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Purpose Estimate effects of ranibizumab on diabetic retinopathy (DR) severity in US Hispanic and non-Hispanic white persons with center-involved diabetic macular edema (DME) causing vision impairment for whom ranibizumab treatment would be considered. Patients and methods This model simulated DR severity outcomes over 2 years in the better-seeing eye using US census, National Health and Nutrition Examination Survey, Wisconsin Epidemiologic Study of Diabetic Retinopathy, and Los Angeles Latino Eye Study data. Baseline DR severity estimated from Diabetic Retinopathy Clinical Research Network trial data. Changes in DR severity after 2 years, with/without monthly ranibizumab (0.3 or 0.5 mg), were estimated from Phase III clinical trial data (RIDE/RISE) using a 2-dimensional Monte Carlo simulation model. Number of patients over a 2-year period for whom 1) DR severity worsening was avoided, 2) DR severity improved, and 3) selected clinical events related to proliferative DR (PDR) occurred, was estimated. Results An estimated 37,274 US Hispanic and non-Hispanic white persons were projected to have DR with center-involved DME and be eligible for ranibizumab treatment. The number of persons with moderately severe non-proliferative DR (NPDR) or less severe DR at baseline who would worsen to PDR and experience a PDR complication over 2 years would be reduced from 437 with no ranibizumab to 19 with ranibizumab (95% reduction; 95% simulation interval [SI], 79-100%). The number of persons with severe NPDR or less severe DR at baseline who would be expected to improve by ≥2 DR severity levels over 2 years would increase from 1706 with no ranibizumab to 13,042 with ranibizumab (682% increase; 95% SI, 478-967%). Conclusion This model estimates that ranibizumab treatment in US Hispanic and non-Hispanic white patients with center-involved DME causing vision impairment would potentially reduce the number of patients with worsening DR and potentially increase the number with DR improvements.

BACKGROUND Clinical trials for antibiotics designed to treat hospital-acquired and ventilator-associated bacterial pneumonias (HABP/VABP) are hampered by making these diagnoses in a way that is acceptable to the United States Food and Drug Administration and consistent with standards of care. We examined laboratory and clinical features that might improve pediatric HABP/VABP trial efficiency by identifying risk factors predisposing children to HABP/VABP and describing the epidemiology of pediatric HABP/VABP. METHODS We prospectively reviewed the electronic medical records of patients

IMPORTANCE: Anomaly detectors could be pursued for retinal diagnoses based on artificial intelligence systems that may not have access to training examples for all retinal diseases in all phenotypic presentations. Possible applications could include screening of population for any retinal disease rather than a specific disease such as diabetic retinopathy, detection of novel retinal diseases or novel presentations of common retinal diseases, and detection of rare diseases with little or no data available for training. OBJECTIVE: To study the application of anomaly detection to retinal diseases. DESIGN, SETTING, AND PARTICIPANTS: High-resolution retinal images from the publicly available EyePACS data set with fundus images with a corresponding label ranging from 0 to 4 for representing different severities of diabetic retinopathy. Sixteen variants of anomaly detectors were designed. For evaluation, a surrogate problem was constructed, using diabetic retinopathy images, in which only retinas with nonreferable diabetic retinopathy, ie, no diabetic macular edema, and no diabetic retinopathy or mild to moderate nonproliferative diabetic retinopathy were used for training an artificial intelligence system, but both nonreferable and referable diabetic retinopathy (including diabetic macular edema or proliferative diabetic retinopathy) were used to test the system for detecting retinal disease. MAIN OUTCOMES AND MEASURES: Anomaly detectors were evaluated by commonly accepted performance metrics, including area under the receiver operating characteristic curve, F1 score, and accuracy. RESULTS: A total of 88 692 high-resolution retinal images of 44 346 individuals with varying severity of diabetic retinopathy were analyzed. The best performing across all anomaly detectors had an area under the receiver operating characteristic of 0.808 (95% CI, 0.789-0.827) and was obtained using an embedding method that involved a self-supervised network. CONCLUSIONS AND RELEVANCE: This study suggests when abnormal (diseased) data, ie, referable diabetic retinopathy in this study, were not available for training of retinal diagnostic systems wherein only nonreferable diabetic retinopathy was used for training, anomaly detection techniques were useful in identifying images with and without referable diabetic retinopathy. This suggests that anomaly detectors may be used to detect retinal diseases in more generalized settings and potentially could play a role in screening of populations for retinal diseases or identifying novel diseases and phenotyping or detecting unusual presentations of common retinal diseases.

Determine correlation between change in central subfield thickness (CST) and change in best-corrected visual acuity (BCVA) in neovascular age-related macular degeneration receiving anti-vascular endothelial growth factor agents.A post hoc analysis of VIEW 1 and 2 randomized clinical trials.This analysis included participants randomized to ranibizumab 0.5 mg every 4 weeks (Rq4), intravitreal aflibercept injection 2 mg every 4 weeks (2q4), and intravitreal aflibercept injection 2 mg every 8 weeks after 3 monthly doses (2q8) to week 52, followed by capped as-needed (at least every 12 weeks) dosing to week 96. Relationship between changes in CST and BCVA was determined using Pearson correlation coefficient.Of 1815 eyes, 595 were assigned to the Rq4, 613 to 2q4, and 607 to 2q8 arms. Correlations (95% confidence intervals [CI]) at weeks 12, 52, and 96 were -0.08 (95% CI, -0.17 to 0.00), -0.05 (95% CI, -0.14 to 0.04), and -0.15 (95% CI, -0.24 to -0.06) for Rq4; -0.13 (95% CI, -0.21 to -0.04), -0.06 (95% CI, -0.14 to 0.03) and -0.04 (95% CI, -0.13 to 0.05) for 2q4, and -0.04 (95% CI, -0.12 to 0.05), -0.01 (95% CI, -0.09 to 0.08), and -0.01 (95% CI, -0.10 to 0.09) for 2q8. Linear regression analysis adjusted for relevant baseline factors showed CST changes accounted for 11% of BCVA changes. Every 100 μm decrease in CST was associated with a 0.3 letter decrease (P = .25) at week 52 and a 0.14 letter decrease (P = .69) at week 96.Weak or no correlation was found between changes in CST and BCVA with either agent or regimen, suggesting changes in CST should not be used as a surrogate for visual acuity outcomes in neovascular age-related macular degeneration.

