PREDICTORS AND IMPORTANCE OF COMPLETE POLYPOIDAL LESION REGRESSION IN THE EVEREST II STUDY: Predictors of Polyp Regression in Polypoidal Choroidal Vasculopathy.

PURPOSE: To evaluate the predictors of complete polypoidal lesion regression (CPREG) in polypoidal choroidal vasculopathy. METHODS: Post hoc analysis of EVEREST II-a 24-month, multicenter, randomized, controlled clinical trial of 322 patients with polypoidal choroidal vasculopathy, randomized to receive ranibizumab with or without photodynamic therapy. Images of indocyanine green angiography (ICGA) were graded by a central reading center. Multiple logistic regression analysis with significant baseline predictors then was conducted to assess adjusted odds ratios for CPREG at month (M) 12. RESULTS: Baseline ICGA characteristics were comparable between the treatment groups. Patients treated with combination therapy had higher odds of achieving CPREG at M12 (adjusted odds ratio = 4.64; 95% confidence interval, 2.85-7.55; P < 0.001) compared with those in the monotherapy group. Absence of polypoidal lesion pulsation on ICGA was also associated with CPREG at M12 (adjusted odds ratio = 2.62; 95% confidence interval, 1.32-5.21; P = 0.006). The presence of CPREG at M3 had higher odds of maintaining CPREG at M12 (adjusted odds ratio = 6.60; 95% confidence interval, 3.77-11.57; P < 0.001) compared with those with persistent polypoidal lesions. CONCLUSION: At M12, treatment with combination therapy was associated with higher probability of achieving CPREG than with ranibizumab monotherapy. The results contribute to the further understanding of the response of polypoidal lesions to treatment.

RANIBIZUMAB WITH OR WITHOUT VERTEPORFIN PHOTODYNAMIC THERAPY FOR POLYPOIDAL CHOROIDAL VASCULOPATHY: Predictors of Visual and Anatomical Response in the EVEREST II Study.

PURPOSE: To evaluate the demographic and imaging factors at baseline and Month 3 (M3) that predict visual or anatomical responses at Month 12 (M12) in the EVEREST-II study for polypoidal choroidal vasculopathy. METHODS: Post-hoc analysis of 322 participants in the EVEREST-II study. Patient factors, best-corrected visual acuity (BCVA), treatment, and imaging parameters at baseline and M3 were evaluated with respect to outcomes at M12 using univariate and multivariable analysis. RESULTS: Younger age (P < 0.001) and lower baseline BCVA (P < 0.001) were associated with higher BCVA gains at M12. Smaller baseline polypoidal lesion area was associated with higher BCVA gains at M12 only in the ranibizumab monotherapy arm (P = 0.008). Central subfield thickness at M3, area of branching vascular network at M3, BCVA at M3, and age were associated with change in BCVA from M3 at M12. Higher odds of fluid-free retina at M12 were associated with lower baseline central subfield thickness (P = 0.006), treatment with combination therapy (baseline and M3 models; P < 0.001), and absence of subretinal fluid at M3 (P < 0.001). CONCLUSION: Several imaging parameters at baseline and M3 can predict treatment outcome. The interaction between treatment arm and total polypoidal lesion area suggests this feature may assist selecting between initial ranibizumab monotherapy or combination therapy.

Comparing efficacy of reduced-fluence and standard-fluence photodynamic therapy in the treatment of polypoidal choroidal vasculopathy.

