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Purpose: We develop a mathematical model that predicts aqueous humor (AH) production rate by the ciliary processes and aqueous composition in the posterior chamber (PC), with the aim of estimating how the aqueous production rate depends on the controlling parameters and how it can be manipulated. Methods: We propose a compartmental mathematical model that considers the stromal region, ciliary epithelium, and PC. All domains contain an aqueous solution with different chemical species. We impose the concentration of all species on the stromal side and exploit the various ion channels present on the cell membrane to compute the water flux produced by osmosis, the solute concentrations in the AH and the transepithelial potential difference. Results: With a feasible set of parameters, the model predictions of water flux from the stroma to the PC and of the solute concentrations in the AH are in good agreement with measurements. Key parameters which impact the aqueous production rate are identified. A relevant role is predicted to be played by cell membrane permeability to K+ and Cl−, by the level of transport due to the Na+-H+ exchanger and to the co-transporter of Na+/K+/2Cl−; and by carbonic anhydrase. Conclusions: The mathematical model predicts the formation and composition of AH, based on the structure of the ciliary epithelium. The model provides insight into the physical processes underlying the functioning of drugs that are adopted to regulate the aqueous production. It also suggests ion channels and cell membrane properties that may be targeted to manipulate the aqueous production rate.

ObjectiveNeovascular age-related macular degeneration (nAMD) causes damage to the macula and severe vision loss. Bevacizumab is the most cost-effective nAMD treatment. The TANDEM trial was designed to determine whether, in patients with nAMD, low-dose bevacizumab is non-inferior to the standard dose in terms of visual deterioration and whether a bimonthly regimen is non-inferior to monthly, treatment as required, regimens.MethodsThis was a multicentre, 2×2 factorial, double-masked, non-inferiority randomised trial with patients considered eligible if they met the National Institute for Health and Care Excellence criteria for nAMD treatment with ranibizumab. Participants were randomly assigned to standard (1.25 mg) or low (0.625 mg) dose bevacizumab and either monthly or bimonthly review regimen. The primary outcome was time to vision deterioration, defined as reduction of ≥15 letters (three lines) during the loading phase (visual acuity scores at visits B and C compared with the initial visit A), or ≥6 letters (one line) during the maintenance phase (visual acuity scores at subsequent visits compared with mean vision at visits A–C).ResultsIn total 812 participants (918 eyes) were randomised into the trial. The low dose showed some evidence of being non-inferior to standard dose (HR 1.07; 95% CI 0.80 to 1.42), however, there was no strong evidence of bimonthly review being non-inferior to monthly review (HR 1.45; 95% CI 1.09 to 1.94). There was no difference in visual acuity when assessed at 9 months and no major differences in the frequency of serious adverse events or reactions between the groups.ConclusionThe standard dose of bevacizumab can be halved without compromising efficacy. Bimonthly review cannot be considered to be no worse than monthly review.

The retina is composed of two main layers—the neuroretina and the retinal pigment epithelium (RPE)—that are separated by a potential gap termed the sub-retinal space (SRS). Accumulation of fluid in the SRS may result in a retinal detachment. A key function of the RPE is to prevent fluid accumulation in the SRS by actively pumping fluid from this space to the choroid. We have developed a mathematical model of this process that incorporates the transport of seven chemical species: Na + , K + , Cl − , HCO 3 − , H + , CO 2 and H 2 CO 3 . This allows us to estimate solute and water fluxes and to understand the role of the different membrane ion channels. We have performed a global sensitivity analysis using the extended Fourier amplitude sensitivity test to investigate the relative importance of parameters in generating the model outputs. The model predicts that flow across the RPE is driven by an osmotic gradient in the cleft gap between adjacent cells. Moreover, the model estimates how water flux is modified in response to inhibition of membrane ion channels and carbonic anhydrase (CA). It provides a possible explanation for how CA inhibitors, which are used clinically to prevent fluid accumulation in the SRS, may be acting.

