Assessment of clinical response to ivacaftor with lung clearance index in cystic fibrosis patients with a G551D-CFTR mutation and preserved spirometry:A randomised controlled trial

Background: Ivacaftor has shown a clinical benefit in patients with cystic fibrosis who have the G551D-CFTR mutation and reduced lung function. Lung clearance index (LCI) using multiple-breath washout might be an alternative to and more sensitive method than forced expiratory volume in 1 s (FEV₁) to assess treatment response in the growing number of children and young adults with cystic fibrosis who have normal spirometry. The aim of the study was to assess the treatment effects of ivacaftor on LCI in patients with cystic fibrosis, a G551D-CFTR mutation, and an FEV₁ >90% predicted. Methods: This phase 2, multicentre, placebo-controlled, double-blind 2×2 crossover study of ivacaftor treatment was conducted in patients with cystic fibrosis, at least one G551D-CFTR allele, and an FEV₁ >90% predicted. Patients also had to have an LCI higher than 7·4 at screening, age of 6 years or older, and a weight higher than or equal to 15 kg. Eligible patients were randomly allocated to receive one of two treatment sequences (placebo first followed by ivacaftor 150 mg twice daily [sequence 1] or ivacaftor 150 mg twice daily first followed by placebo [sequence 2]) of 28 days' treatment in each period, with a 28-day washout between the two treatment periods. Randomisation (ratio 1:1) was done with block sizes of 4, and all site personnel including the investigator, the study monitor, and the Vertex study team were masked to treatment assignment. The primary outcome measure was change from baseline in LCI. The study is registered at ClinicalTrials.gov, NCT01262352. Findings: Between February and November, 2011, 21 patients were enrolled, of which 11 were assigned to the sequence 1 group, and 10 to the sequence 2 group. 20 of these patients received treatment and 17 completed the trial (eight in sequence 1 group and 9 in sequence 2 group). Treatment with ivacaftor led to significant improvements compared with placebo in LCI (difference between groups in the average of mean changes from baseline at days 15 and 29 was -2·16 [95% CI -2·88 to -1·44]; p<0·0001). Adverse events experienced by study participants were similar between treatment groups; at least one adverse event was reported by 15 (79%) of 19 patients who received placebo and 13 (72%) of 18 patients who received ivacaftor. No deaths occurred during study period. Interpretation: In patients with cystic fibrosis aged 6 years or older who have at least one G551D-CFTR allele, ivacaftor led to improvements in LCI. LCI might be a more sensitive alternative to FEV₁ in detecting response to intervention in these patients with mild lung disease. Funding: Vertex Pharmaceuticals Incorporated. © 2013 Elsevier Ltd.

Lung Clearance Index in cystic fibrosis subjects treated for Pulmonary Exacerbations

Pulmonary exacerbations are important clinical events for cystic fibrosis (CF) patients. Studies assessing the ability of the lung clearance index (LCI) to detect treatment response for pulmonary exacerbations have yielded heterogeneous results. Here, we conduct a retrospective analysis of pooled LCI data to assess treatment with intravenous antibiotics for pulmonary exacerbations and to understand factors explaining the heterogeneous response.

A systematic literature search was performed to identify prospective observational studies. Factors predicting the relative change in LCI and spirometry were evaluated while adjusting for within-study clustering.

Six previously reported studies and one unpublished study, which included 176 pulmonary exacerbations in both paediatric and adult patients, were included. Overall, LCI significantly decreased by 0.40 units (95% CI -0.60 -0.19, p=0.004) or 2.5% following treatment. The relative change in LCI was significantly correlated with the relative change in forced expiratory volume in 1 s (FEV1), but results were discordant in 42.5% of subjects (80 out of 188). Higher (worse) baseline LCI was associated with a greater improvement in LCI (slope: -0.9%, 95% CI -1.0- -0.4%).

