Multi-omics informed mathematical model for meropenem and tobramycin against hypermutable Pseudomonas aeruginosa.

Hypermutable P. aeruginosa isolates frequently display resistance emergence during treatment. Mechanisms of such resistance emergence have not been explored using dynamic hollow-fiber studies and multi-omics-informed mathematical modeling.

Aortoduodenal Syndrome: A Rare Case of Duodenal Obstruction Due to Endovascular Aneurysm Endoleak.

Aortoduodenal syndrome results from expansion of an abdominal aortic aneurysm, leading to symptoms of upper gastrointestinal obstruction. Endovascular aneurysm repair of large or symptomatic aortic aneurysms has become an important treatment modality for patients with abdominal aortic aneurysm. However, a large proportion of these grafts are complicated by endoleaks that can lead to a spectrum of significant symptoms.

Cholesterol-terminated cationic lipidated oligomers (CLOs) as a new class of antifungals.

Infections caused by fungal pathogens are a global health problem, and have created an urgent need for new antimicrobial strategies. This report details the synthesis of lipidated 2-vinyl-4,4-dimethyl-5-oxazolone (VDM) oligomers an optimized Cu(0)-mediated reversible-deactivation radical polymerization (RDRP) approach. Cholesterol-Br was used as an initiator to synthesize a library of oligo-VDM (degree of polymerisation = 5, 10, 15, 20, and 25), with an α-terminal cholesterol group.

Sampling and Laboratory Logistics: How to Collect DNA Samples and Overview of Techniques for Laboratory Analysis.

This article discusses different options and best practices for sample types and sample collection devices for downstream genotyping in today's sophisticated animal husbandry systems. Best practices for sample collection, shipping, and submission of samples are shown and an overview of techniques for laboratory analysis is provided. The ultimate goal is to facilitate the generation of useful and meaningful results for the client.

The effects of single and multiple resistance mechanisms on bacterial response to meropenem.

Objectives: Meropenem is commonly used against Pseudomonas aeruginosa. Traditionally, the time unbound antibiotic concentration exceeds the MIC (fT) is used to select carbapenem regimens. We aimed to characterize the effects of different baseline resistance mechanisms on bacterial killing and resistance emergence; evaluate whether fT can predict these effects; and, develop a novel Quantitative and Systems Pharmacology (QSP) model to describe the effects of baseline resistance mechanisms on the time-course of bacterial response.

Providing insight into the mechanism of action of cationic lipidated oligomers using metabolomics.

The increasing resistance of clinically relevant microbes against current commercially available antimicrobials underpins the urgent need for alternative and novel treatment strategies. Cationic lipidated oligomers (CLOs) are innovative alternatives to antimicrobial peptides and have reported antimicrobial potential. An understanding of their antimicrobial mechanism of action is required to rationally design future treatment strategies for CLOs, either in monotherapy or synergistic combinations.

Synergistic effects of inhaled aztreonam plus tobramycin on hypermutable cystic fibrosis Pseudomonas aeruginosa isolates in a dynamic biofilm model evaluated by mechanism-based modelling and whole genome sequencing.

Objective: Hypermutable Pseudomonas aeruginosa strains are highly prevalent in chronic lung infections of patients with cystic fibrosis (CF). Acute exacerbations of these infections have limited treatment options. This study aimed to investigate inhaled aztreonam and tobramycin against clinical hypermutable P.

Identifying and mathematically modeling the time-course of extracellular metabolic markers associated with resistance to ceftolozane/tazobactam in .

Extracellular bacterial metabolites have potential as markers of bacterial growth and resistance emergence but have not been evaluated in dynamic studies. We investigated the dynamic metabolomic footprint of a multidrug-resistant hypermutable isolate exposed to ceftolozane/tazobactam as continuous infusion (4.5 g/day, 9 g/day) in a hollow-fiber infection model over 7-9 days in biological replicates ( = 5).

Ceftolozane-Tazobactam against Pseudomonas aeruginosa Cystic Fibrosis Clinical Isolates in the Hollow-Fiber Infection Model: Challenges Imposed by Hypermutability and Heteroresistance.

