Antimicrobial efficacy of copper surfaces against spores and vegetative cells of Clostridium difficile: the germination theory

OBJECTIVES: Persistent contamination of surfaces by spores of Clostridium difficile is a major factor influencing the spread of C. difficile-associated diarrhoea (CDAD) in the clinical setting. In recent years, the antimicrobial efficacy of metal surfaces has been investigated against microorganisms including methicillin-resistant Staphylococcus aureus. This study compared the survival of C. difficile on stainless steel, a metal contact surface widely used in hospitals, and copper surfaces. METHODS: Antimicrobial efficacy was assessed using a carrier test method against dormant spores, germinating spores and vegetative cells of C. difficile (NCTC 11204 and ribotype 027) over a 3 h period in the presence and absence of organic matter. RESULTS: Copper metal eliminated all vegetative cells of C. difficile within 30 min, compared with stainless steel which demonstrated no antimicrobial activity (P < 0.05). Copper significantly reduced the viability of spores of C. difficile exposed to the germinant (sodium taurocholate) in aerobic conditions within 60 min (P < 0.05) while achieving a >or=2.5 log reduction (99.8% reduction) at 3 h. Organic material did not reduce the antimicrobial efficacy of the copper surface (P > 0.05).

Liposomes:Formulation and characterisation as contrast agents and as vaccine delivery systems

Liposome systems are well reported for their activity as vaccine adjuvants; however novel lipid-based microbubbles have also been reported to enhance the targeting of antigens into dendritic cells (DCs) in cancer immunotherapy (Suzuki et al 2009). This research initially focused on the formulation of gas-filled lipid coated microbubbles and their potential activation of macrophages using in vitro models. Further studies in the thesis concentrated on aqueous-filled liposomes as vaccine delivery systems. Initial work involved formulating and characterising four different methods of producing lipid-coated microbubbles (sometimes referred to as gas-filled liposomes), by homogenisation, sonication, a gas-releasing chemical reaction and agitation/pressurisation in terms of stability and physico-chemical characteristics. Two of the preparations were tested as pressure probes in MRI studies. The first preparation composed of a standard phospholipid (DSPC) filled with air or nitrogen (N2), whilst in the second method the microbubbles were composed of a fluorinated phospholipid (F-GPC) filled with a fluorocarbon saturated gas. The studies showed that whilst maintaining high sensitivity, a novel contrast agent which allows stable MRI measurements of fluid pressure over time, could be produced using lipid-coated microbubbles. The F-GPC microbubbles were found to withstand pressures up to 2.6 bar with minimal damage as opposed to the DSPC microbubbles, which were damaged at above 1.3 bar. However, it was also found that DSPC-filled with N2 microbubbles were also extremely robust to pressure and their performance was similar to that of F-GPC based microbubbles. Following on from the MRI studies, the DSPC-air and N2 filled lipid-based microbubbles were assessed for their potential activation of macrophages using in vitro models and compared to equivalent aqueous-filled liposomes. The microbubble formulations did not stimulate macrophage uptake, so studies thereafter focused on aqueous-filled liposomes. Further studies concentrated on formulating and characterising, both physico-chemically and immunologically, cationic liposomes based on the potent adjuvant dimethyldioctadecylammonium (DDA) and immunomodulatory trehalose dibehenate (TDB) with the addition of polyethylene glycol (PEG). One of the proposed hypotheses for the mechanism behind the immunostimulatory effect obtained with DDA:TDB is the ‘depot effect’ in which the liposomal carrier helps to retain the antigen at the injection site thereby increasing the time of vaccine exposure to the immune cells. The depot effect has been suggested to be primarily due to their cationic nature. Results reported within this thesis demonstrate that higher levels of PEG i.e. 25 % were able to significantly inhibit the formation of a liposome depot at the injection site and also severely limit the retention of antigen at the site. This therefore resulted in a faster drainage of the liposomes from the site of injection. The versatility of cationic liposomes based on DDA:TDB in combination with different immunostimulatory ligands including, polyinosinic-polycytidylic acid (poly (I:C), TLR 3 ligand), and CpG (TLR 9 ligand) either entrapped within the vesicles or adsorbed onto the liposome surface was investigated for immunogenic capacity as vaccine adjuvants. Small unilamellar (SUV) DDA:TDB vesicles (20-100 nm native size) with protein antigen adsorbed to the vesicle surface were the most potent in inducing both T cell (7-fold increase) and antibody (up to 2 log increase) antigen specific responses. The addition of TLR agonists poly(I:C) and CpG to SUV liposomes had small or no effect on their adjuvanticity. Finally, threitol ceramide (ThrCer), a new mmunostimulatory agent, was incorporated into the bilayers of liposomes composed of DDA or DSPC to investigate the uptake of ThrCer, by dendritic cells (DCs), and presentation on CD1d molecules to invariant natural killer T cells. These systems were prepared both as multilamellar vesicles (MLV) and Small unilamellar (SUV). It was demonstrated that the IFN-g secretion was higher for DDA SUV liposome formulation (p<0.05), suggesting that ThrCer encapsulation in this liposome formulation resulted in a higher uptake by DCs.

