Effect of Blood Product Resuscitation on Cefazolin Pharmacokinetics in Trauma Patients.

Antibiotics are frequently administered prophylactically to trauma patients with various injury patterns to prevent infectious complications. Trauma patients may also require large volume resuscitation with blood products. Limited data are available to support antibiotic dosing recommendations in this population.

Imipenem/funobactam (formerly XNW4107) in vivo pharmacodynamics against serine carbapenemase-producing Gram-negative bacteria: a novel modelling approach for time-dependent killing.

Background: Imipenem/funobactam (formerly XNW4107) is a novel β-lactam/β-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains.

Methods: Dose-fractionation was conducted against three strains.

Cefiderocol is Not Sequestered in an Ex Vivo Extracorporeal Membrane Oxygenation (ECMO) Circuit.

Background And Objective: Extracorporeal membrane oxygenation (ECMO) is used in critically ill patients that require respiratory and/or cardiac support. Cefiderocol is a novel siderophore antibiotic that may require use in infected critically ill patients supported by ECMO. The objective of this study was to determine the loss of cefiderocol through an ex vivo adult ECMO circuit using a Quadrox-iD oxygenator.

Pharmacodynamic Thresholds for Beta-Lactam Antibiotics: A Story of Mouse Man.

Beta-lactams remain a critical member of our antibiotic armamentarium and are among the most commonly prescribed antibiotic classes in the inpatient setting. For these agents, the percentage of time that the free concentration remains above the minimum inhibitory concentration (%T > MIC) of the pathogen has been shown to be the best predictor of antibacterial killing effects. However, debate remains about the quantity of T > MIC exposure needed for successful clinical response.

Engineering stability, longevity, and miscibility of microtubule-based active fluids.

Microtubule-based active matter provides insight into the self-organization of motile interacting constituents. We describe several formulations of microtubule-based 3D active isotropic fluids. Dynamics of these fluids is powered by three types of kinesin motors: a processive motor, a non-processive motor, and a motor which is permanently linked to a microtubule backbone.

The potential of a lecture series in changing intent and experience among health professionals to conduct research in a large hospital: a retrospective pre-post design.

Background: Promoting research capacity within public health can encourage and engage employees to undertake research, utilising their understanding of the complex needs that exist within the public health system to provide more relevant research outcomes. Despite this, there are a number of reasons cited by health care professionals as to why research is not undertaken, and a lack of support for research participation results in missed opportunities for experienced clinical and public health staff to gain research experience, expand the evidence base, and promote and support research. The aim of this study is to identify if education in research, delivered through a series of lectures at a large tertiary referral hospital, results in an increase in the experience and intent to conduct research.

In vivo selective inhibition of TRPC6 by antagonist BI 749327 ameliorates fibrosis and dysfunction in cardiac and renal disease.

Transient receptor potential canonical type 6 (TRPC6) is a nonselective receptor-operated cation channel that regulates reactive fibrosis and growth signaling. Increased TRPC6 activity from enhanced gene expression or gain-of-function mutations contribute to cardiac and/or renal disease. Despite evidence supporting a pathophysiological role, no orally bioavailable selective TRPC6 inhibitor has yet been developed and tested in vivo in disease models.

Proteolytic cleavage of host proteins by the Group IV viral proteases of Venezuelan equine encephalitis virus and Zika virus.

The alphaviral nonstructural protein 2 (nsP2) cysteine proteases (EC 3.4.22.

Ethical considerations in the management of Ebola virus disease.

Is it ethically appropriate in some circumstances for HCWs to decline to care for patients with EVD? How should treatment decisions be made regarding limitation of therapy for patients with EVD? There are two main ethical questions regarding the critical care of patients with EVD in an Australian setting: Is it ethically appropriate in some circumstances for HCWs to decline to care for patients with EVD? How should treatment decisions be made regarding limitation of therapy for patients with EVD? The key concern is ensuring that no patient is denied therapy that should be provided, while preventing unnecessary risk to HCWs. It is imperative to develop an approach that facilitates rigorous, evidence-based and ethically justifiable decision making, which should include a predetermined, institutionally endorsed process for assessing difficult clinical scenarios as they arise.

Selective CB2 receptor agonists. Part 3: the optimization of a piperidine-based series that demonstrated efficacy in an in vivo neuropathic pain model.

A novel class of potent cannabinoid receptor 2 (CB2) agonists based on a (S)-piperidine scaffold was identified using ligand-based pharmacophore models. Optimization of solubility and metabolic stability led to the identification of several potent CB2 agonists (e.g.

Selective CB2 receptor agonists. Part 1: the identification of novel ligands through computer-aided drug design (CADD) approaches.

Computer-aided drug design scaffold hopping strategies were utilized to identify new classes of CB2 agonists when compounds of an established series with low nanomolar potency were challenging to optimize for good drug-like properties. Use of ligand-based design strategies through BI Builder (a tool for de novo design) and PharmShape (a virtual screening software package) approaches led to the discovery of new chemotypes. Specifically, compounds containing azetidine-, proline-, and piperidine-based cores were found to have low nanomolar and picomolar CB2 agonist activities with drug-like properties considered appropriate for early profiling.