IMPORTANCE: Enzyme-inducing antiseizure medications (eiASMs) have been hypothesized to be associated with long-term risks of cardiovascular disease. OBJECTIVE: To quantify and model the putative hazard of cardiovascular disease secondary to eiASM use. DESIGN, SETTING, AND PARTICIPANTS: This cohort study covered January 1990 to March 2019 (median [IQR] follow-up, 9 [4-15], years). The study linked primary care and hospital electronic health records at National Health Service hospitals in England. People aged 18 years or older diagnosed as having epilepsy after January 1, 1990, were included. All eligible patients were included with a waiver of consent. No patients were approached who withdrew consent. Analysis began January 2021 and ended August 2021. EXPOSURES: Receipt of 4 consecutive eiASMs (carbamazepine, eslicarbazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, rufinamide, or topiramate) following an adult-onset (age ≥18 years) epilepsy diagnosis or repeated exposure in a weighted cumulative exposure model. MAIN OUTCOMES AND MEASURES: Three cohorts were isolated, 1 of which comprised all adults meeting a case definition for epilepsy diagnosed after 1990, 1 comprised incident cases diagnosed after 1998 (hospital linkage date), and 1 was limited to adults diagnosed with epilepsy at 65 years or older. Outcome was incident cardiovascular disease (ischemic heart disease or ischemic or hemorrhagic stroke). Hazard of incident cardiovascular disease was evaluated using adjusted propensity-matched survival analyses and weighted cumulative exposure models. RESULTS: Of 10 916 166 adults, 50 888 (0.6%) were identified as having period-prevalent cases (median [IQR] age, 32 [19-50] years; 16 584 [53%] female), of whom 31 479 (62%) were diagnosed on or after 1990 and were free of cardiovascular disease at baseline. In a propensity-matched Cox proportional hazards model adjusted for age, sex, baseline socioeconomic status, and cardiovascular risk factors, the hazard ratio for incident cardiovascular disease was 1.21 (95% CI, 1.06-1.39) for those receiving eiASMs. The absolute difference in cumulative hazard diverges by more than 1% and greater after 10 years. For those with persistent exposure beyond 4 prescriptions, the median hazard ratio increased from amedian (IQR) of 1.54 (1.28-1.79) when taking a relative defined daily dose of an eiASM of 1 to 2.38 (1.52-3.56) with a relative defined daily dose of 2 throughout a maximum of 25 years’ follow-up compared with those not receiving an eiASM. The hazard was elevated but attenuated when restricting analyses to incident cases or those diagnosed when older than 65 years. CONCLUSIONS AND RELEVANCE: The hazard of incident cardiovascular disease is higher in those receiving eiASMs. The association is dose dependent and the absolute difference in hazard seems to reach clinical significance by approximately 10 years from first exposure.

According to the National Research Council, the ability to collaboratively solve problems is of the utmost importance in scientific careers, yet students are not exposed to learning experiences that promote such expertise. Recent studies have found that interdependent roles used within collaborative mobile games are an effective way to scaffold collaborative problem solving. School Scene Investigators: The Case of the Mystery Powder, a collaborative mobile game, incorporated interdependent roles in order to foster collaborative problem solving and promote scientific practice. Using epistemic network analysis (ENA), this study examined the conversational discourse of game teams to determine what connections exist between communication responses, language style, and scientific practice. Data included audio transcripts of three teams that played through the game. Transcripts were qualitatively coded for five types of scientific practice aligned to the National Research Council framework for K-12 science education, three types of communication responses (accept/discuss/reject), and an emergent language style (communal). ENA revealed that students developed scientific practices during gameplay. ENA also identified engaged communication responses and communal language style as two types of collaborative discourse used within School Scene Investigators: The Case of the Mystery Powder that fostered key linkages to effective data analysis and interpretation.

Purpose To investigate the natural history and genetic associations of drusenoid pigment epithelial detachment (DPED) associated with age-related macular degeneration (AMD). Design Retrospective analysis of a prospective cohort study. Participants Of the 4203 Age-Related Eye Disease Study 2 (AREDS2) participants, 391 eyes (325 participants) had DPED without late AMD at the time of DPED detection. Genetic analyses included 120 white AREDS2 participants and 145 Age-Related Eye Disease Study (AREDS) participants with DPED. Methods Baseline and annual stereoscopic fundus photographs were graded centrally to detect DPED, a well-defined yellow elevated mound of confluent drusen ≥433 μm in diameter, and to evaluate progression rates to late AMD: geographic atrophy (GA) and neovascular (NV)-AMD. Five single nucleotide polymorphisms (CFH [rs10611670], C3 [rs2230199], CFI [rs10033900], C2/CFB [rs114254831], ARMS2 [rs10490924]) and genetic risk score (GRS) group were investigated for association with DPED development. Kaplan–Meier analyses and multivariable proportional hazard regressions were performed. Main Outcome Measures Progression rates to late AMD and decrease of ≥3 lines in visual acuity (VA) from the time of DPED detection; association of rate of DPED development with genotype. Results Mean (standard deviation [SD]) follow-up time from DPED detection was 4.7 (0.9) years. DPED was associated with increased risk of progression to late AMD (hazard ratio [HR], 2.36; 95% confidence interval [CI], 1.98–2.82; P Conclusions This study replicates the results of previous natural history studies of eyes with DPED including the high rates of progression to late AMD and vision loss (regardless of progression to late AMD). The genetic associations are consistent with genes associated with AMD progression.

