Inhibition of Rho kinase (ROCK) impairs cytoskeletal contractility in human Müller glial cells without effects on cell viability, migration, and extracellular matrix production.

The epiretinal membrane is a fibrocontractile tissue that forms on the inner surface of the retina, causing visual impairment ranging from mild to severe, and even retinal detachment. Müller glial cells actively participate in the formation of this membrane. Current research is constantly seeking for new therapeutic approaches that aim to prevent or treat cellular dysfunctions involved in the progression of this common fibrosis condition. The Rho GTPases signaling pathway regulates several processes associated with the epiretinal membrane, such as cell proliferation, migration, and contraction. Rho kinase (ROCK), an effector of the RhoA GTPase, is an interesting potential therapeutic target. This study aimed to evaluate the effects of a ROCK inhibitor (Y27632) on human Müller cells viability, growth, cytoskeletal organization, expression of extracellular matrix components, myofibroblast differentiation, migration, and contractility. Müller cells of the MIO-M1 lineage were cultured and treated for different periods with the inhibitor. Viability was evaluated by MTT assay and trypan blue exclusion method, and growth was evaluated by growth curve and BrdU incorporation assay. The actin cytoskeleton was stained with fluorescent phalloidin, intermediate filaments and microtubules were analyzed with immunofluorescence for vimentin and α-tubulin. Gene and protein expression of collagens I and V, laminin and fibronectin were evaluated by rt-PCR and immunofluorescence. Chemotactic and spontaneous cell migration were studied by transwell assay and time-lapse observation of live cells, respectively. Cell contractility was assessed by collagen gel contraction assay. The results showed that ROCK inhibition by Y27632 did not affect cell viability, but decreased cell growth and proliferation after 72 h. There was a change in cell morphology and organization of F-actin, with a reduction in the cell body, disappearance of stress fibers and formation of long, branched cell extensions. Microtubules and vimentin filaments were also affected, possibly because of F-actin alterations. The inhibitor also reduced gene expression and immunoreactivity of smooth muscle α-actin, a marker of myofibroblasts. The expression of extracellular matrix components was not affected by the inhibitor. Chemotactic cell migration showed no significant changes, while cell contractility was substantially reduced. No spontaneous migration of MIO-M1 cells was observed. In conclusion, pharmacological inhibition of ROCK in Müller cells could be a potentially promising approach to treat epiretinal membranes by preventing cell proliferation, contractility and transdifferentiation, without affecting cell viability.

Ruminal responses, digestibility, and blood parameters of beef cattle fed diets without forage with different hybrids and processing of the corn.

The objective of this study was to evaluate the effects of corn hybrid and processing methods on intake and digestibility of nutrients, rumen fermentation and blood metabolites of steers fed no-forage finishing diets. Four ruminally fistulated Nellore castrated steers (502 ± 15 kg initial body weight) were distributed in a 4 × 4 Latin square design with a 2 × 2 factorial arrangement consisting of two corn hybrids (semi-dent and flint) and two processing methods (dry milled and high moisture grain). Interactions of hybrid and processing methods were observed on intake of dry matter (DM), organic matter (OM) and crude protein (CP), as well as on digestibility of DM and CP, rumen pH and ammonia nitrogen (N-NH3 ). There was no interaction between hybrid and processing for the volatile fatty acids (VFA) total, acetate (C2), propionate (C3), isobutyric (iC4) and valeric (nC5) concentrations. VFA total concentration shown an average of 103.4 mmol/L. The C2 and C3 concentrations had no effect of the hybrid or processing with averages of 58.7 mmol/L for C2, and 31.3 mmol/l for C3. There was an effect of the processing method on starch consumption and fecal pH, the highest values were observed in grains with high moisture content. Starch digestibility was 0.89 g/g in dry milled and 0.96 g/g in high moisture corn. The greatest digestibility of starch in high moisture corn, irrespective of the corn hybrid, provided evidence of an increase in the energy supply, which may improve the feed efficiency and growth performance of cattle fed no-roughage finishing diets.

Ruminal responses, digestibility, and blood parameters of beef cattle fed diets with different oilseeds.

