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Journal articleMolyneaux PL, Maher TM, authors of CYFRA 21-1 predicts progression in IPF; a prospective longitudinal analysis of the PROFILE cohort, 2022,
Journal articleKing J, Nichols A, Bentley S, et al., 2022,
Over the past decade there have been significant developments in the field of Cystic Fibrosis Transmembrane Regulator modulator drugs. Following treatment in patients with cystic fibrosis with common gating mutations using the potentiator drug ivacaftor, successive development of corrector drugs used in combination has led to highly effective modulator therapy being available to more than 85% of the cystic fibrosis population over 12 years of age in the form of elexacaftor/tezacaftor/ivacaftor. In this article, we review the evidence from clinical trials and mounting real-world observational and registry data that demonstrates the impact highly effective modulators have on both pulmonary and extra-pulmonary manifestations of cystic fibrosis. As clinical trials progress to younger patient groups, we discuss the challenges to demonstrating drug efficacy in early life, and also consider practicalities of drug development in an ever-shrinking modulator-naïve population. Drug–drug interactions are an important consideration in people with cystic fibrosis, where polypharmacy is commonplace, but also as the modulated population look to remain healthier for longer, we identify trials that aim to address treatment burden too. Inequity of care, through drug cost or ineligibility for modulators by genotype, is widening without apparent strategies to address this; however, we present evidence of hopeful early-stage drug development for non-modulatable genes and summarise the current state of gene-therapy development.
Journal articleRicheldi L, Azuma A, Cottin V, et al., 2022,
BACKGROUND: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis. METHODS: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent. RESULTS: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups. CONCLUSIONS: In this placebo-controlled trial, treatment with BI 1015550, either alone or with ba
Journal articleChotirmall SH, Bogaert D, Chalmers JD, et al., 2022,
The last decade of research has revolutionized our understanding of respiratory microbiology, revealing that the lungs and airways contain diverse and dynamic microbial communities in health and disease. This "respiratory ecosystem"-a densely interconnected environment of microbial and host interactions-represents a tremendous and under-appreciated source of biological and clinical heterogeneity across patients with acute and chronic lung disease. Unlike other major sources of heterogeneity, such as comorbidities and host genetics, the respiratory microbiome is readily modifiable by clinical interventions, and therefore represents an untapped opportunity for therapeutic manipulation. As a potential "treatable trait" in efforts to subphenotype patients and deliver precision medicine, the respiratory microbiome is a promising therapeutic target. In this Pulmonary Perspective, we identify and discuss multiple challenges, both conceptual and practical, that must be overcome before the respiratory microbiome can be effectively modulated as a therapeutic target. Barriers include: 1) the need to identify specific microbiologic and ecologic "targets" for therapeutic modulation; 2) the need for an improved understanding of the efficacy and persistence of response to respiratory microbiome-modulating interventions; 3) the need for clinicians to be able to access, understand and utilize microbiome data for sub-phenotyping patients, and 4) specific concerns in special populations (including children, patients with chronic lung disease, and critically ill patients). By delineating these barriers, we identify opportunities for prospective research to advance our understanding of the respiratory microbiome, its role in human respiratory disease, and its genuine potential as a therapeutic target.
Journal articleKraven LM, Taylor AR, Molyneaux PL, et al., 2022,
Background Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.Methods We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).Findings We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).Interpretation We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.
Journal articleYousefi N, Fisher SJ, Burgstaller C, et al., 2022,
Uncured solid bisphenol-A epoxy resins containing up to 20 wt% carbon nanotubes (CNTs) were prepared usingmelt blending in a high shear mixer. The extrudate was ground to produce fine nanocomposite (NC) powders.This simple method produced well-dispersed NC, with CNT agglomerate sizes below 1 μm. Consolidated NCsdisplayed improved tensile moduli and strengths up to 3.3 GPa (+32%) and 78 MPa (+19%), respectively at 15wt% CNT, compared to the pure cured epoxy matrix. The relatively high Tg of 39 ◦C for the uncured NC powderssimplified the manufacture of composite prepregs using wet powder impregnation. The prepregs were laminatedinto hierarchical carbon fibre reinforced composites with improved through-thickness properties. Interlaminarshear strength improved for intermediate CNT loadings in the matrix up to 65 MPa (10 wt% CNT, +19%) butdecreased at higher concentrations. Compression moduli remained constant irrespectively of CNT loading butcompression strength increased with a CNT loading of 2.5 wt% to 772 MPa (+31%). The mechanical propertiesof the hierarchical composites reflect good consolidation (void content <3%) and excellent fibre alignment(<±0.8◦). In addition to the improved mechanical properties, incorporation of CNTs improved the through-thickness electrical conductivity up to 115 S/m
Journal articleHull RC, Huang JTJ, Barton AK, et al., 2022,
Journal articleGhani R, Blanco JM, Forlano R, et al., 2022,
RELATIVE CHANGE OF ENTEROCOCCUS FAECIUM, SELECTED COMMENSAL BACTERIA AND CYTOKINES ARE SEEN IN PATIENTS COLONIZED WITH MULTIDRUG-RESISTANT ORGANISMS WHO UNDERGO INTESTINAL MICROBIOTA TRANSPLANTATION, GASTROENTEROLOGY, Vol: 162, Pages: S218-S219, ISSN: 0016-5085
Journal articleVijayakumar B, Tonkin J, Devaraj A, et al., 2022,
Journal articleMorton R, Singanayagam A, 2022,
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