Theoretical and empirical evaluation of phakic and pseudophakic accomodation

The binding theme of this thesis is the examination of both phakic and pseudophakic accommodation by means of theoretical modelling and the application of a new biometric measuring technique. Anterior Segment Optical Coherence Tomography (AS-OCT) was used to assess phakic accommodative changes in 30 young subjects (19.4 2.0 years; range, 18 to 25 years). A new method of assessing curvature change with this technique was employed with limited success. Changes in axial accommodative spacing, however, proved to be very similar to those of the Scheimpflug-based data. A unique biphasic trend in the position of the posterior crystalline lens surface during accommodation was discovered, which has not been alluded to in the literature. All axial changes with accommodation were statistically significant (p < 0.01) with the exception of corneal thickness (p = 0.81). A two-year follow-up study was undertaken for a cohort of subjects previously implanted with a new accommodating intraocular lens (AIOL) (Lenstec Tetraflex KH3500). All measures of best corrected distance visual acuity (BCDVA; +0.04 0.24 logMAR), distance corrected near visual acuity (DCNVA; +0.61 0.17 logMAR) and contrast sensitivity (+1.35 0.21 log units) were good. The subjective accommodation response quantified with the push-up technique (1.53 0.64 D) and defocus curves (0.77 0.29 D) was greater than the objective stimulus response (0.21 0.19 D). AS-OCT measures with accommodation stimulus revealed a small mean posterior movement of the AIOLs (0.02 0.03 mm for a 4.0 D stimulus); this is contrary to proposed mechanism of the anterior focus-shift principle.

Antibacterial activity of low amperage and low voltage electric current (DC)

Infection is a major clinical problem associated with the use of intravenous catheters.The efficacy of a direct electric current (10µA, 9V) via electrode-conducting carbon impregnated catheters to prevent colonisation of catheters by micro-organisms was investigated. The range of organisms susceptible to 10µA was determined by a zone of inhibition test. The catheters acting as the anode and the cathode were inserted into a nutrient agar plate inoculated with a lawn of bacteria. There was no zone of inhibition observed around the anode. Organisms susceptible to 10µA at the cathode were Staphylococcus aureus (2 strains), Staphylococcus epidermidis (5 strains), Escherichia coli and Klebsiella pneumoniae (2 strains each), and one strain of the following micro-organisms: Staphylococcus hominis, Proteus mirabilis, Pseudomonas aeruginosa and Candida albicans. The zones ranged from 6 to 16 mm in diameter according to the organisms under test. The zone size was proportional to the amperage (10 - 100 µA) and the number of organisms on the plate. Ten µA did not prevent adhesion of staphylococci to the cathode nor did it affect their growth in nutrient broth. However, it was bactericidal to adherent bacteria on the cathodal catheter and significantly reduced the number of bacteria on the catheter after 4 to 24 h application of electricity. The antimicrobial activity of low amperage electric current under anaerobic conditions and in the absence of chloride ions against bacteria attached to the surface of a current carrying electrode was also investigated.The mechanisms of the bactericidal activity associated with the cathode were investigated with S. epidermidis and S. aureus. The inhibition zone was greatly reduced in the presence of catalase. There was no zone around the cathode when the test was carried out under anaerobic conditions. Hydrogen peroxide was produced at the cathode surface under aerobic conditions, but not in the absence of oxygen. A salt-bridge apparatus was used to demonstrate further that hydrogen peroxide was produced at the cathode, and chlorine at the anode. The antimicrobial activity of low amperage electric current under anaerobic conditions and in the absence of chloride ions against bacteria attached to the surface of a current carrying electrode was also investigated. Antibacterial activity was reduced under anaerobic conditions, which is compatible with the role of hydrogen peroxide as a primary bactericidal agent of electricity associated with the cathode. A reduction in chloride ions did not significantly reduce the antibacterial activity suggesting chlorine plays only a minor role in the bactericidal activity against organisms attached to anodal electrode surfaces. The bactericidal activity of electric current associated with the cathode and H202 was greatly reduced in the presence of 50 μM to 0.5 mM magnesium ions in the test menstrum. Ten μA applied via the catheters did not prevent the initial biofilm growth by the adherent bacteria but reduced the number of bacteria in the biofilm by 2 log order aiter 24 h. The results suggested that 10 μA may prevent the colonisation of catheters by both the extra~ and intra-luminal routes. The localised production of hydrogen peroxide and chlorine and the intrinsic activity due to electric current may offer a useful method for the eradication of bacteria from catheter surfaces.

