Myo/Nog Cells: Targets for Preventing the Accumulation of Skeletal Muscle-Like Cells in the Human Lens

Posterior capsule opacification (PCO) is a vision impairing condition that arises in some patients following cataract surgery. The fibrotic form of PCO is caused by myofibroblasts that may emerge in the lens years after surgery. In the chick embryo lens, myofibroblasts are derived from Myo/Nog cells that are identified by their expression of the skeletal muscle specific transcription factor MyoD, the bone morphogenetic protein inhibitor Noggin, and the epitope recognized by the G8 monoclonal antibody. The goal of this study was to test the hypothesis that depletion of Myo/Nog cells will prevent the accumulation of myofibroblasts in human lens tissue. Myo/Nog cells were present in anterior, equatorial and bow regions of the human lens, cornea and ciliary processes. In anterior lens tissue removed by capsulorhexis, Myo/Nog cells had synthesized myofibroblast and skeletal muscle proteins, including vimentin, MyoD and sarcomeric myosin. Alpha smooth muscle actin (a-SMA) was detected in a subpopulation of Myo/Nog cells. Areas of the capsule denuded of epithelial cells were surrounded by Myo/Nog cells. Some of these cell free areas contained a wrinkle in the capsule. Depletion of Myo/Nog cells eliminated cells expressing skeletal muscle proteins in 5-day cultures but did not affect cells immunoreactive for beaded filament proteins that accumulate in differentiating lens epithelial cells. Transforming growth factor-betas 1 and 2 that mediate an epithelial-mesenchymal transition, did not induce the expression of skeletal muscle proteins in lens cells following Myo/Nog cell depletion. This study demonstrates that Myo/Nog cells in anterior lens tissue removed from cataract patients have undergone a partial differentiation to skeletal muscle. Myo/Nog cells appear to be the source of skeletal muscle-like cells in explants of human lens tissue. Targeting Myo/Nog cells with the G8 antibody during cataract surgery may reduce the incidence of PCO

Predictors of photic phenomena with a trifocal IOL

© 2021 Espaillat et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.Aim: To assess predictive factors associated with glares and halos in patients undergoing cataract surgery with PanOptix trifocal IOL implantation. Methods: Single-center retrospective study. One hundred and forty eyes from 70 patients with cataract were bilaterally implanted with a trifocal PanOptix aspherical diffractive lens between 2017 and 2019 and followed-up for six months. All patients were evaluated for refraction, corneal topography, and aberrometry pre- and post-operatively. Patients were assessed at 1 day, 6 days, 1 and 6 months after surgery. One and six months post-operatively patients were asked to complete a satisfaction questionnaire that included photic phenomena assessment. Main outcome measures were photic phenomena at 1 and 6 months of follow-up. Predictors of photic phenomena at 1 and 6 months were also analyzed. Results: A higher corneal coma was associated with more mild halos at 6 months with no association regarding other degrees of severity. The lower the age the higher the glare or halos, the higher the lens thickness and the lower the anterior chamber depth or chord μ the less halos at 1 month. A significant proportion of patients had more none/mild compared to moderate/severe glare and halos both at 1 and 6 months post-operatively. Baseline BCVA was the only predictor of halos at 1 month and glare and halos at 6 months post-surgery. Conclusion: On multivariate regression analyses, the only predictor of photic phenomena was baseline visual acuity, suggesting that patients that have a better visual acuity before surgery are more demanding regarding visual outcomes after surgery.info:eu-repo/semantics/publishedVersio

Comparison of visual and optical quality of monofocal versus multifocal intraocular lenses

Postprint (author's final draft

Evaluating techniques to improve visual performance with and assessment of premium intraocular lenses