Pseudomonas aeruginosa remains a challenge in chronic respiratory infections in cystic fibrosis (CF). Ceftolozane-tazobactam has not yet been evaluated against multidrug-resistant hypermutable P. aeruginosa isolates in the hollow-fiber infection model (HFIM).

Development of a sustained release implant of benzathine penicillin G for secondary prophylaxis of rheumatic heart disease.

Background: Regular intramuscular (i.m.) benzathine penicillin G (BPG) injections have been the cornerstone of rheumatic heart disease (RHD) secondary prophylaxis since the 1950s.

Penicillin G concentrations required for prophylaxis against Group A Streptococcus infection evaluated using a hollow fibre model and mathematical modelling.

Background: Acute rheumatic fever (ARF), an autoimmune reaction to Group A Streptococcus (Streptococcus pyogenes; Strep A) infection, can cause rheumatic heart disease (RHD). New formulations of long-acting penicillins are being developed for secondary prophylaxis of ARF and RHD.

Objectives: To evaluate the penicillin G concentrations required to suppress growth of Strep A.

Effect of Different Piperacillin-Tazobactam Dosage Regimens on Synergy of the Combination with Tobramycin against for the Pharmacokinetics of Critically Ill Patients in a Dynamic Infection Model.

We evaluated piperacillin-tazobactam and tobramycin regimens against isolates from critically ill patients. Static-concentration time-kill studies (SCTK) assessed piperacillin-tazobactam and tobramycin monotherapies and combinations against four isolates over 72 h. A 120 h-dynamic in vitro infection model (IVM) investigated isolates Pa1281 (MIC 4 mg/L, MIC 0.

Simulated Intravenous versus Inhaled Tobramycin with or without Intravenous Ceftazidime Evaluated against Hypermutable Pseudomonas aeruginosa via a Dynamic Biofilm Model and Mechanism-Based Modeling.

Acute exacerbations of chronic respiratory infections in patients with cystic fibrosis are highly challenging due to hypermutable Pseudomonas aeruginosa, biofilm formation and resistance emergence. We aimed to systematically evaluate the effects of intravenous versus inhaled tobramycin (TOB) with and without intravenous ceftazidime (CAZ). Two hypermutable P.

Relationship of molecular breeding value for beef tenderness with heifer traits through weaning of their first calf.

Polymorphisms in μ-calpain (CAPN1) that beneficially associate with beef tenderness are reported to antagonistically associate with calving day in beef heifers and post-partum interval to estrus in beef cows. We, therefore, hypothesized that a molecular breeding value for slice shear force, calculated based on CAPN1 and calpastatin (CAST) genotypes, would demonstrate an antagonistic relationship between genomically predicted slice shear force and ordinal calving date in replacement beef heifers. A secondary objective of this study was to evaluate the association of a polymorphism in diacylglycerol O-acyltransferase (DGAT1) with reproductive traits in beef heifers.

Pharmacodynamics of ceftazidime plus tobramycin combination dosage regimens against hypermutable Pseudomonas aeruginosa isolates at simulated epithelial lining fluid concentrations in a dynamic in vitro infection model.

Objectives: Hypermutable Pseudomonas aeruginosa strains are a major challenge in cystic fibrosis. We investigated bacterial killing and resistance emergence for approved ceftazidime and tobramycin regimens, alone and in combination.

Methods: Pseudomonas aeruginosa PAOΔmutS and six hypermutable clinical isolates were examined using 48-h static concentration time-kill (SCTK) studies (inoculum ~10 CFU/mL); four strains were also studied in a dynamic in vitro model (IVM) (inoculum ~10 CFU/mL).

Evaluation of Meropenem-Ciprofloxacin Combination Dosage Regimens for the Pharmacokinetics of Critically Ill Patients With Augmented Renal Clearance.

Augmented renal clearance (ARC, creatinine clearance > 130 mL/minute) makes difficult achievement of effective concentrations of renally cleared antibiotics in critically ill patients. This study examined the synergistic killing and resistance suppression for meropenem-ciprofloxacin combination dosage regimens against Pseudomonas aeruginosa isolates within the context of ARC. Clinically relevant meropenem and ciprofloxacin concentrations, alone and in combinations, were studied against three clinical isolates with a range of susceptibilities to each of the antibiotics.

A Causality Perspective of Genomic Breed Composition for Composite Animals.