It aimed to evaluate the effects of different whole oilseeds in lipid-rich diets on nutrient intake, apparent digestibility, ingestive behavior, and ruminal and blood parameters of steers. A control diet (without oilseed) and four diets containing whole oilseeds (cotton, canola, sunflower, and soybean) were tested. All diets used the whole-plant corn silage at 400 g/kg as roughage. Five diets, being a control diet (without oilseed) and four diets containing whole oilseeds (cotton, canola, sunflower, and soybean), were tested. All diets used the whole-plant corn silage at 400 g/kg as roughage. Five rumen fistulated crossbreed steers, in a 5 × 5 Latin square design were distributed using five periods of 21 days. The steers fed cottonseed and canola diets had lower dry matter intakes (6.6 kg/day). Steers showed higher averages of time in rumination for treatments with sunflower, soybean, and cottonseed (406, 362, and 361 min/day, respectively). There was no treatment effect for the ruminal pH and ammonia (NH3) variables. There was an effect of the treatment on the volatile fatty acid concentrations. The animals that received soybean showed a higher plasma urea concentration (50.7 mg/dL). Animals fed the control diet showed lower serum cholesterol levels (111.8 mg/dL) than those fed diets containing whole cottonseed, canola, sunflower, and soybean (152.7, 137.1, 146.9, and 138.2 mg/dL, respectively). We recommended using whole soybean or sunflower seeds to formulate lipid-rich diets with 70 g/kg of ether extract for crossbreed steers in the feedlot.

Effect of whole oilseeds in the diet on bacterial diversity in the solid fraction of the ruminal content of steers.

Our hypothesis was that different whole oilseeds included in the diet for steers confined could alter the diversity of rumen bacteria compared to a diet without oilseeds or an exclusively forage diet. It was aimed to evaluate the effects of oilseeds inclusion in the diet on bacterial diversity in the solid fraction of the ruminal content of steers, by gene sequences of the conserved 16S rDNA region. Six crossbred steers castrated males, fitted with ruminal cannula were used in a 6 × 6 Latin square design, using 21-day period. At the start of the experiment, the live weight of the animals averaged 416 ± 9.7 kg (mean ± SD). A total of 2,180,562 16S rDNA sequences were generated for the Bacteria domain by MiSeq sequencing. The bacterial diversity was composed of 24 bacterial phyla, with the most abundant being Firmicutes, Bacteroidetes, and Proteobacteria. Other phyla with less diversity were also identified including Eurychaeota, Tenericutes, SR1 Absconditalbacteria, Synergistetes, Actinobacteria, Saccharibacteria, Elusimicrobia, Cyanobacteria, Verrucomicrobia, Fusobacteria, Lentisphaerae. The similarity in the bacterial community averaged 50% for all the experimental diets. Steers-fed corn silage exhibited a great diversity of bacteria of the Firmicutes phylum. The steers-fed oilseeds in the diet had a great diversity of bacteria from the phylum Bacteroidetes and Proteobacteria. The inclusion of whole oilseeds in the steer diets can alter the rumen bacteria population by up to 50% of total diversity.

Effect of physically effective neutral detergent fiber on nutrient intake and digestibility, ruminal and blood parameters, and ingestive behavior of confined beef cattle.

We aimed to evaluate the effect of levels of physically effective neutral detergent fiber from forage (NDFfor) on confined cattle's metabolism and ingestive behavior. Four crossbred steers (514.0 ± 4.54 kg BW) rumen-cannulated were used. The animals were randomly distributed in a 4×4 Latin square design, and the treatments were diets with 9.5%, 5.5%, 2.5%, and 0.0% NDF from whole plant corn silage. The trial was divided into 4 periods of 21 days. The dry matter, organic matter (OM), crude protein, neutral detergent fiber (NDF), physically effective NDF 8mm (peNDF8mm) and NDF1.18mm intakes, and the digestibility of OM and NDF showed a quadratic behavior. The rumen pH values showed a decreasing linear, and the time at pH below 5.8 increased linearly in the diets with lower NDFfor. The production of volatile fatty acids and the proportions of propionate and butyrate showed an increasing quadratic behavior. On the other hand, the proportion of acetate fitted a decreasing quadratic equation. With the lower participation of forage in the diets, the time spent on rumination activity decreased in a quadratic way, and the time spent in idleness increased in a quadratic way. The corn silage can be reduced to 135 g/kg DM in the diet to obtain a minimum of 5.5% of NDF from roughage.

Evaluating an automated machine learning model that predicts visual acuity outcomes in patients with neovascular age-related macular degeneration.