Watermarking biomedical time series data

This thesis addresses the problem of information hiding in low dimensional digital data focussing on issues of privacy and security in Electronic Patient Health Records (EPHRs). The thesis proposes a new security protocol based on data hiding techniques for EPHRs. This thesis contends that embedding of sensitive patient information inside the EPHR is the most appropriate solution currently available to resolve the issues of security in EPHRs. Watermarking techniques are applied to one-dimensional time series data such as the electroencephalogram (EEG) to show that they add a level of confidence (in terms of privacy and security) in an individual’s diverse bio-profile (the digital fingerprint of an individual’s medical history), ensure belief that the data being analysed does indeed belong to the correct person, and also that it is not being accessed by unauthorised personnel. Embedding information inside single channel biomedical time series data is more difficult than the standard application for images due to the reduced redundancy. A data hiding approach which has an in built capability to protect against illegal data snooping is developed. The capability of this secure method is enhanced by embedding not just a single message but multiple messages into an example one-dimensional EEG signal. Embedding multiple messages of similar characteristics, for example identities of clinicians accessing the medical record helps in creating a log of access while embedding multiple messages of dissimilar characteristics into an EPHR enhances confidence in the use of the EPHR. The novel method of embedding multiple messages of both similar and dissimilar characteristics into a single channel EEG demonstrated in this thesis shows how this embedding of data boosts the implementation and use of the EPHR securely.

Effects of yellow filters on visual acuity, contrast sensitivity and reading under conditions of forward light scatter

Background Yellow filters are sometimes recommended to people with low vision. Our aim was investigate the effects of three commercial yellow filters on visual acuity and contrast sensitivity (with and without glare) and reading (without glare) under conditions of forward light scatter (FLS). Method Fifty-five healthy subjects were assessed with Corning Photochromic Filters (CPFs) 450, 511 and 527 and a filter producing FLS. The effects on log MAR visual acuity, Pelli–Robson contrast sensitivity with and without glare, and reading (measured with MNRead charts) without glare were determined. Results Statistically significant differences were found between the overall effect of glare and between CPFs for visual acuity and contrast sensitivity. A gradual decline in visual acuity, contrast sensitivity and reading with increasing CPF absorption was noted. Conclusion Effects of CPF450, 511, 527 on visual acuity, contrast sensitivity and reading under conditions of FLS were negative but not clinically significant.

Evaluation of disinfecting procedures for aseptic transfer in hospital pharmacy departments

Current practice in National Health Service (NHS) hospitals employs 70% Industrial Methylated Spirit spray for surface disinfection of components required in Grade A pharmaceutical environments. This study seeks to investigate other agents and procedures that may provide more effective sanitisation. Several methods are available to test the efficacy of disinfectants against vegetative organisms. However, no methods currently available test the efficacy of disinfectants against spores on the hard surfaces encountered in the pharmacy aseptic processing environment. Therefore, a method has been developed to test the efficacy of disinfectants against spores, modified from British Standard 13697 and Association of Analytical Chemists standards. The testing procedure was used to evaluate alternative biocides and disinfection methods for transferring components into hospital pharmacy cleanrooms, and to determine which combinations of biocide and application method have the greatest efficacy against spores of Bacillus subtilis subspecies subtilis 168, Bacillus subtilis American Type Culture Collection (ATCC) 6633, and Bacillus pumilis ATCC 27142. Stainless steel carrier test plates were used to represent the hard surfaces in hospital pharmacy cleanrooms. Plates were inoculated with 10(7)-10(8) colony-forming units per milliliter (CFU/mL) and treated with the various biocide formulations, using different disinfection methods. Sporicidal activity was calculated as log reduction in CFU. Of the biocides tested, 6% hydrogen peroxide and a quaternary ammonium compound/chlorine dioxide combination were most effective compared to a Quat/biguanide, amphoteric surfactant, 70% v/v ethanol in deionised water and isopropyl alcohol in water for injection. Of the different application methods tested, spraying followed by wiping was the most effective, followed closely by wiping alone. Spraying alone was least effective.