Genomic breed composition (GBC) of an individual animal refers to the partition of its genome according to the inheritance from its ancestors or ancestral breeds. For crossbred or composite animals, knowing their GBC is useful to estimate heterosis, to characterize their actual inheritance from foundation breeds, and to make management decisions for crossbreeding programs. Various statistical approaches have been proposed to estimate GBC in animals, but the interpretations of estimates have varied with these methods.

Using triallelic SNPs for determining parentage in North American yak ( ) and estimating cattle ( ) introgression.

 Genetic testing for pedigree accuracy is critical for managing genetic diversity in North American (NA) yak ( ), a population expanded mostly from imported zoological park specimens.  DNA testing also enhances species conservation by identifying recent F1 hybrid ancestors (within three generations).  Biallelic single nucleotide polymorphisms (SNPs) can accomplish either task, but increases the marker count and costs necessary to achieve both.

Genomic mating as sustainable breeding for Chinese indigenous Ningxiang pigs.

An important economic reason for the loss of local breeds is that they tend to be less productive, and hence having less market value than commercial breeds. Nevertheless, local breeds often have irreplaceable values, genetically and sociologically. In the breeding programs with local breeds, it is crucial to balance the selection for genetic gain and the maintaining of genetic diversity.

Estimation of Genomic Breed Composition for Purebred and Crossbred Animals Using Sparsely Regularized Admixture Models.

A variety of statistical methods, such as admixture models, have been used to estimate genomic breed composition (GBC). These methods, however, tend to produce non-zero components to reference breeds that shared some genomic similarity with a test animal. These non-essential GBC components, in turn, offset the estimated GBC for the breed to which it belongs.

Genome-wide association study of milk production traits in a crossbred dairy sheep population using three statistical models.

Milk production is one of the most important characteristics of dairy sheep, and the identification of genes affecting milk production traits is critical to understanding the genetics and improve milk production in future generations. Three statistical techniques, namely GWAS, ridge-regression BLUP and BayesC , were used to identify SNPs in significant association with three milk production traits (milk yield, fat yield and protein yield) in a crossbred dairy sheep population. The results suggested that chromosomes 1, 3, 4, 5, 7 and 11 were likely to harbor genes important to milk production because these chromosomes had the greatest top-100-SNP variance contributions on the three milk production traits.

Clinically Relevant Epithelial Lining Fluid Concentrations of Meropenem with Ciprofloxacin Provide Synergistic Killing and Resistance Suppression of Hypermutable Pseudomonas aeruginosa in a Dynamic Biofilm Model.

Treatment of exacerbations of chronic infections in patients with cystic fibrosis (CF) is highly challenging due to hypermutability, biofilm formation, and an increased risk of resistance emergence. We evaluated the impact of ciprofloxacin and meropenem as monotherapy and in combination in the dynamic CDC biofilm reactor (CBR). Two hypermutable strains, PAOΔ (MIC of ciprofloxacin [MIC], 0.

Estimation of genomic breed composition of individual animals in composite beef cattle.

Three statistical models (an admixture model, linear regression, and ridge-regression BLUP) and two strategies for selecting SNP panels (uniformly spaced vs. maximum Euclidean distance of SNP allele frequencies between ancestral breeds) were compared for estimating genomic-estimated breed composition (GBC) in Brangus and Santa Gertrudis cattle, respectively. Animals were genotyped with a GeneSeek Genomic Profiler bovine low-density version 4 SNP chip.

A unified local objective function for optimally selecting SNPs on arrays for agricultural genomics applications.

Over the years, ad-hoc procedures were used for designing SNP arrays, but the procedures and strategies varied considerably case by case. Recently, a multiple-objective, local optimization (MOLO) algorithm was proposed to select SNPs for SNP arrays, which maximizes the adjusted SNP information (E score) under multiple constraints, e.g.

Evaluation of genotyping concordance for commercial bovine SNP arrays using quality-assurance samples.

SNP arrays are widely used in genetic research and agricultural genomics applications, and the quality of SNP genotyping data is of paramount importance. In the present study, SNP genotyping concordance and discordance were evaluated for commercial bovine SNP arrays based on two types of quality assurance (QA) samples provided by Neogen GeneSeek. The genotyping discordance rates (GDRs) between chips were on average between 0.