LCI response to therapy for pulmonary exacerbations is heterogeneous in CF patients; the overall effect size is small and results are often discordant with FEV1.

Reduced Bacterial Colony Count of Anaerobic Bacteria Is Associated with a Worsening in Lung Clearance Index and Inflammation in Cystic Fibrosis

Anaerobic bacteria have been identified in abundance in the airways of cystic fibrosis (CF) subjects. The impact their presence and abundance has on lung function and inflammation is unclear. The aim of this study was to investigate the relationship between the colony count of aerobic and anaerobic bacteria, lung clearance index (LCI), spirometry and C-Reactive Protein (CRP) in patients with CF. Sputum and blood were collected from CF patients at a single cross-sectional visit when clinically stable. Community composition and bacterial colony counts were analysed using extended aerobic and anaerobic culture. Patients completed spirometry and a multiple breath washout (MBW) test to obtain LCI. An inverse correlation between colony count of aerobic bacteria (n = 41, r = -0.35; p = 0.02), anaerobic bacteria (n = 41, r = -0.44, p = 0.004) and LCI was observed. There was an inverse correlation between colony count of anaerobic bacteria and CRP (n = 25, r = -0.44, p = 0.03) only. The results of this study demonstrate that a lower colony count of aerobic and anaerobic bacteria correlated with a worse LCI. A lower colony count of anaerobic bacteria also correlated with higher CRP levels. These results indicate that lower abundance of aerobic and anaerobic bacteria may reflect microbiota disruption and disease progression in the CF lung.

Effect of turbine inlet temperature on blade tip leakage flow and heat transfer

One of the most critical gas turbine engine components, rotor blade tip and casing, are exposed to high thermal load. It becomes a significant design challenge to protect the turbine materials from this severe situation. As a result of geometric complexity and experimental limitations, Computational Fluid Dynamics (CFD) tools have been used to predict blade tip leakage flow aerodynamics and heat transfer at typical engine operating conditions. In this paper, the effect of turbine inlet temperature on the tip leakage flow structure and heat transfer has been studied numerically. Uniform low (LTIT: 444 K) and high (HTIT: 800 K) turbine inlet temperature have been considered. The results showed the higher turbine inlet temperature yields the higher velocity and temperature variations in the leakage flow aerodynamics and heat transfer. For a given turbine geometry and on-design operating conditions, the turbine power output can be increased by 1.48 times, when the turbine inlet temperature increases 1.80 times. Whereas the averaged heat fluxes on the casing and the blade tip become 2.71 and 2.82 times larger, respectively. Therefore, about 2.8 times larger cooling capacity is required to keep the same turbine material temperature. Furthermore, the maximum heat flux on the blade tip of high turbine inlet temperature case reaches up to 3.348 times larger than that of LTIT case. The effect of the interaction of stator and rotor on heat transfer features is also explored using unsteady simulations.

A Numerical Study of the Flow Fields in a Highly Off-Design Variable Geometry Turbine

Conventionally, radial turbines have almost exclusively used radially fibred blades. While issues of mechanical integrity are paramount, there may be opportunities for improving turbine efficiency through a 3D blade design without exceeding mechanical limits. Off-design performance and understanding of the secondary flow structures now plays a vital role in the design decisions made for automotive turbocharger turbines. Of particular interest is extracting more energy at high pressure ratios and lower rotational speeds. Operating in this region means the rotor will experience high values of positive incidence at the inlet. A CFD analysis has been carried out on a scaled automotive turbine utilizing a swing vane stator system. To date no open literature exists on the flow structures present in a standard VGT system. Investigations were carried out on a 90 mm diameter rotor with the stator vane at the maximum, minimum and 25% mass flow rate positions. In addition stator vane endwall clearance existed at the hub side. From investigation of the internal flow fields of the baseline rotor, a number of areas that could be optimized in the future with three dimensional blading were identified. The blade loading and tip leakage flow near inlet play a significant role in the flow development further downstream at all stator vane positions. It was found that tip leakage flow and flow separation at off-design conditions could be reduced by employing back swept blading and redistributing the blade loading. This could potentially reduce the extent of the secondary flow structures found in the present study.

