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Lancet (London, England) Jun 2024Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents...
BACKGROUND
Neovascular age-related macular degeneration (nAMD) is a leading cause of blindness. The first-line therapy is anti-vascular endothelial growth factor (anti-VEGF) agents delivered by intravitreal injection. Ionising radiation mitigates key pathogenic processes underlying nAMD, and therefore has therapeutic potential. STAR aimed to assess whether stereotactic radiotherapy (SRT) reduces the number of anti-VEGF injections required, without sacrificing visual acuity.
METHODS
This pivotal, randomised, double-masked, sham-controlled trial enrolled participants with pretreated chronic active nAMD from 30 UK hospitals. Participants were randomly allocated in a 2:1 ratio to 16-Gray (Gy) SRT delivered using a robotically controlled device or sham SRT, stratified by treatment centre. Eligible participants were aged 50 years or older and had chronic active nAMD, with at least three previous anti-VEGF injections, including at least one in the last 4 months. Participants and all trial and image reading centre staff were masked to treatment allocation, except one unmasked statistician. The primary outcome was the number of intravitreal ranibizumab injections required over 2 years, tested for superiority (fewer injections). The main secondary outcome was Early Treatment Diabetic Retinopathy Study visual acuity at two years, tested for non-inferiority (five-letter margin). The primary analysis used the intention-to-treat principle, and safety was analysed per-protocol on participants with available data. The study is registered with ClinicalTrials.gov (NCT02243878) and is closed for recruitment.
FINDINGS
411 participants enrolled between Jan 1, 2015, and Dec 27, 2019, and 274 were randomly allocated to the 16-Gy SRT group and 137 to the sham SRT group. 240 (58%) of all participants were female, and 171 (42%) of all participants were male. 241 participants in the 16-Gy SRT group and 118 participants in the sham group were included in the final analysis, and 409 patients were treated and formed the safety population, of whom two patients allocated to sham treatment erroneously received 16-Gy SRT. The SRT group received a mean of 10·7 injections (SD 6·3) over 2 years versus 13·3 injections (5·8) with sham, a reduction of 2·9 injections after adjusting for treatment centre (95% CI -4·2 to -1·6, p<0·0001). The SRT group best-corrected visual acuity change was non-inferior to sham (adjusted mean letter loss difference between groups, -1·7 letters [95% CI -4·2 to 0·8]). Adverse event rates were similar across groups, but reading centre-detected microvascular abnormalities occurred in 77 SRT-treated eyes (35%) and 13 (12%) sham-treated eyes. Overall, eyes with microvascular abnormalities tended to have better best-corrected visual acuity than those without. Fewer ranibizumab injections offset the cost of SRT, saving a mean of £565 per participant (95% CI -332 to 1483).
INTERPRETATION
SRT can reduce ranibizumab treatment burden without compromising vision.
FUNDING
Medical Research Council and National Institute for Health and Care Research Efficacy and Mechanism Evaluation Programme.
PubMed: 38876132
DOI: 10.1016/S0140-6736(24)00687-1 -
JMIR AI Mar 2024Identification and referral of at-risk patients from primary care practitioners (PCPs) to eye care professionals remain a challenge. Approximately 1.9 million Americans...
Machine Learning Methods Using Artificial Intelligence Deployed on Electronic Health Record Data for Identification and Referral of At-Risk Patients From Primary Care Physicians to Eye Care Specialists: Retrospective, Case-Controlled Study.
BACKGROUND
Identification and referral of at-risk patients from primary care practitioners (PCPs) to eye care professionals remain a challenge. Approximately 1.9 million Americans suffer from vision loss as a result of undiagnosed or untreated ophthalmic conditions. In ophthalmology, artificial intelligence (AI) is used to predict glaucoma progression, recognize diabetic retinopathy (DR), and classify ocular tumors; however, AI has not yet been used to triage primary care patients for ophthalmology referral.
OBJECTIVE
This study aimed to build and compare machine learning (ML) methods, applicable to electronic health records (EHRs) of PCPs, capable of triaging patients for referral to eye care specialists.
METHODS
Accessing the Optum deidentified EHR data set, 743,039 patients with 5 leading vision conditions (age-related macular degeneration [AMD], visually significant cataract, DR, glaucoma, or ocular surface disease [OSD]) were exact-matched on age and gender to 743,039 controls without eye conditions. Between 142 and 182 non-ophthalmic parameters per patient were input into 5 ML methods: generalized linear model, L1-regularized logistic regression, random forest, Extreme Gradient Boosting (XGBoost), and J48 decision tree. Model performance was compared for each pathology to select the most predictive algorithm. The area under the curve (AUC) was assessed for all algorithms for each outcome.
