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This review presents the 'Moorfields Safer Surgery System', which is designed to improve the consistency and outcomes of trabeculectomy surgery. Evidence-based recommendations are made for each step of the surgery. This system requires a minimum of equipment and can be easily implemented by most surgeons. The system is ultimately designed to preserve the vision in our patients by minimising complications while maintaining a desired intraocular pressure. [ABSTRACT FROM AUTHOR]

Purpose: To report 3-year results of a randomized, controlled trial comparing the use of a single application of 5-fluorouracil (5-FU) with placebo in trabeculectomy surgery. Design: Prospective, randomized, double-blinded treatment trial. Participants: Two hundred forty-three Asian patients with primary open-angle or primary angle-closure glaucoma undergoing primary trabeculectomy. Methods: One eye of each patient was randomized to receive either intraoperative 5-FU or normal saline (placebo) during trabeculectomy. Main Outcome Measures: Primary outcome measure was the level of intraocular pressure (IOP). Secondary outcomes were progression of visual field loss, rates of adverse events, and interventions after surgery. Results: Of the 288 eligible patients, 243 were enrolled and 228 completed 3 years follow-up; 120 patients received 5-FU and 123 received placebo. Trial failure, according to predefined IOP criteria, was lower in the 5-FU group compared with the placebo group, although the difference was only significant with a failure criterion of IOP >17 mmHg (P = 0.0154). There was no significant difference in progression of optic disc and/or visual field loss over 36 months between 5-FU and placebo (relative risk [RR], 0.67; 95% confidence interval [CI], 0.34–1.31; P = 0.239). Uveitis occurred more often in the 5-FU–treated group (14/115 [12%] vs 5/120 [4%]; P = 0.032). Conclusions: This is the first masked, prospective, randomized trial reporting the effect of adjunctive 5-FU in trabeculectomy surgery in an East Asian population. The trial shows that an increased success rate can be achieved for several years after a single intraoperative treatment with 5-FU. We conclude that 5-FU is relatively safe and can be routinely used in low-risk East Asian patients. Financial Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article. [Copyright &y& Elsevier]

Primary open-angle glaucoma is a progressive optic neuropathy and, perhaps, the most common form of glaucoma. Because the disease is treatable, and because the visual impairment caused by glaucoma is irreversible, early detection is essential. Early diagnosis depends on examination of the optic disc, retinal nerve fibre layer, and visual field. New imaging and psychophysical tests can improve both detection and monitoring of the progression of the disease. Recently completed long-term clinical trials provide convincing evidence that lowering intraocular pressure prevents progression at both the early and late stages of the disease. The degree of protection is related to the degree to which intraocular pressure is lowered. Improvements in therapy consist of more effective and better-tolerated drugs to lower intraocular pressure, and more effective surgical procedures. New treatments to directly treat and protect the retinal ganglion cells that are damaged in glaucoma are also in development. [ABSTRACT FROM AUTHOR]

Abstract A review of the current literature was conducted regarding the effect of corneal thickness on the diagnosis of glaucoma, and the influence of excimer laser refractive surgery on intraocular pressure (IOP) measurement with Goldmann applanation tonometry. In general, normals and primary open angle glaucoma patients have a similar distribution of corneal thickness; however, there is a wide variation, ranging from 427 to 716 µm. Normal tension glaucoma patients have a tendency towards thinner corneas than normals; however, there is an overlap of thickness measurements of more than two-thirds in 95% of patients. There is a trend for ocular hypertensives to have thicker corneas than normals, but again there is an overlap of about one-third in 95% of patients. The general trend after excimer laser refractive surgery is for a decrease in IOP, with a mean fall in IOP measured of 0.63 mmHg per dioptre correction. There is, however, a large scatter of values with some patients having the same or lower IOP post-laser, but with other patients measuring higher pressures. Corneal thickness can influence IOP measurement by Goldmann applanation tonometry; however, the magnitude of the effect is subject to much individual variation. [ABSTRACT FROM AUTHOR]

: PurposeThe human monoclonal antibody that neutralizes the growth factor TGFβ2 (CAT-152) safely and effectively inhibits in vitro and in vivo models of conjunctival scarring. This phase I/IIa clinical trial was designed to assess the safety and tolerability of CAT-152 in patients undergoing trabeculectomy.: DesignProspective randomized placebo-controlled clinical trial.: Participants and controlsTwenty-four patients who were due to undergo primary trabeculectomy at Moorfields or Western Eye Hospitals in London, England, were recruited for this study and randomly assigned to treatment with either CAT-152 (100 μg in 100 μl) (n = 16) or placebo (n = 8).: MethodsThe treatment regimen was a series of four 100-μl subconjunctival injections, given immediately before and after surgery, and at 1 day and 1 week postoperatively. Assessment consisted of a full ophthalmic examination with recordings of the logarithm of the minimum angle of resolution visual acuities performed at baseline and at set intervals after surgery. Any adverse events were recorded.: Main outcome measuresLogarithm of the minimum angle of resolution visual acuity, intraocular pressure, complications, and adverse events.: ResultsThe results of 12 month’s follow-up on all patients are documented. There were no statistically significant differences in the incidence of complications between the two groups, and no serious adverse events related to the study drug occurred. Blebs after CAT-152 antibody treatment were diffuse, noncystic, and nonavascular, unlike blebs associated with antimetabolites. The fall in intraocular pressure was greater in the CAT-152 group at 3 and 6 months (P < 0.05) and approached statistical significance at 12 months. There was a trend toward less intervention in those patients treated with CAT-152. The small number of patients included limited the power of the study (34%) to detect a difference between groups. Sixteen patients in each arm of the study would be required to obtain a power of 90% with a 5% significance level.: ConclusionsThis is the first clinical study of CAT-152 in patients undergoing glaucoma filtration surgery. CAT-152 seems to be well tolerated, and based on these results further multicenter trials are underway. [Copyright &y& Elsevier]

Background and purpose: The eye is a well‐established model of brain structure and function, yet region‐specific structural correlations between the retina and the brain remain underexplored. Therefore, we aim to explore and describe the relationships between the retinal layer thicknesses and brain magnetic resonance image (MRI)‐derived phenotypes in UK Biobank. Methods: Participants with both quality‐controlled optical coherence tomography (OCT) and brain MRI were included in this study. Retinal sublayer thicknesses and total macular thickness were derived from OCT scans. Brain image‐derived phenotypes (IDPs) of 153 cortical and subcortical regions were processed from MRI scans. We utilized multivariable linear regression models to examine the association between retinal thickness and brain regional volumes. All analyses were corrected for multiple testing and adjusted for confounders. Results: Data from 6446 participants were included in this study. We identified significant associations between volumetric brain MRI measures of subregions in the occipital lobe (intracalcarine cortex), parietal lobe (postcentral gyrus), cerebellum (lobules VI, VIIb, VIIIa, VIIIb, and IX), and deep brain structures (thalamus, hippocampus, caudate, putamen, pallidum, and accumbens) and the thickness of the innermost retinal sublayers and total macular thickness (all p < 3.3 × 10−5). We did not observe statistically significant associations between brain IDPs and the thickness of the outer retinal sublayers. Conclusions: Thinner inner and total retinal thicknesses are associated with smaller volumes of specific brain regions. Notably, these relationships extend beyond anatomically established retina–brain connections. [ABSTRACT FROM AUTHOR]

