LPS-TLR4/MD-2-TNF-α signaling mediates alcohol-induced liver fibrosis in rats.

Liver fibrosis results from liver inflammation and progresses to liver cirrhosis or liver cancer. It is known that nonalcoholic liver disease is mediated by the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD-2)-tumor necrosis factor-alpha (TNF-α) signaling pathway. This study aimed to investigate whether alcoholic liver disease is also mediated by this pathway. To this end, we first established rat models of liver fibrosis by administering alcohol. Next, the rats were injected with anti-TLR4 and anti-MD-2 antibodies. Real Time Quantitative PCR (RT-qPCR) and Western blotting were used to detect the activation of the TLR4/MD-2-TNF-α signaling pathway and hepatic stellate cells (HSCs). Moreover, the expression of molecules related to liver fibrosis was estimated. The morphology of rat liver tissue was observed through hematoxylin-eosin staining and Masson staining. For in vitro studies, Kupffer cells (KCs) isolated from the liver were transfected with si-TLR4 and si-MD-2 and co-cultured with HSCs to determine the activity of HSCs. It was found that alcohol treatment activated the TLR4/MD-2-TNF-α signaling pathway and upregulated the molecules associated with liver fibrosis. However, inhibition of TLR4 and MD-2 partially reversed this trend. Notably, in vitro studies indicated that knockdown of TLR4 and MD-2 in KCs partially inhibited LPS-induced activation of KCs and HSCs. Overall, this study showed that alcohol induces liver fibrosis via the LPS-TLR4/MD-2-TNF-α signaling pathway.

Propofol-mediated cardioprotection dependent of microRNA-451/HMGB1 against myocardial ischemia-reperfusion injury.

Administration of propofol at the time of reperfusion has shown to protect the heart from ischemia and reperfusion (I/R) injury. The aim of the present study was to investigate the molecular mechanism underling the cardioprotective effect of propofol against myocardial I/R injury (MIRI) in vivo and in vitro. Rat heart I/R injury was induced by ligation of the left anterior descending (LAD) artery for 30 min followed by 2-hr reperfusion. Propofol pretreatment (0.01 mg/g) was performed 10 min before reperfusion. In vitro MIRI was investigated in cultured cardiomyocytes H9C2 following hypoxia/reoxygenation (H/R) injuries. Propofol pretreatment in vitro was achieved in the medium supplemented with 25 µmol/L propofol before H/R injuries. Propofol pretreatment significantly increased miRNA-451 expression, decreased HMGB1 expression, reduced infarct size, and I/R-induced cardiomyocyte apoptosis in rat hearts undergoing I/R injuries. Knockdown of miRNA-451 48 hr before I/R injury was found to increase HMGB1 expression, infarct size, and I/R-induced cardiomyocyte apoptosis in rat hearts in the presence of propofol pretreatment. These in vivo findings were reproduced in vivo that knockdown of miRNA-451 48 hr before H/R injuries increased HMGB1 expression and H/R-induced apoptosis in cultured H9C2 supplemented with propofol. In addition, luciferase activity assays and gain-of-function studies found that propofol could decrease HMGB1, the target of miRNA-541. Taken together our findings provide a first demonstration that propofol-mediated cardioprotection against MIRI is dependent of microRNA-451/HMGB1. The study provides a novel target to prevent I/R injury during propofol anesthesia.

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

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

Genetical study of mutation in maternal-fetal ABO incompatibility.

This study looked into a family involving a rare mother-child ABO blood type inconsistency and explored its genetic and molecular basis. In the family, the mother had type AB blood and the father was blood type B and they gave birth to a baby of blood type O. Their blood types were phenotypically identified by using different techniques, including micro-column gel test, immune inhibition test, absorption and elution tests. The sequences of all 7 exons of ABO allele from the core family members were determined by using PCR and clone-based sequencing. The loci of mutated gene were compared against normal human genes. The result showed that the mother's erythrocytes were agglutinable with monoclonal anti-A antibody (2+) and had agglutination reaction with anti-B antibody (4+). The mother's serum registered agglutination action with standard blood type A cells. The findings showed an ABO inconsistency. When domestic antibodies were used, the mother's erythrocytes yielded agglutination reaction with humanized anti-B serum (4+) and anti-B monoclonal antibody but were non-agglutinable with humanized anti-A serum and anti-A monoclonal antibody. Upon absorption and elution, the titer of anit-A antibody was 128 both before and after the absorption test, with no significant difference found between pre- and post-absorption values. Our results confirmed that the mother's allelic gene was type B and contained type A. The father's blood type was type B, and son's blood type was type O. Clone-based sequencing revealed that the mother carried a heterozygous gene of B101.01 (ntA640→G)/O01, which contained an M214→V mutation that could express a weak expression of antigen A, resulting in blood type AB. However, their son did not have the M214→V mutation, which yielded a false ABO-inconsistency between him and his mother. We were led to conclude that type B gene with a M214→V mutation can encode both antigen B and weak antigen B that can lead to false ABO-inconsistencies.