PURPOSE: Neovascular age-related macular degeneration (nAMD) is a major global cause of blindness. Whilst anti-vascular endothelial growth factor (anti-VEGF) treatment is effective, response varies considerably between individuals. Thus, patients face substantial uncertainty regarding their future ability to perform daily tasks. In this study, we evaluate the performance of an automated machine learning (AutoML) model which predicts visual acuity (VA) outcomes in patients receiving treatment for nAMD, in comparison to a manually coded model built using the same dataset. Furthermore, we evaluate model performance across ethnic groups and analyse how the models reach their predictions. METHODS: Binary classification models were trained to predict whether patients' VA would be 'Above' or 'Below' a score of 70 one year after initiating treatment, measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The AutoML model was built using the Google Cloud Platform, whilst the bespoke model was trained using an XGBoost framework. Models were compared and analysed using the What-if Tool (WIT), a novel model-agnostic interpretability tool. RESULTS: Our study included 1631 eyes from patients attending Moorfields Eye Hospital. The AutoML model (area under the curve [AUC], 0.849) achieved a highly similar performance to the XGBoost model (AUC, 0.847). Using the WIT, we found that the models over-predicted negative outcomes in Asian patients and performed worse in those with an ethnic category of Other. Baseline VA, age and ethnicity were the most important determinants of model predictions. Partial dependence plot analysis revealed a sigmoidal relationship between baseline VA and the probability of an outcome of 'Above'. CONCLUSION: We have described and validated an AutoML-WIT pipeline which enables clinicians with minimal coding skills to match the performance of a state-of-the-art algorithm and obtain explainable predictions.

Bacterial species in the ruminal content of steers fed oilseeds in the diet.

The aim of this study was to evaluate bacterial species and diversity of methanogenic Archaea in the solid fraction of the ruminal content, through the gene sequences of the conserved 16S rDNA region, in response to the following diets: canola, cottonseed, sunflower, soybean, corn silage, and control diet. Six rumen-fistulated crossbred steers, with body weight (BW) of 416.33 ± 93.30 kg, were distributed in a 6 × 6 Latin square design. Regardless of the diet provided, amylolytic, proteolytic, and lactic bacteria were identified in the rumen fluid. Cellulolytic bacteria were predominant for all diets, reaching 47.75% of operational taxonomic units (OTUs) in animals fed with the cottonseed diet. Amylolytic bacteria reach 62.51% of OTU in animal fed sunflower diet, while proteolytic bacteria correspond to 65.96% of OTU in this same diet. Also, Megasphaera elsdenii bacterium was identified for all diets, with a greater percentage of OTU in steers fed the cottonseed diet. The diversity analysis of the species identified the methanogenic Archaea Methanobrevibacter ruminantium in all diets. We conclude that the control and corn silage diets have the most similar bacterial flora; diets with oilseeds had 47.5% similarity in rumen flora bacteria species. Animals fed with soybean showed a reduced number of methanogenic Archaea in the rumen content, which could be an alternative feed for cattle due to their low potential for energy losses with the production of methane.

Productive characteristics, chemical composition, in vitro digestibility, and degradation kinetics of two Brachiaria grasses at different regrowth ages.

The study aimed at the effect of different regrowth ages on chemical, productive, and morphological characteristics, in addition to the kinetics of gas production and in vitro digestibility of grasses of the genus Brachiaria. The treatments consisted of two regrowth ages (21 and 35 days) and two grass species (Brachiaria brizantha and B. ruziziensis), in plat with a dimension of 10 × 10 with four replications, totaling 16 plats in a completely randomized design. The regrowth age did not change the leaf:stem ratio of the grasses. Ruziziensis-grass had higher crude protein (CP) content in leaves than Marandu-grass (14.0% versus 10.9% respectively). Marandu-grass leaf had higher NDF content than Ruziziensis-grass (65.0 and 58.3%, respectively) and ADF content (39.6 and 33.2%, respectively). The accumulation rate is high in Marandu-grass regardless of the age of regrowth; however, the in vitro digestibility of dry matter of Ruziziensis-grass is better both in the leaf and in the stem. The regrowth age did not influence the dry matter (DM) and neutral detergent fiber (NDF) in vitro digestibility (ivD) of the leaves. The ivDNDF of leaves of both types of grass were similar. There was an increase in the ivDDM of stem when the regrowth age was 21 days. The DM degradation rate was higher in Marandu-grass at both regrowth ages, and the total gas production was higher at 21 days. The parameters evaluated in the dual-pool logistic model showed interaction for age and cultivar, except for fractions λ (lag time) and total gas production. Marandu-grass presented a greater volume of gas for the rapidly degradable fraction and a lower degradation rate. There was a significant interaction for the parameters evaluated in the models between ages and grasses. The exponential model showed interaction in all fractions. Grasses had reduced CP content and increased fibrous fraction as a function of age, with no reduction in leaf DM and NDF digestibility. The Ruziziensis-grass has higher digestibility at the regrowth ages evaluated, while Marandu-grass has higher yields. We recommend adjusting the in vitro degradation kinetics by the dual-pool logistic model.