PURPOSE Compare changes in retinal nerve fiber layer (RNFL) thickness between eyes assigned to intravitreous ranibizumab or panretinal photocoagulation and assess correlations between changes in RNFL and visual field sensitivity and central subfield thickness. METHODS Eyes with proliferative diabetic retinopathy were randomly assigned to ranibizumab or panretinal photocoagulation. Baseline and annual follow-up spectral domain optical coherence tomography RNFL imaging, optical coherence tomography macular imaging, and automated static perimetry (Humphrey visual field 60-4 algorithm) were performed. RESULTS One hundred forty-six eyes from 120 participants were analyzed. At 2 years, for the ranibizumab (N = 74) and panretinal photocoagulation (N = 66) groups, respectively, mean change in average RNFL thickness was -10.9 ± 11.7 μm and -4.3 ± 11.6 μm (difference, -4.9 μm; 95% confidence interval [-7.2 μm to -2.6 μm]; P < 0.001); the correlation between change in RNFL thickness and 60-4 Humphrey visual field mean deviation was -0.27 (P = 0.07) and +0.33 (P = 0.035); the correlation between change in RNFL thickness and central subfield thickness was +0.63 (P < 0.001) and +0.34 (P = 0.005), respectively. CONCLUSION At 2 years, eyes treated with ranibizumab had greater RNFL thinning than eyes treated with panretinal photocoagulation. Correlations between changes in RNFL thickness, visual field, and central subfield thickness suggest that the decrease in RNFL thickness with ranibizumab is likely due to decreased edema rather than loss of axons.

Background/AimsTo better understand the pattern of degeneration progression in cases with choroideremia.MethodsA cohort of genotypically confirmed choroideremia cases who underwent optical coherence tomography (OCT) and fundus autofluorescence (FAF) imaging was studied. Using HEYEX review software, the foveal centre was marked on FAF images under guidance of corresponding OCT images, followed by application of an ETDRS grid. The boundaries of preserved autofluorescence (AF) were manually segmented in each individual ETDRS subfield. The regional distribution of preserved AF was assessed by comparing its area among the various subfields.ResultsA total of 168 eyes from 84 choroideremia cases were enrolled. There was a statistically significant difference in the amount of preserved AF area between inner subfields as determined by one-way analysis of variance (F (3,668)=9.997, pConclusionThe asymmetric spatial distribution of preserved AF in choroideremia (corresponding to the stellate shaped nature of these regions) suggests that the progression of degeneration has directional preference.

To investigate the potential glaucomatous changes caused by scleral cross-linking (CXL) in a guinea pig form-deprivation (FD) myopia model.Eighty 4-week-old tricolor guinea pigs were divided into four groups: FD only, genipin CXL only, FD plus CXL, and control. Refractive error, axial length (AL), intraocular pressure (IOP), and structural and vasculature optic disc changes in optical coherence tomography (OCT) and OCT angiography (OCTA) were measured at baseline and day 21. CXL efficacy was evaluated by scleral rigidity Young's modulus values. Histological and molecular changes in the anterior chamber angle, retina, and sclera were assessed.Baseline parameters were similar among groups (P0.05). The FD plus CXL group at day 21 had the least increase of AL (0.14 ± 0.08 mm) and highest IOP elevation (31.5 ± 3.6 mmHg) compared with the FD-only group (AL: 0.68 ± 0.17 mm; IOP: 22.2 ± 2.6 mmHg) and the control group (AL: 0.24 ± 0.09 mm; IOP: 17.4 ± 1.8 mmHg) (all P0.001). OCT and OCTA parameters of the optic disc in the FD plus CXL group at day 21 showed glaucomatous changes and decreased blood flow signals. Sclera rigidity increased in the CXL and FD plus CXL groups. Advanced glycation end products deposited extensively in the retina, choroid, and sclera of FD plus CXL eyes.CXL causes increased IOP and subsequent optic disc, anterior segment, and scleral changes while inhibiting myopic progression and axial elongation in FD guinea pig eyes. Therefore, applying CXL to control myopia raises safety concerns.

Purpose To analyze the prevalence, incidence, and clinical characteristics of eyes with geographic atrophy (GA) in age-related macular degeneration (AMD), including clinical and genetic factors affecting enlargement. Design Prospective cohort study within a controlled clinical trial. Participants Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50–85 years. Methods Baseline and annual stereoscopic color fundus photographs were evaluated for GA presence and area. Analyses included GA prevalence and incidence rates, Kaplan-Meier rates, mixed-model regression, and multivariable analysis of the square root of GA, area adjusted for covariates, including clinical/imaging characteristics and genotype. Main Outcome Measures (1) Presence or development of GA; (2) change in the square root of GA area over time. Results At baseline, 517 eyes (6.2%) of 411 participants (9.8%) had pre-existing GA (without neovascular AMD), with the following characteristics: 33% central, 67% noncentral; and the following configurations: 36% small, 26% solid/unifocal, 24% multifocal, 9% horseshoe/ring, and 6% indeterminate. Of the remaining 6530 eyes at risk, 1099 eyes (17.3%) of 883 participants developed incident GA without prior neovascular disease during mean follow-up of 4.4 years. The Kaplan-Meier rate of incident GA was 19% of eyes at 5 years. In eyes with incident GA, 4-year risk of subsequent neovascular AMD was 29%. In eyes with incident noncentral GA, 4-year risk of central involvement was 57%. GA enlargement rate (following square root transformation) was similar in eyes with pre-existing GA (0.29 mm/year; 95% confidence interval 0.27–0.30) and incident GA (0.28 mm/year; 0.27–0.30). In the combined group, GA enlargement was significantly faster with noncentrality, multifocality, intermediate baseline size, and bilateral GA (P Conclusions Analyses of AREDS2 data on natural history of GA provide representative data on GA evolution and enlargement. GA enlargement, which was influenced by lesion features, was relentless, resulting in rapid central vision loss. The genetic variants associated with faster enlargement were partially distinct from those associated with risk of incident GA. These findings are relevant to further investigations of GA pathogenesis and clinical trial planning.