Spray dried combinations of lactoferrin with antibiotics appear superior to monotherapy for reducing biofilm formation by pseudomonas aeruginosa

SD Apo Lactoferrin-Tobramycin/Gentamicin Combinations are superior to monotherapy in the eradication of Pseudomonas aeruginosa Biofilm in the lungs Wilson Oguejiofor1, Lindsay J. Marshall1, Andrew J. Ingham1, Robert Price2, Jag. Shur2 1School of Life and Health Sciences, Aston University, Birmingham, UK. 2School of Pharmacy and Pharmacology, University of Bath, Bath, UK. KEYWORDS: lactoferrin, apo lactoferrin, spray drying, biofilm, cystic fibrosis Introduction Chronic lung infections from the opportunistic pathogeen Pseudomonas aeruginosa has been recognised as a major contributor to the incidences of high morbidity and mortality amongst cystic fibrosis (CF) patients (1,2). Currently, strategies for managing lung infections in CF patients involves the aggressive use of aerosolised antibiotics (3), however, increasing evidence suggests that the biofilm component of P. aeruginosa in the lower airway remains unperturbed and is associated with the development of antibiotic resistance. If this is so then, there is an urgent need to suitably adjust the current treatment strategy so that it includes compounds that prevent biofilm formation or disrupt established biofilms. It is well understood that biofilm formation is strongly dependent on iron (Fe3+) availability (4), therefore aerosolised anti-infective formulations which has the ability to chelate iron may essentially be a well suited therapy for eliminating P. aeruginosa biofilms on CF airway epithelial cells (5). In this study, we report the use of combination therapy; an aminoglycosides (tobramycin and gentamicin) and an antimicrobial peptide (lactoferrin) to significantly deplete P. aeruginosa biofilms. We demonstrate that lactoferrin-tobramycin and lactoferrin-gentamicin combinations are superior to the single antibiotic regime currently being employed to combat P. aeruginosa biofilms. MATERIALS AND METHOD Antibiotics: The antibiotics used in this study included gentamicin and tobramycin supplied by Fagron, UK. Bacterial strain and growth conditions: Pseudomonas aeruginosa strain PAO1 was provided by Prof. Peter Lambert of Aston University, Birmingham UK. The Strains were routinely grown from storage in a medium supplemented with magnesium chloride, glucose and casamino acids. Dialysis of lactoferrin: Apo lactoferrin was prepared by dialyzing a suspension of lactoferrin for 24 hrs at 4 °C against 20 mmol/L sodium dihydrogen phosphate, 20 mmol/L sodium acetate and 40 mmol/L EDTA (pH 3.5). Ferric ion (Fe3+) removal was verified by atomic absorption spectroscopy measurements. Spray drying of combinations of lactoferrin and apo lactoferrin with the different aminoglycosides: Combinations of tobramycin and gentamicin with the different preparations of lactoferrin were spray dried (SD) as a 2% (w/v) aqueous suspension. The spray drying parameters utilized for the production of suitable micron-sized particles includes: Inlet temperature, 180°C, spray flow rate, 606 L/hr; pump setting, 10%; aspirator setting, 85% (34m3/hr) to produce various outlet temperatures ranging from 99 - 106°C. Viability assay: To test the bactericidal activity of the various combinations, a viability assay was performed as previously described by Xu, Xiong et al. (6) with some modifications. Briefly, 10µL of ~ c. 6.6 x 107 CFU mL-1 P. aeruginosa strain PAO1 suspension were incubated (37°C, 60 mins) with 90 µL of a 2 µg/mL concentration of the various combinations and sampled every 10 mins. After incubation, the cells were diluted in deionised water and plated in Mueller hinton agar plates. Following 24 h incubation of the plates at 37°C, the percentage of viable cells was determined relative to incubation without added antibiotics. Biofilm assay: To test the susceptibility of the P. aeruginosa strain to various antibiotics in the biofilms mode of growth, overnight cultures of P. aeruginosa were diluted 1:100 into fresh medium supplemented with magnesium chloride, glucose and casamino acids. Aliquots of the dilution were dispensed into a 96 well dish and incubated (37°C, 24 h). Excess broth was removed and the number of colony forming units per milliliter (CFU/mL) of the planktonic bacteria was quantified. The biofilms were then washed and stained with 0.1% (w/v) crystal violet for 15 mins at room temperature. Following vigorous washing with water, the stained