To compare the effectiveness and safety of the MicroShunt (Santen Inc) versus trabeculectomy in patients with primary open-angle glaucoma (POAG). Prospective, randomized, multicenter trial conducted in the United States and Europe. Adult patients (aged 40–85 years) with mild to severe POAG inadequately controlled on maximum tolerated medical therapy and intraocular pressure (IOP) ≥ 15 mmHg and ≤ 40 mmHg. Patients were randomized 3:1 to stand-alone MicroShunt implantation (n = 395) or trabeculectomy (n = 132), both augmented with mitomycin C (MMC) 0.2 mg/ml for 2 minutes. The primary effectiveness end point was surgical success, defined as ≥ 20% reduction in mean diurnal IOP from baseline with no increase in glaucoma medications. Secondary end points included changes in mean IOP and medication use from baseline and the need for postoperative interventions. At 2 years, the rate of surgical success was lower in the MicroShunt group than in the trabeculectomy group (50.6% vs. 64.4%, P = 0.005). Mean diurnal IOP was reduced from 21.1 ± 4.9 mmHg at baseline to 13.9 ± 3.9 mmHg at 24 months in the MicroShunt group and from 21.1 ± 5.0 mmHg at baseline to 10.7 ± 3.7 mmHg at 24 months in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Mean medication use decreased from 3.1 to 0.9 in the MicroShunt group and from 2.9 to 0.4 in the trabeculectomy group (P < 0.001 compared with baseline in both groups). Adverse events at 2 years were generally similar in the 2 groups, except that hypotony was more common in eyes undergoing trabeculectomy (51.1% vs. 30.9%, P < 0.001). Repositioning or explantation of the implant occurred in 6.8% of MicroShunt patients. The majority of these patients had device removal at the time of subsequent glaucoma surgery. Vision-threatening complications were uncommon in both groups. At 2 years, both the MicroShunt and trabeculectomy provided significant reductions in IOP and medication use, with trabeculectomy continuing to have greater surgical success. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article. [ABSTRACT FROM AUTHOR]

Evaluates the ocular-hypertensive response and the anti-inflammatory response of children to corticosteroids after squint surgery. Increase in intraocular pressure; Difference in steroid responsiveness between adults and children; Mechanism of steriod-induced elevated intraocular pressure.

Injectable gels have the potential to encapsulate drugs for sustained release of protein therapeutics for use in the eye. Hyaluronic acid (HA) is a biodegradable clinically used material and poly N -isopropylacrylamide (pNIPAAM) is a stimuli responsive polymer that can display a lower critical solution temperature (LCST) at physiological conditions. Two gel systems incorporating HA were prepared in the presence of the antibody infliximab (INF): i) 1% and 5% tyramine-substituted HA (HA-Tyr) was enzymatically crosslinked in the presence of INF to form HA-Tyr-INF and ii) NIPAAM was chemically crosslinked in the presence of HA and INF with 1 and 3% poly(ethylene glycol) diacrylate (PEGDA) to form PEGDA-pNIPAAM-HA-INF. The PEGDA-pNIPAAM-HA-INF hydrogels displayed LCSTs at temperatures ranging from 31.4 ± 0.2 to 35.7 ± 0.3 °C. Although all the gels prepared were injectable, INF-loaded gels with lower crosslinking density (1% PEGDA-pNIPAAM-HA and 1% HA-Tyr) showed lower elastic ( G′ ) and viscous ( G″ ) moduli compared to higher crosslinked gels (3% PEGDA-pNIPAAM-HA-INF and 5% HA-Tyr-INF) resulting in differences in swelling ratio (SR). Moduli may be correlated with overall stiffness of the gel. All hydrogels demonstrated sustained release of INF in a two-compartment in vitro outflow model of the human eye called the PK-Eye. The 1% PEGDA-pNIPAAM-HA-INF hydrogel displayed the slowest release (24.9 ± 0.4% INF release by day 9) in phosphate buffered saline (PBS, pH 7.4), which is a better release profile than the free drug alone (tested under the same conditions). These results suggest that PEGDA-pNIPAAM-HA has potential for the continued development of formulations to prolong the intraocular release of proteins. [ABSTRACT FROM AUTHOR]

Corticosteroids have long been used to treat intraocular inflammation by intravitreal injection. We describe dexamethasone loaded poly-DL-lactide-co-glycolide (PLGA) microparticles that were fabricated by thermally induced phase separation (TIPS). The dexamethasone loaded microparticles were evaluated using a two-compartment, in vitro aqueous outflow model of the eye (PK-Eye) that estimates drug clearance time from the back of the eye via aqueous outflow by the anterior route. A dexamethasone dose of 0.20 ± 0.02 mg in a 50 μL volume of TIPS microparticles resulted in a clearance t 1/2 of 9.6 ± 0.3 days using simulated vitreous in the PK-Eye. Since corticosteroids can also clear through the retina, it is necessary to account for clearance through the back of the eye. Retinal permeability data, published human ocular pharmacokinetics (PK) and the PK-Eye clearance times were then used to establish in vitro in vivo correlations (IVIVCs) for intraocular clearance times of corticosteroid formulations. A t 1/2 of 48 h was estimated for the dexamethasone-TIPS microparticles, which is almost 9 times longer than that reported for dexamethasone suspension in humans. The prediction of human clearance times of permeable molecules from the vitreous compartment can be determined by accounting for drug retinal permeation and determining the experimental clearance via the anterior aqueous outflow pathway using the PK-Eye. [ABSTRACT FROM AUTHOR]

Real-time measurement is important in modern dissolution testing to aid in parallel drug characterisation and quality control (QC). The development of a real-time monitoring platform (microfluidic system, a novel eye movement platform with temperature sensors and accelerometers and a concentration probe setup) in conjunction with an in vitro model of the human eye (PK-Eye™) is reported. The importance of surface membrane permeability when modelling the PK-Eye™ was determined with a "pursing model" (a simplified setup of the hyaloid membrane). Parallel microfluidic control of PK-Eye™ models from a single source of pressure was performed with a ratio of 1:6 (pressure source:models) demonstrating scalability and reproducibility of pressure-flow data. Pore size and exposed surface area helped obtain a physiological range of intraocular pressure (IOP) within the models, demonstrating the need to reproduce in vitro dimensions as closely as possible to the real eye. Variation of aqueous humour flow rate throughout the day was demonstrated with a developed circadian rhythm program. Capabilities of different eye movements were programmed and achieved with an in-house eye movement platform. A concentration probe recorded the real-time concentration monitoring of injected albumin-conjugated Alexa Fluor 488 (Alexa albumin), which displayed constant release profiles. These results demonstrate the possibility of real-time monitoring of a pharmaceutical model for preclinical testing of ocular formulations. [ABSTRACT FROM AUTHOR]