Premium Intraocular Lenses (IOLs) such as toric IOLs, multifocal IOLs (MIOLs) and accommodating IOLs (AIOLs) can provide better refractive and visual outcomes compared to standard monofocal designs, leading to greater levels of post-operative spectacle independence. The principal theme of this thesis relates to the development of new assessment techniques that can help to improve future premium IOL design. IOLs designed to correct astigmatism form the focus of the first part of the thesis. A novel toric IOL design was devised to decrease the effect of toric rotation on patient visual acuity, but found to have neither a beneficial or detrimental impact on visual acuity retention. IOL tilt, like rotation, may curtail visual performance; however current IOL tilt measurement techniques require the use of specialist equipment not readily available in most ophthalmological clinics. Thus a new idea that applied Pythagoras’s theory to digital images of IOL optic symmetricality in order to calculate tilt was proposed, and shown to be both accurate and highly repeatable. A literature review revealed little information on the relationship between IOL tilt, decentration and rotation and so this was examined. A poor correlation between these factors was found, indicating they occur independently of each other. Next, presbyopia correcting IOLs were investigated. The light distribution of different MIOLs and an AIOL was assessed using perimetry, to establish whether this could be used to inform optimal IOL design. Anticipated differences in threshold sensitivity between IOLs were not however found, thus perimetry was concluded to be ineffective in mapping retinal projection of blur. The observed difference between subjective and objective measures of accommodation, arising from the influence of pseudoaccommodative factors, was explored next to establish how much additional objective power would be required to restore the eye’s focus with AIOLs. Blur tolerance was found to be the key contributor to the ocular depth of focus, with an approximate dioptric influence of 0.60D. Our understanding of MIOLs may be limited by the need for subjective defocus curves, which are lengthy and do not permit important additional measures to be undertaken. The use of aberrometry to provide faster objective defocus curves was examined. Although subjective and objective measures related well, the peaks of the MIOL defocus curve profile were not evident with objective prediction of acuity, indicating a need for further refinement of visual quality metrics based on ocular aberrations. The experiments detailed in the thesis evaluate methods to improve visual performance with toric IOLs. They also investigate new techniques to allow more rapid post-operative assessment of premium IOLs, which could allow greater insights to be obtained into several aspects of visual quality, in order to optimise future IOL design and ultimately enhance patient satisfaction

Objective and subjective evaluation of dysphotopsia in normal and post-operative eyes

The principle theme of this thesis is the measurement of dysphotopsia, a common complaint in both the ageing population and after cataract or refractive surgery. Despite the availability of multiple objective and subjective methods to measure dysphotopsia, no single method is in common use, nor are photic effects commonly measured prior to cataract or refractives urgery. In this thesis, objective measures are taken using the Aston halometer and C-Quant, whilst subjective complaints are graded using simulated images. Whilst many previously published studies have reported monocular halometry results, an early study in the thesis found monocular halo areas to be approximately 30 % larger (P < 0.001) than the binocular area, indicating the effect of binocular summation on objective measures of halo area. The thesis investigates the link between objective measures and subjective complaints of dysphotopsia. Subjective complaints were not linked to binocular halo area (P = 0.478), monocular halo area (P = 0.896) or C-Quant straylight values(P = 0.128). Halometry and C-Quant also showed no relationship (P = 0.229). The results highlight the difficulties in being able to predict the potential subjective complaints a patient may experience from objective measures alone. However, a weak correlation was found between binocular halo area and subjective night halo complaints (rs = 0.330, rs2 = 0.109, P < 0.001), which may be due to the fact that halo area assessed would relate directly to the night halo image on the photographic images of photic phenomena (PIPP) plates. Binocular and monocular halo areas both increased with age (rs = 0.449, rs2 = 0.202, P < 0.001 and rs = 0.403, rs2 = 0.162, P < 0.001, respectively) in healthy eyes (n = 141, age range 18 – 82 years). Retinal straylight values also increased significantly with age (rs = 0.457, rs2 = 0.209, P < 0.001), as did subjective grading (rs = 0.314, rs2 = 0.099, P < 0.001). The results indicate a significant age-related increase in dysphotopsia, even in healthy eyes, which is attributed to media changes over time. Due to the effects of a bright light source on the pupil size, and the issue of senile miosis, this programme of research considered, for the first time, whether pupil size had an effect on the size of the halo area measured with halometry. No significant difference in halo area with various simulated pupil sizes (4.5, 6.0 and 7.5 mm) was detected (χ2(3) = 7.56, P = 0.056). The Aston halometer is therefore a robust way to evaluate dysphotopsia without measuring or controlling pupil size. A longitudinal study tracked photic effects in individuals for a year after laser-assisted in situ keratomileusis, and another measured dysphotopsia pre- and up to a year post-cataract surgery. Subjective complaints resolved by 3 months post-refractive surgery, objective halo area took 6 months to resolve post cataract surgery and up to 12 months post-corneal refractive surgery. A glare effect ratio was calculated for binocular halometry (median = 1.28; IQR 0.75 – 2.15) and retinal straylight (median = 5.63; IQR 2.72 – 7.97). The glare effect ratio is independent of age, and it is suggested that the glare effect ratio could be used to identify individuals most at risk of significant subjective complaints of dysphotopsia following procedures such as corneal refractive surgery