Quantitative Analysis of OCT for Neovascular Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: To apply a deep learning algorithm for automated, objective, and comprehensive quantification of OCT scans to a large real-world dataset of eyes with neovascular age-related macular degeneration (AMD) and make the raw segmentation output data openly available for further research. DESIGN: Retrospective analysis of OCT images from the Moorfields Eye Hospital AMD Database. PARTICIPANTS: A total of 2473 first-treated eyes and 493 second-treated eyes that commenced therapy for neovascular AMD between June 2012 and June 2017. METHODS: A deep learning algorithm was used to segment all baseline OCT scans. Volumes were calculated for segmented features such as neurosensory retina (NSR), drusen, intraretinal fluid (IRF), subretinal fluid (SRF), subretinal hyperreflective material (SHRM), retinal pigment epithelium (RPE), hyperreflective foci (HRF), fibrovascular pigment epithelium detachment (fvPED), and serous PED (sPED). Analyses included comparisons between first- and second-treated eyes by visual acuity (VA) and race/ethnicity and correlations between volumes. MAIN OUTCOME MEASURES: Volumes of segmented features (mm3) and central subfield thickness (CST) (µm). RESULTS: In first-treated eyes, the majority had both IRF and SRF (54.7%). First-treated eyes had greater volumes for all segmented tissues, with the exception of drusen, which was greater in second-treated eyes. In first-treated eyes, older age was associated with lower volumes for RPE, SRF, NSR, and sPED; in second-treated eyes, older age was associated with lower volumes of NSR, RPE, sPED, fvPED, and SRF. Eyes from Black individuals had higher SRF, RPE, and serous PED volumes compared with other ethnic groups. Greater volumes of the majority of features were associated with worse VA. CONCLUSIONS: We report the results of large-scale automated quantification of a novel range of baseline features in neovascular AMD. Major differences between first- and second-treated eyes, with increasing age, and between ethnicities are highlighted. In the coming years, enhanced, automated OCT segmentation may assist personalization of real-world care and the detection of novel structure-function correlations. These data will be made publicly available for replication and future investigation by the AMD research community.

Natural intoxication caused by protodioscin in lambs kept in Brachiaria pastures.

Protodioscin poisoning of Brachiaria spp. has been a serious problem for lambs in grazing systems. The defoliation process can stimulate the appearance of new leaves and, the younger leaves have a lower concentration of protodioscin. Thus, it was aimed to assess the effect of different leaf offerings on the protodioscin content in forage and if protodioscin can interfere with the dry matter intake (DMI) and on metabolic and productive parameters of lambs. Twelve tester lambs (average weight 17.5 ± 3.48 kg) were divided into four groups of different levels of dry leafy matter (60, 75, 90, or 105 g/kg body weight). In addition to these, 33 regulator lambs were used as needed to adjust the leaf offerings of pasture. The animals were divided and kept in 12 paddocks, each with a tester lamb. The DMI was estimated using chromic oxide as an external marker. In vitro digestibility and degradation kinetics and ruminal, blood, and urinary parameters were measured in the forage sampled by the hand plucking method. The protodioscin concentration in forage was determined by high-performance liquid chromatography. The DMI increased linearly as a result of the supply of leaves. However, the protodioscin content and its consumption showed a quadratic behavior. There was no effect of leaf supply on in vitro digestibility, in vitro degradation kinetics of forage, and on ruminal, blood, and urinary parameters of lambs. However, a negative correlation was observed between the DMI and the concentration of protodioscin at the highest level of leaf supply. This is due to the fact that in the most intense grazing, there is a stimulus for greater regrowth; therefore, there was an increase in the concentration of protodioscin in forages in older forages. Protodioscin poisoning was confirmed by urinary and blood parameters.

Extruded urea could reduce true protein source in beef cattle diets.