BACKGROUND: The EVEREST II study reported superior polyp closure rates and visual outcomes using combination standard photodynamic therapy (PDT) with intravitreal ranibizumab in the treatment of polypoidal choroidal vasculopathy (PCV). The optimal PDT protocol remains controversial and it is postulated that less intensive PDT strategies may reduce complications. We aimed to compare the efficacy of reduced and standard-fluence PDT. METHODS: Case-control review of 38 consecutive PDT-naïve macular PCV patients who underwent verteporfin PDT using one of two PDT regimens at a tertiary referral centre in an Asian population. Comparison of outcomes between standard-fluence PDT (light dose, 50 J/cm2; dose rate, 600 mW/cm2; wavelength, 689 nm PDT applied to the treatment eye for 83 s) and reduced-fluence PDT (light dose, 25 J/cm2; dose rate, 600 mW/cm2; wavelength, 689 nm PDT applied to the treatment eye for 42 s). Primary outcome measure was best corrected LogMAR visual acuity (VA). Secondary outcome measures included OCT measurements such as central retinal thickness (CRT), height of subfoveal sub-retinal fluid (SRF), central choroid thickness (CCT), mean number of PDT treatments needed, mean number of anti-VEGF injections needed, polyp closure and recurrence rates. RESULTS: Of these 38 eyes of 38 patients, an equal number of eyes (19 in each arm) were treated with standard-fluence and reduced-fluence PDT. Mean letter gain at 12 months for the standard-fluence group was 6.0 compared to 4.3 letters for the reduced-fluence group (p = 0.61). Similar results were observed at all time points. There was no statistically significant difference between the retinal and choroidal anatomical OCT outcomes, rates of polyp closure and recurrences between the two PDT regimens. CONCLUSIONS: Reduced-fluence PDT was comparable to standard-fluence PDT in the treatment of PCV in terms of visual gains, clinical and anatomical OCT outcomes.

Predictors of persistent disease activity following anti-VEGF loading dose for nAMD patients in Singapore: the DIALS study.

BACKGROUND: To determine the frequency of persistent disease activity following 3 loading doses of anti- vascular endothelial growth factor (VEGF) agents, and the anatomic and demographic predictors of early persistent disease activity among patients with neovascular age-related macular degeneration (nAMD). METHODS: In a retrospective real-world cohort study, 281 consecutive patients with nAMD were reviewed at baseline and after 3 anti-VEGF injections for pre-defined indicators of disease activity. Optical coherence tomography (OCT) features such as subretinal fluid, intraretinal cysts and intraretinal fluid were assessed by reading-center certified graders. Multiple logistic regression was performed on demographic and anatomic factors. RESULTS: At month 3, 66.1% of patients had persistent disease activity. The best-corrected visual acuity (BCVA) improvement was 0.16 LogMAR for those with no disease activity compared to 0 for patients with persistent activity (p < 0.001). The significant risk factors for persistent activity at 3 months were male gender (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.32-0.93, p = 0.025), intraretinal cysts at baseline (OR 2.95, 95% CI 1.67-5.20, p < 0.001) and subretinal fluid at baseline (OR 3.17, 95% CI 1.62-6.18, p = 0.002). At 3 months, 58% of patients had features of activity on OCT. Patients with intraretinal cysts and intraretinal fluid at baseline had worse BCVA at month 3 compared to patients without these OCT features (0.69 vs. 0.43, p < 0.001, and 0.62 vs. 0.43, p < 0.001, respectively). CONCLUSIONS: In a real-world study, 66.1% of nAMD patients have persistent disease activity after the initial loading dose, with poorer BCVA compared to those without. Baseline OCT features (intraretinal cysts and subretinal fluid) are useful predictors of persistent disease activity at month 3.

Use of Smartphones to Detect Diabetic Retinopathy: Scoping Review and Meta-Analysis of Diagnostic Test Accuracy Studies.