Intravenous (IV) minocycline is increasingly used to treat infections caused by multi-drug resistant (MDR)-Acinetobacter baumannii Despite being approved nearly 50 years ago, published information on its pharmacokinetic (PK) prolife is limited. This multi-center study examined the PK and probability of pharmacokinetic-pharmacodynamic (PK-PD) target attainment profile of IV minocycline in critically ill patients, with suspected or documented infection with Gram-negative bacteria. The PK study population included 55 patients who received a single 200 mg IV dose of minocycline. Plasma PK samples were collected pre-dose and 1, 4, 12, 24, 36, and 48 hours after initiation of minocycline. Total and unbound minocycline concentrations were determined at each timepoint. Probabilities of achieving the PK-PD targets associated with stasis and 1-log killing (fAUC:MIC of 12 and 18, respectively) were evaluated. A two-compartment population PK model with zero-order IV input and first-order elimination, which estimated a constant fraction unbound (fub) for minocycline, best characterized the total and unbound plasma minocycline concentration-time data. The only two covariates retained in the final PK model were body surface area [associated with central volume of distribution] and albumin (associated with fub). In the PK-PD target attainment analyses, minocycline 200 mg IV Q12H was predicted to result in a suboptimal PK-PD profile for patients with A. baumannii infections with MIC values ≥ 1 mg/L. These findings cast uncertainty on the appropriateness of the current minocycline FDA susceptibility breakpoints and suggest that clinicians should strongly consider only combination antibiotic therapy with IV minocycline for all patients with serious Acinetobacter sp infections.

In this chapter, we focus on a series of collaborations between clinicians from the School of Medicine and computer scientists from the Applied Physics Lab at the Johns Hopkins University. The described studies utilized deep learning (DL) and focused on analysis of color fundus photographs (CFP) of patients with age-related macular degeneration (AMD), the leading cause of central vision loss in persons over age 50 in the United States [1] and around the world. The dataset used for training and testing was derived from the Age-Related Eye Disease Studies (AREDS) [2], a longitudinal cohort study funded by the National Eye Institute with over 4500 participants and roughly 130,000 CFPs taken with a 30 degree camera. The ground truth of the deep learning systems (DLS) was based on the annotations (gradings) by trained graders at the University of Wisconsin Fundus Photograph Reading Center, which is the designated reading center for the AREDS.

In this chapter, the authors report on a mobile augmented reality game designed to support serious science learning in a playful, collaborative way. School Scene Investigators: The Case of the Mystery Power immersed eighth grade students in a fictional crime scene investigation at their school. Game-based learning was compared to business-as-usual. In the post-hoc analyses, the authors investigated how individual level factors affected learning. First, girls and boys both learned more during the game, yet boys seemed to experience a slightly bigger impact from the treatment. Second, students from both teachers learned more during gameplay; however, the game seemed to mitigate the novice teacher's inexperience resulting in a teacher effect. Lastly, there is some evidence that treatment varies by prior knowledge; students with lower prior knowledge may have benefited more from the game. This study demonstrates that the non-traditional practice of mobile augmented reality gaming promotes more effective learning than business-as-usual.

Purpose To understand timing of complete polypoidal regression on indocyanine green angiography (ICGA) after aflibercept injections for polypoidal choroidal vasculopathy (PCV). Design Multicenter prospective study. Participants Adults with treatment-naive PCV. Methods After institutional review board approval, participants were enrolled and followed up for 1 year, from Apr 1, 2016, through Dec 30, 2018, at 2 university-based centers in Thailand. Diagnosis of PCV was based on the Efficacy and Safety of Verteporfin Photodynamic Therapy in Combination with Ranibizumab or Alone versus Ranibizumab Monotherapy in Patients with Symptomatic Macular Polypoidal Choroidal Vasculopathy criteria. Eligible eyes received fixed-dose aflibercept injections (3 monthly then every 8 weeks), or monthly if fluid persisted on OCT. Photodynamic therapy (PDT) was administered when fluid persisted despite 6 consecutive injections. Indocyanine green angiography was performed at baseline and then every 8 weeks. The 25-item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) was administered at baseline, 6 months, and 1 year. Two retina specialists reviewed posttreatment ICGA, categorized into: complete regression (complete disappearance of polypoidal lesions), partial regression (reduced in size or number), or no regression. Disagreements were resolved through open adjudication. Main Outcome Measures Timing of complete regression over 1 year. Results Final analysis included 40 eyes (39 participants; 100% Thai, 59% women; mean age±standard deviation, 64 ± 8.3 years). At baseline, 90% had 5 or more polypoidal lesions. Ninety-five percent received aflibercept monotherapy, and 5% received rescue PDT per protocol. Polypoidal statuses at 1 year were 55% complete, 40% partial, and 5% no regression. Cumulative rates of complete regression at 2, 4, 6, and 12 months were 28%, 33%, 43%, and 55%. Of 22 eyes with complete regression at 1 year, complete regression was identified first at 2, 4, 6, 8, 10, 12 months in 50%, 9%, 18%, 5%, 9%, and 9%, respectively. Cumulative rates of complete regression among these eyes at 2, 6, and 12 months were 50%, 77%, and 100%, respectively. Median duration of complete regression was 3 months (interquartile range, 2–6 months). Median visual acuity improved from 20/125 (Snellen equivalent) to 20/50; median NEI VFQ-25 scores improved from 80 to 93 from baseline to 1 year. Conclusions Complete polypoidal regression could occur as early as 2 months after aflibercept injections. Most PCV eyes with complete polypoidal regression at 1 year already showed complete regression within the first 6 months. These findings support consideration of aflibercept for PCV to achieve both anatomic and visual outcomes.

β-Glucans are of significant interest due to their potent antitumor and immunomodulatory activities. Nevertheless, the difficulty in purification, structural heterogenicity, and limited solubility impede the development of structure-property relationships and translation to therapeutic applications. Here, we report the synthesis of a new class of (1→6)-β-glucose-branched poly-amido-saccharides (PASs) as β-glucan mimetics by ring-opening polymerization of a gentiobiose-based disaccharide β-lactam and its copolymerization with a glucose-based β-lactam, followed by post-polymerization deprotection. The molecular weight (Mn) and frequency of branching (FB) of PASs is readily tuned by adjusting monomer-to-initiator ratio and mole fraction of gentiobiose-lactam in copolymerization. Branched PASs stimulate mouse macrophages, and enhance production of pro-inflammatory cytokines in a FB-, dose-, and Mn-dependent manner. The stimulation proceeds via the activation of NF-κB/AP-1 pathway in a Dectin-1-dependent manner, similar to natural β-glucans. The lead PAS significantly polarizes primary human macrophages towards M1 phenotype compared to other β-glucans such as lentinan, laminarin, and curdlan.