biofilms were solubilized in 30% acetic acid and the absorbance at 550nm of a 125 µL aliquot was determined in a microplate reader (Multiskan spectrum, Thermo Scientific) using 30% acetic acid in water as the blank. Aliquots of the broth prior to staining were used as an indicator of the level of planktonic growth. RESULTS AND DISCUSSION Following spray drying, the mean yield, volume weighted mean diameter and moisture content of lactoferrin powder were measured and were as follows (Table 1 and table 2); Table 1: Spray drying parameters FormulationInlet temp (°C)Outlet temp (°C)Airflow rate (L/hr)Mean yield (%)Moisture content (%) SD Lactoferrin18099 - 10060645.2 ±2.75.9 ±0.4 SD Apo Lactoferrin180100 - 10260657.8 ±1.85.7 ±0.2 Tobramycin180102 - 10460682.1 ±2.23.2 ±0.4 Lactoferrin + Tobramycin180104 - 10660687.5 ±1.43.7 ±0.2 Apo Lactoferrin + Tobramycin180103 - 10460676.3 ±2.43.3 ±0.5 Gentamicin18099 - 10260685.4 ±1.34.0 ±0.2 Lactoferrin + Gentamicin180102 - 10460687.3 ±2.13.9 ±0.3 Apo Lactoferrin + Gentamicin18099 -10360680.1±1.93.4 ±0.4 Table 2: Particle size distribution d10 d50d90 SD Lactoferrin1.384.9111.08 SD Apo Lactoferrin1.284.7911.04 SD Tobramycin1.254.9011.29 SD Lactoferrin + Tobramycin1.175.2715.23 SD Apo Lactoferrin + Tobramycin1.115.0614.31 SD Gentamicin1.406.0614.38 SD Lactoferrin + Gentamicin1.476.2314.41 SD Apo Lactoferrin + Gentamicin1.465.1511.53 The bactericidal activity of the various combinations were tested against P. aeruginosa PAO1 following a 60 minute incubation period (Figure 1 and Figure 2). While 2 µg/mL of a 1:1 combination of spray dried apo lactoferrin and Gentamicin was able to completely kill all bacterial cells within 40 mins, the same concentration was not as effective for the other antibiotic combinations. However, there was an overall reduction of bacterial cells by over 3 log units by the other combinations within 60 mins. Figure 1: Logarithmic plot of bacterial cell viability of various combinations of tobramycin and lactoferrin preparations at 2µg/mL (n = 3). Figure 2: Logarithmic plot of bacterial cell viability of various combinations of gentamicin and lactoferrin preparations at 2µg/mL (n = 3). Crystal violet staining showed that biofilm formation by P. aeruginosa PAO1 was significantly (ANOVA, p < 0.05) inhibited in the presence of the different lactoferrin preparations. Interestingly, apo lactoferrin and spray dried lactoferrin exhibited greater inhibition of both biofilm formation and biofilm persistence (Figure 2). Figure 2: Crystal violet staining of residual biofilms of P. aeruginosa following a 24hr incubation with the various combinations of antibiotics and an exposure to 48 hr formed biofilms. CONCLUSION In conclusion, combination therapy comprising of an antimicrobial peptide (lactoferrin) and an aminoglycosides (tobramycin or gentamicin) provides a feasible and alternative approach to monotherapy since the various combinations are more efficient than the respective monotherapy in the eradication of both planktonic and biofilms of P. aeruginosa. ACKNOWLEDGEMENT The authors would like to thank Mr. John Swarbrick and Friesland Campina for their generous donation of the Lactoferrin. REFERENCES 1.Hassett, D.J., Sutton, M.D., Schurr, M.J., Herr, A.B., Caldwell, C.C. and Matu, J.O. (2009), "Pseudomonas aeruginosa hypoxic or anaerobic biofilm infections within cystic fibrosis airways". Trends in Microbiology, 17, 130-138. 2.Trust, C.F. (2009), "Antibiotic treatment for cystic fibrosis". Report of the UK Cystic Fibrosis Trust Antibiotic Working Group. Consensus document. London: Cystic Fibrosis Trust. 3.Garcia-Contreras, L. and Hickey, A.J. (2002), "Pharmaceutical and biotechnological aerosols for cystic fibrosis therapy". Advanced Drug Delivery Reviews, 54, 1491-1504. 4.O'May, C.Y., Sanderson, K., Roddam, L.F., Kirov, S.M. and Reid, D.W. (2009), "Iron-binding compounds impair Pseudomonas aeruginosa biofilm formation, especially under anaerobic conditions". J Med Microbiol, 58, 765-773. 5.Reid, D.W., Carroll, V., O'May, C., Champion, A. and Kirov, S.M. (2007), "Increased airway iron as a potential factor in the persistence of Pseudomonas aeruginosa infection in cystic fibrosis". European Respiratory Journal, 30, 286-292. 6.Xu, G., Xiong, W., Hu, Q., Zuo, P., Shao, B., Lan, F., Lu, X., Xu, Y. and Xiong, S. (2010), "Lactoferrin-derived peptides and Lactoferricin chimera inhibit virulence factor production and biofilm formation in Pseudomonas aeruginosa". J Appl Microbiol, 109, 1311-1318.

