Anterior segment anomalies and effects on visual quality

The tear film, cornea and lens dictate the refractive power of the eye and the retinal image quality is principally defined by diffraction, whole eye wavefront error, scatter, and chromatic aberration. Diffraction and wave aberration are fundamentally pupil diameter dependent; however scatter can be induced by refractive surgery and in the normal ageing eye becomes an increasingly important factor defining retinal image quality. The component of visual quality most affected by the tear film, refractive surgery and multifocal contact and intraocular lenses is the wave aberration of the eye. This body of work demonstrates the effects of each of these anomalies on the visual quality of the eye. When assessing normal or borderline self-diagnosed dry eye subjects using aberrometry, combining lubricating eye drops and spray does not offer any benefit over individual products. However, subjects perceive a difference in comfort for all interventions after one hour. Total higher order aberrations increase after laser assisted sub-epithelial keratectomy performed using a solid-state laser on myopes, but this causes no significant decrease in contrast sensitivity or increase in glare disability. Mean sensitivity and reliability indices for perimetry were comparable to pre-surgery results. Multifocal contact lenses and intraocular lenses are designed to maximise vision when the patient is binocular, so any evaluation of the eyes individually is confounded by reduced individual visual acuity and visual quality. Different designs of aspheric multifocal contact lenses do not provide the same level of visual quality. Multifocal contact lenses adversely affect mean deviation values for perimetry and this should be considered when screening individuals with multifocal contact or intraocular lenses. Photographic image quality obtained through a multifocal contact or intraocular lens appears to be unchanged. Future work should evaluate the effect of these anomalies in combination; with the aim of providing the best visual quality possible and supplying normative data for screening purposes.

Formant-frequency variation and its effects on across-formant grouping in speech perception

How speech is separated perceptually from other speech remains poorly understood. In a series of experiments, perceptual organisation was probed by presenting three-formant (F1+F2+F3) analogues of target sentences dichotically, together with a competitor for F2 (F2C), or for F2+F3, which listeners must reject to optimise recognition. To control for energetic masking, the competitor was always presented in the opposite ear to the corresponding target formant(s). Sine-wave speech was used initially, and different versions of F2C were derived from F2 using separate manipulations of its amplitude and frequency contours. F2Cs with time-varying frequency contours were highly effective competitors, whatever their amplitude characteristics, whereas constant-frequency F2Cs were ineffective. Subsequent studies used synthetic-formant speech to explore the effects of manipulating the rate and depth of formant-frequency change in the competitor. Competitor efficacy was not tuned to the rate of formant-frequency variation in the target sentences; rather, the reduction in intelligibility increased with competitor rate relative to the rate for the target sentences. Therefore, differences in speech rate may not be a useful cue for separating the speech of concurrent talkers. Effects of competitors whose depth of formant-frequency variation was scaled by a range of factors were explored using competitors derived either by inverting the frequency contour of F2 about its geometric mean (plausibly speech-like pattern) or by using a regular and arbitrary frequency contour (triangle wave, not plausibly speech-like) matched to the average rate and depth of variation for the inverted F2C. Competitor efficacy depended on the overall depth of frequency variation, not depth relative to that for the other formants. Furthermore, the triangle-wave competitors were as effective as their more speech-like counterparts. Overall, the results suggest that formant-frequency variation is critical for the across-frequency grouping of formants but that this grouping does not depend on speech-specific constraints.

Multiple component patient safety intervention in English hospitals:controlled evaluation of second phase

