PCSK9 inhibitors and osteoporosis: mendelian randomization and meta-analysis.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors represent an effective strategy for reducing cardiovascular disease risk. Yet, PCSK9's impact on osteoporosis remains unclear. Hence, we employed Mendelian randomization (MR) analysis for examining PCSK9 inhibitor effects on osteoporosis. METHODS: Single nucleotide polymorphisms (SNPs) for 3-hydroxy-3-methylglutaryl cofactor A reductase (HMGCR) and PCSK9 were gathered from available online databases for European pedigrees. Four osteoporosis-related genome-wide association studies (GWAS) data served as the main outcomes, and coronary artery disease (CAD) as a positive control for drug-targeted MR analyses. The results of MR analyses examined by sensitivity analyses were incorporated into a meta-analysis for examining causality between PCSK9 and HMGCR inhibitors and osteoporosis. RESULTS: The meta-analysis involving a total of 1,263,102 subjects, showed that PCSK9 inhibitors can increase osteoporosis risk (P < 0.05, I2, 39%). However, HMGCR inhibitors are not associated with osteoporosis risk. Additionally, a replication of the analysis was conducted with another exposure-related GWAS dataset, which led to similar conclusions. CONCLUSION: PCSK9 inhibitors increase osteoporosis risk. However, HMGCR inhibitors are unremarkably linked to osteoporosis.

The association between osteoporosis and frailty: a cross-sectional observational study and mendelian randomization analysis.

BACKGROUND: Osteoporosis and frailty are two common features in the elderly population. Despite many review articles mentioning the association between osteoporosis and frailty, there is a lack of original research directly investigating their relationship. Therefore, this study was conducted to examine the correlation between osteoporosis and frailty. METHODS: We conducted a cross-sectional study using data from the National Health and Nutrition Examination Survey (NHANES), using logistic regression analysis to assess the association of osteoporosis with the frailty index. In addition, we further explored the causal relationship between them using Mendelian randomization (MR) study. RESULTS: In the cross-sectional study, 19,091 non-frailty participants and 5878 frailty participants were included in this study. We observed a significant positive association between osteoporosis and frailty after adjusting for demographic characteristics, body mass index (BMI), smoking, and alcohol use (OR = 1.454, 95% CI [1.142,1.851], P = 0.003). Moreover, the MR study showed a bidirectional causal relationship between osteoporosis and frailty. When osteoporosis was used as an exposure factor, the frailty pooled OR value calculated utilizing the inverse variance weighted (IVW) method was 2.81 (95% CI [1.69, 4.68], P = 6.82 × 10- 5). When frailty was used as an exposure factor, the OR value calculated using the IVW method was 1.01 (95% CI [1.00,1.01], P = 3.65 × 10- 7). CONCLUSIONS: Osteoporosis was positively correlated with frailty, and the results remained robust after adjusting for covariates. Further, MR studies have shown a bidirectional causal relationship between osteoporosis and frailty.

Discovering potential mechanisms of intervertebral disc disease using systematic Mendelian randomization of human circulating immunocytomics.

BACKGROUND: Although intervertebral disc degeneration (IVDD) is a critical factor in many spine-related diseases and has an extremely high prevalence in the aging population, the potential pathogenesis remains to be clarified entirely. Immune cells have been found to perform an essential function during the onset and progression of IVDD in recent years. Therefore, we explored the association between immune cell characteristics and IVDD through Mendelian randomization (MR) analysis and further delved into the mediating role of potential metabolites. METHODS: Based on the MR analysis, the association of 731 immune cell phenotypes and 1400 metabolites on IVDD were assessed. Single nucleotide polymorphisms (SNPs) were closely associated the expression levels of immune cell characteristics and the concentrations of metabolites and have been used as instrumental variables (IVs) for deducing them as risk factors or protective factors for IVDD. In addition, mediation analyses have been performed to identify potential metabolite mediators between immune cell characteristics and IVDD. RESULTS: MR analysis identified 27 immune cell phenotypes and 79 metabolites significantly associated with IVDD. In addition, mediation analysis was performed by selecting the immune cell phenotype that most significantly increased the risk of IVDD - CD86 on monocytes. A total of four metabolite-mediated mediation relationships were revealed (3b-hydroxy-5-cholenoic acid, X-22509, N-acetyl-L-glutamine, and N2-acetyl, N6, N6-dimethyllysine). CONCLUSION: The findings of this analysis identified underlying association between immune cell phenotypes, metabolite, and IVDD that may serve as predictive and prognostic clinical biomarkers and benefit IVDD pathogenesis research.