We consider a theoretical model for the flow of Newtonian fluid through a long flexible-walled channel which is formed from four compliant and rigid compartments arranged alternately in series. We drive the flow using a fixed upstream flux and derive a spatially one-dimensional model using a flow profile assumption. The compliant compartments of the channel are assumed subject to a large external pressure, so the system admits a highly collapsed steady state. Using both a global (linear) stability eigensolver and fully nonlinear simulations, we show that these highly collapsed steady states admit a primary global oscillatory instability similar to observations in a single channel. We also show that in some regions of the parameter space the system admits a secondary mode of instability which can interact with the primary mode and lead to significant changes in the structure of the neutral stability curves. Finally, we apply the predictions of this model to the flow of blood through the central retinal vein and examine the conditions required for the onset of self-excited oscillation. We show that the neutral stability curve of the primary mode of instability discussed above agrees well with canine experimental measurements of the onset of retinal venous pulsation, although there is a large discrepancy in the oscillation frequency. doi:10.1017/S1446181119000117

PURPOSE: To describe changes in intraocular pressure (IOP) in the 'alternative treatments to Inhibit VEGF in Age-related choroidal Neovascularisation (IVAN)' trial (registered as ISRCTN92166560).DESIGN: Randomised controlled clinical trial with factorial design.PARTICIPANTS: Patients (n=610) with treatment naïve neovascular age-related macular degeneration were enrolled and randomly assigned to receive either ranibizumab or bevacizumab and to two regimens, namely monthly (continuous) or as needed (discontinuous) treatment.METHODS: At monthly visits, IOP was measured preinjection in both eyes, and postinjection in the study eye.OUTCOME MEASURES: The effects of 10 prespecified covariates on preinjection IOP, change in IOP (postinjection minus preinjection) and the difference in preinjection IOP between the two eyes were examined.RESULTS: For every month in trial, there was a statistically significant rise in both the preinjection IOP and the change in IOP postinjection during the time in the trial (estimate 0.02 mm Hg, 95% CI 0.01 to 0.03, pCONCLUSIONS: Anti-vascular endothelial growth factor agents induce increases in IOP of small and uncertain clinical significance.TRIAL REGISTRATION NUMBER: ISRCTN92166560.

PurposeTo determine the opinions from a patient perspective on relevant variables in the delivery of treatment for neovascular age-related macular degeneration (nAMD).MethodsPilot interviews with patients and doctors were conducted to identify what variables in the provision of a nAMD service were important. This led to the generation of two sets of scenario options. Subsequently 100 patients undergoing active treatment for nAMD in the National Health Service University Hospital, United Kingdom underwent interview assessment. They were asked to rank their preferences for provision of their care with reference to these two sets of scenario options. Using conjoint analysis, percentage preferences, and utility scores for each variable in each scenario design were calculated.ResultsNinety-five patients completed the preference ranking for both scenarios. Eight patients ranked worse vision as preferable to better vision and were excluded on the basis that they had not understood the task. The results of the remaining 87 patients are presented. The most important factor to patients was having good vision, followed by a one-stop service and less frequent follow up. The least important factors were label status of the drug, cost to the health service, and grade of the injector.ConclusionPatients regard good vision and minimal visits to the hospital above the status of injector, label status of drug, or cost to the NHS.

Amblyopia is a common condition affecting 2% of all children and traditional treatment consists of either wearing a patch or penalisation. We have developed a treatment using stereo technology, not to provide a 3D image but to allow dichoptic stimulation. This involves presenting an image with the same background to both eyes but with features of interest removed from the image presented to the normal eye with the aim to preferentially stimulated visual development in the amblyopic, or lazy, eye. Our system, called I-BiT can use either a game or a video (DVD) source as input. Pilot studies show that this treatment is effective with short treatment times and has proceeded to randomised controlled clinical trial. The early indications are that the treatment has a high degree of acceptability and corresponding good compliance. © (2015) COPYRIGHT Society of Photo-Optical Instrumentation Engineers (SPIE).