BACKGROUND: Diabetic retinopathy (DR), a common complication of diabetes mellitus, is the leading cause of impaired vision in adults worldwide. Smartphone ophthalmoscopy involves using a smartphone camera for digital retinal imaging. Utilizing smartphones to detect DR is potentially more affordable, accessible, and easier to use than conventional methods. OBJECTIVE: This study aimed to determine the diagnostic accuracy of various smartphone ophthalmoscopy approaches for detecting DR in diabetic patients. METHODS: We performed an electronic search on the Medical Literature Analysis and Retrieval System Online (MEDLINE), EMBASE, and Cochrane Library for literature published from January 2000 to November 2018. We included studies involving diabetic patients, which compared the diagnostic accuracy of smartphone ophthalmoscopy for detecting DR to an accurate or commonly employed reference standard, such as indirect ophthalmoscopy, slit-lamp biomicroscopy, and tabletop fundus photography. Two reviewers independently screened studies against the inclusion criteria, extracted data, and assessed the quality of included studies using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, with disagreements resolved via consensus. Sensitivity and specificity were pooled using the random effects model. A summary receiver operating characteristic (SROC) curve was constructed. This review is reported in line with the Preferred Reporting Items for a Systematic Review and Meta-analysis of Diagnostic Test Accuracy Studies guidelines. RESULTS: In all, nine studies involving 1430 participants were included. Most studies were of high quality, except one study with limited applicability because of its reference standard. The pooled sensitivity and specificity for detecting any DR was 87% (95% CI 74%-94%) and 94% (95% CI 81%-98%); mild nonproliferative DR (NPDR) was 39% (95% CI 10%-79%) and 95% (95% CI 91%-98%); moderate NPDR was 71% (95% CI 57%-81%) and 95% (95% CI 88%-98%); severe NPDR was 80% (95% CI 49%-94%) and 97% (95% CI 88%-99%); proliferative DR (PDR) was 92% (95% CI 79%-97%) and 99% (95% CI 96%-99%); diabetic macular edema was 79% (95% CI 63%-89%) and 93% (95% CI 82%-97%); and referral-warranted DR was 91% (95% CI 86%-94%) and 89% (95% CI 56%-98%). The area under SROC curve ranged from 0.879 to 0.979. The diagnostic odds ratio ranged from 11.3 to 1225. CONCLUSIONS: We found heterogeneous evidence showing that smartphone ophthalmoscopy performs well in detecting DR. The diagnostic accuracy for PDR was highest. Future studies should standardize reference criteria and classification criteria and evaluate other available forms of smartphone ophthalmoscopy in primary care settings.

Multicolour imaging for the detection of polypoidal choroidal vasculopathy and age-related macular degeneration.

IMPORTANCE: Multicolour is a new imaging technology and its sensitivity for detecting polypoidal choroidal vasculopathy (PCV) and age-related macular degeneration (AMD) has not been well described. BACKGROUND: To evaluate the accuracy of multicolour imaging compared to colour fundus photography (CFP) in differentiating AMD and PCV from normal eyes, and in detecting PCV. DESIGN: Prospective cohort study at a tertiary referral centre. PARTICIPANTS: Fifty consecutive patients with PCV or AMD. METHODS: Standardized multimodal imaging, including CFP, multicolour imaging, and fluorescein and indocyanine green angiography, were graded by a Central Reading Center using standardized grading protocols. MAIN OUTCOMES AND MEASURES: Sensitivity, specificity, positive and negative predictive values (PPV and NPV). RESULTS: Of 100 eyes, 44 had PCV, 33 had AMD, and 23 were normal. Multicolour imaging had higher specificity (73.9% vs 52.2%) and NPV (94% vs 85.7%) compared to CFP for detecting all types of AMD. For the detection of PCV, multicolour had higher sensitivity (86.4% vs 59.1%) and NPV (89.3% vs 74.3%). Polypoidal lesions were detected in 39 of 44 eyes (88.6%) using multicolour imaging, while the branching vascular network (BVN) was detected in 16 of 44 eyes (36.4%). Using BVN as a parameter, infrared imaging specificity and PPV for detecting PCV were 96.6% and 88.9%, respectively. CONCLUSIONS AND RELEVANCE: Multicolour imaging is superior to standard CFP in differentiating AMD and PCV from normal eyes, and in detecting features of PCV. Specific features seen on multicolour imaging can alert ophthalmologists to the likely presence of these diseases so that additional definitive investigations can be performed.