Selective CB2 receptor agonists. Part 2: Structure-activity relationship studies and optimization of proline-based compounds.

Through a ligand-based pharmacophore model (S)-proline based compounds were identified as potent cannabinoid receptor 2 (CB2) agonists with high selectivity over the cannabinoid receptor 1 (CB1). Structure-activity relationship investigations for this compound class lead to oxo-proline compounds 21 and 22 which combine an impressive CB1 selectivity profile with good pharmacokinetic properties. In a streptozotocin induced diabetic neuropathy model, 22 demonstrated a dose-dependent reversal of mechanical hyperalgesia.

Identification of highly efficacious glucocorticoid receptor agonists with a potential for reduced clinical bone side effects.

Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21.

Medications at school: disposing of pharmaceutical waste.

Background: This project quantified and categorized medications left unclaimed by students at the end of the school year. It determined the feasibility of a model medication disposal program and assessed school nurses' perceptions of environmentally responsible medication disposal.

Methods: At a large urban school district all unclaimed medications were collected at the end of a school year to determine the extent and nature of this problem.

Non-steroidal dissociated glucocorticoid agonists: indoles as A-ring mimetics and function-regulating pharmacophores.

We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays.

Consensus based clinical guideline for oral hygiene in the critically ill.

Objectives: Oropharyngeal colonisation has been identified as a factor contributing to ventilator associated pneumonia (VAP) in the Intensive Care Unit (ICU). We sought to develop a clinical practice guideline for providing oral hygiene in the critically ill.

Research Methodology: Following a systematic literature review a prospectively derived consensus development conference was convened and sponsored by a clinical governance unit.

Worksite wellness program for respiratory disease prevention in heavy-construction workers.

Objective: To describe a respiratory disease prevention program in a US heavy-construction company.

Methods: The program uses periodic spirometry and questionnaires and is integrated into a worksite wellness program involving individualized intervention. Spirometry Longitudinal Data Analysis (SPIROLA) technology is used to assist the physician with (i) management and evaluation of longitudinal spirometry and questionnaire data; (ii) designing, recoding, and implementing intervention; and (iii) evaluation of impact of the intervention.

1,4-Diazepane compounds as potent and selective CB2 agonists: optimization of metabolic stability.

A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified.

Morpholine containing CB2 selective agonists.

Identification and optimization of two classes of CB2 selective agonists are described. A representative from each class is profiled in a murine model of inflammation and each shows similar efficacy to prednisolone upon oral dosing.

Effects of D-cycloserine administration on weekly nonemotional memory tasks in healthy participants.

Background: The application of weekly doses of D-cycloserine (DCS) to the enhancement of exposure-based treatments has been a particular achievement of translational research. It is not known, however, whether this enhancement effect can be extended to other forms of learning. In this study, we investigated the relative benefit of DCS versus placebo for enhancing nonemotional verbal and nonverbal memory across weekly trials.

Extinction retention predicts improvement in social anxiety symptoms following exposure therapy.

Background: Several researchers have argued that basic research on extinction learning can guide efforts to enhance the efficacy of exposure-based therapy. At the basis of this translational research paradigm is the assumption that extinction retention is important to the outcome of exposure-based therapy. This study is the first to examine the relationship between extinction retention, which comprises the amount of fear reduction that is retained between two exposure sessions and improvement in anxiety symptoms following exposure treatment.

Reducing anxiety sensitivity with exercise.

Background: Exercise interventions repeatedly have been shown to be efficacious for the treatment of depression, and initial studies indicate similar efficacy for the treatment of anxiety conditions. To further study the potential beneficial role of prescriptive exercise for anxiety-related conditions, we examined the role of exercise in reducing fears of anxiety-related sensations (anxiety sensitivity).

Methods: We randomly assigned 60 participants with elevated levels of anxiety sensitivity to a 2-week exercise intervention, a 2-week exercise plus cognitive restructuring intervention, or a waitlist control condition.

The efficacy of cognitive-behavioral interventions for reducing anxiety sensitivity: a meta-analytic review.

The present study meta-analytically reviewed the efficacy of cognitive-behavioral therapy (CBT) vs. control conditions in the reduction of anxiety sensitivity. A computerized search was conducted to identify CBT outcome studies that included the Anxiety Sensitivity Index as a dependent variable.

Systematic literature review of oral hygiene practices for intensive care patients receiving mechanical ventilation.

Background: Oropharyngeal colonization with pathogenic organisms contributes to the development of ventilator-associated pneumonia in intensive care units. Although considered basic and potentially nonessential nursing care, oral hygiene has been proposed as a key intervention for reducing ventilator-associated pneumonia. Nevertheless, evidence from randomized controlled trials that could inform best practice is limited.

Discovery and optimization of p38 inhibitors via computer-assisted drug design.

Integration of computational methods, X-ray crystallography, and structure-activity relationships will be disclosed, which lead to a new class of p38 inhibitors that bind to p38 MAP kinase in a Phe out conformation.