Müller glia play very important and diverse roles in retinal homeostasis and disease. Although much is known of the physiological and morphological properties of mammalian Müller glia, there is still the need to further understand the profile of these cells during human retinal development. Using human embryonic stem cell-derived retinal organoids, we investigated the transcriptomic profiles of CD29+/CD44+ cells isolated from early and late stages of organoid development. Data showed that these cells express classic markers of retinal progenitors and Müller glia, including NFIX, RAX, PAX6, VSX2, HES1, WNT2B, SOX, NR2F1/2, ASCL1 and VIM, as early as days 10–20 after initiation of retinal differentiation. Expression of genes upregulated in CD29+/CD44+ cells isolated at later stages of organoid development (days 50–90), including NEUROG1, VSX2 and ASCL1 were gradually increased as retinal organoid maturation progressed. Based on the current observations that CD24+/CD44+ cells share the characteristics of early and late-stage retinal progenitors as well as of mature Müller glia, we propose that these cells constitute a single cell population that upon exposure to developmental cues regulates its gene expression to adapt to functions exerted by Müller glia in the postnatal and mature retina. [ABSTRACT FROM AUTHOR]

Presents a response to letters to the editor of the "British Medical Journal" as of March 13, 2004. Use of eye patches in corneal abrasion; Relief of abrasion pain with the use of cycloplegic drugs; Discussion of topical antibiotics; Statement that orbital fractures are best managed in conjunction with a department for maxillofacial surgery.

New in vitro prototypes (PK-Eye™) were tested with and without eye movement to understand diffusion and convection effects on intraocular clearance. Port placement in front ((i) ciliary inflow model) and behind the model lens ((ii) posterior inflow model) was used to study bevacizumab (1.25 mg/50 µL) and dexamethasone (0.1 mg/100 µL) in phosphate-buffered saline (PBS, pH 7.4) and simulated vitreal fluid (SVF). Dexamethasone was studied in a (iii) retinal-choroid-sclera (RCS) outflow model (with ciliary inflow and two outflow pathways). Ciliary vs. posterior inflow placement did not affect the half-life for dexamethasone at 2.0 µL/min using PBS (4.7 days vs. 4.8 days) and SVF (4.9 days with ciliary inflow), but it did decrease the half-life for bevacizumab in PBS (20.4 days vs. 2.4 days) and SVF (19.2 days vs. 10.8 days). Eye movement only affected the half-life of dexamethasone in both media. Dexamethasone in the RCS model showed approximately 20% and 75% clearance from the RCS and anterior outflows, respectively. The half-life of the protein was comparable to human data in the posterior inflow model. Shorter half-life values for a protein in a ciliary inflow model can be achieved with other eye movements. The RCS flow model with eye movement was comparable to human half-life data for dexamethasone. [ABSTRACT FROM AUTHOR]

Purpose: Primary congenital glaucoma (isolated trabeculodysgensis, PCG) generally presents between birth and 3 years of age. Recently, mutations in Latent Transforming Growth Factor (TGF)-beta Binding Protein 2 ( LTBP2) have been reported in several families that were diagnosed with PCG, who actually had a more complex ocular phenotype with ectopia lentis and Marfanoid features. We screened this gene for mutations in the original Turkish GLC3C-linked PCG family and in a group of CYP1B1-negative British PCG cases and their matched normal control subjects. Methods: The 36-coding exons of the LTBP2 gene were sequenced in 94 familial or sporadic CYP1B1-negative PCG cases and 96 matched normal control subjects. Results: No disease-causing mutations were identified in the original GLC3C-linked family. Screening of LTBP2 in 94 PCG and 96 control subjects identified three novel synonymous variations (L429L, P680P, S1031S) in 12 PCG and seven control subjects. A novel heterozygous missense mutation (R538W) was also identified in 1 of 90 PCG cases that is unlikely to be disease-causative. Conclusions: LTBP2 mutations were not found in the Turkish GLC3C-linked PCG family or in 94 British CYP1B1-negative PCG cases. Our data suggest that LTBP2 mutations are not a significant cause for isolated trabeculodysgenesis. [ABSTRACT FROM AUTHOR]

Despite the advent of many new devices for glaucoma surgery, scarring is the main cause of suboptimal pressure control and surgical failure in all forms of surgery. The cytotoxic antimetabolites, 5-flurouracil and mitomycin C both prolong success but with the increased risk of blinding complications. A greater understanding of the cellular mechanisms of the wound healing response has led to the identification and modulation of potential therapeutic targets. These include transforming factor β, inflammatory mediators, the acute phase protein serum amyloid P, vascular endothelial growth factor and the matrix metallaproteinases. While optimal drug delivery is still a major challenge, modulating these effects either directly or through downstream signalling promises to yield anti-scarring efficacy, while minimising side effects. [ABSTRACT FROM AUTHOR]

A bstract Background: To evaluate long-term outcomes and complication rates following trabeculectomy with mitomycin C in a case series of African Caribbean patients. Design: A prospective, observational and non-comparative case series. Participants: Forty-seven consecutive African Caribbean patients (47 eyes) with glaucoma. Methods: All patients underwent augmented trabeculectomy with mitomycin C for uncontrolled intraocular pressure (IOP). Survival analysis was performed with a minimum of 12 months' follow up. Main Outcome Measures: Surgical success was based upon IOP reduction to ≤21 mmHg, ≤18 mmHg and ≤15 mmHg without glaucoma medication (complete); or IOP reduction to ≤21 mmHg, ≤18 mmHg and ≤15 mmHg with or without glaucoma medication (qualified). Results: The mean follow-up period was 48.6 months. At 3 years post-trabeculectomy 92.6% achieved a qualified success and 59.3% a complete success for an IOP ≤21 mmHg. At final follow up the mean IOP reduced from 33.7 mmHg to 13.1 mmHg ( P < 0.0001). Survival rates were 96%, 90% and 86% at 12, 24 and 36 months, respectively, with a mean survival time of 97.4 months (95% confidence interval, 86.0-108.8) for an IOP ≤21 mmHg. Early postoperative hypotony requiring surgical intervention occurred in four (8.5%) patients. There were no cases of blebitis, endophthalmitis, suprachoroidal haemorrhage, malignant glaucoma or hypotony maculopathy. Conclusions: Good long-term stable IOP can be achieved with low complication rates and high success rates amongst African Caribbean patients following trabeculectomy with mitomycin C. A proactive postoperative management regime is needed to ensure trabeculectomy survival in high-risk populations. [ABSTRACT FROM AUTHOR]

The ultimate goal of cataract surgery, besides the restoration of distance visual acuity, is the restoration of accommodation. Lens refilling with an injectable polymer has the potential of restoring accommodation following cataract surgery. Two main difficulties have hampered the success of lens refilling strategies in the past. First was leakage of the injectable material from the capsular bag and second was after-cataract formation resulting in loss of elasticity and opacification of the lens–bag complex. Recently, simplified and highly reproducible lens refilling procedures have been introduced with a potential for clinical application to restore accommodation. We present a summary of the existing methods of lens refilling for restoration of accommodation and some obstacles to clinical application that remain. [Copyright &y& Elsevier]