EVEREST study report 4: Fluorescein angiography features predictive of polypoidal choroidal vasculopathy.

IMPORTANCE: It is important to identify features of polypoidal choroidal vasculopathy (PCV) that differentiate it from typical neovascular age-related macular degeneration (nAMD) on various imaging modalities, including fluorescein angiography (FA). BACKGROUND: PCV was thought to be indistinguishable from nAMD using FA alone. In real-world practice, indocyanine-green angiography may often be unavailable or contraindicated. DESIGN: Analysis of FA images from a prospective, multicentre study. PARTICIPANTS: Study images of both PCV and nAMD patients from the EVEREST study. METHODS: FA features at baseline were independently graded by masked graders (fellowship-trained ophthalmologists) using standardized diagnostic algorithms. MAIN OUTCOME MEASURES: Predictive indicators (sensitivity, specificity, positive and negative predictive values) for PCV. RESULTS: Of the 95 patients screened, 61 had PCV. Of the 34 screening failures, 15 were diagnosed as nAMD. Hyperfluorescent nodules on FA were observed in 80% of patients with PCV vs 20% with nAMD (P < 0.001). Blocked fluorescence on FA, which corresponded to the presence of subretinal haemorrhage, occurred more frequently among patients with PCV vs nAMD (61.7% vs 13.3%, P = 0.001). Similarly, the leakage characteristic of occult choroidal neovascularization occurred more frequently among patients with PCV vs nAMD (95.0% vs 73.3%, P = 0.026). The positive predictive value for PCV was 94.1% for hyperfluorescent nodules, 94.9% for blocked fluorescence, 83.8% for occult choroidal neovascularization and 82.0% for pigment epithelial detachment. CONCLUSIONS AND RELEVANCE: This study demonstrated that certain FA features can be predictive of PCV and may be considered as an indication for retina specialists to perform indocyanine green angiography as confirmatory test.

Safety and complications of intravitreal injections performed in an Asian population in Singapore.

There has been a rapid rise in the use of intravitreal injections, such as anti-vascular endothelial growth factor (anti-VEGF) agents, performed over the past few years for the treatment of ocular neovascular diseases. This study aims to review the systemic and ocular adverse events among patients treated at a tertiary eye center over a period of 8 years. A retrospective review of all intravitreal injections of anti-VEGF performed over an 8-year period at a tertiary eye care center in Singapore was done. We report the frequency of systemic and ocular adverse events and compared it among the various anti-VEGF agents. A total of 14 001 intravitreal injections were performed on 2225 patients from January 1, 2007 to December 31, 2014, and this included 9992 bevacizumab (71.4 %), 3306 ranibizumab (23.6 %) and 703 aflibercept (5.0 %) injections. Systemic complications related to treatment were 26 (1.17 %) deaths (from any cause), of which 11 (0.49 %) were from fatal thromboembolic events, 7 (0.31 %) non-fatal thromboembolic events and two (0.09 %) serious non-ocular hemorrhage. Ocular complications included one (0.007 %) endophthalmitis, three (0.021 %) traumatic cataracts, and one (0.007 %) retinal detachment. Rates of death and thromboembolic events were similar among ranibizumab (lucentis), bevacizumab (avastin) and aflibercept (Eylea). The systemic and ocular complications associated with intravitreal injections among Asian patients at a tertiary eye center are relatively low and reflect the safety of the treatments.

Cost-effectiveness of a National Telemedicine Diabetic Retinopathy Screening Program in Singapore.