Global emergence of double and multi-carbapenemase producing organisms: epidemiology, clinical significance, and evolutionary benefits on antimicrobial resistance and virulence.

Redundant carbapenemase-producing (RCP) bacteria, which carry double or multiple carbapenemases, represent a new and concerning phenomenon. The objective of this study is to conduct a comprehensive analysis of the epidemiology and genetic mechanisms of RCP strains to support targeted surveillance and control measures. A retrospective analysis was conducted using surveillance data from 277 articles. Statistical analysis was performed to determine and evaluate species prevalence, proportions of carbapenemases, antibiotic susceptibility profiles, sample information, and patient outcomes. Complete plasmid sequencing data were utilized to investigate potential antimicrobial resistance or virulence advantages that strains may gain from acquiring redundant carbapenemases. RCP bacteria are widely distributed globally, and their prevalence is increasing over time. Several countries, including China, India, Iran, Turkey, and South Korea, have reported more than 100 RCP strains. The most commonly reported RCP species are Klebsiella pneumoniae and Acinetobacter baumannii, which exhibit varying proportions of carbapenemase combinations. Certain species-carbapenemase combinations, such as K. pneumoniae carrying New Delhi metallo-ß-lactamase (NDM) + oxacillinase (OXA) (56.76%) and K. pneumoniae carbapenemase (KPC) + Verona integron-encoded metallo-ß-lactamase (VIM) (50.00%) carbapenemases, are associated with high mortality rates. In patients with RCP strains isolated from the bloodstream and respiratory system, the mortality rates are 58.70% and 69.23%, respectively. Analysis of plasmids from RCP strains suggests that they may acquire additional antibiotic resistance phenotypes and virulence factors. Carbapenem-resistant bacteria carrying redundant carbapenemases pose a significant global health threat. This study provides valuable insights into the epidemiology and genetic mechanisms of these bacteria, supporting the development of effective control and prevention strategies to mitigate their transmission.IMPORTANCEThis study examined the global distribution patterns of 1,780 bacteria with double or multiple carbapenemases from 277 articles and assessed their clinical impact. The presence of multiple carbapenemases increases the chances of co-resistance to other classes of antibiotics and more virulence factors, further complicating the clinical management of infections.

Therapeutic potential of single-nucleotide polymorphism-mediated IL6R inhibitors in ankylosing spondylitis treatment.

Objective: Interleukin-6 (IL-6) is a multiple-effect cell factor implicated in the etiopathogenesis of several rheumatologic disorders. The blockade of the IL-6 pathway via IL6R inhibitors effectively treats these disorders. However, the clinical significance of the IL6R blockade for ankylosing spondylitis (AS) therapy remains controversial. With advances in genomics, increasing evidence has revealed the role of heritability in the etiology of disease, and Mendelian randomization (MR) analyses are being used more broadly to infer causation. Therefore, this MR study aims to evaluate the potential therapeutic utility of IL6R-targeted approaches in AS. Methods: The C-reactive protein (CRP) level was used as an exposure factor, and rheumatoid arthritis (RA) was used as a positive control. As-related genome-wide association study (GWAS) data were used as the primary outcome of drug-targeted MR analyses to test the relation between IL6R blockers and AS. Inverse variance weighting (IVW) is the primary analytical approach. Various sensitivity tests were performed to check the robustness and trustworthiness of the causality estimation, including consistency, heterogeneity, and pleiotropy analyses. In addition, repeated analysis was conducted using different GWAS data related to exposures and outcomes to examine the results for stability. Results: According to the IVW results, IL6R inhibitors significantly reduced the risk of AS in ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.996, P = 5.12 × 10-08) and ukb-a-88 (OR: 0.994, 95% CI 0.993-0.996, P = 6.25 × 10-15). Moreover, repeated analyses were performed using different exposure-related GWAS data, yielding similar results, ukb-b-18194 (OR: 0.995, 95% CI 0.993-0.997, P = 1.25 × 10-06) and ukb-a-88 (OR: 0.995, 95% CI 0.994-0.997, P = 7.81 × 10-09). Heterogeneity analyses and pleiotropy analyses indicated no significant heterogeneity or pleiotropy. Conclusion: This MR analysis result further validates that the IL-6 pathway may contribute to the pathogenesis of AS and that the inhibition of IL6R reduces the risk of AS. These findings may guide future studies and provide more favorable drug treatment options for people at high risk of AS.