Shortened Lung Clearance Index is a repeatable and sensitive test in children and adults with cystic fibrosis

Background: Lung clearance index (LCI) derived from sulfur hexafluoride (SF6) multiple breath washout (MBW) is a sensitive measure of lung disease in people with cystic fibrosis (CF). However, it can be time-consuming, limiting its use clinically. Aim: To compare the repeatability, sensitivity and test duration of LCI derived from washout to 1/30th (LCI1/30), 1/20th (LCI1/20) and 1/10th (LCI1/10) to ‘standard’ LCI derived from washout to 1/40th initial concentration (LCI1/40). Methods: Triplicate MBW test results from 30 clinically stable people with CF and 30 healthy controls were analysed retrospectively. MBW tests were performed using 0.2% SF6 and a modified Innocor device. All LCI end points were calculated using SimpleWashout software. Repeatability was assessed using coefficient of variation (CV%). The proportion of people with CF with and without abnormal LCI and forced expiratory volume in 1 s (FEV1) % predicted was compared. Receiver operating characteristic (ROC) curve statistics were calculated. Test duration of all LCI end points was compared using paired t tests. Results: In people with CF, LCI1/40 CV% (p=0.16), LCI1/30 CV%, (p=0.53), LCI1/20 CV% (p=0.14) and LCI1/10 CV% (p=0.25) was not significantly different to controls. The sensitivity of LCI1/40, LCI1/30 and LCI1/20 to the presence of CF was equal (67%). The sensitivity of LCI1/10 and FEV1% predicted was lower (53% and 47% respectively). Area under the ROC curve (95% CI) for LCI1/40, LCI1/30, LCI1/20, LCI1/10 and FEV1% predicted was 0.89 (0.80 to 0.97), 0.87 (0.77 to 0.96), 0.87 (0.78 to 0.96), 0.83 (0.72 to 0.94) and 0.73 (0.60 to 0.86), respectively. Test duration of LCI1/30, LCI1/20 and LCI1/10 was significantly shorter compared with the test duration of LCI1/40 in people with CF (p<0.0001) equating to a 5%, 9% and 15% time saving, respectively. Conclusions: In this study, LCI1/20 was a repeatable and sensitive measure with equal diagnostic performance to LCI1/40. LCI1/20 was shorter, potentially offering a more feasible research and clinical measure.

Manipulating plasmon modes in tip-enhanced Raman microscopy

The influence of polarization on the plasmon modes excited in tip-enhanced near-field optical microscopy have been investigated using the Finite Difference Time Domain Method. Analysis of the calculated results have laid particular emphasis on the ability to align local field enhancements with the orientation of molecules in order to optimize Raman signals, with particular relevance to recent experimental work on carbon nanotubes.

Estimating the net contribution of interleukin-28B variation to spontaneous hepatitis C virus clearance.

The identification of associations between interleukin-28B (IL-28B) variants and the spontaneous clearance of hepatitis C virus (HCV) raises the issues of causality and the net contribution of host genetics to the trait. To estimate more precisely the net effect of IL-28B genetic variation on HCV clearance, we optimized genotyping and compared the host contributions in multiple- and single-source cohorts to control for viral and demographic effects. The analysis included individuals with chronic or spontaneously cleared HCV infections from a multiple-source cohort (n = 389) and a single-source cohort (n = 71). We performed detailed genotyping in the coding region of IL-28B and searched for copy number variations to identify the genetic variant or haplotype carrying the strongest association with viral clearance. This analysis was used to compare the effects of IL-28B variation in the two cohorts. Haplotypes characterized by carriage of the major alleles at IL-28B single-nucleotide polymorphisms (SNPs) were highly overrepresented in individuals with spontaneous clearance versus those with chronic HCV infections (66.1% versus 38.6%, P = 6 × 10(-9) ). The odds ratios for clearance were 2.1 [95% confidence interval (CI) = 1.6-3.0] and 3.9 (95% CI = 1.5-10.2) in the multiple- and single-source cohorts, respectively. Protective haplotypes were in perfect linkage (r(2) = 1.0) with a nonsynonymous coding variant (rs8103142). Copy number variants were not detected. We identified IL-28B haplotypes highly predictive of spontaneous HCV clearance. The high linkage disequilibrium between IL-28B SNPs indicates that association studies need to be complemented by functional experiments to identify single causal variants. The point estimate for the genetic effect was higher in the single-source cohort, which was used to effectively control for viral diversity, sex, and coinfections and, therefore, offered a precise estimate of the net host genetic contribution.

