Optimising bronchoalveolar lavage: lessons from alpha-1 antitrypsin deficiency.

Background: Bronchoalveolar lavage (BAL) is essential in determining the efficacy of novel therapies in alpha-1 antitrypsin deficiency (AATD). These require initial proof-of-concept demonstration that treatment administration increases alpha-1 antitrypsin (AAT) levels and/or anti-neutrophil elastase inhibitory capacity (ANEC) in the lung. Early-phase studies often encounter high interindividual variability of BAL results, primarily stemming from the inherent dilution characteristics of returned BAL fluid.

Time-to-event estimands and loss to follow-up in oncology in light of the estimands guidance.

Time-to-event estimands are central to many oncology clinical trials. The estimands framework (addendum to the ICH E9 guideline) calls for precisely defining the treatment effect of interest to align with the clinical question of interest and requires predefining the handling of intercurrent events (ICEs) that occur after treatment initiation and "affect either the interpretation or the existence of the measurements associated with the clinical question of interest." We discuss a practical problem in clinical trial design and execution, that is, in some clinical contexts it is not feasible to systematically follow patients to an event of interest.

Monocyte NLRP3 inflammasome and interleukin-1β activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

Introduction: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1β secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers.

Chronic pain in female breast cancer survivors - prevalence, characteristics and contributing factors: a cross-sectional pilot study.

Background: While the global incidence of breast cancer is increasing, there is also an increase in the numbers of breast cancer survivors and in survival duration, as early detection programs are implemented, and treatments are optimized. Breast cancer survivors in several countries commonly struggle with a range of symptoms (fatigue, insomnia, depression) with 25-80% of survivors suffering from chronic pain. There is a paucity of literature reporting on breast cancer survivors in South Africa.

Effect of elexacaftor/tezacaftor/ivacaftor on airway and systemic inflammation in cystic fibrosis.

Treatment with elexacaftor/tezacaftor/ivacaftor (ETI) has been shown to improve lung function in people with cystic fibrosis (PWCF). However, its biological effects remain incompletely understood. Here we describe alterations in pulmonary and systemic inflammation in PWCF following initiation of ETI.

Tracheostomy insertion in COVID-19: insertion practice and factors leading to unplanned tube exchange.

Background: Tracheostomy insertion in patients with coronavirus disease 2019 (COVID-19) presents unique challenges. Patients frequently have high ventilatory requirements, and as an aerosol generating procedure, tracheostomy insertion creates the potential for staff transmission. Problems with tracheostomies contribute to morbidity and mortality, and tracheostomy changes may increase risks of staff transmission.

Global series: Complex regional pain syndrome: abstracts from the International Association for the Study of Pain complex regional pain syndrome SIG virtual symposia 2021.

The aim of this IASP complex regional pain syndrome (CRPS) SIG Global Series 2021 was to bring together clinicians including those from developing countries to better understand the clinical presentation of complex regional pain syndrome in countries with less well-published patient populations. The purpose was to learn from each other about the range of treatments, successful outcomes, and challenges experienced. These meeting proceedings comprise abstracts from nine countries that span 4 continents and are summaries of online presentations delivered by speakers representing these countries over the course of 2 symposia.

Estimating the Effect of Tafamidis on Cardiovascular-Related Hospitalization in NYHA Class III Patients with Transthyretin Amyloid Cardiomyopathy in the Presence of Death.

Background: The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) demonstrated the effectiveness of tafamidis for the treatment of patients with transthyretin amyloid cardiomyopathy (ATTR-CM). Tafamidis reduced mortality in all subgroups of patients studied. Tafamidis also reduced observed frequency of cardiovascular (CV)-related hospitalizations in all subgroups except those who were New York Heart Association (NYHA) class III at baseline who, paradoxically, had a higher frequency of CV-related hospitalizations than placebo.

Targeting of Glycosaminoglycans in Genetic and Inflammatory Airway Disease.

In the lung, glycosaminoglycans (GAGs) are dispersed in the extracellular matrix (ECM) occupying the interstitial space between the capillary endothelium and the alveolar epithelium, in the sub-epithelial tissue and in airway secretions. In addition to playing key structural roles, GAGs contribute to a number of physiologic processes ranging from cell differentiation, cell adhesion and wound healing. Cytokine and chemokine-GAG interactions are also involved in presentation of inflammatory molecules to respective receptors leading to immune cell migration and airway infiltration.

Integrating geographic ranges across temporal scales.

Geographic ranges are a fundamental unit of biogeography and macroecology. Increasingly, paleontologists and ecologists alike are reconstructing geographic ranges of species from fossils, in order to understand the long-term processes governing biogeographic and macroevolutionary patterns. As these reconstructions have become increasingly common, uncertainty has arisen over the equivalency of paleo-ranges and modern ranges.

Alpha-1 Antitrypsin Therapy Modifies Neutrophil Adhesion in Patients with Obstructive Lung Disease.

Alpha-1 antitrypsin deficiency (AATD) is characterized by neutrophil-dominated inflammation resulting in emphysema. The cholesterol-rich neutrophil outer plasma membrane plays a central role in adhesion and subsequent transmigration to underlying tissues. This study aimed to investigate mechanisms of increased neutrophil adhesion in AATD and whether alpha-1 antitrypsin (AAT) augmentation therapy abrogates this effect.