Emergence and ongoing outbreak of ST80 vancomycin-resistant Enterococcus faecium in Guangdong province, China from 2021 to 2023: a multicenter, time-series and genomic epidemiological study.

BACKGROUND: Surveillance systems revealed that the prevalence of vancomycin-resistant Enterococcus faecium (VREfm) has increased. We aim to investigate the epidemiological and genomic characteristics of VREfm in China. METHODS: We collected 20,747 non-redundant E. faecium isolates from inpatients across 19 hospitals in six provinces between January 2018 and June 2023. VREfm was confirmed by antimicrobial susceptibility testing. The prevalence was analyzed using changepoint package in R. Genomic characteristics were explored by whole-genome sequencing. RESULTS: 5.59% (1159/20,747) of E. faecium isolates were resistant to vancomycin. The prevalence of VREfm increased in Guangdong province from 5% before 2021 to 20-50% in 2023 (p < 0.0001), but not in the other five provinces. Two predominant clones before 2021, ST17 and ST78, were substituted by an emerging clone, ST80, from 2021 to 2023 (88.63%, 195/220). All ST80 VREfm from Guangdong formed a single lineage (SC11) and were genetically distant from the ST80 VREfm from other countries, suggesting a regional outbreak. All ST80 VREfm in SC11 carried a new type of plasmid harbouring a vanA cassette, which was embedded in a Tn1546-like structure flanked by IS1678 and ISL3. However, no conjugation-related gene was detected and no transconjugant was obtained in conjugation experiment, indicating that the outbreak of ST80 VREfm could be attributed to clonal transmission. CONCLUSIONS: We revealed an ongoing outbreak of ST80 VREfm with a new vanA-harbouring plasmid in Guangdong, China. This clone has also been identified in other provinces and countries, foreboding a risk of wider spreading shortly. Continuous surveillance is needed to inform public health interventions.

A mini review of reinfection with the SARS-CoV-2 Omicron variant.

Background: COVID-19 has caused severe morbidity and mortality worldwide. After the end of the dynamic zero-COVID policy in China in December, 2022, concerns regarding reinfection were raised while little was known due to the lack of surveillance data in this country. Aims: This study reviews the probability, risk factors, and severity of severe acute respiratory syndrome coronavirus 2 Omicron variant reinfection, as well as the interval between infections, risk of onward transmission by reinfected cases, and the role of booster vaccination against reinfection. Sources: References for this review were identified through searches of PubMed and Web of Science up to September 24, 2023. Results: The rate of reinfection ranges from 3.1% to 13.0%. Factors associated with a higher risk of reinfection include being female, having comorbidities, and being unvaccinated. Reinfection with the BA.4 or BA.5 variant occurs approximately 180 days after the initial infection. Reinfections are less clinically severe than primary infections, and there is evidence of lower transmissibility. The debate surrounding the effectiveness and feasibility of booster vaccinations in preventing reinfection continues. Conclusions: The reinfection rate during the Omicron epidemic is significantly higher than in previous epidemic periods. However, the symptoms and infectivity of reinfection were weaker than those of the prior infection. Medical staff and individuals at high risk of reinfection should be vigilant. The efficacy of booster vaccinations in reducing reinfection is currently under debate.

