Optimizing the Entrainment Geometry of a Dry Powder Inhaler: Methodology and Preliminary Results.

This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s11095-016-1992-3PURPOSE: For passive dry powder inhalers (DPIs) entrainment and emission of the aerosolized drug dose depends strongly on device geometry and the patient's inhalation manoeuvre. We propose a computational method for optimizing the entrainment part of a DPI. The approach assumes that the pulmonary delivery location of aerosol can be determined by the timing of dose emission into the tidal airstream. METHODS: An optimization algorithm was used to iteratively perform computational fluid dynamic (CFD) simulations of the drug emission of a DPI. The algorithm seeks to improve performance by changing the device geometry. Objectives were to achieve drug emission that was: A) independent of inhalation manoeuvre; B) similar to a target profile. The simulations used complete inhalation flow-rate profiles generated dependent on the device resistance. The CFD solver was OpenFOAM with drug/air flow simulated by the Eulerian-Eulerian method. RESULTS: To demonstrate the method, a 2D geometry was optimized for inhalation independence (comparing two breath profiles) and an early-bolus delivery. Entrainment was both shear-driven and gas-assisted. Optimization for a delay in the bolus delivery was not possible with the chosen geometry. CONCLUSIONS: Computational optimization of a DPI geometry for most similar drug delivery has been accomplished for an example entrainment geometry.Engineering and Physical Sciences Research Council PhD studentship (Grant ID: EP/ M506485/1

The Effects of Cooling and Shrinkage on the Life of Polymer 3D Printed Injection Moulds

3D Printed Injection Moulds (3DIM), commonly used for low volume production and prototyping purposes, are known to fail abruptly and have a comparatively shorter life than conventional moulds. Investigating the underlying critical factors affecting failure may help in reducing the risk of abrupt failures and possibly prolong the 3DIM tool life. A hypothesis that the cooling time of the Injection Moulding (IM) process is a critical factor for 3DIM tool failure has been pro-posed. The failure hypothesis has been validated by theoretical calculations, FEA simulations and experimental investigations. Experiments were performed using two different materials for the 3DIM tool (Visijet M3-X and Digital ABS) and an engineering thermoplastic (Lexan 943-A) as the moulding material. Results showed that cooling time was a critical factor on tool life and managing the thermal loading on a 3DIM tool could lead to increased tool life. The paper identifies cooling time as the critical factor affecting 3DIM tool life and presents a cooling regime that could possibly lead to prolonged tool life

Multiscale Analogue Modelling of Clinching Process to Investigate Thickness Tolerance and Tool Misalignment

NEED—The effect of dimensional variability of sheet thickness (tolerance) and tool misalignment is poorly understood for the clinching process. Finite element analysis (FEA) is valuable but requires a lot of and is difficult to verify in this situation due to the asymmetrical geometry and nonlinear plasticity. OBJECTIVE—The objective of this work was to determine the effect of thickness tolerance, tool misalignment and sheet placement (top vs. bottom) in the clinching process, by use of analogue modelling with plasticine. METHOD—Experiments used a scaled-up punch and die, with plasticine as the analogue. Thickness tolerances were represented by sheet thicknesses of 11 and 7 mm, 12 and 8 mm, 8 and 12 mm and 13 and 9 mm for upper and lower sheets, respectively. Two types of lubricant were tested between sheets: glycerine and silicone oil. Angular variability was also introduced. Measured parameters were interlock (also called undercut) and neck thickness. Analogue results for deformation were compared with microscopy of metal clinching. FINDINGS—The results reveal that the multiscale analogue model is an efficient tool for studying the effect of dimensional deviation on a clinch joint. Thickness tolerance showed a critical relationship with interlock, namely a reduction to about half that of the nominal, for both maximum and least material conditions. Increased angular misalignment also reduced the interlock. Compared with glycerine, silicone oil tests showed reduced interlock, possibly the result of a lower coefficient of friction. ORIGINALITY—This work demonstrates the usefulness of analogue modelling for exploring process variability in clinching. The results also show that significant effects for sheet placement are ductility, lubricant (friction), thickness of samples and tool misalignment