Empirical prediction of peptide octanol-water partition coefficients

Peptides are of great therapeutic potential as vaccines and drugs. Knowledge of physicochemical descriptors, including the partition coefficient P (commonly expressed in logarithm form: logP), is useful for screening out unsuitable molecules and also for the development of predictive Quantitative Structure-Activity Relationships (QSARs). In this paper we develop a new approach to the prediction of LogP values for peptides based on an empirical relationship between global molecular properties and measured physical properties. Our method was successful in terms of peptide prediction (total r2 = 0.641). The final model consisted of 5 physicochemical descriptors (molecular weight, number of single bonds, 2D-VDW volume, 2D-VSA hydrophobic and 2D-VSA polar). The approach is peptide specific and its predictive accuracy was high. Overall, 67% of the peptides were able to be predicted within +/-0.5 log units from the experimental values. Our method thus represents a novel prediction method with proven predictive ability.

Normative contrast sensitivity values for the back-lit Melbourne Edge Test and the effect of visual impairment

Background: The Melbourne Edge Test (MET) is a portable forced-choice edge detection contrast sensitivity (CS) test. The original externally illuminated paper test has been superseded by a backlit version. The aim of this study was to establish normative values for age and to assess change with visual impairment. Method: The MET was administered to 168 people with normal vision (18-93 years old) and 93 patients with visual impairment (39-97 years old). Distance visual acuity (VA) was measured with a log MAR chart. Results: In those eyes without disease, MET CS was stable until the age of 50 years (23.8 ± .7 dB) after which it decreased at a rate of ≈1.5 dB per decade. Compared with normative values, people with low vision were found to have significantly reduced CS, which could not be totally accounted for by reduced VA. Conclusions: The MET provides a quick and easy measure of CS, which highlights a reduction in visual function that may not be detectable using VA measurements. © 2004 The College of Optometrists.

