combination of MINO with FLU prolonged the survival rate of Galleria mellonella larvae infected with FLU-resistant C. neoformans, and also significantly decreased the fungal burden of infected larvae and reduced the tissue damage and destruction caused by FLU-resistant C. neoformans. These findings will contribute to the discovery of antifungal agents and may yield a new approach for the treatment of cryptococcosis caused by FLU-resistant C. neoformans.

Corrigendum: Alterations of Gut Microbiome in the Patients With Severe Fever With Thrombocytopenia Syndrome.

[This corrects the article DOI: 10.3389/fmicb.2018.02315.].