Potential of a cyclone prototype spacer to improve in vitro dry powder delivery

Copyright The Author(s) 2013. This article is published with open access at Springerlink.com. This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are creditedPurpose: Low inspiratory force in patients with lung disease is associated with poor deagglomeration and high throat deposition when using dry powder inhalers (DPIs). The potential of two reverse flow cyclone prototypes as spacers for commercial carrierbased DPIs was investigated. Methods: Cyclohaler®, Accuhaler® and Easyhaler® were tested with and without the spacers between 30-60 Lmin-1. Deposition of particles in the next generation impactor and within the devices was determined by high performance liquid chromatography. Results: Reduced induction port deposition of the emitted particles from the cyclones was observed due to the high retention of the drug within the spacers (e.g. salbutamol sulphate (SS): 67.89 ± 6.51 % at 30 Lmin-1 in Cheng 1). Fine particle fractions of aerosol as emitted from the cyclones were substantially higher than the DPIs alone. Moreover, the aerodynamic diameters of particles emitted from the cyclones were halved compared to the DPIs alone (e.g. SS from the Cyclohaler® at 4 kPa: 1.08 ± 0.05 μm vs. 3.00 ± 0.12 μm, with and without Cheng 2, respectively) and unaltered with increased flow rates. Conclusion: This work has shown the potential of employing a cyclone spacer for commercial carrier-based DPIs to improve inhaled drug delivery.Peer reviewe

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

An Application of the CEN/TC350 standards to an Energy and Carbon LCA of timber used in construction, and the effect of end-of-life scenarios

The use of timber construction products and their environmental impacts is growing in Europe. This paper examines the LCA approach adopted in the European CEN/TC350 standards, which are expected to improve the comparability and availability of Environmental Product Declarations (EPDs). The embodied energy and carbon (EE and EC) of timber products is discussed quantitatively, with a case study of the Forte building illustrating the significance of End-of-Life (EoL) impacts. The relative importance of timber in the context of all construction materials is analysed using a new LCA tool, Butterfly. The tool calculates EE and EC at each life cycle stage, and results show that timber products are likely to account for the bulk of the EoL impacts for a typical UK domestic building

Impact damage tolerance of carbon fibre reinforced plastics

Carbon fibre reinforced plastic (CFRP) is a composite composed of very high strength and stiffness carbon fibres within a polymer matrix. Low mass and cost make CFRP attractive for aerospace applications. At present application of CFRP is limited by the poor residual strength and fatigue properties of the material following impact damage, and because of the limited understanding of the problem. Damage to CFRP results in a combination of fibre fracture and matrix cracking. The strength of CFRP perpendicular to the fibre direction is relatively poor and so the material is generally used as a laminate of unidirectional plies of different fibre orientations. Laminates are particularly prone to delamination, this is matrix cracking which separates plies. In this thesis techniques for measurement of damage type and severity in CFRP are evaluated. These are used to quantify the distribution of damage resulting from hard body impacts at high, low and quasi-static incident velocities. A composite material damage model in a dynamic finite element analysis computer program (DYNA 3D) was used to predict the experimentally measured impact damage. However the prediction was found to be insufficiently accurate for reliable use by designers. Recommendations are made for improvements in the numerical modelling of impact damage in CFRP. Mechanical tests that provide data on the effect of impact damage on the residual strength of CFRP specimens are reported. These show that providing impact damage is limited to delamination, with little fibre fracture ocurring, the compressive residual strength will be more severely reduced than the tensile property. Strain gauge measurements show that this effect is caused by local compressive buckling of the delaminated plies in the impact damaged area. Lquivalent hole sizes, causing the same residual strengths as in the impact damaged specimens, are given. Cyclic load tests were conducted providing stress-life data for impact damaged specimens of CFRP. The data fit a stress-life diagram divided into three scatter band regions: static fracture; cycle dependent damage growth; and infinite life. Qualitative and quantitative observations are given of the progression of damage in a fatigue after impact damage test. Strain gauge and force/extension measurements show the presence of creep and energy absorption in undamaged and impact damaged CFRP. Much of the observed behaviour may be explained by a viscoelastic model. Because of the presence of viscoelastic creep it is suggested that the fatigue mechanism must depend on interacting cycle dependent and time dependent mechanisms.</p

Energy absorption of FDM 3D printed TPMS structures

Triply Periodic Minimal Surfaces (TPMS) have been shown by previous research to exhibit high energy absorption with a symmetrical, 3D structure