During January 1, 2020-May 18, 2020, approximately 1.3 million cases of coronavirus disease 2019 (COVID-19) and 83,000 COVID-19-associated deaths were reported in the United States (1). Understanding the demographic and clinical characteristics of decedents could inform medical and public health interventions focused on preventing COVID-19-associated mortality. This report describes decedents with laboratory-confirmed infection with SARS-CoV-2, the virus that causes COVID-19, using data from 1) the standardized CDC case-report form (case-based surveillance) (https://www.cdc.gov/coronavirus/2019-ncov/php/reporting-pui.html) and 2) supplementary data (supplemental surveillance), such as underlying medical conditions and location of death, obtained through collaboration between CDC and 16 public health jurisdictions (15 states and New York City).

IMPORTANCE: Among eyes with center-involved diabetic macular edema (CI-DME) and good visual acuity (VA), randomized clinical trial results showed no difference in VA loss between initial observation plus aflibercept only if VA decreased, initial focal/grid laser plus aflibercept only if VA decreased, or prompt aflibercept. Understanding the initial observation approach is relevant to patient management. OBJECTIVE: To assess the DRCR Retina Network protocol-defined approach and outcomes of initial observation with aflibercept only if VA worsened. DESIGN, SETTING, AND PARTICIPANTS: This was a post hoc secondary analyses of a randomized clinical trial of the DRCR Retina Network Protocol V that included 91 US and Canadian sites from November 2013 to September 2018. Participants were adults (n = 236) with type 1 or 2 diabetes, 1 study eye with CI-DME, and VA letter score at least 79 (Snellen equivalent, 20/25 or better) assigned to initial observation. Data were analyzed from March 2019 to November 2019. INTERVENTIONS: Initial observation and follow-up with aflibercept only for VA loss of at least 10 letters from baseline at 1 visit or 5 to 9 letters at 2 consecutive visits. Follow-up occurred at 8 weeks and then every 16 weeks unless VA or optical coherence tomography central subfield thickness worsened. MAIN OUTCOMES AND MEASURES: Whether individuals received aflibercept. RESULTS: Among 236 eyes in 236 individuals (149 [63%] male; median age, 60 years [interquartile range, 53-67 years]) randomly assigned to initial observation, 80 (34%) were treated with aflibercept during 2 years of follow-up. At 2 years, the median VA letter score was 86.0 (interquartile range, 89.0-81.0; median Snellen equivalent, 20/20 [20/16-20/25]). Receipt of aflibercept was more likely in eyes with baseline central subfield thickness at least 300 μm (Zeiss-Stratus equivalent) vs less than 300 μm (45% vs 26%; hazard ratio [HR], 1.98 [95% CI, 1.26-3.13], continuous P = .005), moderately severe nonproliferative diabetic retinopathy (Early Treatment Diabetic Retinopathy Study retinopathy severity level 47) and above vs moderate nonproliferative diabetic retinopathy (retinopathy severity level 43) and below (51% vs 27%; HR, 2.22 [95% CI, 1.42-3.47], ordinal P

Importance Preservation of peripheral visual field (VF) is considered an advantage for anti–vascular endothelial growth factor agents compared with panretinal photocoagulation (PRP) for treatment of proliferative diabetic retinopathy. Long-term data on VF are important when considering either treatment approach. Objective To further evaluate changes in VF throughout 5 years among eyes enrolled in the Protocol S clinical trial, conducted by the DRCR Retina Network. Design, Setting, and Participants Post hoc analyses of an ancillary study within a multicenter (55 US sites) randomized clinical trial. Individuals with eyes with proliferative diabetic retinopathy enrolled in Protocol S were included. Data were collected from February 2012 to February 2018. Analysis began in June 2018. Interventions Panretinal photocoagulation or intravitreous injections of 0.5-mg ranibizumab. Diabetic macular edema, whenever present, was treated with ranibizumab in both groups. Panretinal photocoagulation could be administered to eyes in the ranibizumab group when failure or futility criteria were met. Main Outcomes and Measures Mean change in total point score on VF testing with the Humphrey Field Analyzer 30-2 and 60-4 test patterns. Results Of 394 eyes enrolled in Protocol S, 234 (59.4%) were targeted for this ancillary study. Of these, 167 (71.4%) had VF meeting acceptable quality criteria at baseline (median [interquartile range] age, 50 [43-58] years; 90 men [53.9%]). At 5 years, 79 (33.8%) had results available. The mean (SD) change in total point score in the PRP and ranibizumab groups was −305 (521) dB and −36 (486) dB at 1 year, respectively, increasing to −527 (635) dB and −330 (645) dB at 5 years, respectively (P = .04). After censoring VF results after PRP treatments in the ranibizumab group, the 5-year mean change in total point score was −201 (442) dB. In a longitudinal regression analysis of change in total point score including both treatment groups, laser treatment was associated with a mean point decrease of 208 (95% CI, 112-304) dB for the initial PRP session, 77 (95% CI, 21-132) dB for additional PRP sessions, and 325 (95% CI, 211-439) dB for endolaser. No association was found between change in point score and the number of ranibizumab injections during the previous year (−9 per injection [95% CI, −22 to 3]). Conclusions and Relevance The limited data available from Protocol S suggest that there are factors besides PRP associated with VF loss in eyes treated for proliferative diabetic retinopathy. Further clinical research is warranted to clarify the finding. Trial Registration ClinicalTrials.gov identifier:NCT01489189