Clinical relevance of plasma miR-21 in new-onset systemic lupus erythematosus patients.

BACKGROUND: Plasma miR-21 is widely investigated as biomarker in many diseases. Recent studies show that miR-21 participates in the development of systemic lupus erythematosus (SLE). The aim of this study was to evaluate the expression profile of miR-21 in the plasma of SLE patients. METHODS: Relative quantities of plasma miR-21 both in SLE patients and healthy controls were determined by relative qRT-PCR under endogenous and exogenous controls. The diagnostic value of plasma miR-21 was evaluated in SLE patients. Data of some SLE-associated clinical parameters were collected. RESULTS: Eighty participants from Central China were recruited. Forty-four participants were new-onset SLE patients and the others were healthy controls. Plasma miR-21 level in SLE patients was higher than that of healthy controls (P = 0.031). Receiver operating characteristic analysis of plasma miR-21 revealed an Area Under Curve (AUC) of 0.64 ± 0.06 (95% CI: 0.51-0.76, P = 0.03854) when differentiating SLE from healthy controls. The level of plasma miR-21 was not associated with the level of white blood cells (P = 0.4284), red blood cells (P = 0.4079), and platelets (P = 0.4961), but significantly correlated with the level of plasma complement C3 (r = -0.5297, P = 0.0004), C4 (r = -0.4732, P = 0.0020), and serum uric acid (r = 0.3932, P = 0.0121) in SLE patients. CONCLUSIONS: Plasma miR-21 in SLE patients from Central China is overexpressed. Since circulating miR-21 is aberrantly expressed in many diseases, the applying of it as a disease biomarker should be considered carefully.

Evaluation of Neisseria gonorrhoeae Isolates Susceptibility to Antibiotics in Zhejiang Province Since 2007.

Objective: This study aimed to assess the drug susceptibility of clinical isolates of Neisseria gonorrhoeae to spectinomycin, ceftriaxone and azithromycin. Moreover, the temporal trends in the minimum inhibitory concentration (MIC) of five antibiotics from Zhejiang, China, are also in the scope of this study. Methods: A total of 1710 gonococcal clinical strains were collected between 2007 and 2021 from health-care institutions in Zhejiang. The MICs of ceftriaxone, azithromycin, spectinomycin, penicillin and ciprofloxacin were assessed by agar dilution method on 1710 Neisseria gonorrhoeae isolates. Count data were expressed as strains and rates, and MICs distribution was elucidated using descriptive statistics. Results: The total resistance rates of gonococci to azithromycin, spectinomycin, penicillin and ciprofloxacin in this study were 19.3%, 0.3%, 75.4% and 99.7%, respectively. Conclusion: The in vitro results showed a high prevalence of resistance to ciprofloxacin and penicillin. Azithromycin resistance rate has exceeded 5%, suggested a high prevalence of resistance. Ceftriaxone and spectinomycin are suggested based on this study for the treatment of Neisseria gonorrhoeae in Zhejiang.

The sensitivity of mechanical properties and pore structures of Beishan granite to large variation of temperature in nuclear waste storage sites.