PURPOSE: To determine the incremental cost-effectiveness of a new telemedicine technician-based assessment relative to an existing model of family physician (FP)-based assessment of diabetic retinopathy (DR) in Singapore from the health system and societal perspectives. DESIGN: Model-based, cost-effectiveness analysis of the Singapore Integrated Diabetic Retinopathy Program (SiDRP). PARTICIPANTS: A hypothetical cohort of patients aged 55 years with type 2 diabetes previously not screened for DR. METHODS: The SiDRP is a new telemedicine-based DR screening program using trained technicians to assess retinal photographs. We compared the cost-effectiveness of SiDRP with the existing model in which FPs assess photographs. We developed a hybrid decision tree/Markov model to simulate the costs, effectiveness, and incremental cost-effectiveness ratio (ICER) of SiDRP relative to FP-based DR screening over a lifetime horizon. We estimated the costs from the health system and societal perspectives. Effectiveness was measured in terms of quality-adjusted life-years (QALYs). Result robustness was calculated using deterministic and probabilistic sensitivity analyses. MAIN OUTCOME MEASURES: The ICER. RESULTS: From the societal perspective that takes into account all costs and effects, the telemedicine-based DR screening model had significantly lower costs (total cost savings of S$173 per person) while generating similar QALYs compared with the physician-based model (i.e., 13.1 QALYs). From the health system perspective that includes only direct medical costs, the cost savings are S$144 per person. By extrapolating these data to approximately 170 000 patients with diabetes currently being screened yearly for DR in Singapore's primary care polyclinics, the present value of future cost savings associated with the telemedicine-based model is estimated to be S$29.4 million over a lifetime horizon. CONCLUSIONS: While generating similar health outcomes, the telemedicine-based DR screening using technicians in the primary care setting saves costs for Singapore compared with the FP model. Our data provide a strong economic rationale to expand the telemedicine-based DR screening program in Singapore and elsewhere.

EVEREST study report 3: diagnostic challenges of polypoidal choroidal vasculopathy. Lessons learnt from screening failures in the EVEREST study.

PURPOSE: To describe screening failures in the EVEREST study by examining the imaging characteristics that enabled differentiation of polypoidal choroidal vasculopathy (PCV) from cases that were subsequently diagnosed not to be PCV. METHODS: Post-hoc analysis of 34 patients with PCV reported as screening failures from EVEREST study. Standardised confocal scanning laser indocyanine green angiography (ICGA) images were graded by the Central Reading Centre to confirm PCV diagnosis based on the presence of early focal sub-retinal hyperfluorescence on ICGA and at least one of the following six diagnostic criteria: (1) nodular appearance of polyp(s) on stereoscopic examination, (2) hypofluorescent halo around nodule(s), (3) presence of a branching vascular network, (4) pulsation of polyp(s) on dynamic ICGA, (5) orange sub-retinal nodules on colour fundus photography, or (6) massive sub-macular haemorrhage (≥4 disc areas in size). Additional detailed image grading was performed with stereo-imaging and dynamic early-phase ICGA. RESULTS: Of the 95 screened PCV cases, 34 were excluded: (1) cases not suitable for recruitment as per the study protocol (n = 14), (2) equivocal lesions on ICGA characterised by small hyperfluorescent dots (n = 9), and (3) cases that were definitely not PCV (non-PCV, n = 11), identified by definitive diagnoses which included one case each of micro-aneurysm, retinal angiomatous proliferation, retino-choroidal anastomosis, small type-2 choroidal neovascularisation, retinal pigment epithelial (RPE) window defect and disciform scar; two cases of lesions where the choroidal vessel changed its course; and three cases of late-onset RPE staining. CONCLUSIONS: Standardised image grading techniques used in EVEREST study enabled effective differentiation of non-PCV from actual PCV.

MYOPIC RETINOSCHISIS IN ASIANS: Structural Features and Determinants of Visual Acuity and Prognostic Factors for Progression.

