PI3Kγδ inhibition suppresses key disease features in a rat model of asthma.

Background: Two isoforms of Phosphoinositide 3-kinase (PI3K), p110γ and p110δ, are predominantly expressed in leukocytes and represent attractive therapeutic targets for the treatment of allergic asthma. The study aim was to assess the impact of administration of an inhaled PI3Kγδ inhibitor (AZD8154) in a rat model of asthma.

Methods: Firstly, we checked that the tool compound, AZD8154, inhibited rat PI3K γ & δ kinases using rat cell-based assays.

Risk of Lower Extremity Ligamentous Injury Following Concussion Diagnosis: A TriNetX Database Study.

Background Concussion is one of the most frequently reported sports-related injuries in the United States; there is evidence that residual deficits in neurocognition may increase the risk of lower extremity musculoskeletal injury after concussion in high school, college, and professional athletes. The purpose of this study is to identify whether similar trends are identified in community-based populations.  Methods The TriNetX Research Network database was queried for patients 10-60 years old who experienced an ambulatory or emergency visit from 2018-2020.

Uncertainty Quantification in Constitutive Models of Highway Bridge Components: Seismic Bars and Elastomeric Bearings.

Bridges are essential structures in the logistic chain of countries, making it critical to design them to be as resilient as possible. One way to achieve this is through performance-based seismic design (PBSD), which involves using nonlinear Finite Element (FE) models to predict the response and potential damage of different structural components under earthquake excitations. Nonlinear FE models need accurate constitutive models of material and components.

Characterization of Selective and Potent JAK1 Inhibitors Intended for the Inhaled Treatment of Asthma.

Purpose: Janus kinase 1 (JAK1) is implicated in multiple inflammatory pathways that are critical for the pathogenesis of asthma, including the interleukin (IL)-4, IL-5, IL-13, and thymic stromal lymphopoietin cytokine signaling pathways, which have previously been targeted to treat allergic asthma. Here, we describe the development of AZD0449 and AZD4604, two novel and highly selective JAK1 inhibitors with promising properties for inhalation.

Methods: The effects of AZD0449 and AZD4604 in JAK1 signaling pathways were assessed by measuring phosphorylation of signal transducer and activator of transcription (STAT) proteins and chemokine release using immunoassays of whole blood from healthy human volunteers and rats.

Potential interventions for an antimicrobial stewardship bundle for Escherichia coli bacteraemia.

Introduction: Escherichia coli is the most commonly identified bacteraemia, and causes a broad spectrum of diseases. The range of clinical conditions associated with E. coli bacteraemia mean that antimicrobial therapy is highly variable.

COVID-MATCH65-A prospectively derived clinical decision rule for severe acute respiratory syndrome coronavirus 2.

Objectives: We report on the key clinical predictors of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and present a clinical decision rule that can risk stratify patients for COVID-19.

Design, Participants And Setting: A prospective cohort of patients assessed for COVID-19 at a screening clinic in Melbourne, Australia. The primary outcome was a positive COVID-19 test from nasopharyngeal swab.

Aprepitant for Cough in Lung Cancer. A Randomized Placebo-controlled Trial and Mechanistic Insights.

Effective cough treatments are a significant unmet need in patients with lung cancer. Aprepitant is a licensed treatment for nausea and vomiting, which blocks substance P activation of NK-1 (neurokinin 1) receptors, a mechanism also implicated in cough. To assess aprepitant in patients with lung cancer with cough and evaluate mechanisms in vagal nerve tissue.

Back to the future: re-establishing guinea pig in vivo asthma models.

Research using animal models of asthma is currently dominated by mouse models. This has been driven by the comprehensive knowledge on inflammatory and immune reactions in mice, as well as tools to produce genetically modified mice. Many of the identified therapeutic targets influencing airway hyper-responsiveness and inflammation in mouse models, have however been disappointing when tested clinically in asthma.

Novel airway smooth muscle-mast cell interactions and a role for the TRPV4-ATP axis in non-atopic asthma.

Mast cell-airway smooth muscle (ASM) interactions play a major role in the immunoglobulin (Ig)E- dependent bronchoconstriction seen in asthma but less is known about IgE-independent mechanisms of mast cell activation. Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) activation causes contraction of human ASM the release of cysteinyl leukotrienes (cysLTs) but the mechanism is unknown. The objective of the present study was to investigate a role for IgE-independent, mast cell-ASM interaction in TRPV4-induced bronchospasm.

Clinical manifestations of invasive meningococcal disease in Victoria with the emergence of serogroup W and serogroup Y Neisseria meningitidis.

Background: Historically, Australian cases of invasive meningococcal disease (IMD) have been most frequently caused by Neisseria meningitidis serogroup B, but recently an increase in cases due to serogroup W (MenW) and serogroup Y (MenY) has occurred.

Aim: To determine whether clinical manifestations of IMD have changed due to increased incidence of MenW and MenY.

Methods: We performed a retrospective review of IMD cases notified to the Department of Health and Human Services in Victoria, Australia.

Twice daily cefazolin is effective for treatment of serious methicillin-sensitive infection in an outpatient parenteral antimicrobial therapy program.

