Reducing pressure with the goal of improving outcomes: a retrospective chart review of cushion evaluations and recommendations at one seating clinic.

Purpose: To describe the current seating recommendations made by a seating clinic for wheelchair users who presented with a Pressure Injury (PrI) or history of PrI.

Methods: Retrospective review of electronic medical records of 133 adults who used a wheelchair as their primary means of mobility who had a cushion evaluation during which interface pressure mapping data was documented.

Results: Clinicians adjusted 71% of participants' wheelchair cushions, including 49% who received a new cushion, and 37% of participants' wheelchairs.

Discovery of Covalent Bruton's Tyrosine Kinase Inhibitors with Decreased CYP2C8 Inhibitory Activity.

Bruton's tyrosine kinase (BTK) is a member of the Tec kinase family that is expressed in cells of hematopoietic lineage. Evidence has shown that inhibition of BTK has clinical benefit for the treatment of a wide array of autoimmune and inflammatory diseases. Previously we reported the discovery of a novel nicotinamide selectivity pocket (SP) series of potent and selective covalent irreversible BTK inhibitors.

Flexible Fragment Growing Boosts Potency of Quorum-Sensing Inhibitors against Pseudomonas aeruginosa Virulence.

Hit-to-lead optimization is a critical phase in drug discovery. Herein, we report on the fragment-based discovery and optimization of 2-aminopyridine derivatives as a novel lead-like structure for the treatment of the dangerous opportunistic pathogen Pseudomonas aeruginosa. We pursue an innovative treatment strategy by interfering with the Pseudomonas quinolone signal (PQS) quorum sensing (QS) system leading to an abolishment of bacterial pathogenicity.

Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa.

The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target.

Crocadepsins-Depsipeptides from the Myxobacterium Chondromyces crocatus Found by a Genome Mining Approach.

Analysis of the genome sequence of the myxobacterium Chondromyces crocatus Cm c5 revealed the presence of numerous cryptic megasynthetase gene clusters, one of which we here assign to two previously unknown chlorinated metabolites by a comparative gene inactivation and secondary metabolomics approach. Structure elucidation of these compounds revealed a unique cyclic depsipeptide skeleton featuring β- and δ-amide bonds of aspartic acid and 3-methyl ornithine moieties, respectively. Insights into their biosynthesis were obtained by targeted gene inactivation and feeding experiments employing isotope-labeled precursors.

In-depth Profiling of MvfR-Regulated Small Molecules in after Quorum Sensing Inhibitor Treatment.

is a Gram-negative bacterium, which causes opportunistic infections in immuno-compromised individuals. Due to its multiple resistances toward antibiotics, the development of new drugs is required. Interfering with Quorum Sensing (QS), a cell-to-cell communication system, has shown to be highly efficient in reducing pathogenicity.

Discovery of the first small-molecule CsrA-RNA interaction inhibitors using biophysical screening technologies.

Aim: CsrA is a global post-transcriptional regulator protein affecting mRNA translation and/or stability. Widespread among bacteria, it is essential for their full virulence and thus represents a promising anti-infective drug target. Therefore, we aimed at the discovery of CsrA-RNA interaction inhibitors.

Dissecting the Multiple Roles of PqsE in Pseudomonas aeruginosa Virulence by Discovery of Small Tool Compounds.

Pseudomonas aeruginosa uses quorum sensing (QS) as a cell-to-cell communication system to orchestrate the expression of virulence determinants. The biosynthesis of the important Pseudomonas quinolone signal (PQS) requires the pqsABCDE operon. Here, PqsE acts as a pathway-specific thioesterase, but it also contributes to the regulation of bacterial virulence via an unknown mechanism.

Antibiotic-free nanotherapeutics: ultra-small, mucus-penetrating solid lipid nanoparticles enhance the pulmonary delivery and anti-virulence efficacy of novel quorum sensing inhibitors.

Cystic fibrosis (CF) is a genetic disease mainly manifested in the respiratory tract. Pseudomonas aeruginosa (P. aeruginosa) is the most common pathogen identified in cultures of the CF airways, however, its eradication with antibiotics remains challenging as it grows in biofilms that counterwork human immune response and dramatically decrease susceptibility to antibiotics.

Optimization of anti-virulence PqsR antagonists regarding aqueous solubility and biological properties resulting in new insights in structure-activity relationships.

Increasing antibiotic resistance urgently requires novel therapeutic options to combat bacterial infections. The anti-virulence therapy selectively intervening with pathogenicity without affecting bacterial viability is such a strategy to overcome resistance. We consider the virulence regulator PqsR as an attractive target in the human pathogen Pseudomonas aeruginosa, and recently discovered the first PqsR antagonists, which, however, suffered from poor aqueous solubility.