PURPOSE: To describe microstructural changes and schisis extent in eyes with myopic retinoschisis and to determine their influence on visual acuity at baseline and follow-up. METHODS: In this prospective observational study, 50 eyes of 38 patients with myopic retinoschisis were evaluated using spectral domain optical coherence tomography, and the patients were followed for at least 12 months. The presence of microstructural changes and the extent of retinoschisis at baseline on spectral domain optical coherence tomography, and the association between these parameters and the risk of visual acuity deterioration were analyzed. RESULTS: Median presenting visual acuity and central retinal thickness were 0.31 logMAR (≈20/40) and 395 µm, respectively. Twenty-six eyes (52%) had entire macular area retinoschisis. Common microstructural changes included photoreceptor detachment (24%), foveal ellipsoid zone (EZ) disruption (34%), partial-thickness macular hole (26%), and full-thickness macular hole (16%). Visual acuity was poorer in eyes with photoreceptor detachment, EZ disruption, full-thickness macular hole, and central retinal thickness >300 µm. Eyes with entire macular area retinoschisis had the poorest visual acuity and thickest central retinal thickness, and they were more likely to have photoreceptor detachment, EZ disruption, and retinal detachment. Over a mean follow-up of 31.7 ± 7.7 months, 14 eyes (28%) had worsening visual acuity of ≥2 lines. Ten of these 14 eyes had entire macular retinoschisis at baseline. CONCLUSION: Most eyes with myopic retinoschisis remain stable. However, eyes with extensive retinoschisis involving the entire macular area are more likely to progress and have microstructural abnormalities and poorer vision. Early surgery should be considered for these eyes.

Comparability of retinal thickness measurements using different scanning protocols on spectral-domain optical coherence tomography.

Retinal thickness measurements obtained using optical coherence tomography (OCT) play an essential role both in multi-center clinical trials and in normal clinical practice. Different scanning protocols are available on most OCT devices, and it is important to ascertain whether the retinal thickness measurements obtained from these are comparable. This study aimed to compare retinal thickness measurements between raster and radial scanning protocols using spectral-domain OCT (SD-OCT). In a prospective study, 32 healthy subjects were scanned sequentially using raster and radial protocols from a SD-OCT device. For both the raster and radial OCT scans, retinal thicknesses were measured manually subfoveally and at 12 other points at 0.5 mm intervals temporally and nasally on the horizontal OCT B-scan passing through the fovea. The retinal thickness measurements were compared using intraclass correlation (ICC) and Bland-Altman plots. Subfoveal retinal thickness was 227.0 µm when measured on the raster scan and 229.2 µm on the radial scan, with a mean difference of 2.2 µm (P = 0.141).The ICC for agreement was 0.889 (95 % confidence interval 0.818-0.933). Similar results were observed for retinal thickness measurements at all other points, with mean differences ranging from -3.37 to 2.59 µm, and ICC values ranging from 0.837 to 0.972. The retinal thickness measurements obtained by the raster and radial scans of the same SD-OCT device are comparable, with differences of less than 4 µm. This is of relevance when measurements made using different OCT scan protocols are compared.

Calculating the predicted retinal thickness from spectral domain and time domain optical coherence tomography - comparison of different methods.

PURPOSE: To compare the accuracy of different methods of calculating predicted central retinal thickness values in order to allow comparison between results of spectral-domain optical coherence tomography (SD-OCT) and time-domain OCT (TD-OCT) devices. METHODS: In a prospective cohort study, 100 consecutive healthy individuals without ocular disease underwent sequential scanning with SD-OCT (Spectralis OCT) and TD-OCT (Stratus OCT). A group of 60 eyes was used to generate the conversion equations, which were tested on the remaining 140 eyes. Four equations were used: 1. Mean difference between SD-OCT and TD-OCT; 2. Multiplying a ratio by the original retinal thickness; 3. Linear regression analysis using retinal thickness; and 4. Regression analysis using retinal thickness and spherical equivalent. All four methods were used to calculate predicted SD-OCT values from TD-OCT measurements, and vice versa. RESULTS: For all four equations, the predicted SD-OCT central retinal thickness values were similar to the actual SD-OCT, with mean difference ranging from 0.78 to 1.01 µm, and intraclass correlation coefficients >0.88. Both regression equations and mean difference showed greater accuracy, with variation between calculated and actual retinal thickness values ≤5 µm in 60% of eyes. In contrast, the ratio method was less accurate, with 15.8 % of eyes showing differences >15 µm. Similar results were found for predicted TD-OCT values. CONCLUSIONS: Several methods can be used to convert central retinal thickness values from SD-OCT to the predicted TD-OCT value, or vice versa, with high degrees of accuracy and reliability. These methods may allow comparison of OCT values from SD-OCT and TD-OCT devices in clinical trials and standard patient care.