Objective: To independently evaluate the impact of the second phase of the Health Foundation's Safer Patients Initiative (SPI2) on a range of patient safety measures. Design: A controlled before and after design. Five substudies: survey of staff attitudes; review of case notes from high risk (respiratory) patients in medical wards; review of case notes from surgical patients; indirect evaluation of hand hygiene by measuring hospital use of handwashing materials; measurement of outcomes (adverse events, mortality among high risk patients admitted to medical wards, patients' satisfaction, mortality in intensive care, rates of hospital acquired infection). Setting: NHS hospitals in England. Participants: Nine hospitals participating in SPI2 and nine matched control hospitals. Intervention The SPI2 intervention was similar to the SPI1, with somewhat modified goals, a slightly longer intervention period, and a smaller budget per hospital. Results: One of the scores (organisational climate) showed a significant (P=0.009) difference in rate of change over time, which favoured the control hospitals, though the difference was only 0.07 points on a five point scale. Results of the explicit case note reviews of high risk medical patients showed that certain practices improved over time in both control and SPI2 hospitals (and none deteriorated), but there were no significant differences between control and SPI2 hospitals. Monitoring of vital signs improved across control and SPI2 sites. This temporal effect was significant for monitoring the respiratory rate at both the six hour (adjusted odds ratio 2.1, 99% confidence interval 1.0 to 4.3; P=0.010) and 12 hour (2.4, 1.1 to 5.0; P=0.002) periods after admission. There was no significant effect of SPI for any of the measures of vital signs. Use of a recommended system for scoring the severity of pneumonia improved from 1.9% (1/52) to 21.4% (12/56) of control and from 2.0% (1/50) to 41.7% (25/60) of SPI2 patients. This temporal change was significant (7.3, 1.4 to 37.7; P=0.002), but the difference in difference was not significant (2.1, 0.4 to 11.1; P=0.236). There were no notable or significant changes in the pattern of prescribing errors, either over time or between control and SPI2 hospitals. Two items of medical history taking (exercise tolerance and occupation) showed significant improvement over time, across both control and SPI2 hospitals, but no additional SPI2 effect. The holistic review showed no significant changes in error rates either over time or between control and SPI2 hospitals. The explicit case note review of perioperative care showed that adherence rates for two of the four perioperative standards targeted by SPI2 were already good at baseline, exceeding 94% for antibiotic prophylaxis and 98% for deep vein thrombosis prophylaxis. Intraoperative monitoring of temperature improved over time in both groups, but this was not significant (1.8, 0.4 to 7.6; P=0.279), and there were no additional effects of SPI2. A dramatic rise in consumption of soap and alcohol hand rub was similar in control and SPI2 hospitals (P=0.760 and P=0.889, respectively), as was the corresponding decrease in rates of Clostridium difficile and meticillin resistant Staphylococcus aureus infection (P=0.652 and P=0.693, respectively). Mortality rates of medical patients included in the case note reviews in control hospitals increased from 17.3% (42/243) to 21.4% (24/112), while in SPI2 hospitals they fell from 10.3% (24/233) to 6.1% (7/114) (P=0.043). Fewer than 8% of deaths were classed as avoidable; changes in proportions could not explain the divergence of overall death rates between control and SPI2 hospitals. There was no significant difference in the rate of change in mortality in intensive care. Patients' satisfaction improved in both control and SPI2 hospitals on all dimensions, but again there were no significant changes between the two groups of hospitals. Conclusions: Many aspects of care are already good or improving across the NHS in England, suggesting considerable improvements in quality across the board. These improvements are probably due to contemporaneous policy activities relating to patient safety, including those with features similar to the SPI, and the emergence of professional consensus on some clinical processes. This phenomenon might have attenuated the incremental effect of the SPI, making it difficult to detect. Alternatively, the full impact of the SPI might be observable only in the longer term. The conclusion of this study could have been different if concurrent controls had not been used.

Formant-frequency variation and its effects on across-formant grouping in speech perception

How speech is separated perceptually from other speech remains poorly understood. In a series of experiments, perceptual organisation was probed by presenting three-formant (F1+F2+F3) analogues of target sentences dichotically, together with a competitor for F2 (F2C), or for F2+F3, which listeners must reject to optimise recognition. To control for energetic masking, the competitor was always presented in the opposite ear to the corresponding target formant(s). Sine-wave speech was used initially, and different versions of F2C were derived from F2 using separate manipulations of its amplitude and frequency contours. F2Cs with time-varying frequency contours were highly effective competitors, whatever their amplitude characteristics, whereas constant-frequency F2Cs were ineffective. Subsequent studies used synthetic-formant speech to explore the effects of manipulating the rate and depth of formant-frequency change in the competitor. Competitor efficacy was not tuned to the rate of formant-frequency variation in the target sentences; rather, the reduction in intelligibility increased with competitor rate relative to the rate for the target sentences. Therefore, differences in speech rate may not be a useful cue for separating the speech of concurrent talkers. Effects of competitors whose depth of formant-frequency variation was scaled by a range of factors were explored using competitors derived either by inverting the frequency contour of F2 about its geometric mean (plausibly speech-like pattern) or by using a regular and arbitrary frequency contour (triangle wave, not plausibly speech-like) matched to the average rate and depth of variation for the inverted F2C. Competitor efficacy depended on the overall depth of frequency variation, not depth relative to that for the other formants. Furthermore, the triangle-wave competitors were as effective as their more speech-like counterparts. Overall, the results suggest that formant-frequency variation is critical for the across-frequency grouping of formants but that this grouping does not depend on speech-specific constraints. © Springer Science+Business Media New York 2013.