: PurposeTo report the efficacy and complications of diode laser cyclophotocoagulation (cyclodiode) in the management of refractory pediatric glaucomas.: DesignNoncomparative interventional case series.: ParticipantsPediatric patients with uncontrolled glaucoma. Seventy-seven eyes of 61 patients underwent cyclodiode. Mean age was 7.4 years (range, 0.4–17 years).: Main outcome measuresIntraocular pressure (IOP), visual acuity, complications.: ResultsDiagnoses included aphakic glaucoma, congenital glaucoma, juvenile chronic arthritis, aniridia, anterior segment dysgenesis, and Sturge-Weber syndrome. Sixty percent of eyes were aphakic, and 64% had undergone at least one previous surgical procedure for glaucoma. Patients underwent a mean of 2.3 treatment sessions per eye (maximum, 8 sessions). Mean pretreatment IOP was 32.0 mmHg. After one treatment session, 62% had a clinically useful reduction in IOP (<22 mmHg or by 30%), but this had fallen to 37% by 12 months. With repeat cyclodiode, 72% had a clinically useful reduction in IOP for a year or more (mean, 8.4-month interval between treatments). Aphakic eyes had a more sustained IOP reduction (P < 0.01 log rank test). Of treatment failures, 13% had no useful IOP response, and three eyes developed subsequent retinal detachment and loss of vision. No other eyes lost vision because of cyclodiode-related complications. In 5.5% of the treatment sessions there was a significant posttreatment inflammatory episode. Cyclodiode treatment did not enable a reduction in the number of medications.: ConclusionsWith repeated treatment, cyclodiode can provide effective control of IOP. However, the success rate is lower than with adults, and younger eyes may recover from treatment more rapidly. Although response may be temporary, cyclodiode has a lower rate of severe adverse effects than surgical modalities and has roles as a temporizing measure, as an adjunct to surgery, or in managing selected patients in whom surgery is undesirable because of a high risk of surgical complications. [Copyright &y& Elsevier]

To examine the association of alcohol consumption and type of alcoholic beverage with incident cataract surgery in 2 large cohorts. Longitudinal, observational study. We included 469 387 participants of UK Biobank with a mean age of 56 years and 23 162 participants of European Prospective Investigation of Cancer (EPIC)-Norfolk with a mean age of 59 years. Self-reported alcohol consumption at baseline was ascertained by a touchscreen questionnaire in UK Biobank and a food-frequency questionnaire in EPIC-Norfolk. Cases were defined as participants undergoing cataract surgery in either eye as ascertained via data linkage to National Health Service procedure statistics. We excluded participants with cataract surgery up to 1 year after the baseline assessment visit or those with self-reported cataract at baseline. Cox proportional hazards models were used to examine the associations of alcohol consumption with incident cataract surgery, adjusted for age, sex, ethnicity, Townsend deprivation index, body mass index (BMI), smoking, and diabetes status. Incident cataract surgery. There were 19 011 (mean cohort follow-up of 95 months) and 4573 (mean cohort follow-up of 193 months) incident cases of cataract surgery in UK Biobank and EPIC-Norfolk, respectively. Compared with nondrinkers, drinkers were less likely to undergo cataract surgery in UK Biobank (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.85–0.93) and EPIC-Norfolk (HR, 0.90; 95% CI, 0.84–0.97) after adjusting for covariables. Among alcohol consumers, greater alcohol consumption was associated with a reduced risk of undergoing cataract surgery in EPIC-Norfolk (P < 0.001), whereas a U-shaped association was observed in the UK Biobank. Compared with nondrinkers, subgroup analysis by type of alcohol beverage showed the strongest protective association with wine consumption; the risk of incident cataract surgery was 23% and 14% lower among those in the highest category of wine consumption in EPIC-Norfolk and UK Biobank, respectively. Our findings suggest a lower risk of undergoing cataract surgery with low to moderate alcohol consumption. The association was particularly apparent with wine consumption. We cannot exclude the possibility of residual confounding, and further studies are required to determine whether this association is causal in nature. [ABSTRACT FROM AUTHOR]

Optical Coherence Tomography (OCT) enables non-invasive imaging of the retina and is used to diagnose and manage ophthalmic diseases including glaucoma. We present the first large-scale genome-wide association study of inner retinal morphology using phenotypes derived from OCT images of 31,434 UK Biobank participants. We identify 46 loci associated with thickness of the retinal nerve fibre layer or ganglion cell inner plexiform layer. Only one of these loci has been associated with glaucoma, and despite its clear role as a biomarker for the disease, Mendelian randomisation does not support inner retinal thickness being on the same genetic causal pathway as glaucoma. We extracted overall retinal thickness at the fovea, representative of foveal hypoplasia, with which three of the 46 SNPs were associated. We additionally associate these three loci with visual acuity. In contrast to the Mendelian causes of severe foveal hypoplasia, our results suggest a spectrum of foveal hypoplasia, in part genetically determined, with consequences on visual function. Author summary: The thickness of the inner retinal layers is one of the biomarkers for glaucoma, the leading cause of irreversible blindness globally. Here we utilised the large-scale of the UK Biobank and the images of the retina it contains to look for genetic variants that effect the thickness of the inner retina. We find many variants associated with this variable, but surprisingly only one that also affects glaucoma. Further analysis shows that glaucoma and genetically determined inner retinal thickness are not on the same genetic pathway and it is rather the change of thickness over time that is indicative of the disease. This is important as it invites the potential for the discovered variants to be used as a representation of baseline thickness in the clinic in the future. We also show that foveal hypoplasia, the lack of the normal valley-like shape of the central retina, is present at a population level in a mild form and is affected by three variants that also affect visual acuity. This is an interesting discovery as foveal hypoplasia was previously thought of as an outcome of rare Mendelian disease. [ABSTRACT FROM AUTHOR]

Background and purpose: Current methods to diagnose neurodegenerative diseases are costly and invasive. Retinal neuroanatomy may be a biomarker for more neurodegenerative processes and can be quantified in vivo using optical coherence tomography (OCT), which is inexpensive and noninvasive. We examined the association of neuroretinal morphology with brain MRI image‐derived phenotypes (IDPs) in a large cohort of healthy older people. Methods: UK Biobank participants aged 40 to 69 years old underwent comprehensive examinations including ophthalmic and brain imaging assessments. Macular retinal nerve fibre layer (mRNFL), macular ganglion cell‐inner plexiform layer (mGCIPL), macular ganglion cell complex (mGCC) and total macular thicknesses were obtained from OCT. Magnetic resonance imaging (MRI) IDPs assessed included total brain, grey matter, white matter and hippocampal volume. Multivariable linear regression models were used to evaluate associations between retinal layers thickness and brain MRI IDPs, adjusting for demographic factors and vascular risk factors. Results: A total of 2131 participants (mean age 55 years; 51% women) with both gradable OCT images and brain imaging assessments were included. In multivariable regression analysis, thinner mGCIPL, mGCC and total macular thickness were all significantly associated with smaller total brain (p < 0.001), grey matter and white matter volume (p < 0.01), and grey matter volume in the occipital pole (p < 0.05). Thinner mGCC and total macular thicknesses were associated with smaller hippocampal volume (p < 0.02). No association was found between mRNFL and the MRI IDPs. Conclusions: Markers of retinal neurodegeneration are associated with smaller brain volumes. Our findings suggest that retinal structure may be a biomarker providing information about important brain structure in healthy older adults. [ABSTRACT FROM AUTHOR]

