Preparation of Dienyl Boronates by Tandem Ene-Yne Metathesis/Dienyl Isomerization: Ready Access to Diene Building Blocks for the Synthesis of Polyenes.

The ene-yne metathesis of alkenyl boronates with terminal alkynes is reported. These challenging metatheses were accomplished using a Grubbs catalyst bearing the cyclic alkyl amino carbene (CAAC) ligand, whereas -heterocyclic carbene (NHC) derived catalysts gave lower yields. Subsequent dienyl isomerization via a cobalt-catalyzed hydrogen atom transfer (HAT) furnished the more substituted dienyl boronate with high / ratios.

Stereoconvergent Synthesis of Z-1,3-Disubstituted-1,3-Dienes by Uphill Photocatalysis.

A variety of 1-aryl-1,3-dienes were isomerized from E to Z isomers by photocatalysis using Ru(bpy) [PF ] and blue LED light. Enrichment of the Z-isomer is thought to occur by selective triplet energy transfer from the photocatalyst to the stereoisomeric mixture. The 1,3-diene starting materials are easily made by catalytic ene-yne metathesis (EYM).

Novel Therapeutic Strategies in Asthma-Chronic Obstructive Pulmonary Disease Overlap.

The term asthma-chronic obstructive pulmonary disease (COPD) overlap applies where there are features of asthma and COPD. Agents targeting eosinophilic inflammation have transformed asthma management and indicate promise across airways disease, whereas agents targeting neutrophilic inflammation have demonstrated limited efficacy. Successful treatment of airway dysbiosis, mucous hypersecretion, or airway remodeling may occur with better understanding of the impact of current agents on specific clinical end points or through novel approaches.

Corticosteroid Responsiveness Following Mepolizumab in Severe Eosinophilic Asthma-A Randomized, Placebo-Controlled Crossover Trial (MAPLE).

Background: Mepolizumab inhibits IL-5 activity and reduces exacerbation frequency and maintenance oral corticosteroid (OCS) dosage in patients with severe eosinophilic asthma (SEA). Some patients remain dependent on OCS despite anti-IL-5 treatment, suggesting residual corticosteroid-responsive mechanisms.

Objective: To determine the clinical and anti-inflammatory effects of OCS in patients with SEA on mepolizumab.

Relationship between inflammatory status and microbial composition in severe asthma and during exacerbation.

Background: In T2-mediated severe asthma, biologic therapies, such as mepolizumab, are increasingly used to control disease. Current biomarkers can indicate adequate suppression of T2 inflammation, but it is unclear whether they provide information about airway microbial composition. We investigated the relationships between current T2 biomarkers and microbial profiles, characteristics associated with a Proteobacteria microbial profile and the effects of mepolizumab on airway ecology.

Exacerbation Profile and Risk Factors in a Type-2-Low Enriched Severe Asthma Cohort: A Clinical Trial to Assess Asthma Exacerbation Phenotypes.

The past 25 years have seen huge progress in understanding of the pathobiology of type-2 (T2) asthma, identification of measurable biomarkers, and the emergence of novel monoclonal antibody treatments. Although present in a minority of patients with severe asthma, very little is known about the mechanisms underlying T2-low asthma, making it a significant unmet need in asthma research. The objective of this study was to explore the differences between study exacerbators and nonexacerbators, to describe physiological changes at exacerbation in those who are T2 and T2 at the time of exacerbation, and to evaluate the stability of inflammatory phenotypes when stable and at exacerbation.

Feno differentiates epithelial gene expression clusters: Exploratory analysis from the MESOS randomized controlled trial.

Background: Understanding how asthma biomarkers relate to gene expression signatures could help identify drivers of pathogenesis.

Objective: This post hoc exploratory analysis of the phase II tralokinumab trial MESOS (ClinicalTrials.gov identifier NCT02449473) aimed to profile baseline airway inflammation in patients with moderate-to-severe asthma.

The inflammatory profile of exacerbations in patients with severe refractory eosinophilic asthma receiving mepolizumab (the MEX study): a prospective observational study.

Background: Clinical trials with mepolizumab, a humanised monoclonal antibody against interleukin-5, show a 50% reduction in severe asthma exacerbations in people with severe eosinophilic asthma. Exacerbations in patients treated with mepolizumab seem to be different to exacerbations in those given placebo, as patients treated with mepolizumab report fewer symptoms, have a lower sputum eosinophil count, and smaller fall in peak expiratory flow. We aimed to investigate the inflammatory phenotype and physiological characteristics of exacerbation events in patients with severe eosinophilic asthma who were treated with mepolizumab.

The value of healthcare worker support strategies to enhance wellbeing and optimise patient care.

The World Health Organization has recognised the impact of the SARS-CoV-2 pandemic on healthcare worker (HCW) mental health and wellbeing. Anticipating these effects locally, we developed strategies to support our team, to equip them to care for themselves as well as our patients. We implemented a series of interventions to increase staff support, highlighting the importance of team and individual morale.

