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Recently, a cross-talk error with commercial multiple breath nitrogen washout (MBWN2) software was discovered, which produced an absolute over-reading of N2 of approximately 1%, i.e., 2% N2 read as 3%. This caused an extended tail to the washout, and over-estimated lung clearance index (LCI2.5) values. Subsequently an updated and corrected software version has been released. Within the field there have been discussions on how to correct legacy data, whether to migrate or completely “rerun” raw data A-files from the old software into the new corrected software. To our knowledge, no research has been published assessing whether either method is equivalent to directly collecting data in the new corrected software. We prospectively recruited 19 participants, 10 adult healthy controls and 9 people with cystic fibrosis (CF). MBWN2 was performed using the Exhalyzer® D first on the old 3.1.6 software and next, directly on corrected 3.3.1 software. Multiple breath washout (MBW) data directly collected in 3.3.1 was significantly different from both migrated and rerun data. A total of 7 of the 19 participants (37%; 4 CF) had a relative difference in LCI2.5 > 10% for both migrated and rerun data compared to 3.3.1 collected data. Our findings have implications for the Global Lung Initiative MBW project, which is accepting a combination of directly collected, A-file reruns and migrated data to establish normative values. Further, caution must be used in clinical practice when comparing corrected legacy data versus 3.3.1 collected data for clinical interpretation. We recommend that a new baseline is collected directly on 3.3.1. before clinical interpretation and decisions are determined when comparing consecutive MBW tests.

Recently, a cross-talk error with commercial multiple breath nitrogen washout (MBWN

Rationale: Ivacaftor's clinical effects in the residual function mutations 3849+10kb C →T and D1152H warrant further characterization. Objectives: Evaluate ivacaftor's effect in people with cystic fibrosis aged ≥6 years with 3849+10kb C→T or D1152H residual function mutations; explore the correlation between ivacaftor-induced organoid-based cystic fibrosis transmembrane conductance regulator function measurements and clinical response to ivacaftor. Methods: Participants were randomized (1:1) in this placebo-controlled crossover study; each treatment sequence included two 8-week treatments with an 8-week washout period. The primary endpoint was absolute change in lung clearance index2.5 from baseline through Week 8. Additional endpoints included lung function, patient-reported outcomes, and in vitro intestinal organoid-based measurements of ivacaftor-induced cystic fibrosis transmembrane conductance regulator function. Results: Of 38 participants, 37 completed the study. The primary endpoint was met; the Bayesian posterior probability of improvement in lung clearance index2.5 with ivacaftor vs placebo was >99%. Additional endpoints improved with ivacaftor. Safety findings were consistent with ivacaftor's known safety profile. Dose-dependent swelling was observed in 23/25 viable organoid cultures with ivacaftor treatment. Correlations between ivacaftor-induced organoid swelling and clinical endpoints were negligible to low. Conclusions: In people with cystic fibrosis aged ≥6 years with a 3849+10kb C →T or D1152H mutation, ivacaftor treatment improved clinical endpoints vs placebo; however, there was no correlation between organoid swelling and change in clinical endpoints. The organoid assay may assist in identification of ivacaftor-responsive mutations but in this study did not predict magnitude of clinical benefit for individual people with cystic fibrosis with these two mutations. Clinical trial registered with ClinicalTrials.gov (NCT03068312).

Introduction The multiple breath nitrogen washout (MBW) test offers a sensitive measure of airway function. In this study we aim to (a) assess the validity of the EasyOne Pro LAB (MBWndd) in an in vitro lung model, (b) assess the feasibility, repeatability, and reproducibility of MBWndd and (c) compare outcomes with the Exhalyzer D (MBWEM) and body plethysmography.Methods In vitro, functional residual capacity (FRC) measurements were assessed using a lung model under quasi-physiological conditions and compared to measured FRC. In vivo plethysmography and MBW were performed in a prospective study of children at two visits (n = 45 healthy; n = 41 cystic fibrosis [CF]). Bland-Altman plots were used to compare agreement between FRC and lung clearance index (LCI) measurements.Results In vitro FRCndd measurements were repeatable but lung volumes were underestimated (mean relative difference -5.4% (limits of agreement [LA] -9.6%; -1.1%), 95% confidence interval (CI) -6.27; -4.45). In vivo, compared to plethysmography, FRCndd was consistently lower (-19.3% [-40.5; 1.9], 95% CI [-23.9; -14.7]), and showed a volume dependency. LCIndd values were also higher in children with smaller lung volumes. The within-test coefficient of variation of the FRCndd and LCIndd were 4.9% in health, and 5.6% and 6.9% in CF respectively. LCIndd was reproducible between-visits (mean relative difference [LA] -3.7% [-14.8, -7.5; 95% CI -6.6; -0.73] in health [n = 17] and 0.34% [-13.2, 22.8; 95% CI -5.0; 5.69] in CF [n = 23]). When calculated using the same algorithm, LCIndd was similar to LCIEM in health.Conclusions MBWndd measurements are feasible, repeatable, and reproducible, however, MBW-derived outcomes are not interchangeable with MBWEM.