Background: The use of cefazolin for infections caused by has been demonstrated to be effective, and associated with fewer adverse effects compared with anti-staphylocccal penicillins; however, use of cefazolin on outpatient parenteral antimicrobial therapy (OPAT) programs often requires the use of continuous infusions. We report the outcomes of patients with serious infections caused by methicillin-sensitive (MSSA) treated using twice daily cefazolin by a large tertiary hospital OPAT program. The aim of this study was to evaluate the safety, efficacy and outcomes after 90 days of follow up for patients with serious infections caused by MSSA treated with twice daily cefazolin by our OPAT program.

Protein Phosphatase 2A Reduces Cigarette Smoke-induced Cathepsin S and Loss of Lung Function.

CTSS (cathepsin S) is a cysteine protease that is observed at higher concentrations in BAL fluid and plasma of subjects with chronic obstructive pulmonary disease (COPD). To investigate whether CTSS is involved in the pathogenesis of cigarette smoke-induced COPD and determine whether targeting upstream signaling could prevent the disease. CTSS expression was investigated in animal and human tissue and cell models of COPD.

Cerdulatinib Pharmacodynamics and Relationships to Tumor Response Following Oral Dosing in Patients with Relapsed/Refractory B-cell Malignancies.

Purpose: Preclinical studies suggest SYK and JAK contribute to tumor-intrinsic and microenvironment-derived survival signals. The pharmacodynamics of cerdulatinib, a dual SYK/JAK inhibitor, and associations with tumor response were investigated.

Patients And Methods: In a phase I dose-escalation study in adults with relapsed/refractory B-cell malignancies, cerdulatinib was administered orally to sequential dose-escalation cohorts using once-daily or twice-daily schedules.

Modelling the asthma phenotype: impact of cigarette smoke exposure.

Background: Asthmatics that are exposed to inhaled pollutants such as cigarette smoke (CS) have increased symptom severity. Approximately 25% of adult asthmatics are thought to be active smokers and many sufferers, especially in the third world, are exposed to high levels of inhaled pollutants. The mechanism by which CS or other airborne pollutants alter the disease phenotype and the effectiveness of treatment in asthma is not known.

Predictive value of quick Sepsis-Related Organ Failure Scores following sepsis-related Medical Emergency Team calls: a retrospective cohort study.

We conducted a cohort study of adult ward patients who had a Medical Emergency Team (MET) call triggered by confirmed or suspected sepsis in an Australian tertiary centre to assess the predictive utility of systemic inflammatory response syndrome (SIRS) and quick Sepsis-Related Organ Failure Assessment (qSOFA) scores for 28-day mortality over a 12-month period. Sepsis was the causative aetiology in 970 MET calls for 646 patients with a mean age of 68 years and median Charlson Comorbidity score (CCS) of 3.0.

Neutrophils drive alveolar macrophage IL-1β release during respiratory viral infection.

Background: Alveolar macrophages are sentinels of the airways that must exhibit immune restraint to innocuous antigens but elicit a robust inflammatory response to pathogenic threats. How distinction between these dichotomous functions is controlled is poorly defined.Neutrophils are the first responders to infection, and we hypothesised that they may free alveolar macrophages from their hyporesponsive state, promoting their activation.

Targeting fatty acid amide hydrolase as a therapeutic strategy for antitussive therapy.

Cough is the most common reason to visit a primary care physician, yet it remains an unmet medical need. Fatty acid amide hydrolase (FAAH) is an enzyme that breaks down endocannabinoids, and inhibition of FAAH produces analgesic and anti-inflammatory effects. Cannabinoids inhibit vagal sensory nerve activation and the cough reflex, so it was hypothesised that FAAH inhibition would produce antitussive activity elevation of endocannabinoids.

The emerging role of transient receptor potential channels in chronic lung disease.

Chronic lung diseases such as asthma, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis are a major and increasing global health burden with a high unmet need. Drug discovery efforts in this area have been largely disappointing and so new therapeutic targets are needed. Transient receptor potential ion channels are emerging as possible therapeutic targets, given their widespread expression in the lung, their role in the modulation of inflammatory and structural changes and in the production of respiratory symptoms, such as bronchospasm and cough, seen in chronic lung disease.

XEN-D0501, a Novel Transient Receptor Potential Vanilloid 1 Antagonist, Does Not Reduce Cough in Patients with Refractory Cough.

Rationale: Heightened cough responses to inhaled capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, are characteristic of patients with chronic cough. However, previously, a TRPV1 antagonist (SB-705498) failed to improve spontaneous cough frequency in these patients, despite small reductions in capsaicin-evoked cough.

Objectives: XEN-D0501 (a potent TRPV1 antagonist) was compared with SB-705498 in preclinical studies to establish whether an improved efficacy profile would support a further clinical trial of XEN-D0501 in refractory chronic cough.

Mechanistic link between diesel exhaust particles and respiratory reflexes.

Background: Diesel exhaust particles (DEPs) are a major component of particulate matter in Europe's largest cities, and epidemiologic evidence links exposure with respiratory symptoms and asthma exacerbations. Respiratory reflexes are responsible for symptoms and are regulated by vagal afferent nerves, which innervate the airway. It is not known how DEP exposure activates airway afferents to elicit symptoms, such as cough and bronchospasm.