Use of digital measurement of medication adherence and lung function to guide the management of uncontrolled asthma (INCA Sun):a multicentre, single-blinded, randomised clinical trial

BACKGROUND: The clinical value of using digital tools to assess adherence and lung function in uncontrolled asthma is not known. We aimed to compare treatment decisions guided by digitally acquired data on adherence, inhaler technique, and peak flow with existing methods.METHODS: A 32-week prospective, multicentre, single-blinded, parallel, randomly controlled trial was done in ten severe asthma clinics across Ireland, Northern Ireland, and England. Participants were 18 years or older, had uncontrolled asthma, asthma control test (ACT) score of 19 or less, despite treatment with high-dose inhaled corticosteroids, and had at least one severe exacerbation in the past year despite high-dose inhaled corticosteroids. Patients were randomly assigned in a 1:1 ratio to the active group or the control group, by means of a computer-generated randomisation sequence of permuted blocks of varying sizes (2, 4, and 6) stratified by fractional exhaled nitric oxide (FeNO) concentration and recruitment site. In the control group, participants were masked to their adherence and errors in inhaler technique data. A statistician masked to study allocation did the statistical analysis. After a 1-week run-in period, both groups attended three nurse-led education visits over 8 weeks (day 7, week 4, and week 8) and three physician-led treatment adjustment visits at weeks 8, 20, and 32. In the active group, treatment adjustments during the physician visits were informed by digital data on inhaler adherence, twice daily digital peak expiratory flow (ePEF), patient-reported asthma control, and exacerbation history. Treatment was adjusted in the control group on the basis of pharmacy refill rates (a measure of adherence), asthma control by ACT questionnaire, and history of exacerbations and visual management of inhaler technique. Both groups used a digitally enabled Inhaler Compliance Assessment (INCA) and PEF. The primary outcomes were asthma medication burden measured as proportion of patients who required a net increase in treatment at the end of 32 weeks and adherence rate measured in the last 12 weeks by area under the curve in the intention-to-treat population. The safety analyses included all patients who consented for the trial. The trial is registered with ClinicalTrials.gov, NCT02307669 and is complete.FINDINGS: Between Oct 25, 2015, and Jan 26, 2020, of 425 patients assessed for eligibility, 220 consented to participate in the study, 213 were randomly assigned (n=108 in the active group; n=105 in the control group) and 200 completed the study (n=102 in the active group; n=98 in the control group). In the intention-to-treat analysis at week 32, 14 (14%) active and 31 (32%) control patients had a net increase in treatment compared with baseline (odds ratio [OR] 0·31 [95% CI 0·15-0·64], p=0·0015) and 11 (11%) active and 21 (21%) controls required add-on biological therapy (0·42 [0·19-0·95], p=0·038) adjusted for study site, age, sex, and baseline FeNO. Three (16%) of 19 active and 11 (44%) of 25 control patients increased their medication from fluticasone propionate 500 μg daily to 1000 μg daily (500 μg twice a day; adjusted OR 0·23 [0·06-0·87], p=0·026). 26 (31%) of 83 active and 13 (18%) of 73 controls reduced their medication from fluticasone propionate 1000 μg once daily to 500 μg once daily (adjusted OR 2·43 [1·13-5·20], p=0·022. Week 20-32 actual mean adherence was 64·9% (SD 23·5) in the active group and 55·5% (26·8) in the control group (between-group difference 11·1% [95% CI 4·4-17·9], p=0·0012). A total of 29 serious adverse events were recorded (16 [55%] in the active group, and 13 [45%] in the control group), 11 of which were confirmed as respiratory. None of the adverse events reported were causally linked to the study intervention, to the use of salmeterol-fluticasone inhalers, or the use of the digital PEF or INCA.INTERPRETATION: Evidence-based care informed by digital data led to a modest improvement in medication adherence and a significantly lower treatment burden.FUNDING: Health Research Board of Ireland, Medical Research Council, INTEREG Europe, and an investigator-initiated project grant from GlaxoSmithKline.</p

Trace metal distribution in the bed, bank and suspended sediment of the Ravensbourne River and its implication for sediment monitoring in an urban river