A Review of Alpha-1 Antitrypsin Binding Partners for Immune Regulation and Potential Therapeutic Application.

Alpha-1 antitrypsin (AAT) is the canonical serine protease inhibitor of neutrophil-derived proteases and can modulate innate immune mechanisms through its anti-inflammatory activities mediated by a broad spectrum of protein, cytokine, and cell surface interactions. AAT contains a reactive methionine residue that is critical for its protease-specific binding capacity, whereby AAT entraps the protease on cleavage of its reactive centre loop, neutralises its activity by key changes in its tertiary structure, and permits removal of the AAT-protease complex from the circulation. Recently, however, the immunomodulatory role of AAT has come increasingly to the fore with several prominent studies focused on lipid or protein-protein interactions that are predominantly mediated through electrostatic, glycan, or hydrophobic potential binding sites.

Trikafta Rescues CFTR and Lowers Monocyte P2X7R-induced Inflammasome Activation in Cystic Fibrosis.

Cystic fibrosis (CF) is caused by mutations in the CFTR (CF transmembrane conductance regulator) gene and is characterized by sustained inflammation. ATP triggers IL-1β secretion via P2X7R (P2X7 receptor) and activation of the NLRP3 (NOD-, LRR-, and pyrin domain-containing protein 3) inflammasome. To explore the effect of the CFTR modulator elexacaftor/tezacaftor/ivacaftor (Trikafta) on CFTR expression and the ATP/P2X7R signaling axis in monocytes and on circulating proinflammatory markers.

C3d Elicits Neutrophil Degranulation and Decreases Endothelial Cell Migration, with Implications for Patients with Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin (AAT) deficiency (AATD) is characterized by increased risk for emphysema, chronic obstructive pulmonary disease (COPD), vasculitis, and wound-healing impairment. Neutrophils play a central role in the pathogenesis of AATD. Dysregulated complement activation in AATD results in increased plasma levels of C3d.

Current evidence on the effect of highly effective CFTR modulation on interleukin-8 in cystic fibrosis.

Introduction: Cystic fibrosis (CF) is a genetically inherited disease, with mortality and morbidity associated with respiratory disease. The inflammatory response in CF is characterized by excessive neutrophil influx to the airways, mainly due to the increased local production and retention of interleukin-8 (IL-8), a potent neutrophil chemoattractant.

Areas Covered: We discuss how the chemokine IL-8 dominates the inflammatory profile of the airways in CF lung disease.

The preservation potential of terrestrial biogeographic patterns.

Extinction events in the geological past are similar to the present-day biodiversity crisis in that they have a pronounced biogeography, producing dramatic changes in the spatial distributions of species. Reconstructing palaeobiogeographic patterns from fossils therefore allows us to examine the long-term processes governing the formation of regional biotas, and potentially helps build spatially explicit models for future biodiversity loss. However, the extent to which biogeographic patterns can be preserved in the fossil record is not well understood.

Use of exhaled breath condensate (EBC) in the diagnosis of SARS-COV-2 (COVID-19).

False negatives from nasopharyngeal swabs (NPS) using reverse transcriptase PCR (RT-PCR) in SARS-CoV-2 are high. Exhaled breath condensate (EBC) contains lower respiratory droplets that may improve detection. We performed EBC RT-PCR for SARS-CoV-2 genes (E, S, N, ORF1ab) on NPS-positive (n=16) and NPS-negative/clinically positive COVID-19 patients (n=15) using two commercial assays.

High Preservation Potential of Paleogeographic Range Size Distributions in Deep Time.

AbstractReconstructing geographic range sizes from fossil data is a crucial tool in paleoecology, elucidating macroecological and macroevolutionary processes. Studies examining links between range size and extinction risk may also offer a predictive tool for identifying species most vulnerable in the "sixth mass extinction." However, the extent to which paleogeographic ranges can be recorded reliably in the fossil record is unknown.

A method to measure the partitioning coefficient of volatile organic compounds in nanoparticles.

The partitioning behavior of volatile organic compounds (VOCs) into nanoparticles is less studied compared to those of semivolatile organic compounds (SVOCs) because of the lower concentration of the VOCs that is expected to partition into particles. One challenge in measuring the accurate partition coefficient of VOCs is quantifying their low mass fraction that sorbed on nanoparticles and differentiating them from the high VOC concentrations present in the gas-phase. Systematically characterizing the partitioning coefficient at a specific environmental condition is also difficult when sampling in the field.

Time taken from primary care referral to a specialist centre diagnosis of idiopathic pulmonary fibrosis: an opportunity to improve patient outcomes?

https://bit.ly/2TkO26r.

Disparities in Geographic Access to Hospital Outpatient Pulmonary Rehabilitation Programs in the United States.

Background: For individuals with COPD, pulmonary rehabilitation (PR) improves outcomes in terms of exercise capacity, severity of dyspnea, and health-related quality of life. However, many US patients with COPD do not use PR services. There has been limited research on geographic access to needed health-care services for individuals who live in rural communities in the United States.