Granite is the host rock of the Beishan Underground Research Laboratory (URL) for geological disposal of high-level radioactive waste in China. The mechanical behavior of Beishan granite is the key in determining whether the repository can serve safely for a long time. The surrounding rock of the repository will be exposed to thermal environment induced by radionuclide decay, resulting in significant changes in the physical and mechanical properties of the Beishan granite. This study investigated the pore structure and mechanical properties of Beishan granite after thermal treatment. The T2 spectrum distribution, pore size distribution, porosity, and magnetic resonance imaging (MRI) were obtained through nuclear magnetic resonance (NMR); uniaxial compressive strength (UCS) and acoustic emission (AE) signal characteristic of granite were investigated through uniaxial compression tests. The results showed that high temperature significantly affected the T2 spectrum distribution, pore size distribution, porosity, compressive strength, and elastic modulus of granite, and porosity gradually increases, whereas the strength and elastic modulus gradually decline with increasing temperature. The porosity of granite has a linear relationship with UCS and elastic modulus, indicating that the essential mechanism for the deterioration of macroscopic mechanical properties lies in changes of microstructure. In addition, the thermal damage mechanism of granite was revealed, and a damage variable was defined based on porosity and uniaxial compressive strength.

IL-17A and TNF-α inhibitors induce multiple molecular changes in psoriasis.

Adalimumab and secukinumab are commonly used for moderate to severe psoriasis vulgaris (PV). Although distinct individual responses to and impaired effectiveness of these biological agents occur occasionally, little is known about the underlying reasons. Here, we report a proteomic analysis of psoriatic lesions from patients treated with these drugs using data-independent acquisition mass spectrometry (DIA-MS). Thousands of differentially expressed proteins (DEPs) changed over 12 weeks of treatment. Network analysis showed that DEPs could interact and induce transformation in matrix components, metabolic regulation, and immune response. The results of parallel reaction monitoring (PRM) analysis suggested that S100s, STAT1, KRT2, TYMP, SOD2, HSP90AB1, TFRC, and COL5A1 were the most significantly changed proteins in both groups. There was a positive association between the Psoriasis Area and Severity Index (PASI) score and three proteins (TFRC, IMPDH2, KRT2). Our study findings suggest that inhibition of IL-17A and TNF-α can induce changes in multiple molecules in psoriatic lesions and have an overlapping influence on the immune response and process through direct or indirect effects.

Programmed cell death 1 gene polymorphisms is associated with ankylosing spondylitis in Chinese Han population.

Programmed cell death 1 (PD-1) has been reported to have a genetic association in several autoimmune diseases. The aim of this study was to investigate the association of PD-1 polymorphisms and haplotypes with ankylosing spondylitis (AS) in Chinese Han population. In a case-control association study, three single-nucleotide polymorphisms (SNP), PD-1.3 G/A, PD-1.5 C/T and PD-1.9 T/C, were genotyped in 216 AS patients and 264 healthy controls using polymerase chain reaction-restriction fragment length polymorphism assay. All genotype distributions in the patients and in the controls were in Hardy-Weinberg equilibrium. The associations of genotypes and alleles with AS were analyzed. The genotype distributions of PD-1.9 were significantly different between the patients with AS and the controls (P = 0.025). The frequencies of TC genotype and T allele of PD-1.9 were higher in the patients than those in the controls (P = 0.026 and 0.004). No association for PD-1.5 in AS was found, and PD-1.3 was non-polymorphic in Chinese Han population. Moreover, the frequency of the CT haplotype (PD-1.5 C/T, PD-1.9 T/C) was significantly higher in AS patients than the controls (21.6 vs. 13.9%, P = 0.002). The CC haplotype was more common in the controls than in the patients (57.1 vs. 44.6%, P = 0.000). The results support a genetic association between the PD-1 polymorphism and susceptibility to AS in Chinese Han population.

Cd(II)-binding transcriptional regulator interacts with isoniazid and regulates drug susceptibility in mycobacteria.

It is urgent to understand the regulatory mechanism of drug resistance in widespread bacterial pathogens. In Mycobacterium tuberculosis, several transcriptional regulators have been found to play essential roles in regulating its drug resistance. In this study, we found that an ArsR family transcription regulator encoded by Rv2642 (CdiR) responds to isoniazid (INH), a widely used anti-tuberculosis (TB) drug. CdiR negatively regulates self and adjacent genes, including arsC (arsenic-transport integral membrane protein ArsC). CdiR directly interacts with INH and Cd(II). The binding of INH and Cd(II) both reduce its DNA-binding activity. Disrupting cdiR increased the drug susceptibility to INH, whereas overexpressing cdiR decreased the susceptibility. Strikingly, overexpressing arsC increased the drug susceptibility as well as cdiR. Additionally, both changes in cdiR and arsC expression caused sensitivity to other drugs such as rifamycin and ethambutol, where the minimal inhibitory concentrations in the cdiR deletion strain were equal to those of the arsC-overexpressing strain, suggesting that the function of CdiR in regulating drug resistance primarily depends on arsC. Furthermore, we found that Cd(II) enhances bacterial resistance to INH in a CdiR-dependent manner. As a conclusion, CdiR has a critical role in directing the interplay between Cd(II) metal ions and drug susceptibility in mycobacteria.