Background Adding a slow vital capacity (SVC) to multiple breath washout (MBW) allows quantification of otherwise overlooked signal from under/un-ventilated lung units (UVLU) and may provide a more comprehensive assessment of airway disease than conventional lung clearance index (LCI2.5). Methods We conducted a pilot study on people undergoing MBW tests: 10 healthy controls (HC) and 43 cystic fibrosis (CF) subjects performed an SVC after the standard end of test. We term the new outcome LCI with Short extension (LCIShX). We assessed (i) CF/ HC differences, (ii) variability (iii) effect of pulmonary exacerbation (PEx)/treatment and (iv) relationship with CF computed tomography (CFCT) scores. Results HC/ CF group differences were larger with LCIShX than LCI2.5 (P Conclusions UVLU captured within the LCIShX varies between individuals; the lack of relationship with LCI2.5 demonstrates that new, additional information is being captured. LCIShX repeatability during clinical stability combined with its larger signal around episodes of PEx may lend it superior sensitivity as an outcome measure. Further studies will build on this pilot data to fully establish its utility in monitoring disease status.

An active colloidal fluid comprised of self-propelled spinning particles injecting energy and angular momentum at the microscale demonstrates spontaneous collective states that range from flocks to coherent vortices. Despite their seeming simplicity, the emergent far-from-equilibrium behavior of these fluids remains poorly understood, presenting a challenge to the design and control of next-generation active materials. When confined in a ring, such so-called polar active fluids acquire chirality once the spontaneous flow chooses a direction. In a perfect ring, this chirality is indefinitely long-lived. Here, we combine experiments on self-propelled colloidal Quincke rollers and mesoscopic simulations of continuum Toner-Tu equations to explore how such chiral states can be controlled and manipulated by obstacles. For different obstacle geometries three dynamic steady states have been realized: long-lived chiral flow, an apolar state in which the flow breaks up into counter-rotating vortices and an unconventional collective state with flow having an oscillating chirality. The chirality reversal proceeds through the formation of intermittent vortex chains in the vicinity of an obstacle. We demonstrate that the frequency of collective states with oscillating chirality can be tuned by obstacle parameters. We vary obstacle shapes to design chiral states that are independent of initial conditions. Building on our findings, we realize a system with two triangular obstacles that force the active fluid towards a state with a density imbalance of active particles across the ring. Our results demonstrate how spontaneous polar active flows in combination with size and geometry of scatterers can be used to control dynamic patterns of polar active liquids for materials design., 13 pages, 5 figures

Background Evaluation of multiple breath washout (MBW) set-up including staff training, certification and central “over-reading” for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies. Aims To assess the outcomes of a MBW training, certification and central over-reading programme. Methods MBW training and certification was conducted in European sites collecting lung clearance index (LCI) data in the BronchUK Clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality. Results Thirteen training days were delivered to 56 participants from 22 sites. Of 22 sites, 18 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p, LCI is feasible in a bronchiectasis multicentre clinical trial setting; however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to optimise data quality https://bit.ly/2WZ4L1e

Background The lung clearance index (LCI), derived from the Multiple Breath Washout (MBW) test, is sensitive to treatment effects and compared with spirometry has higher feasibility in younger children and requires smaller sample sizes. As a result, the LCI has been endorsed by the European CF Society Clinical Trials Network for use as a primary outcome measure in CF clinical trials. Methods Here we describe the implementation of standardised protocols for MBW test performance, data collection and quality control to successfully incorporate LCI as a novel outcome measure in a large multicentre phase III clinical trial. Results Three regional (North America (NA), Europe (EU), Australia (AUS)) central over-reading centres (CORC) were established to provide a collaborative platform for MBW training, certification and quality control of data. One hundred and thirty-two naive operators from 53 sites across NA, EU and AUS were successfully trained and certified to perform MBW testing. Incorporation of a re-screening opportunity in the study protocol resulted a final screening feasibility rate of 93%, success remained high throughout the study resulting in an overall feasibility of MBW study data of 88.1% (1107/1257). MBW test acceptability was similar between geographical regions: NA (88%), EU (89%) and AUS (89%). Conclusion With this approach we achieved high MBW test feasibility and sustained collection of good quality data, demonstrating the utility of LCI as an effective primary endpoint in the first international phase III clinical trial to report LCI as the primary outcome.