Background/Aims: In clinical trials, participant retention is critical to reduce bias and maintain statistical power for hypothesis testing. Within a multi-center clinical trial of diabetic retinopathy, we investigated whether regular phone calls to participants from the coordinating center improved long-term participant retention. Methods: Among 305 adults in the Diabetic Retinopathy Clinical Research Retina Network Protocol S randomized trial, 152 participants were randomly assigned to receive phone calls at baseline, 6 months, and annually through 3 years (annual contact group) while 153 participants were assigned to receive a phone call at baseline only (baseline contact group). All participants could be contacted if visits were missed. The main outcomes were visit completion, excluding deaths, at 2 years (the primary outcome time point) and at 5 years (the final time point). Results: At baseline, 77% (117 of 152) of participants in the annual contact group and 76% (116 of 153) in the baseline contact group were successfully contacted. Among participants in the annual contact group active at each annual visit (i.e. not dropped from the study or deceased), 85% (125 of 147), 79% (108 of 136), and 88% (110 of 125) were contacted successfully by telephone around the time of the 1-, 2-, and 3-year visits, respectively. In the annual and baseline contact groups, completion rates for the 2-year primary outcome visit were 88% (129 of 147) versus 87% (125 of 144), respectively, with a risk ratio of 1.01 (95% confidence interval: 0.93–1.10, p = .81). At 5 years, the final study visit, participant completion rates were 67% (96 of 144) versus 66% (88 of 133) with a risk ratio of 1.01 (95% confidence interval = 0.85–1.19, p = .93). At 2 years, the completion rate of participants successfully contacted at baseline was 89% (202 of 226) versus 80% (52 of 65) among those not contacted successfully (risk ratio = 1.12, 95% confidence interval = 0.98–1.27, p = .09); at 5 years, the completion percentages by baseline contact success were 69% (148 of 213) versus 56% (36 of 64; risk ratio = 1.24, 95% confidence interval = 0.98–1.56, p = .08). Conclusion: Regular phone calls from the coordinating center to participants during follow-up in this randomized clinical trial did not improve long-term participant retention.

To describe applicant characteristics and outcomes associated with the ophthalmology fellowship match.Retrospective case-control study.This study took place in San Francisco and matched data for ophthalmology fellowship applicants in the USA. The study population was registrants for the 2010-2017 ophthalmology fellowship match cycles. The match rate took place during the 8-year study period. Applicant characteristics were stratified by match status and factors associated with matching to ophthalmology fellowship positions.Between 2010 and 2017, most applicants (2,558/3,471; 73.7%) were matched into ophthalmology fellowship programs. No difference over time in the proportion of applicants that matched for fellowship was identified (P = .41). On average, ophthalmology residents who were matched into fellowships had higher step 1 (difference: 9; 99% confidence interval [CI]: 6.8-10.9; P.001), step 2 (difference: 9.5; 99% CI: 7-12; P.001), and step 3 (difference: 7.4; 99% CI: 5-9.7; P.001) scores than those who did not match. Applicants who matched also had a greater number of application distributions (difference: 9.6; 99% CI: 7.9-11.2; P.001), and ranked programs on the match list (difference: 6.2; 99% CI: 5.8-6.7; P.001). Among applicants who matched, 15% matched at the same institute, 29% matched in the same state, and 45% matched in the same region. On multivariable analysis, factors associated with an increased likelihood of matching into an ophthalmology fellowship program included graduates from the US versus graduates from non-US residency programs (odds ratio [OR]: 2.09; 99% CI: 1.27-3.44; P.001), increasing percentage of applications ranked (number of ranked programs and/or number of applications distributed) (OR: 1.02; 99% CI: 1.02-1.03; P.001) as well as having ranked more programs (OR: 1.24; 99% CI: 1.17-1.31; P.001). Medical graduate status outside of the US (OR: 0.58; 99% CI: 0.36-0.93; P.001) was associated with decreased odds of matching for fellowship.From 2010 to 2017, approximately three-quarters of residents applying for an ophthalmology fellowship position matched. Factors associated with increased likelihood of matching included the applicant's graduating from a U.S. residency, graduating from a U.S. medical school, ranking more programs, and having a higher percentage of applications ranked (number of programs ranked by applicant and/or number of applications distributed). The information gained from this study may help applicants as they consider applying to fellowship programs.

We report an unusual case of Aeromonas hydrophilia septicemia in a nonmobile diabetic patient secondary to contaminated well water used for bathing with a portal of entry through chronic forefoot and heel ulcers. To date, there are no documented cases similar to this patient's presentation. Aeromonas hydrophilia is commonly distributed among aquatic environments and tends to be found during warmer months. It is a rare cause of disease but can be life threatening and deadly, as in our case, in immunocompromised individuals. As podiatric physicians, we must remain diligent and have a high index of suspicion to identify patients at risk for this rare but serious infection and administer treatment aggressively to limit morbidity and mortality.

Purpose Estimate effects of ranibizumab on diabetic retinopathy (DR) severity in US Hispanic and non-Hispanic white persons with center-involved diabetic macular edema (DME) causing vision impairment for whom ranibizumab treatment would be considered. Patients and Methods This model simulated DR severity outcomes over 2 years in the better-seeing eye using US census, National Health and Nutrition Examination Survey, Wisconsin Epidemiologic Study of Diabetic Retinopathy, and Los Angeles Latino Eye Study data. Baseline DR severity estimated from Diabetic Retinopathy Clinical Research Network trial data. Changes in DR severity after 2 years, with/without monthly ranibizumab (0.3 or 0.5 mg), were estimated from Phase III clinical trial data (RIDE/RISE) using a 2-dimensional Monte Carlo simulation model. Number of patients over a 2-year period for whom 1) DR severity worsening was avoided, 2) DR severity improved, and 3) selected clinical events related to proliferative DR (PDR) occurred, was estimated. Results An estimated 37,274 US Hispanic and non-Hispanic white persons were projected to have DR with center-involved DME and be eligible for ranibizumab treatment. The number of persons with moderately severe non-proliferative DR (NPDR) or less severe DR at baseline who would worsen to PDR and experience a PDR complication over 2 years would be reduced from 437 with no ranibizumab to 19 with ranibizumab (95% reduction; 95% simulation interval [SI], 79–100%). The number of persons with severe NPDR or less severe DR at baseline who would be expected to improve by ≥2 DR severity levels over 2 years would increase from 1706 with no ranibizumab to 13,042 with ranibizumab (682% increase; 95% SI, 478–967%). Conclusion This model estimates that ranibizumab treatment in US Hispanic and non-Hispanic white patients with center-involved DME causing vision impairment would potentially reduce the number of patients with worsening DR and potentially increase the number with DR improvements.