Multi-omics links IL-6 trans-signalling with neutrophil extracellular trap formation and infection in COPD.

Background: Interleukin (IL)-6 trans-signalling (IL-6TS) is emerging as a pathogenic mechanism in chronic respiratory diseases; however, the drivers of IL-6TS in the airways and the phenotypic characteristic of patients with increased IL-6TS pathway activation remain poorly understood.

Objective: Our aim was to identify and characterise COPD patients with increased airway IL-6TS and to elucidate the biological drivers of IL-6TS pathway activation.

Methods: We used an IL-6TS-specific sputum biomarker profile (soluble IL-6 receptor (sIL-6R), IL-6, IL-1β, IL-8, macrophage inflammatory protein-1β) to stratify sputum data from patients with COPD (n=74; Biomarkers to Target Antibiotic and Systemic Corticosteroid Therapy in COPD Exacerbation (BEAT-COPD)) by hierarchical clustering.

Ene-Yne Metathesis of Allylphosphonates and Allylphosphates: Synthesis of Phosphorus-Containing 1,3-Dienes.

A variety of ene-yne cross metathesis reactions were performed using unsaturated phosphonate and phosphate reagents, affording the corresponding phosphorylated 1,3-diene products in good to excellent yields. These difficult ene-yne metatheses employed a Grubbs catalyst bearing a cyclic amino alkyl carbene ligand. A variety of terminal alkynes of varying substitution underwent the reaction, and different phosphorus-containing alkenes were found to give the conjugated diene products in high yields.

A Macrocyclic Ruthenium Carbene for Size-Selective Alkene Metathesis.

The synthesis of a macrocyclic Ru carbene catalyst for selective cross alkene metathesis is reported. The new catalyst showed different reactivity for various type 1 alkenes in homodimerization which correlated with the aggregrate size of the allylic substituent. The altered reactivity profile allowed for selective product formation in competition cross alkene metathesis between two different type 1 alkenes and -butyl acrylate.

Does clinical validation and the implementation of new models of outpatient service delivery have the potential to reduce waiting lists? A pilot study in Letterkenny University Hospital.

Introduction: The traditional outpatient paradigm of seeing patients prior to diagnostic tests and treatment is unsustainable without additional funding. New models of service delivery such as "one-stop clinics", direct access to diagnostics and advanced nurse practitioner (ANP)-led clinics have the potential to improve the efficiency of existing services.

Methods: To determine the most effective changes to improve service provision, the reasons for encounter (RFE) to a urology clinic were assessed using the International Classification Primary Care.

Mild Isomerization of Conjugated Dienes Using Co-Mediated Hydrogen Atom Transfer.

A mild and high yielding rearrangement of 1,3-disubstituted-1,3-dienes to 1,1,4-trisubstituted-1,3-dienes using a cobaloxime catalyst and a silane cocatalyst is reported. Chiral centers near the conjugated diene were not racemized. Deuterium labeling studies are consistent with a hydrogen atom transfer mechanism, and radical intermediates were found to be accessible due to the observed ring opening of a cyclopropane ring.

Management of severe asthma: a European Respiratory Society/American Thoracic Society guideline.

This document provides clinical recommendations for the management of severe asthma. Comprehensive evidence syntheses, including meta-analyses, were performed to summarise all available evidence relevant to the European Respiratory Society/American Thoracic Society Task Force's questions. The evidence was appraised using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the results were summarised in evidence profiles.

Sputum microbiomic clustering in asthma and chronic obstructive pulmonary disease reveals a Haemophilus-predominant subgroup.

Background: Airway ecology is altered in asthma and chronic obstructive pulmonary disease (COPD). Anti-microbial interventions might have benefit in subgroups of airway disease. Differences in sputum microbial profiles at acute exacerbation of airways disease are reflected by the γProteobacteria:Firmicutes (γP:F) ratio.

ERS/EAACI statement on severe exacerbations in asthma in adults: facts, priorities and key research questions.

Despite the use of effective medications to control asthma, severe exacerbations in asthma are still a major health risk and require urgent action on the part of the patient and physician to prevent serious outcomes such as hospitalisation or death. Moreover, severe exacerbations are associated with substantial healthcare costs and psychological burden, including anxiety and fear for patients and their families. The European Academy of Allergy and Clinical Immunology (EAACI) and the European Respiratory Society (ERS) set up a task force to search for a clear definition of severe exacerbations, and to also define research questions and priorities.

Cough and Eosinophilia.

Eosinophilic airway inflammation is observed in 30% to 50% of chronic cough sufferers. It is a common feature of asthma and upper airway cough syndrome, and it is required in the diagnosis of nonasthmatic eosinophilic bronchitis. Our understanding of the mechanisms underlying allergic and nonallergic eosinophilic inflammation have evolved tremendously in the last 2 decades, but the cause of this inflammation in any individual is often uncertain.