Blood culture quality and turnaround time of clinical microbiology laboratories in Chinese Teaching Hospitals: A multicenter study.

PURPOSE: Blood culture (BC) remains the gold standard for the diagnosis of bloodstream infections. Improving the quality of clinical BC samples, optimizing BC performance, and accelerating antimicrobial susceptibility test (AST) results are essential for the early detection of bloodstream infections and specific treatments. METHODS: We conducted a retrospective multicenter study using 450,845 BC specimens from clinical laboratories obtained from 19 teaching hospitals between 1 January 2021 and 31 December 2021. We evaluated key performance indicators (KPIs), turnaround times (TATs), and frequency distributions of processing in BC specimens. We also evaluated the AST results of clinically significant isolates for four different laboratory workflow styles. RESULTS: Across the 10 common bacterial isolates (n = 16,865) and yeast isolates (n = 1011), the overall median (interquartile range) TATs of AST results were 2.67 (2.05-3.31) and 3.73 (2.98-4.64) days, respectively. The specimen collections mainly occurred between 06:00 and 24:00, and specimen reception and loadings mainly between 08:00 and 24:00. Based on the laboratory workflows of the BCs, 16 of the 19 hospitals were divided into four groups. Time to results (TTRs) from specimen collection to the AST reports were 2.35 (1.95-3.06), 2.61 (1.98-3.32), 2.99 (2.60-3.87), and 3.25 (2.80-3.98) days for groups I, II, III, and IV, respectively. CONCLUSION: This study shows the related BC KPIs and workflows in different Chinese hospitals, suggesting that laboratory workflow optimization can play important roles in shortening time to AST reports and initiation of appropriate timely treatment.

Co-Occurrence of tet(X4) and blaNDM-5 in Escherichia coli Isolates of Inpatient Origin in Guangzhou, China.

Tigecycline, one of the last-resort therapeutic options for complicated infections caused by multidrug-resistant pathogens, especially carbapenem-resistant Enterobacterales and Acinetobacter in recent years. The emergence of antibiotic-resistant bacteria and antibiotic-resistant genes has threatened the effectiveness of antibiotics and public health with the excessive use of antibiotics in clinics. However, the emergence and dissemination of high-level mobile tigecycline-resistance gene tet(X) is challenging for clinical effectiveness of antimicrobial agent. This study aimed to characterize an E. coli strain T43, isolated from an inpatient in a teaching hospital in China. The E. coli T43 was resistant to almost all antimicrobials except colistin and consisted of a 4,774,080 bp chromosome and three plasmids. Plasmids pT43-1 and pT43-2 contained tigecycline-resistance gene tet(X4). Plasmid pT43-1 had a size of 152,423 bp with 51.05% GC content and harbored 151 putative open reading frames. pT43-1 was the largest plasmid in strain T43 and carried numerous resistance genes, especially tigecycline resistance gene tet(X4) and carbapenemase resistance gene blaNDM-5. The tet(X) gene was associated with IS26. Co-occurrence of numerous resistance genes in a single plasmid possibly contributed to the dissemination of these genes under antibiotics stress. It might explain the presence of clinically crucial resistance genes tet(X) and blaNDM-5 in clinics. This study suggested the applicable use of antibiotics and continued surveillance of tet(X) and blaNDM-5 in clinics are imperative.

Genomic Characterization of Escherichia coli Co-Producing KPC-2 and NDM-5 Carbapenemases Isolated from Intensive Care Unit in a Chinese Hospital.