PURPOSE: Assess systemic vascular endothelial growth factor-A (VEGF) levels after treatment with intravitreous aflibercept, bevacizumab or ranibizumab. DESIGN: Comparative-effectiveness trial with participants randomly assigned to 2-mg aflibercept, 1.25-mg bevacizumab, or 0.3-mg ranibizumab following a retreatment algorithm. PARTICIPANTS: Participants with available plasma samples (N=436) METHODS: Plasma samples were collected before injections at baseline, 4-week, 52-week and 104-week visits. In a pre-planned secondary analysis, systemic free-VEGF levels from an ELISA immunoassay were compared across anti-VEGF agents and correlated with systemic side effects. MAIN OUTCOME MEASURES: Changes in the natural log (ln) of plasma VEGF levels. RESULTS: Baseline free-VEGF levels were similar across all 3 groups. At 4 weeks, mean ln(VEGF) changes were −0.30±0.61, −0.31±0.54, −0.02±0.44 pg/ml for the aflibercept, bevacizumab, and ranibizumab groups, respectively. The adjusted differences between treatment groups (adjusted CI; P-value) were −0.01 (−0.12, +0.10; P=0.89), −0.31 (−0.44, −0.18; P

The PICO Collaboration wishes to thank SNOLAB and its staff for support through underground space, logistical and technical services. SNOLAB operations are supported by the Canada Foundation for Innovation and the Province of Ontario Ministry of Research and Innovation, with underground access provided by Vale at the Creighton mine site. We wish to acknowledge the support of the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) for funding. We acknowledge the support from National Science Foundation (NSF) (Grants No. 0919526, No. 1506337, No. 1242637, No. 1205987, and No. 1806722). We acknowledge that this work is supported by the U.S. Department of Energy (DOE) Office of Science, Office of High Energy Physics (under Award No. DE-SC-0012161), by DGAPA-UNAM (PAPIIT No. IA100118) and Consejo Nacional de Ciencia y Tecnologia (CONACyT, M?exico, Grants No. 252167 and No. A1-S-8960), by the Department of Atomic Energy (DAE), Government of India, under the Centre for AstroParticle Physics II project (CAPP-II) at the Saha Institute of Nuclear Physics (SINP), European Regional Development Fund?Project ?Engineering Applications of Microworld Physics? (Project No. CZ.02.1.01/0.0/0.0/ 16_019/0000766), and the Spanish Ministerio de Ciencia, Innovacion y Universidades (Red Consolider MultiDark, Grant No. FPA2017-90566-REDC). This work is partially supported by the Kavli Institute for Cosmological Physics at the University of Chicago through NSF Grant No. 1125897, and an endowment from the Kavli Foundation and its founder Fred Kavli. We also wish to acknowledge the support from Fermi National Accelerator Laboratory under Contract No. DE-AC02-07CH11359, and Pacific Northwest National Laboratory, which is operated by Battelle for the U.S. Department of Energy under Contract No. DE-AC05- 76RL01830. We also thank Compute Canada [75] and the Center for Advanced Computing, ACENET, Calcul Qu?ebec, Compute Ontario, and WestGrid for computational support.

Geographic atrophy (GA) is an advanced form of age-related macular degeneration characterized by progressive, irreversible visual function loss. This analysis evaluates the psychometric properties of the 25-Item National Eye Institute Visual Function Questionnaire (NEI VFQ-25) composite, near activity, and distance activity scores in patients with GA.Reliability and validity study.Reliability and validity were tested with NEI VFQ-25 data collected from 100 subjects with GA from United States' sites of the phase 2 Mahalo study of lampalizumab (ClinicalTrials.gov identifier: NCT01229215).Strong internal consistency and reproducibility were demonstrated for the NEI VFQ-25 composite (Cronbach's α, 0.95; intraclass correlation coefficient [ICC], 0.86), near activity (Cronbach's α, 0.84; ICC, 0.80), and distance activity (Cronbach's α, 0.84; ICC, 0.84) scores. Convergent validity with the binocular measures, Minnesota Low-Vision Reading Test (MNRead) reading speed and Functional Reading Independence (FRI) index score, was demonstrated for baseline NEI VFQ-25 composite (Pearson correlation [r] = 0.61 and 0.69, respectively), near activities (r = 0.69 and 0.73), and distance activities (r = 0.57 and 0.64) scores. Known-group validity testing for baseline mean NEI VFQ-25 scores (composite, near activities, and distance activities) showed differences between patients with mean maximum MNRead reading speed ≥ 80 vs80 words per minute, and between mean FRI index score ≥ 2.5 vs2.5 (all P.0001).Psychometric evidence supports the NEI VFQ-25 as a reliable and valid cross-sectional measure of the impact of GA on patient visual function and vision-related quality of life.

While poly(lactic-co-glycolic acid)-block-polyethylene glycol (PLGA-PEG) nanoparticles (NPs) can encapsulate drug cargos and prolong circulation times, they show nonspecific accumulation in off-target tissues. Targeted delivery of drugs to tumor tissue and tumor vasculature is a promising approach for treating solid tumors while enhancing specificity and reducing systemic toxicity. AXT050, a collagen-IV derived peptide with both antitumor and antiangiogenic properties, is shown to bind to tumor-associated integrins with high affinity, which leads to targeted accumulation in tumor tissue. AXT050 conjugated to PLGA-PEG NPs at precisely controlled surface density functions both as a targeting agent to human tumor cells and demonstrates potential for simultaneous antitumorigenic and antiangiogenic activity. These targeted NPs cause inhibition of adhesion and proliferation in vitro when added to human triple-negative breast cancer cells and microvascular endothelial cells through binding to integrin αV β3 . Furthermore, we find an in vivo biphasic relationship between tumor targeting and surface coating density of NPs coated with AXT050. NPs with an intermediate level of 10% peptide surface coating show approximately twofold greater accumulation in tumors and lower accumulation in the liver compared to nontargeted PLGA-PEG NPs in a murine biodistribution model. Display of biomimetic peptides from NP surfaces to both target and inhibit cancer cells has the potential to enhance the activity of cancer nanomedicines. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 1753-1764, 2018.