RESULTS
XGBoost demonstrated the best performance, showing, respectively, a prediction accuracy and an AUC of 78.6% (95% CI 78.3%-78.9%) and 0.878 for visually significant cataract, 77.4% (95% CI 76.7%-78.1%) and 0.858 for exudative AMD, 79.2% (95% CI 78.8%-79.6%) and 0.879 for nonexudative AMD, 72.2% (95% CI 69.9%-74.5%) and 0.803 for OSD requiring medication, 70.8% (95% CI 70.5%-71.1%) and 0.785 for glaucoma, 85.0% (95% CI 84.2%-85.8%) and 0.924 for type 1 nonproliferative diabetic retinopathy (NPDR), 82.2% (95% CI 80.4%-84.0%) and 0.911 for type 1 proliferative diabetic retinopathy (PDR), 81.3% (95% CI 81.0%-81.6%) and 0.891 for type 2 NPDR, and 82.1% (95% CI 81.3%-82.9%) and 0.900 for type 2 PDR.
CONCLUSIONS
The 5 ML methods deployed were able to successfully identify patients with elevated odds ratios (ORs), thus capable of patient triage, for ocular pathology ranging from 2.4 (95% CI 2.4-2.5) for glaucoma to 5.7 (95% CI 5.0-6.4) for type 1 NPDR, with an average OR of 3.9. The application of these models could enable PCPs to better identify and triage patients at risk for treatable ophthalmic pathology. Early identification of patients with unrecognized sight-threatening conditions may lead to earlier treatment and a reduced economic burden. More importantly, such triage may improve patients' lives.
PubMed: 38875582
DOI: 10.2196/48295 -
Translational Vision Science &... Jun 2024The subsidence of the outer plexiform layer (OPL) is an important imaging biomarker on optical coherence tomography (OCT) associated with early outer retinal atrophy and...
PURPOSE
The subsidence of the outer plexiform layer (OPL) is an important imaging biomarker on optical coherence tomography (OCT) associated with early outer retinal atrophy and a risk factor for progression to geographic atrophy in patients with intermediate age-related macular degeneration (AMD). Deep neural networks (DNNs) for OCT can support automated detection and localization of this biomarker.
METHODS
The method predicts potential OPL subsidence locations on retinal OCTs. A detection module (DM) infers bounding boxes around subsidences with a likelihood score, and a classification module (CM) assesses subsidence presence at the B-scan level. Overlapping boxes between B-scans are combined and scored by the product of the DM and CM predictions. The volume-wise score is the maximum prediction across all B-scans. One development and one independent external data set were used with 140 and 26 patients with AMD, respectively.
RESULTS
The system detected more than 85% of OPL subsidences with less than one false-positive (FP)/scan. The average area under the curve was 0.94 ± 0.03 for volume-level detection. Similar or better performance was achieved on the independent external data set.
CONCLUSIONS
DNN systems can efficiently perform automated retinal layer subsidence detection in retinal OCT images. In particular, the proposed DNN system detects OPL subsidence with high sensitivity and a very limited number of FP detections.
TRANSLATIONAL RELEVANCE
DNNs enable objective identification of early signs associated with high risk of progression to the atrophic late stage of AMD, ideally suited for screening and assessing the efficacy of the interventions aiming to slow disease progression.
Topics: Humans; Tomography, Optical Coherence; Aged; Female; Neural Networks, Computer; Male; Macular Degeneration; Geographic Atrophy; Disease Progression; Retina; Middle Aged; Aged, 80 and over
PubMed: 38874975
DOI: 10.1167/tvst.13.6.7 -
Translational Vision Science &... Jun 2024Both hypertension and diabetes are known to increase the wall-to-lumen ratio (WLR) of retinal arterioles, but the differential effects are unknown. Here, we study the...
PURPOSE
Both hypertension and diabetes are known to increase the wall-to-lumen ratio (WLR) of retinal arterioles, but the differential effects are unknown. Here, we study the timing and relative impact of hypertension versus diabetes on the WLR in diabetic retinopathy (DR) to address this unresolved question.
METHODS
This prospective cross-sectional study compared the retinal arteriolar WLR in 17 healthy eyes, 15 with diabetes but no apparent DR (DM no DR), and 8 with diabetic macular edema (DME) and either nonproliferative or proliferative DR. We imaged each arteriole using adaptive optics scanning laser ophthalmoscopy and measured the WLR using ImageJ. Multiple linear regression (MLR) was performed to estimate the effects of hypertension, diabetes, and age on the WLR.