Overcoming the unexpected functional inversion of a PqsR antagonist in Pseudomonas aeruginosa: an in vivo potent antivirulence agent targeting pqs quorum sensing.

The virulence regulator PqsR of Pseudomonas aeruginosa is considered as an attractive target for attenuating the bacterial pathogenicity without eliciting resistance. However, despite efforts and desires, no promising PqsR antagonist has been discovered thus far. Now, a surprising functionality change of a highly affine PqsR antagonist in P.

Development and validation of a UHPLC-MS/MS procedure for quantification of the Pseudomonas Quinolone Signal in bacterial culture after acetylation for characterization of new quorum sensing inhibitors.

The appearance of antibiotic resistance requires novel therapeutic strategies. One approach is to selectively attenuate bacterial pathogenicity by interfering with bacterial cell-to-cell communication known as quorum sensing. The PQS quorum sensing system of Pseudomonas aeruginosa employs as signal molecule the Pseudomonas Quinolone Signal (PQS; 2-heptyl-3-hydroxy-4-(1H)-quinolone), a key contributor to virulence and biofilm formation.

Discovery and biophysical characterization of 2-amino-oxadiazoles as novel antagonists of PqsR, an important regulator of Pseudomonas aeruginosa virulence.

The human pathogen Pseudomonas aeruginosa employs alkyl quinolones for cell-to-cell communication. The Pseudomonas quinolone signal (PQS) regulates various virulence factors via interaction with the transcriptional regulator PqsR. Therefore, we consider the development of PqsR antagonists a novel strategy to limit the pathogenicity of P.

Molecular basis of HHQ biosynthesis: molecular dynamics simulations, enzyme kinetic and surface plasmon resonance studies.

Background: PQS (PseudomonasQuinolone Signal) and its precursor HHQ are signal molecules of the P. aeruginosa quorum sensing system. They explicate their role in mammalian pathogenicity by binding to the receptor PqsR that induces virulence factor production and biofilm formation.

Validation of PqsD as an anti-biofilm target in Pseudomonas aeruginosa by development of small-molecule inhibitors.

2-Heptyl-4-hydroxyquinoline (HHQ) and Pseudomonas quinolone signal (PQS) are involved in the regulation of virulence factor production and biofilm formation in Pseudomonas aeruginosa. PqsD is a key enzyme in the biosynthesis of these signal molecules. Using a ligand-based approach, we have identified the first class of PqsD inhibitors.

Influence of DNA template choice on transcription and inhibition of Escherichia coli RNA polymerase.

In recent decades, quantitative transcription assays using bacterial RNA polymerase (RNAP) have been performed under widely diverse experimental conditions. We demonstrate that the template choice can influence the inhibitory potency of RNAP inhibitors. Furthermore, we illustrate that the sigma factor (σ(70)) surprisingly increases the transcription efficiency of templates with nonphysiological nonprokaryotic promoters.

Discovery of antagonists of PqsR, a key player in 2-alkyl-4-quinolone-dependent quorum sensing in Pseudomonas aeruginosa.

The pqs quorum sensing communication system of Pseudomonas aeruginosa controls virulence factor production and is involved in biofilm formation, therefore playing an important role for pathogenicity. In order to attenuate P. aeruginosa pathogenicity, we followed a ligand-based drug design approach and synthesized a series of compounds targeting PqsR, the receptor of the pqs system.

Load redistribution in variable position wheelchairs in people with spinal cord injury.

Background/objective: Tilt and recline variable position seating systems are most commonly used for pressure relief to decrease potential for skin breakdown. This study provides quantitative information on the magnitudes of loading on the seat and back during phases of tilt, recline, and standing. The objective of this study was to show that the amount of force reduction at the seat would differ across these 3 methods within their respective clinical ranges.

The participation and activity measurement system: an example application among people who use wheeled mobility devices.

Purpose: To present the Participation and Activity Measurement System (PAMS), a system designed to examine activity and participation among people who use wheeled mobility devices.

Methods: Description of PAMS' components and an example of its application among people who use tilt-in-space wheelchairs.

Results: PAMS combines objective and subjective descriptions of mobility-based activities within a person's home and community.

Use of power tilt systems in everyday life.

Purpose: The goal of this study was to monitor and describe the use of power tilt systems in everyday life. Additionally, tilt measurements were used to determine if participants performed regular pressure relieves.

Methods: Wheelchair occupancy and seat position of 16 fulltime power wheelchair users were monitored regularly for 1-2 weeks.