A major challenge in glaucoma research is the lack of reproducible animal models of RGC and optic nerve damage, the characteristic features of this condition. We therefore examined the glaucomatous responses of two different rat strains, the Brown Norway (BN) and Lister Hooded (LH) rats, to high intraocular pressure (IOP) induced by injection of magnetic beads into the anterior chamber. Magnetic microsphere suspensions (20 µl of 5–20 mg/ml) were injected into the anterior chamber of BN (n = 9) or LH (N = 15) rats. Animals from each strain were divided into three groups, each receiving a different dose of microspheres. IOP was measured over 4 weeks using a rebound tonometer. Retinal ganglion cell (RGC) damage and function were assessed using scotopic electroretinograms (ERGs), retinal flatmounts and optic nerve histology. ANOVA and Student's t-tests were used to analyse the data. A significant elevation in IOP was observed in BN rats receiving injections of 20 mg (37.18 ± 12.28 mmHg) or 10 mg microspheres/ml (36.95 ± 13.63 mmHg) when compared with controls (19.63 ± 4.29 mmHg) (p <.001) over 2 weeks. This correlated with a significant impairment of RGC function, as determined by scotopic ERG (p <.001), reduction in axon number (p <.05) and lower RGC density (P <.05) in animals receiving 20 mg or 10 mg microspheres/ml as compared with controls. LH rats receiving similar microsphere doses showed reduced scotopic ERG function (p <.001) after 2 weeks. No changes in IOP was seen in this strain, although a reduction in axon density was observed in optic nerve cross-sections (p <.05). Initial changes in IOP and ERG responses observed in BN rats remained unchanged for a duration of 7 weeks. In LH animals, ERG responses were decreased at 1–2 weeks and returned to control levels after 5 weeks. Although this model was easily reproducible in BN rats, the phenotype of injury observed in LH rats was very different from that observed in BN animals. We suggest that differences in the glaucomatous response observed in these two strains may be ascribed to anatomical and physiological differences and merits further investigation. [ABSTRACT FROM AUTHOR]

• Dual acting therapeutic proteins may be a better strategy than drug combinations for treatment of chronic retinal diseases. • Several targets to treat neovascularisation and inflammation have been identified. • A dual acting molecule to increase the duration of action in the vitreous has potential for treatment of chronic retinal diseases. • The key challenge in developing intraocular medicines is ensuring there is minimal ocular toxicity. • Maintaining protein stability and avoiding protein aggregation and misfolding are necessary. Antibody-based medicines that target vascular endothelial growth factor (VEGF) are administered by intravitreal injection (IVI) to treat chronic neovascular retinal diseases. Much ongoing effort is focussed on enhancing therapeutic outcome of these medicines. One strategy is the use of dual-acting drugs (e.g., bispecific antibodies) to simultaneously bind to more than one intraocular biological target. A dual-acting molecule targeting components within the vitreal cavity could also extend vitreous residence time. In this review, we describe the applications of bispecific antibodies within the eye, with consideration of potential targets, applications, and suitable bispecific formats. Intravitreally injected antibody-based medicines have revolutionised the treatment of retinal disease. Bispecific and dual-functional antibodies and therapeutic proteins have the potential to further increase the efficacy of intraocular medicines. [ABSTRACT FROM AUTHOR]

The diagnosis of multiple sclerosis is based on a combination of clinical and paraclinical tests. The potential contribution of retinal optical coherence tomography (OCT) has been recognized. We tested the feasibility of OCT measures of retinal asymmetry as a diagnostic test for multiple sclerosis at the community level. In this community-based study of 72 120 subjects, we examined the diagnostic potential of the inter-eye difference of inner retinal OCT data for multiple sclerosis using the UK Biobank data collected at 22 sites between 2007 and 2010. OCT reporting and quality control guidelines were followed. The inter-eye percentage difference (IEPD) and inter-eye absolute difference (IEAD) were calculated for the macular retinal nerve fibre layer (RNFL), ganglion cell inner plexiform layer (GCIPL) complex and ganglion cell complex. Area under the receiver operating characteristic curve (AUROC) comparisons were followed by univariate and multivariable comparisons accounting for a large range of diseases and co-morbidities. Cut-off levels were optimized by ROC and the Youden index. The prevalence of multiple sclerosis was 0.0023 [95% confidence interval (CI) 0.00229-0.00231]. Overall the discriminatory power of diagnosing multiple sclerosis with the IEPD AUROC curve (0.71, 95% CI 0.67-0.76) and IEAD (0.71, 95% CI 0.67-0.75) for the macular GCIPL complex were significantly higher if compared to the macular ganglion cell complex IEPD AUROC curve (0.64, 95% CI 0.59-0.69, P = 0.0017); IEAD AUROC curve (0.63, 95% CI 0.58-0.68, P < 0.0001) and macular RNFL IEPD AUROC curve (0.59, 95% CI 0.54-0.63, P < 0.0001); IEAD AUROC curve (0.55, 95% CI 0.50-0.59, P < 0.0001). Screening sensitivity levels for the macular GCIPL complex IEPD (4% cut-off) were 51.7% and for the IEAD (4 μm cut-off) 43.5%. Specificity levels were 82.8% and 86.8%, respectively. The number of co-morbidities was important. There was a stepwise decrease of the AUROC curve from 0.72 in control subjects to 0.66 in more than nine co-morbidities or presence of neuromyelitis optica spectrum disease. In the multivariable analyses greater age, diabetes mellitus, other eye disease and a non-white ethnic background were relevant confounders. For most interactions, the effect sizes were large (partial ω2 > 0.14) with narrow confidence intervals. In conclusion, the OCT macular GCIPL complex IEPD and IEAD may be considered as supportive measurements for multiple sclerosis diagnostic criteria in a young patient without relevant co-morbidity. The metric does not allow separation of multiple sclerosis from neuromyelitis optica. Retinal OCT imaging is accurate, rapid, non-invasive, widely available and may therefore help to reduce need for invasive and more costly procedures. To be viable, higher sensitivity and specificity levels are needed. [ABSTRACT FROM AUTHOR]

The majority of blinding conditions arise due to chronic pathologies in the retina. During the last two decades, antibody-based medicines administered by intravitreal injection directly into the back of the eye have revolutionised the treatment of chronic retinal diseases characterised by uncontrolled blood vessel growth, e.g. wet age-related macular degeneration (wAMD), diabetic retinopathy (DR) and choroidal neovascularisation (CNV). Although intravitreal injections have become a commonly performed ophthalmic procedure that provides a reproducible dose to maximise drug exposure in the back of the eye, there is a need to minimise the frequency and cumulative number of intravitreal injections. Developing longer acting intraocular therapies is one key strategy that is being pursued. Pharmaceutical preclinical development of intraocular medicines is heavily reliant on the use of animal models to determine ocular tolerability, pharmacokinetics, biodistribution and drug stability. Animal eyes are different from human eyes, such as the anatomy, organisation of vitreous macromolecular structure, aqueous outflow and immune response; all which impacts the ability to translate preclinical data into a clinical product. The development of longer acting protein formulations using animals is also limited because animals reject human proteins. Preclinical strategies also do not account for differences in the vitreous due to ageing and whether a vitrectomy has been performed. Intraocular formulations must reside and clear from the vitreous body, so there is a need for the formulation scientist to have knowledge about vitreous structure and physiology to facilitate preclinical development strategies. Preclinical pharmaceutical development paradigms used to create therapies for other routes of administration (e.g. oral, subcutaneous, pulmonary and intravenous) are grounded on the use of preclinical in vitro models. Analogous pharmaceutical strategies with appropriately designed in vitro models that can account for intraocular mass transfer to estimate pharmacokinetic profiles can be used to develop in vitro-in vivo correlations (IVIVCs) to accelerate the preclinical optimisation of long-acting intraocular formulations. Data obtained can then inform preclinical in vivo and clinical studies. With the now widespread use of intravitreal injections, it is also important during early preclinical studies to ensure there is a viable regulatory pathway for new therapies. Knowledge of the physiological, pharmaceutical and regulatory factors will help in the development of long-acting intravitreal medicines, which is rapidly evolving into a distinct pharmaceutical discipline. [ABSTRACT FROM AUTHOR]