Rumen micro-organisms are capable of producing microbial protein from ammonia and carbon skeleton, and non-protein nitrogen (NPN) may be one of the sources of ammonia. Alternative source of NPN is the slow release of ammonia sources in which the product is the extrusion of starch with urea. This work aimed to determine the effects on nutrient intake, ingestive behaviour, digestibility, nitrogen balance, ruminal pH, rumen ammonia nitrogen, volatile fatty acids (VFA) and blood parameters with increased levels of extruded urea (50, 60, 70 and 80 g/100 kg of body weight [BW]) in beef cattle diet. Four rumen cannulated crossbred steers with initial mean weight of 336 ± 47 kg in a 4 × 4 Latin square design were distributed. Diets were formulated with 400:600 g/kg roughage:concentrate ratio on dry matter based and provided once per day, being used whole corn silage as roughage. There were no effects on nutrient intake (kg/day), ingestive behaviour, apparent digestibility, nitrogen balance, volatile fatty acid (VFA) and blood parameters in extruded urea treatment groups. Similar results were observed on time spent on feeding, rumination and idleness. There were positive linear effects (p = 0.022) on rumen pH in the time of 8 hr after feeding and also on plasma concentration of the extruded urea levels (p = 0.039); whereas a linear negative effect (p = 0.030) was observed on ammonia nitrogen for the collection time of 2 hr after feeding. Increased levels of extruded urea could maintain nutrient intake, digestibility, ingestive behaviour, rumen pH and blood parameters in normal conditions. In conclusion, we recommend the extruded urea use with values up to 80 g/100 kg BW in confined beef cattle that receive balanced diets with 140 g/kg of crude protein.

Changes in the skin characteristics of Nellore steers during the rearing phase in hot climate pasture supplemented with protein sources.

We hypothesized that the protein source in supplements and the insolation and ambient temperature changes in different seasons could cause changes in the skin of Nellore steers during the rearing phase on warm-climate pasture. The objective of this study was to evaluate the effects of replacing true protein (soybean meal) with NPN (extruded urea) in the supplement on the skin characteristics of steers grazing on Marandu grass pastures. Thirty-six Nellore steers with an average initial weight of 250.0 kg and 15 months of age were used. Skin biopsies were performed at three different times: summer, autumn, and winter. The protein source has effects on the length of the glandular portion, number of follicles, and gland area in steers during the rearing phase at different seasons of the year. In the summer, the skin presented a higher compact structure, while in the autumn and winter, the skin presented a sparser arrangement. Skin from steers that received soybean meal in supplement had a more significant number of follicles in the summer and a smaller area and length of sweat glands. The dermis thickness of steers supplemented with soybean meal was greater than that of urea supplemented. The epidermis thickness and dermis of the steers' skin were greater at the autumn (April). Sweat gland depth was greater in autumn (April) and winter (July) than in summer (December). The protein source in the supplement alters the skin characteristics by increasing of dermis thickness of Nellore steers during the growth phase. The insolation and ambient temperature changes in different seasons alter the skin structure by increasing the epidermis and dermis thickness, sweat glands depth, and glands area of the skin of steers during the growth phase.

Pachychoroid spectrum disease.

Recent improvements in ophthalmic imaging have led to the identification of a thickened choroid or pachychoroid to be associated with a number of retinal diseases. The number of conditions linked to this phenotype has continued to widen with specific endophenotypes found within the pachychoroid spectrum. The spectrum includes choroidal features such as focal or diffuse choroidal thickening and thinning of the overlying inner choroid, and choroidal hyperpermeability as demonstrated by indocyanine green angiography. In addition, these diseases are associated with overlying retinal pigmentary changes and retinal pigment epithelial dysfunction and may also be associated with choroidal neovascularization. This article provides a comprehensive review of the literature looking at diseases currently described within the pachychoroid spectrum including central serous chorioretinopathy, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, polypoidal choroidal vasculopathy/aneurysmal type 1 neovascularization, peripapillary pachychoroid disease and focal choroidal excavation. We particularly focus on clinical imaging, genetics and pathological findings in these conditions with the aim of updating evidence suggesting a common aetiology between diseases within the pachychoroid spectrum.

Predicting Incremental and Future Visual Change in Neovascular Age-Related Macular Degeneration Using Deep Learning.