Background: Amblyopia (lazy eye) affects the vision of approximately 2% of all children. Traditional treatment consists of wearing a patch over their ‘good’ eye for a number of hours daily, over several months. This treatment is unpopular and compliance is often low. Therefore results can be poor. A novel binocular treatment which uses 3D technology to present specially developed computer games and video footage (I-BiT™) has been studied in a small group of patients and has shown positive results over a short period of time. The system is therefore now being examined in a randomised clinical trial. Methods/design: Seventy-five patients aged between 4 and 8 years with a diagnosis of amblyopia will be randomised to one of three treatments with a ratio of 1:1:1 - I-BiT™ game, non-I-BiT™ game, and I-BiT™ DVD. They will be treated for 30 minutes once weekly for 6 weeks. Their visual acuity will be assessed independently at baseline, mid-treatment (week 3), at the end of treatment (week 6) and 4 weeks after completing treatment (week 10). The primary endpoint will be the change in visual acuity from baseline to the end of treatment. Secondary endpoints will be additional visual acuity measures, patient acceptability, compliance and the incidence of adverse events. Discussion: This is the first randomised controlled trial using the I-BiT™ system. The results will determine if the I-BiT™ system is effective in the treatment of amblyopia and will also determine the optimal treatment for future development. Trial registration: ClinicalTrials.gov identifier: NCT01702727 Keywords: Amblyopia, I-BiT™, Randomised clinical trial, Lazy eye, Child, Visual acuity, Binocular

To evaluate the safety of an intensive cataract surgery training programme. An intensive cataract surgery training programme was implemented in August 2010 for year 3 ophthalmology trainees in the East Midlands Deanery North Rotation (United Kingdom). Trainees participated in extra-ocular surgery and 50 h of virtual reality cataract surgery simulator training over a 2-year period. Their third year comprised 6 months of intensive phacoemulsification training in a tertiary centre followed by a 6-month period of consolidation in a district general hospital. The complication rates and case numbers were evaluated after the first 2 years of implementation. At 2 years, three trainees had completed a full year of intensive training. In the first 6 months of training, Trainee 1 completed 156 cases, Trainee 2 completed 194 cases, and Trainee 3 completed 151 full cases as primary surgeons with an average rate of posterior capsule rupture (PCR) of 1%. At 12 months, Trainee 1 completed 291, Trainee 2 completed 318, and Trainee 3 completed 294 cases, with an average PCR rate of 0.66%. The trainees required 84 lists on average to complete 150 full cataract procedures. The combination of simulation and the new intensive training programme is safer than the traditional programme for cataract surgery training.

The electrode resolution of current retinal prostheses is still far from matching the densities of retinal neurons. Decreasing electrode diameter increases impedance levels thus deterring effective stimulation of neurons. One solution is to increase the surface roughness of electrodes, which can be done via nanoparticle coatings. This paper explores a Lattice Gas Model of the drying-mediated self-assembly of nanoparticle mixtures. The model includes representations for different types of nanoparticles, solvent, vapour, substrate and the energetic relationships between these elements. The dynamical aspect of the model is determined by energy minimization, stochastic fluctuations and physical constraints. The model attempts to unravel the relationships between different experimental conditions (e.g. evaporation rate, substrate characteristics and solvent viscosity) and the surface roughness of resulting assemblies. Some of the main results include the facts that the assemblies formed by nanoparticles of different sizes can boost roughness in specific circumstances and that the optimized assemblies can exhibit walled or stalagmite structures. This study provides a set of simulation modelling experiments that if confirmed in the laboratory may result in new and useful materials. Refereed/Peer-reviewed

To evaluate the cost-effectiveness of first eye cataract surgery compared with no surgery from a health service and personal social services perspective.An economic evaluation undertaken alongside a randomised controlled trial of first eye cataract surgery in secondary care ophthalmology clinics. A sample of 306 women over 70 years old with bilateral cataracts was randomised to cataract surgery (expedited, approximately four weeks) or control (routine, 12 months wait); 75% of participants had baseline acuity of 6/12 or better. Outcomes included falls and the EuroQol EQ-5D.The operated group cost a mean pounds sterling 2004 (bootstrapped) more than the control group over one year (95% confidence interval (CI), pounds sterling 1363 to pounds sterling 2833) (p0.001), but experienced on average 0.456 fewer falls, an incremental cost per fall prevented of pounds sterling 4390. The bootstrapped mean gain in quality adjusted life years (QALYs) per patient was 0.056 (95% CI, 0.006 to 0.108) (p0.001). The incremental cost-utility ratio was pounds sterling 35 704, above the currently accepted UK threshold level of willingness to pay per QALY of pounds sterling 30 000. However, in an analysis modelling costs and benefits over patients' expected lifetime, the incremental cost per QALY was pounds sterling 13 172, under conservative assumptions.First eye cataract surgery, while cost-ineffective over the trial period, was probably cost-effective over the participants' remaining lifetime.