To describe and compare associations with macular retinal nerve fiber layer (mRNFL), ganglion cell complex (GCC), and ganglion cell–inner plexiform layer (GCIPL) thicknesses in a large cohort. Cross-sectional study. We included 42 044 participants in the UK Biobank. The mean age was 56 years. Spectral-domain OCT macular images were segmented and analyzed. Corneal-compensated intraocular pressure (IOPcc) was measured with the Ocular Response Analyzer (Reichert, Corp., Buffalo, NY). Multivariable linear regression was used to examine associations with mean mRNFL, GCC, and GCIPL thicknesses. Factors examined were age, sex, ethnicity, height, body mass index (BMI), smoking status, alcohol intake, Townsend deprivation index, education level, diabetes status, spherical equivalent, and IOPcc. Thicknesses of mRNFL, GCC, and GCIPL. We identified several novel independent associations with thinner inner retinal thickness. Thinner inner retina was associated with alcohol intake (most significant for GCIPL: –0.46 μm for daily or almost daily intake compared with special occasion only or never [95% confidence interval (CI), 0.61–0.30]; P = 1.1×10–8), greater social deprivation (most significant for GCIPL: –0.28 μm for most deprived quartile compared with least deprived quartile [95% CI, –0.42 to –0.14]; P = 6.6×10–5), lower educational attainment (most significant for mRNFL: –0.36 μm for less than O level compared with degree level [95% CI, –0.45 to 0.26]; P = 2.3×10–14), and nonwhite ethnicity (most significant for mRNFL comparing blacks with whites: –1.65 μm [95% CI, –1.86 to –1.43]; P = 2.4×10–50). Corneal-compensated intraocular pressure was associated most significantly with GCIPL (–0.04 μm/mmHg [95% CI, –0.05 to –0.03]; P = 4.0×10–10) and was not associated significantly with mRNFL (0.00 μm/mmHg [95% CI, –0.01 to 0.01]; P = 0.77). The variables examined explained a greater proportion of the variance of GCIPL (11%) than GCC (6%) or mRNFL (7%). The novel associations we identified may be important to consider when using inner retinal parameters as a diagnostic tool. Associations generally were strongest with GCIPL, particularly for IOP. This suggests that GCIPL may be the superior inner retinal biomarker for macular pathophysiologic processes and especially for glaucoma. [ABSTRACT FROM AUTHOR]

Glaucoma is the leading cause of irreversible blindness with over 70 million people affected worldwide. The surgical management of glaucoma aims to lower intraocular pressure by increasing aqueous outflow facility. The latest manufacturing techniques have allowed for the development of a number of novel implantable devices to improve safety and outcomes of glaucoma surgery. These are collectively referred to as minimally invasive glaucoma surgery (MIGS) devices and are among the smallest devices implanted in the human body. This review discusses the design criterion and constraints as well as the user requirements for MIGS devices. We review how recent devices have attempted to meet these challenges and give our opinion as to the necessary characteristics for the development of future devices. [ABSTRACT FROM AUTHOR]

Clinical grading systems following glaucoma filtration surgery do not include any effects of the bleb on the intra-ocular pressure and are relatively subjective, therefore carrying the risk of inter and/or intra-observer variability. The main objective of the study is to quantify and model the effect of subconjunctival bleb on flow pressure for assessment of clinical grading following glaucoma surgery. Subconjunctival bleb was created by inserting a tube into ex vivo rabbit eyes via an ab externo approach through the anterior chamber and exiting into the subconjunctival space. Sterile dyed water was injected through the tube into the developing bleb. For the in vitro approach a silicone bleb was created by clamping a circular silicone sheet, injecting dyed water through a fixed resistance outlet tube. Photographic measurements of the bleb height, planform area and pressure were taken as a function of time. Clinical blebs were also collected over a few months. Mathematical algorithm software was used to build the bleb model. Bleb height and volume increase as pressure in the bleb increases. The bleb planform area tended to a constant determined by the section of conjunctiva prior to shunt insertion. These increases were in accordance with the bleb model developed in the Appendix. They show that the pressure in the bleb is related to the resistance of the outflow. The linearity of clinical grading systems is reviewed and a new grading approach is proposed. The pressure in the bleb has a strong dependence on bleb extent, height and a weak dependence on conjunctival thickness. The pressure in a bleb can be estimated from bleb height, radius, and flow rate inlet in agreement with the bleb flow model. These results provide support for an improved bleb categorization system. [ABSTRACT FROM AUTHOR]

Highlights • OMC transplant rescues loss of optic nerve axons induced by raised IOP. • The pERG suggests the functional activities of the axons are protected. • The findings provide a basis for future human clinical trials. • Autografting OMCs from nasal epithelial biopsy to treat or delay glaucoma diseases. Abstract Purpose To determine whether transplantation of olfactory mucosal cells (OMCs) is able to rescue the loss of optic nerve axons after the intraocular pressure (IOP) is elevated in rats. Methods The IOP was raised by injection of magnetic microspheres into the anterior chamber of the eye. OMCs cultured from the adult olfactory mucosa were transplanted into the region of the optic disc. Results We demonstrated that although the raised IOP returned to its normal level at six weeks, there was an irreversible 58% loss of optic nerve axons in the control group. However, the loss of the axons was reduced to 23% in the group with the transplanted OMCs. The Pattern Electroretinograms (pERG) showed that the decrement of the voltage amplitudes in association with the raised IOP was significantly alleviated in the group with transplantation of OMC. Conclusions Transplantation of OMCs is able to rescue loss of optic nerve axons induced by raised IOP in the rats. The pERG recording suggested that the functional activities of the axons are also protected. Translational relevance The results demonstrated the ability of the transplanted OMCs to protect against the loss of the optic nerve axons and the loss of function caused by raised IOPs. The findings provide a basis for future human clinical trials by autografting OMCs from autologous nasal epithelial biopsies to treat or delay glaucoma diseases. [ABSTRACT FROM AUTHOR]