Area of peripheral retinal nonperfusion and treatment response in branch and central retinal vein occlusion.

PURPOSE: To evaluate the extent of peripheral retinal nonperfusion in retinal vein occlusion and to determine its effect on the severity of macular edema and response to treatment. METHODS: This prospective clinic-based cohort study included 32 consecutive patients with retinal vein occlusion and refractory macular edema evaluated using spectral domain optical coherence tomography and wide-field fluorescein angiography. Areas of ischemia were calculated as a percentage of the total visible retina (ischemic index), which was evaluated when macular edema was present (foveal central subfield >300 µm) and when edema had resolved (foveal central subfield ≤ 300 µm). Ischemic index was the main outcome measure. RESULTS: The mean ischemic index at study enrollment was 14.8% and was larger when macular edema was present compared with when edema had resolved (14.8 vs. 10.3%, P < 0.001). Compared with those with less nonperfusion, patients with ischemic index >10% had thicker mean foveal central subfield on optical coherence tomography (520.8 vs. 424.5 µm, P = 0.029) and worse visual acuity (56.3 vs. 59 letters) with the presence of macular edema and experienced greater decrease in optical coherence tomography (296.1 vs. 165.3 µm, P = 0.019) and gain in visual acuity (12.4 vs. 0.9 letters, P = 0.036) in response to treatment. CONCLUSION: The area of peripheral retinal nonperfusion is variable in patients with retinal vein occlusion and affects its clinical course and response to treatment.

Peripheral autofluorescence and clinical findings in neovascular and non-neovascular age-related macular degeneration.

PURPOSE: To characterize peripheral fundus autofluorescence (FAF) abnormalities in patients with age-related macular degeneration (AMD), correlate these with clinical findings, and identify risk factors associated with these FAF abnormalities. DESIGN: Clinic-based, cross-sectional study. PARTICIPANTS: A total of 119 consecutive patients: 100 patients with AMD (200 eyes) and 19 patients without AMD (38 eyes). METHODS: In a prospective study performed at the Doheny Eye Institute, University of Southern California, widefield 200-degree FAF and color images were obtained by the Optos 200Tx Ultra-Widefield device (Optos, Dunfermline, Scotland) using a standardized imaging protocol. The FAF images were captured centered on the fovea, and additional images were captured after steering the field of view inferiorly and superiorly. All FAF and color images were graded independently by 2 masked ophthalmologists with respect to the presence, location, extent, and type of peripheral (defined as outside the central 30 degrees) FAF abnormality. MAIN OUTCOME MEASURES: Presence and type of peripheral FAF abnormalities. RESULTS: Peripheral FAF abnormalities were evident in 164 eyes (68.9%), with several distinct FAF patterns identified: granular (46.2%), mottled (34.0%), and nummular (18.1%). A 90% concordance of FAF patterns was observed between both eyes. Abnormal FAF occurred more frequently in neovascular compared with non-neovascular AMD or normal eyes (86% vs. 72.8% vs. 18.4%, respectively, P<0.001). Significant risk factors for peripheral FAF abnormalities were AMD type (neovascular AMD odds ratio [OR], 12.7 and non-neovascular AMD OR, 6.2 compared with normal eyes, P<0.001), older age (OR, 6.5; 95% confidence interval [CI], 2.4-17.8; P<0.001 for the oldest quartile compared with the youngest), and female sex (OR, 4.1; 95% CI, 1.9-8.9; P<0.001). Clinical features on color photography were detected in 174 eyes (73.1%): peripheral drusen (51.7%), retinal pigment epithelium (RPE) depigmentation (34.9%), RPE hyperpigmentation (branching reticular pigmentation) (22.7%), and atrophic patches (16.8%). There was a high correlation between specific FAF and clinical findings: granular FAF with peripheral drusen (P<0.001) and mottled FAF with RPE depigmentation (P<0.001). CONCLUSIONS: Several distinct patterns of peripheral FAF abnormalities were observed in 68.9% of patients, with AMD type, female sex, and age being independent risk factors. The peripheral FAF patterns correlate strongly with specific clinical features seen in eyes with AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Heat profiling of phacoemulsification tip using a thermal scanning camera.