BACKGROUND/AIM—There has been no consistent pattern reported on how mortality for uveal melanoma varies with age. This information can be useful to model the complexity of the disease. The authors have examined ocular cancer trends, as an indirect measure for uveal melanoma mortality, to see how rates vary with age and to compare the results with their other studies on predicting metastatic disease. METHODS—Age specific mortality was examined for England and Wales, the USA, and Canada. A log-log model was fitted to the data. The slopes of the log-log plots were used as measure of disease complexity and compared with the results of previous work on predicting metastatic disease. RESULTS—The log-log model provided a good fit for the US and Canadian data, but the observed rates deviated for England and Wales among people over the age of 65 years. The log-log model for mortality data suggests that the underlying process depends upon four rate limiting steps, while a similar model for the incidence data suggests between three and four rate limiting steps. Further analysis of previous data on predicting metastatic disease on the basis of tumour size and blood vessel density would indicate a single rate limiting step between developing the primary tumour and developing metastatic disease. CONCLUSIONS—There is significant underreporting or underdiagnosis of ocular melanoma for England and Wales in those over the age of 65 years. In those under the age of 65, a model is presented for ocular melanoma oncogenesis requiring three rate limiting steps to develop the primary tumour and a fourth rate limiting step to develop metastatic disease. The three steps in the generation of the primary tumour involve two key processes—namely, growth and angiogenesis within the primary tumour. The step from development of the primary to development of metastatic disease is likely to involve a single rate limiting process.

AIM—To determine whether fetal and infant growth, as assessed by weight at birth and weight at 1 year, are related to intraocular pressure. METHODS—717 men and women born in Hertfordshire between 1920 and 1930, for whom records of birth weight and weight at 1 year were available, were examined. Visual fields were assessed using the Takagi central 25 degree 75 point static threshold screening program. Tonometry was performed using the Perkin's tonometer. The disc was assessed by direct ophthalmoscopy through dilated pupils. RESULTS—A significant inverse relation was found between systolic blood pressure and birth weight. However, no association was found between birth weight or weight at 1 year and intraocular pressure, cup/disc ratio, or visual field defects. CONCLUSIONS—There was no evidence to support fetal or infant growth as being important factors for the subsequent development of raised intraocular pressure. Keywords: birth weight; intraocular pressure; cup/disc ratio; visual field defects

AIMS—To examine the course taken by individual retinal ganglion cell axons through the human lamina cribrosa. METHODS—Retinal ganglion cell axons were labelled using the retrograde tracer horseradish peroxidase applied directly to the optic nerve in two normal human eyes removed during the course of treatment for extraocular disease. RESULTS—A majority of axons took a direct course through the lamina cribrosa but a significant minority, in the range 8-12%, deviated to pass between the cribrosal plates in both central and peripheral parts of the optic disc. CONCLUSIONS—It is postulated that these axons would be selectively vulnerable to compression of the lamina cribrosa in diseases such as glaucoma in which the intraocular pressure is increased. Keywords: retina; optic nerve; glaucoma; lamina cribrosa

The development of retinal detachment is reported in three eyes, of two patients, following implantation of an anterior chamber intraocular lens (AC-IOL) in phakic eyes for the correction of ultra-high myopia. The presence of an AC-IOL may hamper the identification of retinal breaks and removal of the intraocular lens may prove necessary to improve visualisation. Shallowing of the anterior chamber may also occur during, or following, vitreoretinal surgery with risk of endothelial contact. The risks and relative contraindications of AC-IOL implantation into phakic eyes are discussed.