High frequencies of HLA-B27 in Chinese patients with suspected of ankylosing spondylitis.

This study was performed to investigate the frequency of human leukocyte antigen (HLA)-B27 in Chinese patients with suspected of ankylosing spondylitis (AS) and to assess the clinical significance of HLA-B27 typing. A total of 1,016 patients suspected of AS were classified into six groups based on one major AS-related clinical manifestation. HLA-B27 was determined by polymerase chain reaction using sequence-specific primers. The frequency of B27 ranged between 24.3 and 46.7% among the patient groups, significantly higher than in healthy controls (2.4%). In the same group, the frequency of B27 in young (< or = 40 years) and in male patients was significantly higher than in the old and in female (P < 0.01). During a 1-year follow-up, 102 subjects were definitely diagnosed as AS, but only one B27(-) patient. Of the 102 definite patients, 69 (67.6%) definite patients were distributed in group 1 (low back pain and stiffness) with the higher incidence (28.5%) of AS. The incidence of AS in the same group was found with a similar pattern to the frequency of B27, in male and young patients significantly greater, except groups 4 and 6 (peripheral arthritis and alteration of skin). These findings confirm that HLA-B27 is one of sensitive diagnostic tools for early AS and suggest that there was a remarkable clinical significance of HLA-B27 typing in Chinese patients suspected of AS, particularly a young man who presents with low back pain and stiffness for > 3 months.

The association of HLA-B*27 subtypes with ankylosing spondylitis in Wuhan population of China.

The aim of this study was to investigate the association of the B27 subtypes with ankylosing spondylitis (AS) in the Wuhan population of China. We selected 317 HLA-B27-positive individuals (145 controls and 172 patients with ankylosing spondylitis). The B27 subtypes were characterized using a PCR-SSP method. Six B27 subtypes were determined: B*2702, 03, 04, 05, 06 and B*13. HLA-B*2704 and HLA-B*2705 were the two high frequency genotypes in controls and patients. Compared with the controls, the AS patients had high frequency of B*2704 (patients 69.2% vs. controls 53.8%) and low frequency of B*2705 (patients 23.8% vs. controls 33.1%). B*2703 was detected in 10 (5.8%) patients and in 13 (8.9%) controls. B*2702, 06 and B*2713 were relatively rare. Our results show that the allele conferring risk to AS in the Wuhan population of China was B*2704 and B*2705. B*2704 is strongly associated with AS.

Eradication of Helicobacter Pylori Infections and GERD: A systematic review and meta-analysis.

BACKGROUND/AIMS: This study evaluates the association between the eradication of Helicobacter pylori (H. pylori) and gastroesophageal reflux disease (GERD). MATERIALS AND METHODS: Relevant studies were identified by conducting literature search in PubMed, Cochrane, Embase, CNKI, VANFUN, and VIP databases. The prevalence rates of gastroesophageal reflux, heartburn, epigastric pain, and nausea were extracted from the identified research articles and were used in meta-analysis of relative risks (RR) to achieve an overall effect size of the relationship between H. pylori eradication and GERD. RESULTS: A total of 19 randomized controlled trials were included in this meta-analysis. The prevalence of gastroesophageal reflux was significantly higher in patients with H. pylori eradication compared with patients without it (RR: 1.54, 95% CI: 1.06-2.24; p=0.02). A subgroup analysis did not identify any significant difference in GERD prevalence in studies conducted outside China (RR: 1.62, 95% CI: 0.98-2.68) or in China (RR: 1.30, 95% CI: 0.76-2.22). There were no significant differences in heartburn (RR: 1.03, 95% CI: 0.88-1.20), epigastric pain (RR: 0.98, 95% CI: 0.13-7.56), or nausea (RR: 0.44, 95% CI: 0.07-2.72) risk between patients with and without H. pylori eradication. CONCLUSION: Eradication of H. pylori infection is found to be associated with GERD, although regional differences may exist in the prevalence. Well-designed studies especially those with stratification of patients' basic conditions are needed to seek refined evidence of the association between H. pylori eradication and the GERD.