To develop a comprehensive next-generation sequencing panel assay that screens genes known to cause developmental eye disorders and inherited eye disease and to evaluate its diagnostic yield in a pediatric cohort with malformations of the globe, anterior segment anomalies, childhood glaucoma, or a combination thereof. Evaluation of diagnostic test. Two hundred seventy-seven children, 0 to 16 years of age, diagnosed with nonsyndromic or syndromic developmental eye defects without a genetic diagnosis. We developed a new oculome panel using a custom-designed Agilent SureSelect QXT target capture method (Agilent Technologies, Santa Clara, CA) to capture and perform parallel high-throughput sequencing analysis of 429 genes associated with eye disorders. Bidirectional Sanger sequencing confirmed suspected pathogenic variants. Collated clinical details and oculome molecular genetic results. The oculome design covers 429 known eye disease genes; these are subdivided into 5 overlapping virtual subpanels for anterior segment developmental anomalies including glaucoma (ASDA; 59 genes), microphthalmia–anophthalmia–coloboma (MAC; 86 genes), congenital cataracts and lens-associated conditions (70 genes), retinal dystrophies (RET; 235 genes), and albinism (15 genes), as well as additional genes implicated in optic atrophy and complex strabismus (10 genes). Panel development and testing included analyzing 277 clinical samples and 3 positive control samples using Illumina sequencing platforms; more than 30× read depth was achieved for 99.5% of the targeted 1.77-Mb region. Bioinformatics analysis performed using a pipeline based on Freebayes and ExomeDepth to identify coding sequence and copy number variants, respectively, resulted in a definitive diagnosis in 68 of 277 samples, with variability in diagnostic yield between phenotypic subgroups: MAC, 8.2% (8 of 98 cases solved); ASDA, 24.8% (28 of 113 cases solved); other or syndromic, 37.5% (3 of 8 cases solved); RET, 42.8% (21 of 49 cases solved); and congenital cataracts and lens-associated conditions, 88.9% (8 of 9 cases solved). The oculome test diagnoses a comprehensive range of genetic conditions affecting the development of the eye, potentially replacing protracted and costly multidisciplinary assessments and allowing for faster targeted management. The oculome enabled molecular diagnosis of a significant number of cases in our sample cohort of varied ocular birth defects. [ABSTRACT FROM AUTHOR]

Purpose To compare Schlemm canal (SC) and trabecular meshwork (TM) in children with healthy eyes and those with and without glaucoma after lensectomy. Design Cross-sectional observational study. Participants Fifty children 4 to 16 years of age with healthy eyes and 48 children who underwent lensectomy (124 healthy and 72 postlensectomy eyes). Methods Anterior segment (AS) OCT (Tomey SS-1000 CASIA; Tomey, Nagoya, Japan) of the nasal iridocorneal angle at 2 levels of accommodative effort (2.5 diopters [D] and 15 D). For each parameter and state of accommodation, a random effects model was fitted to estimate differences between healthy eyes and eyes with history of lensectomy. Main Outcome Measures Dimensions of SC and TM and conventional AS OCT iridocorneal angle measurements. Results The horizontal diameter of SC and its cross-sectional area (CSA) are significantly smaller in eyes that have undergone lensectomy versus healthy eyes. Accommodative effort increases SC size in healthy eyes, but not in eyes that have undergone lensectomy. Conclusions Lensectomy is associated with a reduction in SC size and a loss of physiologic SC dilatation during accommodative effort, which may reflect a reduction in outflow facility and may contribute to the development of glaucoma after lensectomy. [ABSTRACT FROM AUTHOR]

Abstract A circular silicone sheet is clamped at its edge and pressurised by the injection of a liquid beneath creating a pocket. We study experimentally the deformation and pressure increase caused by the compression of a pressurised pocket. Excellent agreement is found between experimental observations and numerical predictions based on an axisymmetric thin hyperelastic material; an approximate analytical model explains the link between changes in shape and the applied force. Highlights • Numerical model explains change in shape with applied force of compressed pocket. • Pressure and volume relations between pressurised and compressed pocket defined. • Pressure and compressive force between pressurised and compressed pocket defined. • Numerical model validated experimentally with pockets of thin silicone sheet. • Model to design soft button [ABSTRACT FROM AUTHOR]

Abstract Müller glia are responsible for the neural retina regeneration observed in fish and amphibians throughout life. Despite the presence of these cells in the adult human retina, there is no evidence of regeneration occurring in humans following disease or injury. It may be possible that factors present in the degenerated retina could prevent human Müller glia from proliferating and neurally differentiating within the diseased retina. On this basis, investigations into the proteomic profile of these cells and the abundance of key proteins associated to Müller glia in the gliotic PVR retina, may assist in the identification of factors with the potential to control Müller proliferation and neural differentiation in vivo. Label free mass spectrometry identified 1527 proteins in Müller glial cell preparations, 1631 proteins in normal retina and 1074 in gliotic PVR retina. Compared to normal retina, 28 proteins were upregulated and 196 proteins downregulated by 2-fold or more in the gliotic PVR retina. As determined by comparative proteomic analyses, of the proteins highly upregulated in the gliotic PVR retina, the most highly abundant proteins in Müller cell lysates included vimentin, GFAP, polyubiquitin and HSP90a. The observations that proteins highly upregulated in the gliotic retina constitute major proteins expressed by Müller glia provide the basis for further studies into mechanisms that regulate their production. In addition investigations aimed at controlling the expression of these proteins may aid in the identification of factors that could potentially promote endogenous regeneration of the adult human retina after disease or injury. Highlights • Proteomic analyses showed evidence for Müller glia contribution to retinal gliosis. • Polyubiquitin-C and HSP90a produced by Müller glia, are upregulated in gliotic retina. • Müller glia are a source of prelamin, elongation factor and serpin found in retina. [ABSTRACT FROM AUTHOR]

Ilomastat is a matrix metalloproteinase inhibitor (MMPi) that has shown the potential to inhibit scarring (fibrosis) by mediating healing after injury or surgery. A long lasting ocular implantable pharmaceutical formulation of ilomastat is being developed to mediate the healing process to prevent scarring after glaucoma filtration surgery. The ilomastat implant was coated with water permeable and biocompatible phosphoryl choline polymer (PC1059) displayed extended slow release of ilomastat in vitro and in vivo . The ocular distribution of ilomastat from the implant in rabbits at day 30 post surgery was determined by the extraction of ilomastat and its internal standard marimastat from the ocular tissues, plasma, aqueous humour and vitreous fluid followed by capillary-flow liquid chromatography (cap-LC), the column effluent was directed into a triple quadrupole mass spectrometer operating in product scan mode. The lower limits of quantification (LLOQs) were 0.3 pg/μL for ocular fluids and plasma, and 3 pg/mg for ocular tissues. The extraction recoveries were 90–95% for ilomastat and its internal standard from ocular tissues. Ilomastat was found in ocular fluids and tissues at day 30 after surgery. The level of ilomastat was 18 times higher in the aqueous humour than vitreous humour. The concentration ranking of ilomastat in the ocular tissues was sclera > bleb conjunctiva > conjunctiva (rest of the eye) > cornea. Mass spectrometry analysis to confirm the presence of ilomastat in the ocular tissues and fluids at day 30 post-surgery establishes the extended release of ilomastat can be achieved in vivo , which is crucial information for optimisation of the ilomastat coated implant. [ABSTRACT FROM AUTHOR]