PURPOSE: To evaluate the predictive usefulness of quantitative imaging biomarkers, acquired automatically from OCT scans, of cross-sectional and future visual outcomes of patients with neovascular age-related macular degeneration (AMD) starting anti-vascular endothelial growth factor (VEGF) therapy. DESIGN: Retrospective cohort study. PARTICIPANTS: Treatment-naive, first-treated eyes of patients with neovascular AMD between 2007 and 2017 at Moorfields Eye Hospital (a large, United Kingdom single center) undergoing anti-VEGF therapy. METHODS: Automatic segmentation was carried out by applying a deep learning segmentation algorithm to 137 379 OCT scans from 6467 eyes of 3261 patients with neovascular AMD. After applying selection criteria, 926 eyes of 926 patients were analyzed. MAIN OUTCOME MEASURES: Correlation coefficients (R2 values) and mean absolute error (MAE) between quantitative OCT (qOCT) parameters and cross-sectional visual function, as well as the predictive value of these parameters for short-term visual change, that is, incremental visual acuity (VA) resulting from an individual injection, as well as VA at distant time points (up to 12 months after baseline). RESULTS: Visual acuity at distant time points could be predicted: R2 = 0.80 (MAE, 5.0 Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and R2 = 0.7 (MAE, 7.2 ETDRS letters) after injection at 3 and at 12 months after baseline (P < 0.001 for both), respectively. Best performing models included both baseline qOCT parameters and treatment response. Furthermore, we present proof-of-principle evidence that the incremental change in VA from an injection can be predicted: R2 = 0.14 (MAE, 5.6 ETDRS letters) for injection 2 and R2 = 0.11 (MAE, 5.0 ETDRS letters) for injection 3 (P < 0.001 for both). CONCLUSIONS: Automatic segmentation enables rapid acquisition of quantitative and reproducible OCT biomarkers with potential to inform treatment decisions in the care of neovascular AMD. This furthers development of point-of-care decision-aid systems for personalized medicine.

Insights From Survival Analyses During 12 Years of Anti-Vascular Endothelial Growth Factor Therapy for Neovascular Age-Related Macular Degeneration.

Importance: Although multiple imputation models for missing data and the use of mixed-effects models generally provide better outcome estimates than using only observed data or last observation carried forward in clinical trials, such approaches usually cannot be applied to visual outcomes from retrospective analyses of clinical practice settings, also called real-world outcomes. Objective: To explore the potential usefulness of survival analysis techniques for retrospective clinical practice visual outcomes. Design, Setting, and Participants: This retrospective cohort study covered a 12-year observation period at a tertiary eye center. Of 10 744 eyes with neovascular age-related macular degeneration receiving anti-vascular endothelial growth factor (VEGF) therapy between October 28, 2008, and February 1, 2020, 7802 eyes met study criteria (treatment-naive, first-treated eyes starting anti-VEGF therapy). Eyes were excluded from the analysis if they received photodynamic therapy or macular laser, any previous anti-VEGF therapy, treatment with anti-VEGF agents other than ranibizumab or aflibercept, or had an unknown date or visual acuity (VA) value at first injection. Main Outcomes and Measures: Kaplan-Meier estimates and Cox proportional hazards modeling were used to consider VA reaching an Early Treatment Diabetic Retinopathy Study (ETDRS) letter score of 70 (Snellen equivalent, 20/40) or better, duration of VA sustained at or better than 70 (20/40), and VA declining to 35 (20/200) or worse. Results: A total of 7802 patients (mean [SD] age, 78.7 [8.8] years; 4776 women [61.2%]; and 4785 White [61.3%]) were included in the study. The median time to attaining a VA letter score greater than or equal to 70 (20/40) was 2.0 years (95% CI, 1.87-2.32) after the first anti-VEGF injection. Predictive features were baseline VA (hazard ratio [HR], 1.43 per 5 ETDRS letter score or 1 line; 95% CI, 1.40-1.46), baseline age (HR, 0.88 per 5 years; 95% CI, 0.86-0.90), and injection number (HR, 1.12; 95% CI, 1.10-1.15). Of the 4439 of 7802 patients (57%) attaining this outcome, median time sustained at an ETDRS letter score of 70 (20/40) or better was 1.1 years (95% CI, 1.1-1.2). Conclusions and Relevance: In this cohort study, patients with neovascular age-related macular degeneration beginning anti-VEGF therapy were more likely to experience positive visual outcomes within the first 2.0 years after treatment, typically maintaining this outcome for 1.1 years but then deteriorating to poor vision within 8.7 years. These findings demonstrate the potential usefulness of the proposed analyses. This data set, combined with the statistical approach for retrospective analyses, may provide long-term prognostic information for patients newly diagnosed with this condition.

Ten-year survival trends of neovascular age-related macular degeneration at first presentation.