Effects of microstructure on long and short crack growth in nickel base superalloys

The use of engineering materials in critical applications necessitates the accurate prediction of component lifetime for inspection and renewal purposes. In fatigue limited situations, it is necessary to be able to predict the growth rates of cracks from initiation at a defect through to final fracture. To this end, fatigue crack growth data are presented for different microstructures of typical nickel base superalloys used in gas turbine engines. Crack growth behaviour throughout the life history of the crack, i.e. from the short crack through to the long crack propagation regime, is described for each microstructural condition and discussed in terms of current theories of fatigue crack propagation.

IL-8 released constitutively by primary bronchial epithelial cells in culture forms an inactive complex with secretory component

The bronchial epithelium is a source of both α and β chemokines and, uniquely, of secretory component (SC), the extracellular ligand-binding domain of the polymeric IgA receptor. Ig superfamily relatives of SC, such as IgG and α2-macroglobulin, bind IL-8. Therefore, we tested the hypothesis that SC binds IL-8, modifying its activity as a neutrophil chemoattractant. Primary bronchial epithelial cells were cultured under conditions to optimize SC synthesis. The chemokines IL-8, epithelial neutrophil-activating peptide-78, growth-related oncogene α, and RANTES were released constitutively by epithelial cells from both normal and asthmatic donors and detected in high m.w. complexes with SC. There were no qualitative differences in the production of SC-chemokine complexes by epithelial cells from normal or asthmatic donors, and in all cases this was the only form of chemokine detected. SC contains 15% N-linked carbohydrate, and complete deglycosylation with peptide N-glycosidase F abolished IL-8 binding. In micro-Boyden chamber assays, no IL-8-dependent neutrophil chemotactic responses to epithelial culture supernatants could be demonstrated. SC dose-dependently (IC50 ∼0.3 nM) inhibited the neutrophil chemotactic response to rIL-8 (10 nM) in micro-Boyden chamber assays and also inhibited IL-8-mediated neutrophil transendothelial migration. SC inhibited the binding of IL-8 to nonspecific binding sites on polycarbonate filters and endothelial cell monolayers, and therefore the formation of haptotactic gradients, without effects on IL-8 binding to specific receptors on neutrophils. The data indicate that in the airways IL-8 may be solubilized and inactivated by binding to SC

Manufacturing and assembly automation by integrated metrology systems for aircraft wing fabrication

Discrepancies of materials, tools, and factory environments, as well as human intervention, make variation an integral part of the manufacturing process of any component. In particular, the assembly of large volume, aerospace parts is an area where significant levels of form and dimensional variation are encountered. Corrective actions can usually be taken to reduce the defects, when the sources and levels of variation are known. For the unknown dimensional and form variations, a tolerancing strategy is typically put in place in order to minimize the effects of production inconsistencies related to geometric dimensions. This generates a challenging problem for the automation of the corresponding manufacturing and assembly processes. Metrology is becoming a major contributor to being able to predict, in real time, the automated assembly problems related to the dimensional variation of parts and assemblies. This is done by continuously measuring dimensions and coordinate points, focusing on the product's key characteristics. In this paper, a number of metrology focused activities for large-volume aerospace products, including their implementation and application in the automation of manufacturing and assembly processes, are reviewed. This is done by using a case study approach within the assembly of large-volume aircraft wing structures.

Validation of a multi-component digital dissolution model for irregular particles

A new mesoscale simulation model for solids dissolution based on an computationally efficient and versatile digital modelling approach (DigiDiss) is considered and validated against analytical solutions and published experimental data for simple geometries. As the digital model is specifically designed to handle irregular shapes and complex multi-component structures, use of the model is explored for single crystals (sugars) and clusters. Single crystals and the cluster were first scanned using X-ray microtomography to obtain a digital version of their structures. The digitised particles and clusters were used as a structural input to digital simulation. The same particles were then dissolved in water and the dissolution process was recorded by a video camera and analysed yielding: the overall dissolution times and images of particle size and shape during the dissolution. The results demonstrate the coherence of simulation method to reproduce experimental behaviour, based on known chemical and diffusion properties of constituent phase. The paper discusses how further sophistications to the modelling approach will need to include other important effects such as complex disintegration effects (particle ejection, uncertainties in chemical properties). The nature of the digital modelling approach is well suited to for future implementation with high speed computation using hybrid conventional (CPU) and graphical processor (GPU) systems.