Background Proline–glycine–proline (PGP) is a bioactive fragment of collagen generated by the action of matrix metalloproteinase-9 (MMP-9) and prolylendopeptidase (PE), and capable of eliciting neutrophil chemotaxis and epithelial remodelling. PGP is normally then degraded by leukotriene A4 hydrolase (LTA4H) to limit inflammation and remodelling. This study hypothesized that early and persistent airway neutrophilia in Cystic Fibrosis (CF) may relate to abnormalities in the PGP pathway and sought to understand underlying mechanisms. Methods Broncho-alveolar lavage (BAL) fluid was obtained from 38 CF (9 newborns and 29 older children) and 24 non-CF children. BAL cell differentials and levels of PGP, MMP-9, PE and LTA4H were assessed. Results Whilst PGP was present in all but one of the older CF children tested, it was absent in non-CF controls and the vast majority of CF newborns. BAL levels of MMP-9 and PE were elevated in older children with CF relative to CF newborns and non-CF controls, correlating with airway neutrophilia and supportive of PGP generation. Furthermore, despite extracellular LTA4H commonly being greatly elevated concomitantly with inflammation to promote PGP degradation, this was not the case in CF children, potentially owing to degradation by neutrophil elastase. Conclusions A striking imbalance between PGP-generating and -degrading enzymes enables PGP accumulation in CF children from early life and potentially supports airway neutrophilia., Graphical abstract Unlabelled Image, Highlights • PGP is a collagen-derived pro-neutrophilic mediator. • PGP accumulates in the airways of children with cystic fibrosis. • Imbalance of PGP generation (MMP/PE) vs degradation (LTA4H) enables PGP build-up. • LTA4H is destroyed by neutrophil elastase to prevent PGP degradation. • Infections are key to spiking PGP generation in setting it cannot be degraded.

Background: Lung clearance index (LCI) is becoming recognized as an important addition in the monitoring of pediatric cystic fibrosis (CF). The non-invasive technique is easy to perform in all ages, reproducible and increasingly being used in clinical trials. There is interest in utilizing it within the clinic setting but its current use is mostly as a research tool. The procedure is highly dependent on skilled operators and a relaxed testing environment is key to obtaining good quality measurements.Conclusions: Standardization of LCI is part of an ongoing collaborative, multicenter process. This review describes the background to LCI, discusses technical issues and limitations and provides examples of its utility in clinical and research contexts.

There are significant differences in the methods employed by various organizations to estimate the cost of carbon capture and storage (CCS) systems for fossil fuel power plants. Such differences often are not apparent in publicly reported CCS cost estimates, and thus contribute to misunderstanding, confusion, and mis-representation of CCS cost information, especially among audiences not familiar with the details of CCS costing. Given the international importance of CCS as an option for climate change mitigation, efforts to harmonize methods of estimating CCS costs and improving the communication of cost assumptions and results are especially urgent and timely. Based on an analysis of current deficiencies, this paper recommends a common costing methodology plus guidelines for CCS cost reporting to improve the clarity and consistency of cost estimates for greenhouse gas mitigation measures.

Vascular endothelial growth factor (VEGF) signaling is involved in the process of blood vessel development and maintenance. Signaling is initiated by binding of the bivalent VEGF ligand to the membrane-bound receptors (VEGFR), which in turn stimulates receptor dimerization. Herein, we discuss experimental evidence that VEGF receptors localize in caveloae and other regions of the plasma membrane, and for other receptors, it has been shown that receptor clustering has an impact on dimerization and thus also on signaling. Overall, receptor clustering is part of a complex ecosystem of interactions and how receptor clustering impacts dimerization is not well understood. To address these questions, we have formulated the simplest possible model. We have postulated the existence of a single high affinity region in the cell membrane, which acts as a transient trap for receptors. We have defined an ODE model by introducing high- and low-density receptor variables and introduce the corresponding reactions from a realistic model of VEGF signal initiation. Finally, we use the model to investigate the relation between the degree of VEGFR concentration, ligand availability, and signaling. In conclusion, our simulation results provide a deeper understanding of the role of receptor clustering in cell signaling., In Proceedings HSB 2013, arXiv:1308.5724

Day 1: Background to MBW Overview of references and Standard Operating Procedure. Familiarisation with equipment components, on-screen menus and consumables. Overview and practice of calibrations. Patient preparation for testing. Day 2: Explanation and demonstration of phases of testing Washin phase, beginning of washout, washout phase. Practice testing with volunteer and quality control of readings. Log keeping, cleaning of equipment and infection control. Accessing and downloading tests. Qualification procedure Collection of 10 tests. 9/10 technically acceptable tests required for qualification.