BACKGROUND: To describe 10-year trends in visual outcomes, anatomical outcomes and treatment burden of patients receiving antivascular endothelial growth factor (anti-VEGF) therapy for neovascular age-related macular degeneration (nAMD). METHODS: Retrospective cohort study of treatment-naïve, first-affected eyes with nAMD started on ranibizumab before January 1, 2009. The primary outcome was time to best-corrected visual acuity (BCVA) falling ≤35 ETDRS letters after initiating anti-VEGF therapy. Secondary outcomes included time to BCVA reaching ≥70 letters, proportion of eyes with BCVA ≥70 and ≤35 letters in 10 years, mean trend of BCVA and central retinal thickness over 10 years, and mean number of injections. RESULTS: For our cohort of 103 patients, Kaplan-Meier analyses demonstrated median time to BCVA reaching ≤35 and ≥70 letters were 37.8 (95% CI 22.2 to 65.1) and 8.3 (95% CI 4.8 to 20.9) months after commencing anti-VEGF therapy, respectively. At the final follow-up, BCVA was ≤35 letters and ≥70 letters in 41.1% and 21%, respectively, in first-affected eyes, while this was the case for 5.4% and 48.2%, respectively, in a patient's better-seeing eye. Mean injection number was 37.0±24.2 per eye and 53.6±30.1 at patient level (63.1% of patients required injections in both eyes). CONCLUSIONS: The chronicity of nAMD disease and its management highlights the importance of long-term visual prognosis. Our analyses suggest that one in five patients will retain good vision (BCVA ≥70 ETDRS letters) in the first-affected eye at 10 years after starting anti-VEGF treatment; yet, one in two patients will have good vision in their better-seeing eye. Moreover, our data suggest that early treatment of nAMD is associated with better visual outcomes.

Moorfields AMD database report 2: fellow eye involvement with neovascular age-related macular degeneration.

BACKGROUND/AIMS: Neovascular age-related macular degeneration (nAMD) is frequently bilateral, and previous reports on 'fellow eyes' have assumed sequential treatment after a period of treatment of the first eye only. The aim of our study was to analyse baseline characteristics and visual acuity (VA) outcomes of fellow eye involvement with nAMD, specifically differentiating between sequential and non-sequential (due to macular scarring in the first eye) antivascular endothelial growth factor treatment and timelines for fellow eye involvement. METHODS: Retrospective, electronic medical record database study of the Moorfields AMD database of 6265 patients/120 286 single entries with data extracted between 21 October 2008 and 9 August 2018. The data set for analysis consisted of 1180 sequential, 807 non-sequential and 3410 unilateral eyes. RESULTS: Mean VA (ETDRS letters±SD) of sequentially treated fellow eyes at baseline was significantly higher (63±13), VA gain over 2 years lower (0.37±14) and proportion of eyes with good VA (≥70 letters) higher (46%) than the respective first eyes (baseline VA 54±16, VA gain at 2 years 5.6±15, percentage of eyes with good VA 39%). Non-sequential fellow eyes showed baseline characteristics and VA outcomes similar to first eyes. Fellow eye involvement rate was 32% at 2 years, and median time interval to fellow eye involvement was 71 (IQR: 27-147) weeks. CONCLUSION: This report shows that sequentially treated nAMD fellow eyes have better baseline and final VA than non-sequentially treated eyes after 2 years of treatment. Sequentially treated eyes also had a greater proportion with good VA after 2 years.

Predicting conversion to wet age-related macular degeneration using deep learning.

Progression to exudative 'wet' age-related macular degeneration (exAMD) is a major cause of visual deterioration. In patients diagnosed with exAMD in one eye, we introduce an artificial intelligence (AI) system to predict progression to exAMD in the second eye. By combining models based on three-dimensional (3D) optical coherence tomography images and corresponding automatic tissue maps, our system predicts conversion to exAMD within a clinically actionable 6-month time window, achieving a per-volumetric-scan sensitivity of 80% at 55% specificity, and 34% sensitivity at 90% specificity. This level of performance corresponds to true positives in 78% and 41% of individual eyes, and false positives in 56% and 17% of individual eyes at the high sensitivity and high specificity points, respectively. Moreover, we show that automatic tissue segmentation can identify anatomical changes before conversion and high-risk subgroups. This AI system overcomes substantial interobserver variability in expert predictions, performing better than five out of six experts, and demonstrates the potential of using AI to predict disease progression.

Automated deep learning design for medical image classification by health-care professionals with no coding experience: a feasibility study.