Mobile app Aston contrast sensitivity test

BACKGROUND: Contrast detection is an important aspect of the assessment of visual function; however, clinical tests evaluate limited spatial frequencies and contrasts. This study validates the accuracy and inter-test repeatability of a swept-frequency near and distance mobile app Aston contrast sensitivity test, which overcomes this limitation compared to traditional charts. METHOD: Twenty subjects wearing their full refractive correction underwent contrast sensitivity testing on the new near application (near app), distance app, CSV-1000 and Pelli-Robson charts with full correction and with vision degraded by 0.8 and 0.2 Bangerter degradation foils. In addition repeated measures using the 0.8 occluding foil were taken. RESULTS: The mobile apps (near more than distance, p = 0.005) recorded a higher contrast sensitivity than printed tests (p < 0.001); however, all charts showed a reduction in measured contrast sensitivity with degradation (p < 0.001) and a similar decrease with increasing spatial frequency (interaction > 0.05). Although the coefficient of repeatability was lowest for the Pelli-Robson charts (0.14 log units), the mobile app charts measured more spatial frequencies, took less time and were more repeatable (near: 0.26 to 0.37 log units; distance: 0.34 to 0.39 log units) than the CSV-1000 (0.30 to 0.93 log units). The duration to complete the CSV-1000 was 124 ± 37 seconds, Pelli-Robson 78 ± 27 seconds, near app 53 ± 15 seconds and distance app 107 ± 36 seconds. CONCLUSIONS: While there were differences between charts in contrast levels measured, the new Aston near and distance apps are valid, repeatable and time-efficient method of assessing contrast sensitivity at multiple spatial frequencies.

CLAE to move to online format

Editorial: The 2015 BCLA annual conference was another fantastic affair. It was the first time the conference was held in the beautiful city of Liverpool. The venue was great and the programme was excellent. The venue overlooked the River Mersey and many of the hotels were local boutique hotels. I stayed in one which was formerly the offices of White Star Liners—where the RMS Titanic was originally registered. The hotel decor was consistent with its historic significance. The BCLA gala dinner was held in the hugely impressive Anglican Cathedral with entertainment from a Beatles tribute band. That will certainly be a hard act to follow at the next conference in 2017. Brian Tompkins took the reigns as the new BCLA president. Professor Fiona Stapleton was the recipient of the BCLA Gold Medal Award. The winner of the poster competition was Dorota Szczesna-Iskander with a poster entitled ‘Dry Contact lens poor wettability and visual performance’. Second place was Renee Reeder with her poster entitled ‘Abnormal Rosacea as a differential diagnosis in corneal scarring’. And third place was Maria Jesus Gonzalez-Garcia with her poster entitled ‘Dry Effect of the Environmental Conditions on Tear Inflammatory Mediators Concentration in Contact Lens Wearers’. The photographic competition winner was Professor Wolfgang Sickenberger from Jena in Germany. The Editorial Panel of CLAE met at the BCLA conference for their first biannual meeting. The journal metrics were discussed. In terms of number of submissions of new papers CLAE seems to have plateaued after seeing a rapid growth in the number of submissions over the last few years. The increase over the last few years could be attributed to the fact that CLAE was awarded an impact factor for the first time in 2012. This year it seems that impact factors across nearly all ophthalmic related journals has dropped. This could in part be due to the fact that last year was a ‘Research Exercise Framework (REF) year for UK universities, where they are judged on quality of their research output. The next REF is in 2020 so we may see changes nearing that time. Looking at article downloads, there seems to be a continued rise in figures. Currently CLAE attracts around 85,000 downloads per year (this is an increase of around 10,000 per year for the last few years) and the 2015 prediction is 120,000! With this in mind and with other contributing factors too, the BCLA has decided to move to online delivery of CLAE to its members starting from issue 5 of 2015. Some members do like to flick through the pages of a hard copy of the journal so members will still have the option of receiving a hard copy through the post but the default journal delivery method will now be online. The BCLA office will send various alerts and content details to members email addresses. To access CLAE online you will need to log in via the BCLA web page, currently you then click on ‘Resources’ and then under ‘Free and Discounted Publications’ you will see CLAE. This actually takes you to CLAE’s own webpage (www.contactlensjournal.com) but you need to log in via the BCLA web page. The BCLA plans to change these weblinks so that from the BCLA web page you can link to the journal website much more easily and you have the choice of going directly into the general website for CLAE or straight to the current issue. In 2016 you will see an even easier way of accessing CLAE online as the BCLA will launch a CLAE application for mobile devices where the journal can be downloaded as a ‘flick-book’. This is a great way of bringing CLAE into the modern era where people access their information in newer ways. For many the BCLA conference was part of a very busy conference week as it was preceded by the International Association of Contact Lens Educators’ (IACLE) Third World Congress, held in Manchester on the 4 days before the BCLA conference. The first and second IACE World Congresses were held in Waterloo, Canada in 1994 and 2000 respectively and hosted by Professor Des Fonn. Professor Fonn was the recipient of the first ever IACLE lifetime achievement award. The Third IACLE World Congress saw more than 100 contact lens educators and industry representatives from around 30 countries gather in the UK for the four-day event, hosted by The University of Manchester. Delegates gained hands-on experience of innovations in teaching, such as learning delivery systems, the use of iPads in the classroom and for creating ePub content, and augmented and virtual reality technologies. IACLE members around the world also took part via a live online broadcast. The Third IACLE World Congress was made possible by the generous support of Sponsors Alcon, CooperVision and Johnson & Johnson Vision Care., for more information look at the IACLE web page (www.iacle.org).