Background: Around the world, carbapenemase-producing Escherichia coli is becoming more prevalent. The purpose of this research was to analyze the whole plasmid sequences from YL03 isolates of the E. coli strain that produce both KPC-2 and NDM-5 carbapenemases. Materials and Methods: Whole-genome sequencing (WGS) and analysis of E. coli strain YL03, which was isolated from a wound sample, was performed by Illumina Novaseq 6000 and Pacific Biosciences Sequel (PacBio, Menlo Park, CA) sequencers. Following that, the WGS results were used to predict and analyze the YL03 genome composition and function. A complete gene sequence for YL03 with the accession number CP093551 has been uploaded to GenBank. Results: The results showed that YL03 co-carried five resistance genes, which included blaKPC-2, blaNDM-5, blaTEM-1B, blaCTX-M-14, and mdf(A). Furthermore, three resistance plasmids were found in YL03: pYL03-KPC, pYL03-NDM, and pYL03-CTX. Among them, the 53 kb-long pYL03-KPC plasmid belonging to the IncP, carried the replicase gene (repA) and the carbapenemase gene (blaKPC-2). The blaKPC-2 gene was flanked by a composite transposon-like element (Tn3-[Tn3] tnpR-ISKpn27 blaKPC--ISKpn6). Conclusions: The YL03 strain co-carried blaKPC-2 and blaNDM-5 and had a unique multidrug resistance plasmid containing blaKPC-2.

Cerebrospinal fluid metabolomic and proteomic characterization of neurologic post-acute sequelae of SARS-CoV-2 infection.

The mechanism by which SARS-CoV-2 causes neurological post-acute sequelae of SARS-CoV-2 (neuro-PASC) remains unclear. Herein, we conducted proteomic and metabolomic analyses of cerebrospinal fluid (CSF) samples from 21 neuro-PASC patients, 45 healthy volunteers, and 26 inflammatory neurological diseases patients. Our data showed 69 differentially expressed metabolites and six differentially expressed proteins between neuro-PASC patients and healthy individuals. Elevated sphinganine and ST1A1, sphingolipid metabolism disorder, and attenuated inflammatory responses may contribute to the occurrence of neuro-PASC, whereas decreased levels of 7,8-dihydropterin and activation of steroid hormone biosynthesis may play a role in the repair process. Additionally, a biomarker cohort consisting of sphinganine, 7,8-dihydroneopterin, and ST1A1 was preliminarily demonstrated to have high value in diagnosing neuro-PASC. In summary, our study represents the first attempt to integrate the diagnostic benefits of CSF with the methodological advantages of multi-omics, thereby offering valuable insights into the pathogenesis of neuro-PASC and facilitating the work of neuroscientists in disclosing different neurological dimensions associated with COVID-19.

Genetically predicted triglycerides mediate the relationship between type 2 diabetes Mellitus and intervertebral disc degeneration.

BACKGROUND: To validate the causal relationship between type 2 diabetes mellitus (T2DM) and intervertebral disc degeneration (IVDD) and to identify and quantify the role of triglycerides (TGs) as potential mediators. METHODS: A two-sample Mendelian randomization (MR) analyses of T2DM (61,714 cases and 1178 controls) and IVDD (20,001 cases and 164,682 controls) was performed using genome-wide association studies (GWAS). Moreover, two-step MR was employed to quantify the proportionate impact of TG-mediated T2DM on IVDD. RESULTS: MR analysis showed that T2DM increased IVDD risk (OR: 1.0466, 95% CI 1.0049-1.0899, P = 0.0278). Reverse MR analyses demonstrated that IVDD does not affect T2DM risk (P = 0.1393). The proportion of T2DM mediated through TG was 11.4% (95% CI 5.5%-17.4%). CONCLUSION: This work further validates the causality between T2DM and IVDD, with a part of the effect mediated by TG, but the greatest impacts of T2DM on IVDD remain unknown. Further studies are needed to identify other potential mediators.

Trial of the Pluslife SARS-CoV-2 Nucleic Acid Rapid Test Kit: Prospective Cohort Study.