Using an in vitro human airway model to study the toxic effects of components of e-cigarettes

Cigarette smoke is a complex mixture of more than 4000 hazardous chemicals including the carcinogenic benzopyrenes. Nicotine, the most potent component of tobacco, is responsible for the addictive nature of cigarettes and is a major component of e-cigarette cartridges. Our study aims to investigate the toxicity of nicotine with special emphasis on the replacement of animals. Furthermore, we intend to study the effect of nicotine, cigarette smoke and e-cigarette vapours on human airways. In our current work, the BEAS 2B human bronchial epithelial cell line was used to analyse the effect of nicotine in isolation, on cell viability. Concentrations of nicotine from 1.1µM to 75µM were added to 5x105 cells per well in a 96 well plate and incubated for 24 hours. Cell titre blue results showed that all the nicotine treated cells were more metabolically active than the control wells (cells alone). These data indicate that, under these conditions, nicotine does not affect cell viability and in fact, suggests that there is a stimulatory effect of nicotine on metabolism. We are now furthering this finding by investigating the pro-inflammatory response of these cells to nicotine by measuring cytokine secretion via ELISA. Further work includes analysing nicotine exposure at different time points and on other epithelial cells lines like Calu-3.

Nicotine exposure reduces cell viability but induces anti-inflammatory effects in human cystic fibrosis bronchial epithelial cells

Background: Mouse models of cystic fibrosis (CF) fail to truly represent the respiratory pathology. We have consequently developed human airways cell culture models to address this. The impact of cigarette smoke within the CF population is well documented, with exposure being known to worsen lung function. As nicotine is often perceived to be a less harmful component of tobacco smoke, this research aimed to identify its effects upon viability and inflammatory responses of CF (IB3-1) and CF phenotype corrected (C38) bronchial epithelial cells. Methods: IB3-1 and C38 cell lines were exposed to increasing concentrations of nicotine (0.55-75μM) for 24 hours. Cell viability was assessed via Cell Titre Blue and the inflammatory response with IL-6 and IL-8 ELISA. Results: CF cells were more sensitive; nicotine significantly (P<0.05) reduced cell viability at all concentrations tested, but failed to have a marked effect on C38 viability. Whilst nicotine induced anti-inflammatory effects in CF cells with a significant reduction in IL-6 and IL-8 release, it had no effect on chemokine release by C38 cells. Conclusion: CF cells may be more vulnerable to inhaled toxicants than non-CF cells. As mice lack a number of human nicotinic receptor subunits and fail to mimic the characteristic pathology of CF, these data emphasise the importance of employing relevant human cell lines to study a human-specific disease.

What one hand giveth the other taketh away:some unpredicted effects of enantiomers in psychopharmacology

It is well known that many medicines are a mixture of two enantiomers, or mirror-image molecules. Two enantiomers occur when a molecule has a single chiral centre and the two mirror images, called S or L (left handed) and R or D (right handed), are usually found in equal amounts in the parent (racemic) mixture. While for many compounds used in clinical practice the active moiety is found in one of the two enantiomers with the other being seen as an unnecessary and redundant component of the racemic mixture, the difference between enantiomers can mean a difference between therapeutic and adverse effects, as well as in beneficial pharmacological effect and potency. © 2010 The Author(s).

Informational masking and the effects of differences in fundamental frequency and fundamental-frequency contour on phonetic integration in a formant ensemble

This study explored the effects on speech intelligibility of across-formant differences in fundamental frequency (ΔF0) and F0 contour. Sentence-length speech analogues were presented dichotically (left=F1+F3; right=F2), either alone or—because competition usually reveals grouping cues most clearly—accompanied in the left ear by a competitor for F2 (F2C) that listeners must reject to optimize recognition. F2C was created by inverting the F2 frequency contour. In experiment 1, all left-ear formants shared the same constant F0 and ΔF0F2 was 0 or ±4 semitones. In experiment 2, all left-ear formants shared the natural F0 contour and that for F2 was natural, constant, exaggerated, or inverted. Adding F2C lowered keyword scores, presumably because of informational masking. The results for experiment 1 were complicated by effects associated with the direction of ΔF0F2; this problem was avoided in experiment 2 because all four F0 contours had the same geometric mean frequency. When the target formants were presented alone, scores were relatively high and did not depend on the F0F2 contour. F2C impact was greater when F2 had a different F0 contour from the other formants. This effect was a direct consequence of the associated ΔF0; the F0F2 contour per se did not influence competitor impact.