Importance of ENaC-mediated sodium transport in alveolar fluid clearance using genetically-engineered mice.

The lung possesses specific transport systems that intra- and extracellularly maintain salt and fluid balance necessary for its function. At birth, the lungs rapidly transform into a fluid (Na(+))-absorbing organ to enable efficient gas exchange. Alveolar fluid clearance, which mainly depends on sodium transport in alveolar epithelial cells, is an important mechanism by which excess water in the alveoli is reabsorbed during the resolution of pulmonary edema. In this review, we will focus and summarize on the role of ENaC in alveolar lung liquid clearance and discuss recent data from mouse models with altered activity of epithelial sodium channel function in the lung, and more specifically in alveolar fluid clearance. Recent data studying mice with hyperactivity of ENaC or mice with reduced ENaC activity clearly illustrate the impaired lung fluid clearance in these adult mice. Further understanding of the physiological role of ENaC and its regulatory proteins implicated in salt and water balance in the alveolar cells may therefore help to develop new therapeutic strategies to improve gas exchange in pulmonary edema.

ENaC-mediated alveolar fluid clearance and lung fluid balance depend on the channel-activating protease 1.

Sodium transport via epithelial sodium channels (ENaC) expressed in alveolar epithelial cells (AEC) provides the driving force for removal of fluid from the alveolar space. The membrane-bound channel-activating protease 1 (CAP1/Prss8) activates ENaC in vitro in various expression systems. To study the role of CAP1/Prss8 in alveolar sodium transport and lung fluid balance in vivo, we generated mice lacking CAP1/Prss8 in the alveolar epithelium using conditional Cre-loxP-mediated recombination. Deficiency of CAP1/Prss8 in AEC induced in vitro a 40% decrease in ENaC-mediated sodium currents. Sodium-driven alveolar fluid clearance (AFC) was reduced in CAP1/Prss8-deficient mice, due to a 48% decrease in amiloride-sensitive clearance, and was less sensitive to beta(2)-agonist treatment. Intra-alveolar treatment with neutrophil elastase, a soluble serine protease activating ENaC at the cell surface, fully restored basal AFC and the stimulation by beta(2)-agonists. Finally, acute volume-overload increased alveolar lining fluid volume in CAP1/Prss8-deficient mice. This study reveals that CAP1 plays a crucial role in the regulation of ENaC-mediated alveolar sodium and water transport and in mouse lung fluid balance.

Cleanliness versus cow comfort – an insolvable problem?