BACKGROUND: In response to the SARS-CoV-2 epidemic, a convenient, rapid, and sensitive diagnostic method for detecting COVID-19 is crucial for patient control and timely treatment. OBJECTIVE: This study aimed to validate the detection of SARS-CoV-2 with the Pluslife SARS-CoV-2 rapid test kit developed based on a novel thermostatic amplification technique called RNase hybridization-assisted amplification. METHODS: From November 25 to December 8, 2022, patients with suspected or confirmed COVID-19, close contacts, and health care workers at high risk of exposure were recruited from 3 hospitals and 1 university. Respiratory specimens were collected for testing with the Pluslife SARS-CoV-2 rapid test kit and compared with reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and a commercial antigen assay kit. Samples from 1447 cases were obtained from 3 "ready-to-test" scenarios in which samples were collected on site and tested immediately, and samples from 503 cases were obtained from a "freeze-thaw test" scenario in which samples were collected, frozen, and thawed for testing. RESULTS: Pluslife SARS-CoV-2 rapid testing of samples from the "ready-to-test" scenario was found to be accurate (overall sensitivity and specificity of 98.3% and 99.3%, respectively) and diagnostically useful (positive and negative likelihood ratios of 145.45 and 0.02, respectively). Pluslife SARS-CoV-2 rapid testing of samples from the "freeze-thaw test" scenario was also found to be accurate (overall sensitivity and specificity of 71.2% and 98.6%, respectively) and diagnostically useful (positive and negative likelihood ratios of 51.01 and 0.67, respectively). Our findings demonstrated that the time efficiency and accuracy of the results in a "ready-to-test" scenario were better. The time required from sample preparation to the seeing the result of the Pluslife SARS-CoV-2 rapid test was 10 to 38 minutes, which was substantially shorter than that of RT-qPCR (at least 90 minutes). In addition, the diagnostic efficacy of the Pluslife SARS-CoV-2 rapid test was better than that of a commercial antigen assay kit. CONCLUSIONS: The developed RNase hybridization-assisted amplification assay provided rapid, sensitive, and convenient detection of SARS-CoV-2 infection and may be useful for enhanced detection of COVID-19 in homes, high-risk industries, and hospitals.

An unusual presentation of ossified spinal meningioma: case report and literature review.

Background: Spinal meningioma is a common intraspinal tumor, which mainly occurs in the thoracic spine. Ossified meningioma (OSM) is an extremely rare histological variant. Our article reports a rare patient with dorsal complete OSM and reviews this subject. Case presentation: A 68-year-old woman presented with a one-year history of progressive weakness in both lower limbs with gait disturbance. Physical examination revealed hypoesthesia with a sensory level below T10. Babinski and pathological signs on both sides were weakly positive. Magnetic resonance imaging (MRI) showed a mass at the T10 to T11 level causing severe compression of the spinal cord. Computed tomography (CT) showed complete ossification of the mass. 18F-Fluoro-deoxy-glucose positron emission tomography CT (18F-FDG PET/CT) scan combined with MRI revealed that the mass was an intradural extramedullary high-density ossified nodule. The patient underwent a gross total resection of the mass and pathologic examination indicated that the mass was a meningioma with diffused psammomatous bodies. Conclusion: We identified a rare case of dorsal complete OSM occurring in a 68-year-old woman. After complete surgical resection, although there were complications such as cerebral fluid leakage and fever, the patient finally recovered with a satisfactory result.

Resistome and Genome Analysis of an Extensively Drug-Resistant Klebsiella michiganensis KMIB106: Characterization of a Novel KPC Plasmid pB106-1 and a Novel Cointegrate Plasmid pB106-IMP Harboring blaIMP-4 and blaSHV-12.

Klebsiella michiganensis is a recently emerging human pathogen causing nosocomial infections. This study aimed to characterize the complete genome sequence of a clinical Klebsiella michiganensis strain KMIB106 which exhibited extensive drug-resistance. The whole genome of the strain was sequenced using PacBio RS III systems and Illumina Nextseq 500. Annotation, transposable elements and resistance gene identification were analyzed by RAST, prokka and Plasmid Finder, respectively. According to the results, KMIB106 was resistant to multiple antimicrobials, including carbapenems, but it remained susceptible to aztreonam. The genome of KMIB106 consisted of a single chromosome and three predicted plasmids. Importantly, a novel KPC plasmid pB106-1 was found to carry the array of resistance genes in a highly different order in its variable regions, including mphA, msrE, mphE, ARR-3, addA16, sul1, dfrA27, tetD and fosA3. Plasmid pB106-2 is a typical IncFII plasmid with no resistant gene. Plasmid pB106-IMP consists of the IncN and IncX3 backbones, and two resistance genes, blaIMP-4 and blaSHV-12, were identified. Our study for the first time reported an extensively drug-resistant Klebsiella michiganensis strain recovered from a child with a respiratory infection in Southern China, which carries three mega plasmids, with pB106-1 firstly identified to carry an array of resistance genes in a distinctive order, and pB106-IMP identified as a novel IncN-IncX3 cointegrate plasmid harboring two resistance genes blaIMP-4 and blaSHV-12.