BACKGROUND: Deep learning has the potential to transform health care; however, substantial expertise is required to train such models. We sought to evaluate the utility of automated deep learning software to develop medical image diagnostic classifiers by health-care professionals with no coding-and no deep learning-expertise. METHODS: We used five publicly available open-source datasets: retinal fundus images (MESSIDOR); optical coherence tomography (OCT) images (Guangzhou Medical University and Shiley Eye Institute, version 3); images of skin lesions (Human Against Machine [HAM] 10000), and both paediatric and adult chest x-ray (CXR) images (Guangzhou Medical University and Shiley Eye Institute, version 3 and the National Institute of Health [NIH] dataset, respectively) to separately feed into a neural architecture search framework, hosted through Google Cloud AutoML, that automatically developed a deep learning architecture to classify common diseases. Sensitivity (recall), specificity, and positive predictive value (precision) were used to evaluate the diagnostic properties of the models. The discriminative performance was assessed using the area under the precision recall curve (AUPRC). In the case of the deep learning model developed on a subset of the HAM10000 dataset, we did external validation using the Edinburgh Dermofit Library dataset. FINDINGS: Diagnostic properties and discriminative performance from internal validations were high in the binary classification tasks (sensitivity 73·3-97·0%; specificity 67-100%; AUPRC 0·87-1·00). In the multiple classification tasks, the diagnostic properties ranged from 38% to 100% for sensitivity and from 67% to 100% for specificity. The discriminative performance in terms of AUPRC ranged from 0·57 to 1·00 in the five automated deep learning models. In an external validation using the Edinburgh Dermofit Library dataset, the automated deep learning model showed an AUPRC of 0·47, with a sensitivity of 49% and a positive predictive value of 52%. INTERPRETATION: All models, except the automated deep learning model trained on the multilabel classification task of the NIH CXR14 dataset, showed comparable discriminative performance and diagnostic properties to state-of-the-art performing deep learning algorithms. The performance in the external validation study was low. The quality of the open-access datasets (including insufficient information about patient flow and demographics) and the absence of measurement for precision, such as confidence intervals, constituted the major limitations of this study. The availability of automated deep learning platforms provide an opportunity for the medical community to enhance their understanding in model development and evaluation. Although the derivation of classification models without requiring a deep understanding of the mathematical, statistical, and programming principles is attractive, comparable performance to expertly designed models is limited to more elementary classification tasks. Furthermore, care should be placed in adhering to ethical principles when using these automated models to avoid discrimination and causing harm. Future studies should compare several application programming interfaces on thoroughly curated datasets. FUNDING: National Institute for Health Research and Moorfields Eye Charity.

One- and two-year visual outcomes from the Moorfields age-related macular degeneration database: a retrospective cohort study and an open science resource.

OBJECTIVES: To analyse treatment outcomes and share clinical data from a large, single-centre, well-curated database (8174 eyes/6664 patients with 120 756 single entries) of patients with neovascular age-related macular degeneration (AMD) treated with anti-vascular endothelial growth factor (VEGF). By making our depersonalised raw data openly available, we aim to stimulate further research in AMD, as well as set a precedent for future work in this area. SETTING: Retrospective, comparative, non-randomised electronic medical record (EMR) database cohort study of the UK Moorfields AMD database with data extracted between 2008 and 2018. PARTICIPANTS: Including one eye per patient, 3357 eyes/patients (61% female). Extraction criteria were ≥1 ranibizumab or aflibercept injection, entry of 'AMD' in the diagnosis field of the EMR and a minimum of 1 year of follow-up. Exclusion criteria were unknown date of first injection and treatment outside of routine clinical care at Moorfields before the first recorded injection in the database. MAIN OUTCOME MEASURES: Primary outcome measure was change in VA at 1 and 2 years from baseline as measured in Early Treatment Diabetic Retinopathy Study letters. Secondary outcomes were the number of injections and predictive factors for VA gain. RESULTS: Mean VA gain at 1 year and 2 years were +5.5 (95% CI 5.0 to 6.0) and +4.9 (95% CI 4.2 to 5.6) letters, respectively. Fifty-four per cent of eyes gained ≥5 letters at 2 years, 63% had stable VA (±≤14 letters), 44% of eyes maintained good VA (≥70 letters). Patients received a mean of 7.7 (95% CI 7.6 to 7.8) injections during year 1 and 13.0 (95% CI 12.8 to 13.2) injections over 2 years. Younger age, lower baseline VA and more injections were associated with higher VA gain at 2 years. CONCLUSION: This study benchmarks high quality EMR study results of real life AMD treatment and promotes open science in clinical AMD research by making the underlying data publicly available.