Purpose This study aims to identify a suitable sediment compartment for sediment quality monitoring by: (a) studying the concentration of trace metals (Cd, Cu, Ni, Pb and Zn) in the bed, bank and suspended sediment compartments of the Ravensbourne River to establish any differences in trace metal concentrations with compartment; (b) determining the influence of sediment particle size fractions ( 0.05) in the concentrations of metals between the suspended sediment and the < 63 μm bed sediment fraction, but there was a significant difference (p < 0.05) between the suspended sediment and the < 63 μm bank sediment fraction. There were also significant differences between the concentrations of metals in the < 63 μm and the 63 μm–2 mm fractions. Generally, the Ravensbourne River did not comply with the draft UK sediment quality guidelines for the metals analysed. Conclusions This study shows the importance of identifying a suitable sediment compartment to sample for compliance with sediment quality standards. The bed and suspended sediments are the most widely used sediment compartments for sediment monitoring, but collecting sufficient mass of the < 63 μm sediment fraction for monitoring presents a challenge for urban gravel bed rivers like the Ravensbourne River. It seems appropriate to establish individual monitoring regimes for different rivers

CXCR3 requirement for the interleukin-13–mediated up-regulation of interleukin-13Rα2 in pulmonary fibroblasts

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibrosis and abnormal vascularity. IL-13, a profibrotic cytokine that plays a role in IPF, functions through the Jak/STAT pathway after binding to the IL-13 receptor α1 (IL-13Rα1)/IL-4Rα complex. IL-13 also binds to IL-13Rα2, which has been thought to function as a nonsignaling decoy receptor, although possible signaling roles of this receptor have been proposed. CXCR3 and its IFN-inducible ligands—CXCL9, CXCL10, and CXCL11—have been implicated in vascular remodeling and fibroblast motility during the development of IPF. In this study, CXCR3 expression was demonstrated in cultured pulmonary fibroblasts from wild-type BALB/c mice and was found to be necessary for the IL-13–mediated gene and protein up-regulation of IL-13Rα2. In fibroblasts from CXCR3-deficient mice, STAT6 activation was prolonged. This study is the first to demonstrate the expression of CXCR3 in fibroblasts and its association with the expression of IL-13Rα2. Taken together, the results from this study point strongly to a requirement for CXCR3 for IL-13–mediated IL-13Rα2 gene expression. Understanding the function of CXCR3 in IL-13–mediated lung injury may lead to novel approaches to combat the development of pulmonary fibrosis, whether by limiting the effects of IL-13 or by manipulation of angiostatic pathways. The elucidation of the complex relationship between these antifibrotic receptors and manipulation of the CXCR3-mediated regulation of IL-13Rα2 may represent a novel therapeutic modality in cases of acute lung injury or chronic inflammation that may progress to fibrosis

Modulation of pulmonary fibrosis by IL-13Rα2

Pulmonary fibrosis is a progressive and fatal disease that involves the remodeling of the distal airspace and the lung parenchyma, which results in compromised gas exchange. The median survival time once diagnosed is less than three years. Interleukin (IL)-13 has been shown to play a role in a number of inflammatory and fibrotic diseases. IL-13 modulates its effector functions via a complex receptor system that includes the IL-4 receptor (R) α, IL-13Rα1, and the IL-13Rα2. IL-13Rα1 binds IL-13 with low affinity, yet, when it forms a complex with IL-4α, it binds with much higher affinity, inducing the effector functions of IL-13. IL-13Rα2 binds IL-13 with high affinity but has a short cytoplasmic tail and has been shown to act as a nonsignaling decoy receptor. Transfection of fibroblasts and epithelial cells with IL-13Rα2 inhibited the IL-13 induction of soluble collagen, TGF-β, and CCL17. Adenoviral overexpression of IL-13Rα2 in the lung reduced bleomycin-induced fibrosis. Our work shows that overexpression of IL-13Rα2 inhibits the IL-13 induction of fibrotic markers in vitro and inhibits bleomycin-induced pulmonary fibrosis. In summary our study highlights the antifibrotic nature of IL-13Ra2

CXCL9 regulates TGF-β1–induced epithelial to mesenchymal transition in human alveolar epithelial cells

