Broemckee5899

Antibiotic collateral sensitivity (CS) occurs when a bacterium that acquires resistance to a treatment drug exhibits decreased resistance to a different drug. Here we identify reciprocal CS networks and candidate genes in Burkholderia multivorans. B. multivorans was evolved to become resistant to each of six antibiotics. The antibiogram of the evolved strain was compared to the immediate parental strain to determine CS and cross-resistance (CR). The evolution process was continued for each resistant strain. CS interactions were observed in 170 of 279 evolved strains. CS patterns grouped into two clusters based on the treatment drug being a beta-lactam antibiotic or not. Reciprocal pairs of CS antibiotics arose in at least 25% of all evolved strains. Sixty-eight evolved strains were subjected to whole-genome sequencing and the resulting mutation patterns were correlated with antibiograms. Analysis revealed there was no single gene responsible for collateral sensitivity (CS), and that CS seen in B. multivorans is likely due to a combination of specific and non-specific mutations. The frequency of reciprocal CS, and the degree to which resistance changed, suggests a long-term treatment strategy; when resistance to one drug occurs, switch to use of the other member of the reciprocal pair. This switching could theoretically be continued indefinitely, allowing life-long treatment of chronic infections with just two antibiotics. V.BACKGROUND We aimed to describe the effect of initial antifungal therapy on the fatality and detail the current distribution and resistance patterns of Candida species among the patients with Candidemia. METHODS A prospective observational study was performed among the consequent patients with Candidemia from 10 medical centers, between January 2015 and November 2018. Primary outcome was defined as 10-day mortality. For species level identification Matrix Assisted Laser Desorption Ionization Time of Flight Mass Spectrometer (MALDI-TOF) was used. RESULTS A total of 342 patients with candidemia were included, 175 (51.2%) were males and 68 (20%) patients were under 18 years old. The most common Candida species were C. albicans (47%), C. parapsilosis (27%), C. tropicalis (10%), C. glabrata (7%). Among all Candida species, the 10-day case fatality rate (CFR) was 32%. The highest CFR was among the patients with C.albicans (57%), the lowest was among C. parapsilosis (22%). The rate of resistance against fluconazole was 13% in C.parapsilosis isolates with no significant effect on fatality. No resistance against echinocandins was detected. In multivariate analysis, being in intensive care unit (OR2.1, CI 1.32-3.57, p=0.002), renal failure (OR2.4, CI 1.41-3.97, p=0.001), total parenteral nutrition (OR2, CI 1.22-3.47, p=0,006) detection of C. albicans (OR1,7 CI 1.06- 2.82, p=0.027), using echinocandin as the primary agent (OR0.6, CI0.36-0.99, p=0.047) were found to be significantly associated with fatality CONCLUSIONS Candidemia is one of the most fatal infections. Resistance to fluconazole is emerging, although it was not related to fatality, significantly. Using echinocandins as the primary agent could be life saving. V.INTRODUCTION Co-existence of both virulence and multidrug-resistant (MDR) determinants on a self-transmissible plasmid facilitates simultaneous transfer of virulence and resistance in a single event and rapid emergence of virulent and MDR Klebsiella pneumoniae clones. METHOD This study identified extensively drug-resistant ST15 strains, KP17-15 and KP17-16, from clinical cases with microbiological and genomical approaches. MK-2206 RESULTS The chromosomes of KP17-15 and KP17-16 were highly homologous with 12 SNP differences, indicating that the two strains were derived from the same clone. Multiple plasmids existed in the isolates, including novel virulence plasmids p17-15-vir (479 kb) and p17-16-vir (290 kb) for KP17-15 and KP17-16, respectively. Notably, the plasmid p17-15-vir (479 kb) was a hybrid plasmid that might be formed by recombination of two homologous regions encoding group II intron reverse transcriptase and mobile element ISShes11 shared by p17-16-vir (290 kb) and a conjugative MDR plasmid p17-16-CTX (188 kb). p17-15-vir was readily transferable to ST11 Klebsiella pneumoniae by conjugation. Moreover, p17-16-vir, a non-conjugative virulence plasmid lacking the transfer (tra) operon, was also transferable by conjugation under the help of p17-16-CTX or p17-16-KPC. Fusion of p17-16-vir with p17-16-CTX into a p17-15-vir-like plasmid was also observed in the transconjugant. CONCLUSION The findings uncover the evolutionary pathway of a novel hybrid virulence MDR plasmid and transfer mechanism of a non-conjugative virulence plasmid. Systematic surveillance of such hybrid virulence MDR plasmids in clinical Klebsiella pneumoniae should be performed. Microglia are the main innate immune cells of the central nervous system (CNS). Unlike neurons and glial cells, which derive from ectoderm, microglia migrate early during embryo development from the yolk-sac, a mesodermal-derived structure. Microglia regulate synaptic pruning during development and induce or modulate inflammation during aging and chronic diseases. Microglia are sensitive to brain injuries and threats, altering their phenotype and function to adopt a so-called immune-activated state in response to any perceived threat to the CNS integrity. Here, we present a short overview on the role of microglia in human neurodegenerative diseases and provide an update on the current model systems to study microglia, including cell lines, iPSC-derived microglia with an emphasis in their transcriptomic profile and integration into 3D brain organoids. We present various strategies to model and study their role in neurodegeneration providing a relevant platform for the development of novel and more effective therapies. Amyotrophic lateral sclerosis (ALS) is a relentless and fatal neurological disease characterized by the