Gonococcal urethritis caused by a multidrug resistant Neisseria gonorrhoeae strain with high-level resistance to spectinomycin in China.

We report a recent (2018) gonorrhoeal urethritis caused by a multidrug-resistant Neisseria gonorrhoeae strain in China. The isolated N. gonorrhoeae strain from a male and female pair expressed high-level resistance to spectinomycin (SPC), azithromycin, and other antibiotics but was sensitive to ceftriaxone. The SPC high-level resistance (MIC = 2048 mg/L) was due to a small deletion in rspE that caused two amino acid changes in ribosomal protein S5.

Efficacy of concentrated growth factors combined with mineralized collagen on quality of life and bone reconstruction of guided bone regeneration.

To evaluate the clinical efficacy of concentrated growth factors (CGFs) combined with mineralized collagen (MC) in guided bone regeneration (GBR). A retrospective study involving 29 patients treated with GBR technique, which was performed either CGF and MC complexes or MC alone. Implants were inserted simultaneously and cone-beam computed tomography was taken immediately, at 3 and 6 months postoperation. Questionnaires were completed by all patients so as to evaluate the main symptoms and daily activities during the first week after surgery. The outcomes of the two groups were statistically compared. All implants healed uneventfully. Patients in both groups suffered from different levels of discomfort for the reason of swelling, pain and chewing impairment on 1-2 days. Meanwhile, swelling of the Trial group was weaker than the Control group. When compared with the Control group, pain levels in Trial group were more rapidly reduced and patients took fewer analgesics from Day 3. Furthermore, the reconstitution mean value of the graft was thicker at 3 and 6 months in Trial group. CGFs complex with MC were beneficial to relieve the clinical symptoms, promote the peri-implant bone regeneration and shorten the healing time.

Association between body mass index and the risk of bleeding in elderly patients with non-valvular atrial fibrillation taking dabigatran: a cohort study.

BACKGROUND: Uncertainty remains regarding the association between body mass index (BMI) and the risk of bleeding in patients with non-valvular atrial fibrillation (NVAF). We aimed to investigate the association between BMI and the risk of bleeding in elderly NVAF patients taking dabigatran. METHODS: A total of 509 elderly NVAF patients, who were being treated at twelve centers in China from February 2015 to December 2017 and taking dabigatran, were analyzed. The exposure and outcome variables were BMI at baseline and bleeding events within the subsequent six months, respectively. Cox proportional hazards regression analysis was used to evaluate the association between BMI and the risk of bleeding. Moreover, the Cox proportional hazards regression with cubic spline functions and smooth curve fitting was conducted. RESULTS: During the six-month follow-up, 50 participants experienced bleeding. Every 1 kg/m2 increase in BMI was associated with a 12% increased risk of bleeding (P = 0.021). Compared to those with BMI values in Tertile 1 (< 22.5 kg/m2), the adjusted hazard ratio (HR) of bleeding for participants in Tertile 2 (22.5-25.3 kg/m2) and Tertile 3 (> 25.3 kg/m2) were 2.71 (95% CI: 1.02-7.17) and 3.5 (95% CI: 1.21-8.70), respectively. The P trend-value was significant in all models. The adjusted smooth curve showed a linear association between BMI and bleeding. None of the stratified variables showed significant effect modification on the association between BMI and bleeding (P interaction > 0.05). CONCLUSIONS: BMI was significantly and positively associated with the risk of bleeding in elderly NVAF patients treated with dabigatran.

Family-based association study of Tim-1 and Tim-3 gene polymorphisms with childhood asthma in Chinese trios.