The eye is a highly specialized organ that is subject to a huge range of pathology. Both local and systemic disease may affect different anatomical regions of the eye. The least invasive routes for ocular drug administration are topical (e.g. eye drops) and systemic (e.g. tablets) formulations. Barriers that subserve as protection against pathogen entry also restrict drug permeation. Topically administered drugs often display limited bioavailability due to many physical and biochemical barriers including the pre-corneal tear film, the structure and biophysiological properties of the cornea, the limited volume that can be accommodated by the cul-de-sac, the lacrimal drainage system and reflex tearing. The tissue layers of the cornea and conjunctiva are further key factors that act to restrict drug delivery. Using carriers that enhance viscosity or bind to the ocular surface increases bioavailability. Matching the pH and polarity of drug molecules to the tissue layers allows greater penetration. Drug delivery to the posterior segment is a greater challenge and, currently, the standard route is via intravitreal injection, notwithstanding the risks of endophthalmitis and retinal detachment with frequent injections. Intraocular implants that allow sustained drug release are at different stages of development. Novel exciting therapeutic approaches include methods for promoting transscleral delivery, sustained release devices, nanotechnology and gene therapy. [ABSTRACT FROM AUTHOR]

Purpose To evaluate the effect of glaucoma on functional vision and on vision-related (VR) and health-related (HR) quality of life (QoL) in children up to 16 years of age. Design Cross-sectional observational study. Participants One hundred nineteen children 2 to 16 years of age (mean age, 9.4 years; standard deviation [SD], 4.56 years) with glaucoma and their parents. Methods Completion of 3 validated instruments for children to assess (1) functional visual ability (FVA) with the Cardiff Visual Ability Questionnaire for Children (CVAQC), (2) VR QoL with the Impact of Vision Impairment for Children (IVI-C), and (3) HR QoL with the Pediatric Quality of Life Inventory (PedsQL) version 4.0. Main Outcome Measures Cardiff Visual Ability Questionnaire for Children, IVI-C, and PedsQL scores. Results Scores for FVA, VR QoL, and HR QoL were reduced in children with glaucoma: median CVAQC score, –1.24 (interquartile range [IQR], –2.2 to –0.11; range, –3.00 higher visual ability to +2.80 lower visual ability); mean IVI-C score, 67.3 (SD, 14.4; normal VR QoL, 96); median PedsQL self-report, 78.8 (IQR, 67.4–90.2); parent report, 71.2 (IQR, 55.7–85.8); and family impact score, 74.3 (IQR, 56.9–88.5; normal HR QoL, 100). Psychosocial subscores were lower than physical subscores on the PedsQL. Older children reported less impairment on CVAQC, IVI-C, and PedsQL than younger children. Parents reported greater impact on their child's HR QoL than children reported themselves. Conclusions Glaucoma and its management have a marked impact on a child's FVA and QoL. Children with glaucoma report HR QoL scores similar to those described by children with severe congenital cardiac defects, who have undergone liver transplants, or who have acute lymphoblastic leukemia. [ABSTRACT FROM AUTHOR]

The pursing of a simply- or doubly-connected planar elastic pocket by an applied pressure is analysed from the bending to the stretching regimes. The response is evaluated in terms of maximum deflection and profiles across a range of simply- and doubly-connected circular and square shapes. The study is conducted using experimental and numerical methods and supported by previous analytical results. The experimental method is based on an original 2D optical method that gives access to the pursing direction perpendicular to each image across the field of view. The equations for maximum pursing deflections are developed and compared for a range of thicknesses of silicone samples and shapes from the bending to the stretching regimes. In the case of doubly-connected shapes, dependence of maximum pursing deflection on clamped central circular and square areas or holes is quantified for both regimes. Good agreement is established between the three methods and the study also shows that the optical method may as well be successfully applied to problems of pursing of rubber pockets. [ABSTRACT FROM AUTHOR]

Infliximab is an antibody that neutralizes TNF-α and is used principally by systemic administration to treat many inflammatory disorders. We prepared the antibody mimetic Fab-PEG-Fab (FpFinfliximab) for direct intravitreal injection to assess whether such formulations have biological activity and potential utility for ocular use. FpFinfliximab was designed to address side effects caused by antibody degradation and the presence of the Fc region. Surface plasmon resonance analysis indicated that infliximab and FpFinfliximab maintained binding affinity for both human and murine recombinant TNF-α. No Fc mediated RPE cellular uptake was observed for FpFinfliximab. Both Infliximab and FpFinfliximab suppressed ocular inflammation by reducing the number of CD45+ infiltrate cells in the EAU mice after a single intravitreal injection at the onset of peak disease. These results offer an opportunity to develop and formulate for ocular use, FpF molecules designed for single and potentially multiple targets using bi-specific FpFs. [ABSTRACT FROM AUTHOR]

We report molecular genetic analysis of 42 affected individuals referred with a diagnosis of aniridia who previously screened as negative for intragenic PAX6 mutations. Of these 42, the diagnoses were 31 individuals with aniridia and 11 individuals referred with a diagnosis of Gillespie syndrome (iris hypoplasia, ataxia and mild to moderate developmental delay). Array-based comparative genomic hybridization identified six whole gene deletions: four encompassing PAX6 and two encompassing FOXC1. Six deletions with plausible cis-regulatory effects were identified: five that were 3ʹ (telomeric) to PAX6 and one within a gene desert 5ʹ (telomeric) to PITX2. Sequence analysis of the FOXC1 and PITX2 coding regions identified two plausibly pathogenic de novo FOXC1 missense mutations (p.Pro79Thr and p.Leu101Pro). No intragenic mutations were detected in PITX2. FISH mapping in an individual with Gillespie-like syndrome with an apparently balanced X;11 reciprocal translocation revealed disruption of a gene at each breakpoint: ARHGAP6 on the X chromosome and PHF21A on chromosome 11. In the other individuals with Gillespie syndrome no mutations were identified in either of these genes, or in HCCS which lies close to the Xp breakpoint. Disruption of PHF21A has previously been implicated in the causation of intellectual disability (but not aniridia). Plausibly causative mutations were identified in 15 out of 42 individuals (12/32 aniridia; 3/11 Gillespie syndrome). Fourteen of these mutations presented in the known aniridia genes; PAX6, FOXC1 and PITX2. The large number of individuals in the cohort with no mutation identified suggests greater locus heterogeneity may exist in both isolated and syndromic aniridia than was previously appreciated. [ABSTRACT FROM AUTHOR]

Two series of fibers containing the active ingredients acyclovir, ciprofloxacin and cyanocobalamin, and combinations of these drugs, were prepared by electrospinning. One set used the hydrophilic poly(vinylpyrrolidone) (PVP) as the filament-forming polymer, while the other used the slow-dissolving poly(ε-caprolactone) (PCL). The fibers were found to have cylindrical morphologies, although there was evidence for solvent occlusion with the PVP systems and for some drug particles in the PCL materials. The active ingredients were generally present in the amorphous physical form in the case of PVP, but evidence of crystallinity was observed with PCL. The existence of intermolecular interactions between the drugs and polymers was proven using simple molecular modeling calculations. Drug release from the various fibers was tested in a validated in vitro outflow model of the eye, and the fiber formulations found to be capable of extending drug release. We thus conclude that electrospun matrices such as those prepared in this work have potential for use as intravitreal implants. [ABSTRACT FROM AUTHOR]