An experimental study to measure the heat profile of the phacoemulsification (phaco) tip using standard continuous phaco and hyperpulse phaco with and without waveform power modulation in the Millennium Microsurgical System with Custom Control Software (CCS). The phaco tip was imaged in air using a thermal camera. The highest temperature was measured 15 s after application of phaco power. Continuous, hyperpulse and waveform power modulations of the Millennium Microsurgical System were used with different power settings (20, 50 and 100 %) and duty cycles (40, 60 and 90 %), with the irrigation turned on and off. Using continuous phaco with the irrigation on, the phaco tip temperature remains <28.0 °C. With irrigation off, the temperature is higher compared to irrigation on but still remains <45.0 °C. Comparing the temperatures for all three power modulations when irrigation is on, at each phaco power and duty cycle setting, the temperature of the phaco tip is highest with continuous phaco, followed by hyperpulse with rise time 1, then hyperpulse with rise time 2. When irrigation is off, the highest temperatures are recorded using the hyperpulse with rise time 2, followed by continuous phaco, then hyperpulse with rise time 1. Hyperpulse and waveform modulations reduce heat generation compared to the continuous mode when irrigation is turned on. Lower duty cycles and lower ultrasound power produce less heat at the phaco tip.

Generalized metabolic flux analysis framework provides mechanism-based predictions of ophthalmic complications in type 2 diabetes patients.

Chronic metabolic diseases arise from changes in metabolic fluxes through biomolecular pathways and gene networks accumulated over the lifetime of an individual. While clinical and biochemical profiles present just real-time snapshots of the patients' health, efficient computation models of the pathological disturbance of biomolecular processes are required to achieve individualized mechanistic insights into disease progression. Here, we describe the Generalized metabolic flux analysis (GMFA) for addressing this gap. Suitably grouping individual metabolites/fluxes into pools simplifies the analysis of the resulting more coarse-grain network. We also map non-metabolic clinical modalities onto the network with additional edges. Instead of using the time coordinate, the system status (metabolite concentrations and fluxes) is quantified as function of a generalized extent variable (a coordinate in the space of generalized metabolites) that represents the system's coordinate along its evolution path and evaluates the degree of change between any two states on that path. We applied GMFA to analyze Type 2 Diabetes Mellitus (T2DM) patients from two cohorts: EVAS (289 patients from Singapore) and NHANES (517) from the USA. Personalized systems biology models (digital twins) were constructed. We deduced disease dynamics from the individually parameterized metabolic network and predicted the evolution path of the metabolic health state. For each patient, we obtained an individual description of disease dynamics and predict an evolution path of the metabolic health state. Our predictive models achieve an ROC-AUC in the range 0.79-0.95 (sensitivity 80-92%, specificity 62-94%) in identifying phenotypes at the baseline and predicting future development of diabetic retinopathy and cataract progression among T2DM patients within 3 years from the baseline. The GMFA method is a step towards realizing the ultimate goal to develop practical predictive computational models for diagnostics based on systems biology. This tool has potential use in chronic disease management in medical practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13755-023-00218-x.