selective degeneration of motor neurons. No effective therapy is available for this disease. Several lines of evidence indicate that alteration of RNA metabolism, including microRNA (miRNA) processing, is a relevant pathogenetic factor and a possible therapeutic target for ALS. Here, we showed that the abundance of components in the miRNA processing machinery is altered in a SOD1-linked cellular model, suggesting consequent dysregulation of miRNA biogenesis. Indeed, high-throughput sequencing of the small RNA fraction showed that among the altered miRNAs, miR-129-5p was increased in different models of SOD1-linked ALS and in peripheral blood cells of sporadic ALS patients. We demonstrated that miR-129-5p upregulation causes the downregulation of one of its targets the RNA-binding protein ELAVL4/HuD. ELAVL4/HuD is predominantly expressed in neurons, where it controls several key neuronal mRNAs. Overexpression of pre-miR-129-1 inhibited neurite outgrowth and differentiation via HuD silencing in vitro, while its inhibition with an antagomir rescued the phenotype. Remarkably, we showed that administration of an antisense oligonucleotide (ASO) inhibitor of miR-129-5p to an ALS animal model, SOD1 (G93A) mice, result in a significant increase in survival and improved the neuromuscular phenotype in treated mice. These results identify miR-129-5p as a therapeutic target that is amenable to ASO modulation for the treatment of ALS patients. BACKGROUND CONTEXT Posterior vertebral column resection (PVCR) has several advantages over a combined anterior-posterior procedure for management of severe, rigid spinal deformities. The technique, described by Suk and colleagues, has a high complication rate. Modifications of the technique which can reduce this complication rate might make this challenging procedure safer. PURPOSE To report the results of posterior vertebral column resection (PVCR) in severe, rigid spinal deformity; to describe a modified technique for PVCR and compare its results with the conventional technique STUDY DESIGN Retrospective cohort PATIENT SAMPLE A total of 38 patients who underwent PVCR for severe, rigid spinal deformities OUTCOME MEASURES Mean correction of deformity (sagittal and/or coronal), estimated blood loss (EBL), operation time, neurological and non-neurological complications, patient-reported outcome score (SRS-22r) METHODS Thirty-eight patients underwent PVCR for severe, rigid spinal deformities. These patients had ications with the authors' modified technique. CONCLUSION Our retrospective study with a small cohort suggests that the authors' modified technique of PVCR, wherein the posterior elements are preserved until just prior to attempting to correct the deformity, may be safer in terms of neurological complications when compared to the conventional technique. However, larger studies are warranted to conclusively establish this. Ethanol intake increases plasma concentrations of triglycerides and chronic ethanol use impairs lipid metabolism and causes chronic inflammation. The gut plays an important role in metabolic handling of nutrients, including lipids, and a leaky gut associated with alcohol intake, allowing inflammatory signals to the portal vein, has been proposed to constitute a mechanism by which ethanol induces hepatic inflammation. We compared the effects of enteral and parenteral administration of ethanol on a range of circulating inflammation markers (including soluble CD163, a marker of liver macrophage activation), lipids, cholecystokinin (CCK) and fibroblast growth factor 19 (FGF19) as well as gallbladder volume. On two separate and randomized study days, we subjected healthy men (n=12) to double-blinded intragastric ethanol infusion (IGEI) and isoethanolemic intravenous ethanol infusion (IVEI). Blood was sampled and ultrasonographic evaluation of gallbladder volume was performed at frequent intervals for 4 hours afterth neutral effect on gallbladder volume), increased plasma VLDL cholesterol and triglyceride concentrations; indicating that the enteral route of administration may influence ethanol's effects on lipid metabolism. Alcohol withdrawal syndrome (AWS) is a serious medical condition of high variability in alcohol use disorder (AUD) after drinking cessation. Identifying clinical biomarkers capable of detecting severe AWS is needed. While alcohol consumption and withdrawal are linked with lipid profile dysregulation, the relationship between lipid levels (high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides), and AWS is unknown. Therefore, this study investigated whether HDL-C, LDL-C, and triglycerides conferred risk for moderate-to-severe AWS symptoms in treatment-seeking individuals (N=732) admitted to the National Institute on Alcohol Abuse and Alcoholism (NIAAA) alcohol treatment program. Lipid levels were measured upon admission and the Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) assessed AWS severity for generating a three-level AWS typology (none-to-mild, moderate, and severe). Multivariable multinomial logistic regression examined whether lipid levels were associated with risk for moderate-to-severe AWS. We found significant predictive relationships between AWS and HDL-C, LDL-C, and triglycerides. While extreme-high HDL-C, (≥100 mg/dL), conferred the highest odds for moderate (4.405, 95% CI, 2.572-7.546, P less then 0.001) and severe AWS (5.494, 95% CI, 3.541-8.523, P less then 0.001), lowest odds ratios for moderate AWS (0.493, 95% CI, 0.248-0.981, P = 0.044) and severe AWS (0.303, 95% CI, 0.223-0.411, P less then 0.001) were associated with high LDL-C (≥ 160 mg/dL). The present study demonstrates that altered lipid levels, measured upon admission for inpatient AUD treatment, may help to predict individuals at risk for medically relevant moderate-to-severe AWS. This suggest that further research into the role of lipid biomarkers in AWS may be beneficial for identifying biologically determined risk profiles in AUD. Published by Elsevier Inc.