Raman-Based Antimicrobial Susceptibility Testing on Antibiotics of Last Resort.

Background: Antibiotic resistance represents a serious global health challenge, particularly with the emergence of strains resistant to last-resort antibiotics such as tigecycline, polymyxin B, and vancomycin. Urgent measures are required to alleviate this situation. To facilitate the judicious use of antibiotics, rapid and precise antimicrobial susceptibility testing (AST) is essential. Heavy water (deuterium oxide, D2O)-labeled Raman spectroscopy has emerged as a promising time-saving tool for microbiological testing. Methods: Deuterium incorporation and experimental conditions were examined to develop and apply a Raman-based AST method to evaluate the efficacy of last-resort antibiotics, including tigecycline, polymyxin B, and vancomycin, against Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecium. Essential agreement and categorical agreement were used to assess the metabolism inactivation concentration based on Raman spectroscopy (R-MIC)-a new metric developed in this study-and minimum inhibitory concentration (MIC) determined via the traditional microdilution broth method. Spearman's rank correlation coefficient was employed to measure the association between R-MIC and MIC values. Results: The Raman-based AST method achieved a 100% categorical agreement (92/92) with the traditional microdilution broth method within five hours, while the traditional method required approximately 24 h. The R-MIC values shared 68.5% (63/92) consistency with the MIC values. In addition, the R-MIC and MIC values were highly correlated (Spearman's r=0.96), resulting in an essential agreement of 100%. Conclusion: Our optimized experimental method and conditions indicate that Raman-based AST holds great promise as a solution to overcome the time-consuming challenges of traditional AST methods.

Pan-cancer analysis of the intervertebral-disc-degeneration-related innate immunity gene NAIP.

BACKGROUND: Intervertebral disc degeneration (IDD) is a progressive chronic condition that commonly causes low back pain. Cancer is among the primary reasons for deaths worldwide. Our purpose was to identify the characteristic genes of IDD and explore the potential association between IDD and cancer. METHODS: Immune cell infiltration and differentially expressed analysis were conducted utilizing data from the GSE124272 database. Enrichment analysis of differentially expressed genes (DEGs) was performed to explore the possible mechanisms underlying IDD development. Moreover, weighted gene correlation network analysis (WGCNA) was applied to select IDD-related hub genes. The immune-related key genes were determined by intersecting DEGs, IDD-related hub genes, and immune genes. Subsequently, machine learning models based on these genes were built to identify and verify the characteristic genes. RNA sequencing and clinical data of 33 carcinoma categories were obtained from the Cancer Genome Atlas (TCGA). The association between NAIP expression and prognosis was calculated using the Kaplan-Meier analysis. To gain a deeper understanding of the impact of NAIP in tumor immunotherapy, the association between NAIP and immune infiltration and two immunotherapeutic biomarkers were explored. Ultimately, the association between NAIP and immunotherapeutic response was investigated utilizing two independent cohorts. RESULTS: NAIP was identified as an immune-related characteristic gene between IDD and normal intervertebral disc tissue. In certain carcinoma categories, NAIP expression levels were elevated (4/33) and significantly correlated to the respective tumor stage (4/21). Survival analysis revealed that the expression levels of NAIP have prognostic significance in different cancer types. Generally, NAIP presented a strong association with immune cell infiltration and modulators. NAIP may influence immunotherapy effects through tumor mutational burden and microsatellite instability. No remarkable association between NAIP and immunotherapy response was found in either cohort. CONCLUSION: Our study is the first to identify NAIP as an immune-related characteristic gene. Pan-cancer analysis revealed that NAIP could serve as a novel clinical prognostic marker and therapeutic target for a variety of carcinoma categories, reducing the risk of IDD in tumor patients.