Epidemiology of eye disease in the UK: the Bridlington Eye Assessment Project

Purpose; To determine the prevalence of and impact of eye disease in an elderly population and the diagnostic accuracy of a novel artificial intelligence algorithm for the detection of glaucoma Design; population based, cross sectional study Participants; 3549 Caucasian individuals over the age of 65 years Methods: A directed general and ophthalmic history was obtained from all subjects. Slit lamp eye examination including applanation tonometry and dilated examination of the fundus was performed by one of four specially trained optometrists and supplemented with fundus photography, visual field testing and Heidelberg Retinal Tomography (HRT). Those with reduced vision, raised intraocular pressure, visual field defects or other abnormalities were referred for further assessment by a consultant ophthalmologist and followed longitudinally until a definitive diagnosis was made. All diagnoses of glaucoma were made retrospectively using at least 5 years of longitudinal data to determine status at incident examination. All fundus photographs were reviewed by a single ophthalmologist for signs of age related macula degeneration (AMD) and other retinal disease. HRT outputs were analysed using the device’s proprietary software which produced results for normative based Moorfield’s regression analysis (MRA) and the shape analysis tool Glaucoma Probability Score (GPS). We used a bespoke Matlab based machine learning classifier to providing two further measures based on shape analysis which were termed shape abnormality score (SAS) and abnormal disc score (ADS). Statistical Analysis: Outcomes and associations were explored using t-tests, chi- squared tests and Mantal Haenzel methods. Linear and logistic regression was sed for multivariate analysis. Agreement was measured using kappa, intraclass correlation coefficient and concordance correlation coefficient and plotted using Bland Altman plots. Covariate effects on diagnostic performance were examined using a combination of maximum likelihood probit models and bootstrap analysis. All data analysis was performed using Stata v14 Results; Cataract; Significant lens opacities were present in 45% of individuals of whom 12% went on to have cataract surgery. Women were 29% more likely to have significant cataract than men. 9.5% of eyes showed signs of previous cataract surgery of which 17% either required or had received treatment for subsequent posterior capsular opacification. In the absence of thresholds for surgery 18 cataract operations per thousand ( 95% CI 14 – 23 ) were required for those aged 65-75 years old. For those over 75 years, 76 cataract operations per thousand ( 95% CI 66 – 86 ) were required AMD; Geographic atrophy (grade 4a) occurred in 2.5%, and neovascular AMD (grade 4b) in 1.8% of eyes. Prevalence increased with age with grade 4 (advanced) AMD in 2.2% of those aged 65–69 years, 15.8% for those aged 85– 90 years, and 21.2% for over 90 years. There was significant asymmetry between eyes of individuals with advanced AMD (P<0.001). After correction for age and co-pathology, those with advanced AMD in the better eye were 4 times more likely to be disattisified with their vision. Glaucoma; For tests with a specificity of > 90% for new OAG, intraocular pressure was the least sensitive (48%), while clinical CDR ≥ 0.7 was the most sensitive (76%) test. Optometric impression showed the best specificity (98%) with acceptable sensitivity (51%) but may have been subject to verification bias since final diagnosis was based on clinical impression albeit with the reference to longitudinal results. Because of the low relative prevalence of new glaucoma, the test specificity of 98% still resulted in referral of nearly twice as many false positives as new patients with glaucoma. There was moderate agreement between individual optometrists and the HRT in measuring CDR but wide limits of agreement precluding effective comparison between approaches. Of the disc based measures, SAS and optometric assessment were found to be the most specific but MRA showed the best overall performance. In our subgroup analysis, we found a drop in sensitivity for detection of new disease by HRT using automated shape analysis and by optometrist using Jonas criteria. MRA performed well across all groups and showed similar sensitivity in detection of new and previously diagnosed glaucoma