BACKGROUND: Asthma is a complex genetic disease, caused by the interaction of multiple genetic and environmental factors. T cell immunoglobulin domain and mucin domain (Tim) genes are located in chromosome 5q31-33, a region repeatedly linked to asthma or asthma-related phenotypes in several populations. Two members of Tim families, Tim-1 and Tim-3, which are expressed on T cell surface and potentially involved in T cell proliferation and differentiation, are good candidate genes for asthma. We investigated whether genetic variants or haplotypes in Tim-1 and Tim-3 genes confer susceptibility to asthma in a Chinese population. METHODS: A total of 9 polymorphisms were selected by using the HapMap Han Chinese population data and a haplotype-tagging single nucleotide polymorphism approach. Polymerase chain reaction fragment length polymorphism was adapted to determine the genotype in 118 complete Chinese trios of asthma. Then, transmission disequilibrium test (TDT), haplotypic relative risk (HRR), linkage disequilibrium and haplotype analysis were performed. RESULTS: The single locus TDT and HRR analysis showed the 9 polymorphisms were not transmitted preferentially to asthma-affected children (all p > 0.05). However, in both the haplotypic TDT and HRR analysis, the haplotype G-A-ins-C-G consisting of 5 Tim-1 polymorphisms was found to be overtransmitted to affected offspring (chi(2) = 4.51, p = 0.03) and the haplotype G-G-G consisting of 3 Tim-3 polymorphisms was found to be undertransmitted to asthma children (chi(2) = 8.24, p = 0.004). CONCLUSIONS: We conclude that it is unlikely that the Tim-1 or Tim-3 polymorphisms influence asthma susceptibility individually, but that the haplotypes of variants may be functional or may be in linkage disequilibrium with other functional single nucleotide polymorphisms.

OxiR specifically responds to isoniazid and regulates isoniazid susceptibility in mycobacteria.

The bacteria drug resistance is not only associated with the gain of drug resistance gene but also relied on the adaptation of bacterial cells to antibiotics by transcriptional regulation. However, only a few transcription factors that regulate drug resistance have been characterized in mycobacteria. In this study, a TetR family transcriptional factor (OxiR), encoded by Rv0067c in Mycobacterium tuberculosis, was found to be an isoniazid (INH) resistance regulator. Comparing with the wild-type strain, the oxiR overexpressing strain is four times resistant to INH, whereas the oxiR knockout strain is eight times sensitive to INH. However, the rifamycin and ethambutol resistance were not influenced by oxiR. OxiR can bind to self-promoter at a 66 bp imperfect palindromic motifs. Interestingly, OxiR directly binds to INH, and thereby alleviate the self-repression. Furthermore, OxiR negatively regulated an oxidoreductase encoded by Rv0068. And the susceptibility of the Rv0068-overexpressing and oxiR knockout strains to all the three above-mentioned anti-tuberculosis drugs was equivalent, suggesting that the effect of oxiR to INH susceptibility is attributed to the derepression of Rv0068. In conclusion, we showed that OxiR can specifically modulate INH susceptibility by regulating an oxidoreductase encoding gene, both of which have not been associated with drug-resistance previously.

Peripheral leukocyte count and risk of bleeding in patients with non-valvular atrial fibrillation taking dabigatran: a real-world study.

BACKGROUND: The association between peripheral leukocyte count and bleeding events in nonvalvular atrial fibrillation (NVAF) patients treated with dabigatran remains unclear. This study aimed to explore the association between leukocyte count and bleeding events after excluding other confounders in NVAF patients taking dabigatran. METHODS: A total of 851 NVAF patients treated with dabigatran (110 mg bid) were recruited from 12 centers in China from February 2015 to December 2017. Follow-up was completed by May 2018. The exposure and outcome variables were leukocyte count measured at baseline and the number of bleeding events within the subsequent 6 months. Multivariate Cox proportional hazards models were constructed to analyze independent associations, and a Cox proportional hazards regression with cubic spline functions and smooth curve fitting (penalized spline method) was used to address nonlinearity between leukocyte count and bleeding. The inflection point was calculated using a recursive algorithm, and then a two-piecewise Cox proportional hazards model for both sides of the inflection point was constructed. RESULTS: During 6-month follow-up, 87 participants occurred bleeding events. For every 1 × 10/L increase in leukocyte count, the risk of bleeding increased by 11% (hazard ratio [HR]: 1.11, 95% confidence interval [CI]: 0.99-1.25). The smooth curve showed nonlinear relationship between leukocyte count and bleeding events. The inflection point of the leukocyte count was 6.75 × 10/L. For leukocyte counts < 6.75 × 10/L, the HR (95% CI) was 0.88 (0.69-1.13), and for leukocyte counts ≥ 6.75 × 10/L, the HR (95% CI) was 1.28 (1.09-1.51). CONCLUSION: This study found a J-shaped association between baseline leukocyte count and risk of bleeding in NVAF patients treated with dabigatran. CLINICAL TRIAL REGISTRATION: NCT02414035, https://clinicaltrials.gov.

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

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