Whole-genome sequencing reveals high-risk clones of Pseudomonas aeruginosa in Guangdong, China.

The ever-increasing prevalence of infections produced by multidrug-resistant or extensively drug-resistant Pseudomonas aeruginosa is commonly linked to a limited number of aptly-named epidemical 'high-risk clones' that are widespread among and within hospitals worldwide. The emergence of new potential high-risk clone strains in hospitals highlights the need to better and further understand the underlying genetic mechanisms for their emergence and success. P. aeruginosa related high-risk clones have been sporadically found in China, their genome sequences have rarely been described. Therefore, the large-scale sequencing of multidrug-resistance high-risk clone strains will help us to understand the emergence and transmission of antibiotic resistances in P. aeruginosa high-risk clones. In this study, 212 P. aeruginosa strains were isolated from 2 tertiary hospitals within 3 years (2018-2020) in Guangdong Province, China. Whole-genome sequencing, multi-locus sequence typing (MLST) and antimicrobial susceptibility testing were applied to analyze the genomic epidemiology of P. aeruginosa in this region. We found that up to 130 (61.32%) of the isolates were shown to be multidrug resistant, and 196 (92.45%) isolates were Carbapenem-Resistant Pseudomonas aeruginosa. MLST analysis demonstrated high diversity of sequence types, and 18 reported international high-risk clones were identified. Furthermore, we discovered the co-presence of exoU and exoS genes in 5 collected strains. This study enhances insight into the regional research of molecular epidemiology and antimicrobial resistance of P. aeruginosa in China. The high diversity of clone types and regional genome characteristics can serve as a theoretical reference for public health policies and help guide measures for the prevention and control of P. aeruginosa resistance.

New Insights in Molecular Mechanisms in Antimicrobial Resistance and Strategies in Anti-Biofilms.

This topical collection, entitled "Antimicrobial resistance and anti-biofilms", was first launched in the journal Antibiotics in November of 2020 [...].

Epidemiological and Genetic Characteristics of Clinical Carbapenem-Resistant Pseudomonas aeruginosa Strains in Guangdong Province, China.

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a bacterial pathogen that may cause serious drug-resistant infections that are potentially fatal. To investigate the genetic characteristics of these organisms, we tested 416 P. aeruginosa strains recovered from 12 types of clinical samples collected in 29 different hospital wards in 10 hospitals in Guangdong Province, China, from 2017 to 2020. These strains were found to belong to 149 known sequence types (STs) and 72 novel STs, indicating that transmission of these strains involved multiple routes. A high rate of resistance to imipenem (89.4%) and meropenem (79.4%) and a high prevalence of pathogenic serotypes (76.4%) were observed among these strains. Six STs of global high-risk clones (HiRiCs) and a novel HiRiC strains, ST1971, which exhibited extensive drug resistance, were identified. Importantly, ST1971 HiRiC, which was unique in China, also exhibited high virulence, which alarmed the further surveillance on this highly virulent and highly resistant clone. Inactivation of the oprD gene and overexpression of efflux systems were found to be mainly responsible for carbapenem resistance in these strains; carriage of metallo-ß-lactamase (MBL)-encoding genes was less common. Interestingly, frameshift mutations (49.0%) and introduction of a stop codon (22.4%) into the oprD genes were the major mechanisms of imipenem resistance. On the other hand, expression of the MexAB-OprM efflux pump and MBL-encoding genes were mechanisms of resistance in >70% of meropenem-resistant strains. The findings presented here provide insights into the development of effective strategies for control of worldwide dissemination of CRPA. IMPORTANCE Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a major concern in clinical settings worldwide, yet few genetic and epidemiological studies on CRPA strains have been performed in China. Here, we sequence and analyze the genomes of 416 P. aeruginosa strains from hospitals in China to elucidate the genetic, phenotypic, and transmission characteristics of CRPA strains and to identify the molecular signatures responsible for the observed increase in the prevalence of CRPA infections in China. These findings may provide new insight into the development of effective strategies for worldwide control of CRPA and minimize the occurrence of untreatable infections in clinical settings.