Epithelial to mesenchymal cell transition (EMT), whereby fully differentiated epithelial cells transition to a mesenchymal phenotype, has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). CXCR3 and its ligands are recognized to play a protective role in pulmonary fibrosis. In this study, we investigated the presence and extent of EMT and CXCR3 expression in human IPF surgical lung biopsies and assessed whether CXCR3 and its ligand CXCL9 modulate EMT in alveolar epithelial cells. Coexpression of the epithelial marker thyroid transcription factor-1 and the mesenchymal marker α-smooth muscle actin and CXCR3 expression was examined by immunohistochemical staining of IPF surgical lung biopsies. Epithelial and mesenchymal marker expression was examined by quantitative real-time PCR, Western blotting, and immunofluorescence in human alveolar epithelial (A549) cells treated with TGF-β1 and CXCL9, with Smad2, Smad3, and Smad7 expression and cellular localization examined by Western blotting. We found that significantly more cells were undergoing EMT in fibrotic versus normal areas of lung in IPF surgical lung biopsy samples. CXCR3 was expressed by type II pneumocytes and fibroblasts in fibrotic areas in close proximity to cells undergoing EMT. In vitro, CXCL9 abrogated TGF-β1–induced EMT. A decrease in TGF-β1–induced phosphorylation of Smad2 and Smad3 occurred with CXCL9 treatment. This was associated with increased shuttling of Smad7 from the nucleus to the cytoplasm where it inhibits Smad phosphorylation. This suggests a role for EMT in the pathogenesis of IPF and provides a novel mechanism for the inhibitory effects of CXCL9 on TGF-β1–induced EMT

Identifying monitoring information needs that support the management of fish in large rivers.

Management actions intended to benefit fish in large rivers can directly or indirectly affect multiple ecosystem components. Without consideration of the effects of management on non-target ecosystem components, unintended consequences may limit management efficacy. Monitoring can help clarify the effects of management actions, including on non-target ecosystem components, but only if data are collected to characterize key ecosystem processes that could affect the outcome. Scientists from across the U.S. convened to develop a conceptual model that would help identify monitoring information needed to better understand how natural and anthropogenic factors affect large river fishes. We applied the conceptual model to case studies in four large U.S. rivers. The application of the conceptual model indicates the model is flexible and relevant to large rivers in different geographic settings and with different management challenges. By visualizing how natural and anthropogenic drivers directly or indirectly affect cascading ecosystem tiers, our model identified critical information gaps and uncertainties that, if resolved, could inform how to best meet management objectives. Despite large differences in the physical and ecological contexts of the river systems, the case studies also demonstrated substantial commonalities in the data needed to better understand how stressors affect fish in these systems. For example, in most systems information on river discharge and water temperature were needed and available. Conversely, information regarding trophic relationships and the habitat requirements of larval fishes were generally lacking. This result suggests that there is a need to better understand a set of common factors across large-river systems. We provide a stepwise procedure to facilitate the application of our conceptual model to other river systems and management goals

Can data from disparate long-term fish monitoring programs be used to increase our understanding of regional and continental trends in large river assemblages?

<div><p>Understanding trends in the diverse resources provided by large rivers will help balance tradeoffs among stakeholders and inform strategies to mitigate the effects of landscape scale stressors such as climate change and invasive species. Absent a cohesive coordinated effort to assess trends in important large river resources, a logical starting point is to assess our ability to draw inferences from existing efforts. In this paper, we use a common analytical framework to analyze data from five disparate fish monitoring programs to better understand the nature of spatial and temporal trends in large river fish assemblages. We evaluated data from programs that monitor fishes in the Colorado, Columbia, Illinois, Mississippi, and Tallapoosa rivers using non-metric dimensional scaling ordinations and associated tests to evaluate trends in fish assemblage structure and native fish biodiversity. Our results indicate that fish assemblages exhibited significant spatial and temporal trends in all five of the rivers. We also document native species diversity trends that were variable within and between rivers and generally more evident in rivers with higher species richness and programs of longer duration. We discuss shared and basin-specific landscape level stressors. Having a basic understanding of the nature and extent of trends in fish assemblages is a necessary first step towards understanding factors affecting biodiversity and fisheries in large rivers.</p></div