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Abstract Background Data from clinical trials of lumacaftor-ivacaftor (LUM-IVA) demonstrate improvements in lung clearance index (LCI) but not in FEV1 in children with Cystic Fibrosis (CF) aged 6–11 years and homozygous for the Phe508del mutation. It is not known whether LUM/IVA use in children can impact the progression of structural lung disease. We sought to determine the real-world impact of LUM/IVA on lung structure and function in children aged 6–11 years. Methods This real-world observational cohort study was conducted across four paediatric sites in Ireland over 24-months using spirometry-controlled CT scores and LCI as primary outcome measures. Children commencing LUM-/IVA as part of routine care were included. CT scans were manually scored with the PRAGMA CF scoring system and analysed using the automated bronchus-artery (BA) method. Secondary outcome measures included rate of change of ppFEV1, nutritional indices and exacerbations requiring hospitalisation. Results Seventy-one participants were recruited to the study, 31 of whom had spirometry-controlled CT performed at baseline, and after one year and two years of LUM/IVA treatment. At two years there was a reduction from baseline in trapped air scores (0.13 to 0.07, p = 0.016), but an increase from baseline in the % bronchiectasis score (0.84 to 1.23, p = 0.007). There was no change in overall % disease score (2.78 to 2.25, p = 0.138). Airway lumen to pulmonary artery ratios (AlumenA ratio) were abnormal at baseline and worsened over the course of the study. In 28 participants, the mean annual change from baseline LCI2.5 (-0.055 (-0.61 to 0.50), p = 0.85) measurements over two years were not significant. Improvements from baseline in weight (0.10 (0.06 to 0.15, p

Climate services must provide robust estimates of future changes to precipitation extremes to inform flood risk management and to assess the resilience of existing urban drainage systems in a changing climate. We use an ensemble of convection-permitting UK climate projections, UKCP Local to estimate return levels of 1–24 h precipitation extremes, combining state-of-the-art climate and spatial statistical modelling. We produce low, central and high precipitation return level uplifts at 5 km resolution across the UK. On average across the UK, the 30y return level of 1 and 24 h precipitation is projected to increase by 30–45% and 20–40% respectively by 2070 under RCP8.5, for central-to-high estimates. Uplifts are consistently higher over the northern UK. For 1 h extremes, uplifts here are higher than the official guidance for some parts of the UK, where guidelines pre-date UKCP Local. These spatially-varying uplifts are given for durations out to 24 h with uplifts lower for longer duration extremes. We provide physical explanations for these spatial patterns and the variation with duration. The new uplifts improve on previous official guidance that used a single value for all durations and across most UK nations, and was based on climate models with poor representation of sub-daily precipitation extremes. The results translate the latest UK climate change projections into tailored climate adaptation information useful and suitable for the water industry and flood risk management stakeholders. This is critical for ensuring we benefit from the latest advances in climate modelling and build a society that is resilient to a changing climate.

This is an exciting time for research and novel drug development in cystic fibrosis. However, rarely has the adage, “Children are not just little adults” been more relevant. This article is divided into two main sections. In the first, we explore why it is important to involve children in research. We discuss the potential benefits of understanding a disease and its treatment in children, and we highlight that children have the same legal and ethical right to evidence-based therapy as adults. Additionally, we discuss why extrapolation from adults may be inappropriate, for example, medication pharmacokinetics may be different in children, and there may be unpredictable adverse effects. In the second part, we discuss how to involve children and their families in research. We outline the importance and the complexities of selecting appropriate outcome measures, and we discuss the role co-design may have in improving the involvement of children. We highlight the importance of appropriate staffing and resourcing, and we outline some of the common challenges and possible solutions, including practical tips on obtaining consent/assent in children and adolescents. We conclude that it is unethical to simply rely on extrapolation from adult studies because research in young children is challenging and that research should be seen as a normal part of the paediatric therapeutic journey.

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

An active colloidal fluid composed 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 toward 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.

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.