A Fast Algorithm for Weber Problem on a Grid

AMS subject classification: 90B80.

Using overlay test to evaluate fracture properties of field-aged asphalt concrete

Field material testing provides firsthand information on pavement conditions which are most helpful in evaluating performance and identifying preventive maintenance or overlay strategies. High variability of field asphalt concrete due to construction raises the demand for accuracy of the test. Accordingly, the objective of this study is to propose a reliable and repeatable methodology to evaluate the fracture properties of field-aged asphalt concrete using the overlay test (OT). The OT is selected because of its efficiency and feasibility for asphalt field cores with diverse dimensions. The fracture properties refer to the Paris’ law parameters based on the pseudo J-integral (A and n) because of the sound physical significance of the pseudo J-integral with respect to characterizing the cracking process. In order to determine A and n, a two-step OT protocol is designed to characterize the undamaged and damaged behaviors of asphalt field cores. To ensure the accuracy of determined undamaged and fracture properties, a new analysis method is then developed for data processing, which combines the finite element simulations and mechanical analysis of viscoelastic force equilibrium and evolution of pseudo displacement work in the OT specimen. Finally, theoretical equations are derived to calculate A and n directly from the OT test data. The accuracy of the determined fracture properties is verified. The proposed methodology is applied to a total of 27 asphalt field cores obtained from a field project in Texas, including the control Hot Mix Asphalt (HMA) and two types of warm mix asphalt (WMA). The results demonstrate a high linear correlation between n and −log A for all the tested field cores. Investigations of the effect of field aging on the fracture properties confirm that n is a good indicator to quantify the cracking resistance of asphalt concrete. It is also indicated that summer climatic condition clearly accelerates the rate of aging. The impact of the WMA technologies on fracture properties of asphalt concrete is visualized by comparing the n-values. It shows that the Evotherm WMA technology slightly improves the cracking resistance, while the foaming WMA technology provides the comparable fracture properties with the HMA. After 15 months aging in the field, the cracking resistance does not exhibit significant difference between HMA and WMAs, which is confirmed by the observations of field distresses.

The risk of re-intervention after endovascular aortic aneurysm repair

This thesis studies survival analysis techniques dealing with censoring to produce predictive tools that predict the risk of endovascular aortic aneurysm repair (EVAR) re-intervention. Censoring indicates that some patients do not continue follow up, so their outcome class is unknown. Methods dealing with censoring have drawbacks and cannot handle the high censoring of the two EVAR datasets collected. Therefore, this thesis presents a new solution to high censoring by modifying an approach that was incapable of differentiating between risks groups of aortic complications. Feature selection (FS) becomes complicated with censoring. Most survival FS methods depends on Cox's model, however machine learning classifiers (MLC) are preferred. Few methods adopted MLC to perform survival FS, but they cannot be used with high censoring. This thesis proposes two FS methods which use MLC to evaluate features. The two FS methods use the new solution to deal with censoring. They combine factor analysis with greedy stepwise FS search which allows eliminated features to enter the FS process. The first FS method searches for the best neural networks' configuration and subset of features. The second approach combines support vector machines, neural networks, and K nearest neighbor classifiers using simple and weighted majority voting to construct a multiple classifier system (MCS) for improving the performance of individual classifiers. It presents a new hybrid FS process by using MCS as a wrapper method and merging it with the iterated feature ranking filter method to further reduce the features. The proposed techniques outperformed FS methods based on Cox's model such as; Akaike and Bayesian information criteria, and least absolute shrinkage and selector operator in the log-rank test's p-values, sensitivity, and concordance. This proves that the proposed techniques are more powerful in correctly predicting the risk of re-intervention. Consequently, they enable doctors to set patients’ appropriate future observation plan.