Epidemiology of eye disease in the UK: the Bridlington Eye Assessment Project

Purpose; To determine the prevalence of and impact of eye disease in an elderly population and the diagnostic accuracy of a novel artificial intelligence algorithm for the detection of glaucoma Design; population based, cross sectional study Participants; 3549 Caucasian individuals over the age of 65 years Methods: A directed general and ophthalmic history was obtained from all subjects. Slit lamp eye examination including applanation tonometry and dilated examination of the fundus was performed by one of four specially trained optometrists and supplemented with fundus photography, visual field testing and Heidelberg Retinal Tomography (HRT). Those with reduced vision, raised intraocular pressure, visual field defects or other abnormalities were referred for further assessment by a consultant ophthalmologist and followed longitudinally until a definitive diagnosis was made. All diagnoses of glaucoma were made retrospectively using at least 5 years of longitudinal data to determine status at incident examination. All fundus photographs were reviewed by a single ophthalmologist for signs of age related macula degeneration (AMD) and other retinal disease. HRT outputs were analysed using the device’s proprietary software which produced results for normative based Moorfield’s regression analysis (MRA) and the shape analysis tool Glaucoma Probability Score (GPS). We used a bespoke Matlab based machine learning classifier to providing two further measures based on shape analysis which were termed shape abnormality score (SAS) and abnormal disc score (ADS). Statistical Analysis: Outcomes and associations were explored using t-tests, chi- squared tests and Mantal Haenzel methods. Linear and logistic regression was sed for multivariate analysis. Agreement was measured using kappa, intraclass correlation coefficient and concordance correlation coefficient and plotted using Bland Altman plots. Covariate effects on diagnostic performance were examined using a combination of maximum likelihood probit models and bootstrap analysis. All data analysis was performed using Stata v14 Results; Cataract; Significant lens opacities were present in 45% of individuals of whom 12% went on to have cataract surgery. Women were 29% more likely to have significant cataract than men. 9.5% of eyes showed signs of previous cataract surgery of which 17% either required or had received treatment for subsequent posterior capsular opacification. In the absence of thresholds for surgery 18 cataract operations per thousand ( 95% CI 14 – 23 ) were required for those aged 65-75 years old. For those over 75 years, 76 cataract operations per thousand ( 95% CI 66 – 86 ) were required AMD; Geographic atrophy (grade 4a) occurred in 2.5%, and neovascular AMD (grade 4b) in 1.8% of eyes. Prevalence increased with age with grade 4 (advanced) AMD in 2.2% of those aged 65–69 years, 15.8% for those aged 85– 90 years, and 21.2% for over 90 years. There was significant asymmetry between eyes of individuals with advanced AMD (P<0.001). After correction for age and co-pathology, those with advanced AMD in the better eye were 4 times more likely to be disattisified with their vision. Glaucoma; For tests with a specificity of > 90% for new OAG, intraocular pressure was the least sensitive (48%), while clinical CDR ≥ 0.7 was the most sensitive (76%) test. Optometric impression showed the best specificity (98%) with acceptable sensitivity (51%) but may have been subject to verification bias since final diagnosis was based on clinical impression albeit with the reference to longitudinal results. Because of the low relative prevalence of new glaucoma, the test specificity of 98% still resulted in referral of nearly twice as many false positives as new patients with glaucoma. There was moderate agreement between individual optometrists and the HRT in measuring CDR but wide limits of agreement precluding effective comparison between approaches. Of the disc based measures, SAS and optometric assessment were found to be the most specific but MRA showed the best overall performance. In our subgroup analysis, we found a drop in sensitivity for detection of new disease by HRT using automated shape analysis and by optometrist using Jonas criteria. MRA performed well across all groups and showed similar sensitivity in detection of new and previously diagnosed glaucoma

CLINICAL OUTCOMES POST-IMPLANTATION OF MULTIFOCAL AND TORIC INTRAOCULAR LENSES

In order to increase spectacle independence following cataract surgery and intraocular lens (IOL) implantation; correction of spherical refractive error, astigmatic error and presbyopia should all be given careful consideration. There are many premium IOLs, including multifocal intraocular lenses (MIOLs) and toric intraocular lenses (TIOLs), available to surgeons. In order to select the appropriate IOL to meet a patient’s lifestyle and expectations, clinicians must fully understand the characteristics of MIOL and TIOL designs. To date, there remain unanswered questions pertaining to MIOLs and TIOLs and by rigorous comparison of such lenses, this thesis aims to address some of the gaps in the current literature. This thesis aims to evaluate a robust protocol for investigating clinical outcomes in MIOLs that would allow for comparison between future studies. This methodology was used in a randomised control trial and a cohort study. Included in this protocol is the detailed analysis of defocus profiles. This thesis investigates polynomial curve fitting to establish the most suitable curve and curve fitting method for use in future analysis of MIOLs with detailed defocus metrics. Defocus curves can highlight the differences in optical performance in MIOLs of differing addition powers, however, to add further complexity, previous literature has highlighted that addition power can vary individual to individual based on their ocular anatomy. Thus, investigation of an easily accessible clinical method to predict the likely achieved addition power post-implantation was performed. A randomised intra-patient contralateral eye study assessed refractive outcomes and rotational stability in TIOLs. In addition, the performance of the corresponding manufacturer’s calculators was evaluated in regard to refractive predictability and appropriate TIOL selection. This thesis highlights the clinical features of modern MIOL and TIOL designs, demonstrating both the benefits and challenges incurred following implantation.University of Plymout