RESULTS
Both subjects with DM no DR and subjects with DME had significantly higher WLR than healthy subjects (0.36 ± 0.08 and 0.42 ± 0.08 vs. 0.29 ± 0.07, 1-way ANOVA P = 0.0009). MLR in healthy subjects and subjects with DM no DR showed hypertension had the strongest effect (regression coefficient = 0.08, P = 0.009), whereas age and diabetes were not significantly correlated with WLR. MLR in all three groups together (healthy, DM no DR, and DME) showed diabetes had the strongest effect (regression coefficient = 0.05, P = 0.02), whereas age and hypertension were not significantly correlated with WLR.
CONCLUSIONS
Hypertension may be an early driver of retinal arteriolar wall thickening in preclinical DR, independent of age or diabetes, whereas changes specific to DR may drive wall thickening in DME and later DR stages.
TRANSLATIONAL RELEVANCE
We offer a framework for understanding the relative contributions of hypertension and diabetes on the vascular wall, and emphasize the importance of hypertension control early in diabetes even before DR onset.
Topics: Humans; Cross-Sectional Studies; Male; Diabetic Retinopathy; Female; Middle Aged; Prospective Studies; Arterioles; Hypertension; Ophthalmoscopy; Aged; Adult; Retinal Artery; Macular Edema
PubMed: 38874974
DOI: 10.1167/tvst.13.6.8 -
Investigative Ophthalmology & Visual... Jun 2024To examine if changes in hemodynamic measures during an orthostatic challenge were associated with progression of age-related macular degeneration (AMD) over a 4-year...
PURPOSE
To examine if changes in hemodynamic measures during an orthostatic challenge were associated with progression of age-related macular degeneration (AMD) over a 4-year period in The Irish Longitudinal Study on Ageing.
METHODS
Participants with AMD who underwent an active stand (AS) test at wave 1 (2009/2010) and retinal photographs at both wave 1 and wave 3 (2014/2015) were included (N = 159: 121 with no AMD progression and 38 with progression). Beat-to-beat hemodynamic data were non-invasively collected using a Finometer MIDI device during the AS at wave 1, recording systolic blood pressure (sBP), diastolic blood pressure (dBP), mean arterial pressure (MAP), and heart rate. Cardiac output, stroke volume, and total peripheral resistance (TPR) were derived from these measures. Baseline characteristics were compared between groups with and without AMD progression. Mixed-effects linear regression models were used to assess the association between changes in hemodynamic parameters during the AS and AMD progression, controlling for known AMD-associated risk factors.
RESULTS
At baseline, increasing age and lower dBP were significantly associated with AMD progression. Mixed-effects models for the period between standing and 10 seconds post-stand revealed significant associations with AMD progression with a steeper drop in dBP and a slower drop in TPR. Between 10 and 20 seconds post-stand, AMD progression was significantly associated with less pronounced reduction in heart rate.
CONCLUSIONS
These observational data suggest that impaired hemodynamic responses within the first 20 seconds of orthostasis may be associated with the progression of AMD.
Topics: Humans; Male; Female; Disease Progression; Aged; Macular Degeneration; Ireland; Heart Rate; Aging; Blood Pressure; Longitudinal Studies; Autonomic Nervous System; Aged, 80 and over; Hemodynamics; Middle Aged; Risk Factors
PubMed: 38874963
DOI: 10.1167/iovs.65.6.24 -
Molecular Biology Reports Jun 2024Human Amniotic Membrane (hAM) is endowed with several biological activities and might be considered an optimal tool in surgical treatment for different ophthalmic...
BACKGROUND
Human Amniotic Membrane (hAM) is endowed with several biological activities and might be considered an optimal tool in surgical treatment for different ophthalmic pathologies. We pioneered the surgical use of hAM to treat retinal pathologies such as macular holes, tears, and retinal detachments, and to overcome photoreceptor damage in age-related macular degeneration. Although hAM contributed to improved outcomes, the mechanisms of its effects are not yet fully understood. The characterization and explanation of the effects of hAM would allow the adoption of this new natural product in different retinal pathologies, operative contexts, and hAM formulations. At this end, we studied the properties of a hAM extract (hAME) on the ARPE-19 cells.