Cubicle should provide good resting comfort as well as clean udders. Dairy cows in cubicle houses often face a restrictive environment with regard to resting behaviour, whereas cleanliness may still be impaired. This study aimed to determine reliable behavioural measures regarding resting comfort applicable in on-farm welfare assessments. Furthermore, relationships between cubicle design, cow sizes, management factors and udder cleanliness (namely teats and teat tips) were investigated. Altogether 15 resting measures were examined in terms of feasibility, inter-observer reliability (IOR) and consistency of results per farm over time. They were recorded during three farm visits on farms in Germany and Austria with cubicle, deep litter and tie stall systems. Seven measures occurred to infrequently to allow reliable recording within a limited observation time. IOR was generally acceptable to excellent except for 'collisions during lying down', which only showed good IOR after improvement of the definition. Only three measures were acceptably repeatable over time: 'duration of lying down', 'percentage of collisions during lying down' and 'percentage of cows lying partly or completely outside lying area'. These measures were evaluated as suitable animal based welfare measures regarding resting behaviour in the framework of an on-farm welfare assessment protocol. The second part of the thesis comprises a cross-sectional study on resting comfort and cow cleanliness including 23 Holstein Friesian dairy herds with very low within-farm variation in cubicle measures. Height at withers, shoulder width and diagonal body length were measured in 79-100 % of the cows (herd size 30 to115 cows). Based on the 25 % largest animals, compliance with recommendations for cubicle measures was calculated. Cleanliness of different body parts, the udder, teats and teat tips was assessed for each cow in the herd prior to morning milking. No significant correlation was found between udder soiling and teat or teat tip soiling on herd level. The final model of a stepwise regression regarding the percentage of dirty teats per farm explained 58.5 % the variance and contained four factors. Teat dipping after milking which might be associated with an overall clean and accurate management style, deep bedded cubicles, increasing cubicle maintenance times and decreasing compliance concerning total cubicle length predicted lower teat soiling. The final model concerning teat tip soiling explained 46.0 % of the variance and contained three factors. Increasing litter height in the rear part of the cubicle and increased alley soiling which is difficult to explain, predicted for less soiled teat tips, whereas increasing compliance concerning resting length was associated with higher percentages of dirty teat tips. The dependent variable ‘duration of lying down’ was analysed using again stepwise regression. The final model explained 54.8 % of the total variance. Lying down duration was significantly shorter in deep bedded cubicles. Further explanatory though not significant factors in the model were neck-rail height, deep bedding or comfort mattresses versus concrete floor or rubber mats and clearance height of side partitions. In the attempt to create a more comprehensive lying down measure, another analysis was carried out with percentage of ‘impaired lying down’ (i.e. events exceeding 6.3 seconds, with collisions or being interrupted) as dependent variable. The explanatory value of this final model was 41.3 %. An increase in partition length, in compliance concerning cubicle width and the presence of straw within bedding predicted a lower proportion of impaired lying down. The effect of partition length is difficult to interpret, but partition length and height were positively correlated on the study farms, possibly leading to a bigger zone of clear space for pelvis freedom. No associations could be found between impaired lying down and teat or teat tip soiling. Altogether, in agreement with earlier studies it was found that cubicle dimensions in practice are often inadequate with regard to the body dimensions of the cows, leading to high proportions of impaired lying down behaviour, whereas teat cleanliness is still unsatisfactory. Connections between cleanliness and cow comfort are far from simplistic. Especially the relationship between cubicle characteristics and lying down behaviour apparently is very complex, so that it is difficult to identify single influential factors that are valid for all farm situations. However, based on the results of the present study the use of deep bedded cubicles can be recommended as well as improved management with special regard to cubicle and litter maintenance in order to achieve both better resting comfort and teat cleanliness.

Dos experiencias socialistas de Formaci??n Profesional en el primer tercio del siglo XX : las escuelas de aprendices tip??grafos y de aprendices metal??rgicos

En este art??culo se analizan dos experiencias formativas ocurridas en el primer tercio del siglo XX, concretamente las escuelas de aprendices tip??graficos y de aprendices metal??rgicos. La finalidad de la primera era proporcionar instrucci??n t??cnica elemental a los j??venes que se dedicaran al arte de la imprenta en la secci??n de cajas. La segunda ten??a como objetivo ser el lugar donde completar la educaci??n pr??ctica que los aprendices recib??an en sus centros de trabajo, mediante ciertos conocimientos te??ricos, a fin de perfeccionar su capacidad profesional.