METHODS AND RESULTS
A non-denaturing sonication-based technique was developed to obtain a suitable hAME. Viability, proliferation, apoptosis, oxidative stress, and epithelial-mesenchymal transition (EMT) were studied in hAME-treated ARPE-19 cells. The hAME was able to increase ARPE-19 cell viability even in the presence of oxidative stress (HO, TBHP). Moreover, hAME prevented the expression of EMT features, such as EMT-related proteins, fibrotic foci formation, and migration induced by different cytokines.
CONCLUSIONS
Our results demonstrate that the hAME retains most of the properties observed in the whole tissue by others. The hAME, other than providing a manageable research tool, could represent a cost-effective and abundant drug to treat retinal pathologies in the future.
Topics: Humans; Amnion; Cell Line; Retinal Pigment Epithelium; Cell Survival; Apoptosis; Oxidative Stress; Cell Proliferation; Epithelial-Mesenchymal Transition; Tissue Extracts
PubMed: 38874663
DOI: 10.1007/s11033-024-09647-7 -
Frontiers in Aging Neuroscience 2024Observational studies have reported inconsistent results on the relationship between chronic kidney disease (CKD) and age-related macular degeneration (AMD). The primary...
PURPOSE
Observational studies have reported inconsistent results on the relationship between chronic kidney disease (CKD) and age-related macular degeneration (AMD). The primary objective of this study was to investigate the causal relationships between estimated glomerular filtration rate (eGFR), CKD, its common causes, and AMD among participants of European descent.
METHODS
Genetic variants associated with eGFR, CKD and its common causes, encompassing diabetic nephropathy (DN), immunoglobulin A nephropathy (IgAN), and membranous nephropathy (MN) were obtained from previously published genome-wide association studies (GWAS) and FinnGen database. Summary statistics for early AMD, AMD, dry AMD, and wet AMD were acquired from the GWAS and FinnGen database. Inverse-variance-weighted (IVW) method was the main MR analysis. Sensitivity analyses were performed with Cochran's Q, MR-Egger intercept, and leave-one-out analysis. In addition, RadialMR was utilized to identify and remove outliers.
RESULTS
IVW results showed that CKD, eGFR were not associated with any type of AMD ( > 0.05). DN (OR: 1.042, 95% CI: 1.002-1.083, = 0.037) and MN (OR: 1.023, 95% CI: 1.007-1.040, = 0.005) were associated with an increased risk of earl AMD. DN (OR: 1.111, 95% CI: 1.07-1.154, = 4.87 × 10), IgAN (OR: 1.373, 95% CI: 1.097-1.719, = 0.006), and MN (OR: 1.036, 95% CI: 1.008-1.064, = 0.012) were associated with an increased risk of AMD. DN (OR: 1.090, 95% CI: 1.042-1.140, = 1.57 × 10) and IgAN (OR: 1.480, 95% CI: 1.178-1.858, = 7.55 × 10) were associated with an increased risk of dry AMD. The risk of wet AMD was associated with DN (OR: 1.107, 95% CI: 1.043-1.174, = 7.56 × 10) and MN (OR: 1.071, 95% CI: 1.040-1.103, = 5.48 × 10).
CONCLUSION
This MR study found no evidence of causal relationship between CKD and AMD. DN, IgAN, and MN may increase risk of AMD. This findings underscore the importance of ocular examinations in patients with DN, MN, and IgAN. More studies are needed to support the findings of our current study.
PubMed: 38872627
DOI: 10.3389/fnagi.2024.1399666 -
Scientific Reports Jun 2024We identified characteristics of patients with subretinal fluid (SRF) in macular edema (ME) secondary to branch retinal vein occlusion (BRVO) and determined their...
We identified characteristics of patients with subretinal fluid (SRF) in macular edema (ME) secondary to branch retinal vein occlusion (BRVO) and determined their clinical outcomes after anti-vascular endothelial growth factor (VEGF) treatment. Fifty-seven eyes of BRVO patients with ME were divided into two groups according to the presence or absence of SRF at diagnosis. We compared the aqueous profiles, ocular and systemic characteristics at baseline, and the clinical outcomes. The SRF group had significantly greater central subfield thickness (CST) values and poorer best-corrected visual acuity (BCVA) at baseline compared to the non-SRF group. The former group had significantly higher aqueous levels of interleukin-8, VEGF, and placental growth factor. CST reduction and BCVA improvement during treatment were significantly greater in the SRF group than in the non-SRF group. Consequently, CST values were significantly lower in the SRF group than in the non-SRF group at 12 months, when BCVA did not differ significantly between the two groups. The SRF group required more frequent anti-VEGF treatment over 12 months and exhibited a higher rate of macular atrophy. Based on the aqueous profiles and the number of treatments required, the presence of SRF in BRVO patients appears to be associated with higher disease activity.
Topics: Humans; Retinal Vein Occlusion; Macular Edema; Male; Female; Aged; Subretinal Fluid; Middle Aged; Visual Acuity; Vascular Endothelial Growth Factor A; Tomography, Optical Coherence; Angiogenesis Inhibitors; Aged, 80 and over
PubMed: 38871805
DOI: 10.1038/s41598-024-64047-y -
Stem Cell Research Aug 2024The Stargardt's Disease, Type 1 (STGD1) is associated with the loss of function mutations in ABCA4. This gene codes for a retina-specific, ATP-binding cassette (ABC)...
Generation and characterization of a Stargardt's disease-specific induced pluripotent stem cell line (LVPEIi008-A) with a homozygous nonsense mutation in exon 44 of ABCA4.
The Stargardt's Disease, Type 1 (STGD1) is associated with the loss of function mutations in ABCA4. This gene codes for a retina-specific, ATP-binding cassette (ABC) family transporter, involved in the transport of the key visual cycle intermediate, all-trans-retinaldehyde (atRAL), across the photoreceptor cell membranes. Here, we report the establishment of a patient-specific, iPSC line (LVPEIi008-A), that carries a homozygous nonsense mutation at (c.6088C > T) position, within exon 44 of ABCA4. The patient-specific skin fibroblasts were reprogrammed using episomal plasmids and the stably expanding iPSC line expressed the key stemness and pluripotency markers, maintained its chromosomal integrity and tested negative for mycoplasma.
Topics: Induced Pluripotent Stem Cells; ATP-Binding Cassette Transporters; Stargardt Disease; Humans; Codon, Nonsense; Exons; Homozygote; Cell Line; Macular Degeneration
PubMed: 38870564
DOI: 10.1016/j.scr.2024.103458 -
Journal of Global Health Jun 2024Asia accounts for more than half of the world's population and carries a substantial proportion of the global burden of blindness and vision impairment. Characterising...
BACKGROUND
Asia accounts for more than half of the world's population and carries a substantial proportion of the global burden of blindness and vision impairment. Characterising this burden, as well as its causes and determinants, could help with devising targeted interventions for reducing the occurrence of blindness and visual impairment.
METHODS
Using the Global Burden of Disease Study 2019 database, we retrieved data on the number of disability-adjusted life years (DALYs); crude and age-standardised rates; and the prevalence (with 95% uncertainty intervals (95%UIs)) of blindness and vision loss due to six causes (age-related macular degeneration, cataracts, glaucoma, near-vision impairment, refractive error, and other vision loss) for Asian countries for the period between 1990 and 2019. We defined DALYs as the sum of the years lost due to disability and years of life lost, and calculated age-standardised figures for the number of DALYs and prevalence by adjusting for population size and age structure. We then evaluated the time trend of the disease burden and conducted subgroup analyses by gender, age, geographic locations, and socio-demographic index (SDI).
RESULTS
In 2019, the DALYs and prevalence of blindness and vision loss had risen by 90.1% and 116% compared with 1990, reaching 15.84 million DALYs (95% UI = 15.83, 15.85) and 506.71 million cases (95% UI = 506.68, 506.74). Meanwhile, the age-standardised rate of DALYs decreased from 1990 to 2019. Cataracts, refractive error, and near vision impairment were the three most common causes. South Asia had the heaviest regional disease burden (age-standardised rate of DALYs = 517 per 100 000 population; 95% UI = 512, 521). Moreover, the burden due to cataracts ranked high in most Asian populations. Being a woman; being older; and having a lower national SDI were factors associated with a greater vision loss burden.
CONCLUSIONS
The burden due to vision loss remains high in Asian populations. Cataracts, refractive error, and near vision loss were the primary causes of blindness and vision loss. Greater investment in ocular disease prevention and care by countries with lower socioeconomic status is needed, as well as specific strategies targeting cataract management, women and the elderly.
Topics: Humans; Blindness; Global Burden of Disease; Female; Male; Aged; Middle Aged; Asia; Disability-Adjusted Life Years; Adult; Aged, 80 and over; Prevalence; Young Adult; Adolescent; Child; Child, Preschool; Infant; Cataract; Vision, Low; Refractive Errors
PubMed: 38867671
DOI: 10.7189/jogh.14.04100