Background The NEI VFQ-25 has undergone psychometric evaluation in patients with varying ocular conditions and the general population. However, important limitations which may affect the interpretation of clinical trial results have been previously identified, such as concerns with reliability and validity. The purpose of this study was to evaluate the National Eye Institute Visual Functioning Questionnaire (NEI VFQ­25) and make recommendations for a revised scoring structure, with a view to improving its psychometric performance and interpretability. Methods Rasch Measurement Theory analyses were conducted in two stages using pooled baseline NEI VFQ­25 data for 2487 participants with retinal diseases enrolled in six clinical trials. In stage 1, we examined: scale-to-sample targeting; thresholds for item response options; item fit statistics; stability; local dependence; and reliability. In stage 2, a post-hoc revision of the scoring structure (VFQ-28R) was created and psychometrically re-evaluated. Results In stage 1, we found that the NEI VFQ­25 was mis-targeted to the sample, and had disordered response thresholds (15/25 items) and mis-fitting items (8/25 items). However, items appeared to be stable (differential item functioning for three items), have minimal item dependency (one pair of items) and good reliability (person-separation index, 0.93). In stage 2, the modified Rasch-scored NEI VFQ­28­R was assessed. It comprised two broad domains: Activity Limitation (19 items) and Socio-Emotional Functioning (nine items). The NEI VFQ­28­R demonstrated improved performance with fewer disordered response thresholds (no items), less item misfit (three items) and improved population targeting (reduced ceiling effect) compared with the NEI VFQ­25. Conclusions Compared with the original version, the proposed NEI VFQ­28­R, with Rasch-based scoring and a two-domain structure, appears to offer improved psychometric performance and interpretability of the vision-related quality of life scale for the population analysed.

The purpose of this study was to examine the influence of students' seating location in a large, lecture-style university course on student engagement, attention, classroom learning experience, and course performance. Participants (N = 407) were students in two cohorts of an undergraduate financial accounting course at a large university in the United States. They participated in the Experience Sampling Method measuring their self-reported seating location, engagement, attention, and other experiential dimensions throughout the one-semester course. Results showed that students reported lower engagement, attention, and quality of classroom experience when sitting in the back of the classroom than when sitting in the middle or front. Those sitting in the back of the classroom most of the time also received lower course grades. Engagement, attention, and other experiential factors mediated the influence of seating location on course grade. Multilevel models revealed both within-student and between-student effects of seating on classroom experience.

Purpose To compare patient-centered outcomes in patients with proliferative diabetic retinopathy (PDR) treated with ranibizumab vs panretinal photocoagulation (PRP). Design Randomized clinical trial. Methods Setting: Multicenter (55 U.S. sites). Patient Population: Total of 216 adults with 1 study eye out of 305 adults (excluding participants with 2 study eyes, because each eye received a different treatment) with PDR, visual acuity 20/320 or better, no history of PRP. Intervention: Ranibizumab (0.5 mg/0.05 mL) vs PRP. Main Outcome Measures: Change from baseline to 2 years in composite and prespecified subscale scores from the National Eye Institute Visual Function Questionnaire-25 (NEI VFQ-25), University of Alabama Low Luminance Questionnaire (UAB-LLQ), and Work Productivity and Activity Impairment Questionnaire (WPAIQ). Results For the NEI VFQ-25 and UAB-LLQ composite scores, ranibizumab–PRP treatment group differences (95% CI) were +4.0 (-0.2, +8.3, P = .06) and +1.8 (-3.5, +7.1, P = 0.51) at 1 year, and +2.9 (-1.5, +7.2, P = .20) and +2.3 (-2.9, +7.5, P = .37) at 2 years, respectively. Work productivity loss measured with the WPAIQ was 15.6% less with ranibizumab (-26.3%, −4.8%, P = .005) at 1 year and 2.9% (-12.2%, +6.4%, P = .54) at 2 years. Eighty-three ranibizumab participants (97%) were 20/40 or better in at least 1 eye (visual acuity requirement to qualify for an unrestricted driver's license in many states) at 2 years compared with 82 PRP participants (87%, adjusted risk ratio = 1.1, 95% CI: 1.0, 1.2, P = .005). Conclusions Though differences in some work productivity and driving-related outcomes favored ranibizumab over PRP, no differences between treatment regimens for PDR were identified for most of the other patient-centered outcomes considered.

The PICO Collaboration wishes to thank SNOLAB and its staff for support through underground space, logistical and technical services. SNOLAB operations are supported by the Canada Foundation for Innovation and the Province of Ontario Ministry of Research and Innovation, with underground access provided by Vale at the Creighton mine site. We are grateful to Genevieve Belanger and Alexander Pukhov of the Universit e de Savoie for their useful correspondence regarding the interpretation of PICO results. We wish to acknowledge the support of the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Canada Foundation for Innovation (CFI) for funding. We acknowledge the support from the National Science Foundation (NSF) (Grants No. 0919526, No. 1506337, No. 1242637, No. 1205987, and No. 1806722). We acknowledge that this work is supported by the U.S. Department of Energy (DOE) Office of Science, Office of High Energy Physics (under Award No. DE-SC-0012161), by the DOE Office of Science Graduate Student Research (SCGSR) award, by DGAPA-UNAM (PAPIIT No. IA100118) and Consejo Nacional de Ciencia y Tecnologia (CONACyT, Mexico, Grants No. 252167 and No. A1-S-8960), by the Department of Atomic Energy (DAE), Government of India, under the Centre for AstroParticle Physics II project (CAPP-II) at the Saha Institute of Nuclear Physics (SINP), European Regional Development FundProject "Engineering applications of microworld physics" (No. CZ. 02.1.01/0.0/0.0/16_019/0000766), and the Spanish (Ministry of Science, Innovation and Universities) Ministerio de Ciencia, Innovacion y Universidades (Red Consolider MultiDark, FPA2017-90566-REDC). This work is partially supported by the Kavli Institute for Cosmological Physics at the University of Chicago through NSF Grant No. 1125897, and an endowment from the Kavli Foundation and its founder Fred Kavli. We also wish to acknowledge the support from Fermi National Accelerator Laboratory under Contract No. DE-AC02-07CH11359, and from Pacific Northwest National Laboratory, which is operated by Battelle for the U.S. Department of Energy under Contract No. DE-AC05-76RL01830. We also thank Compute Canada (www.computecanada.ca) and the Centre for Advanced Computing, ACENET, Calcul Quebec, Compute Ontario and WestGrid for computational support.

Since 2016 much progress has been made in the automatic analysis of age related macular degeneration (AMD). Much of it was dedicated to the classification of referable vs. non-referable AMD, fine-grained AMD severity classification, and assessing the five-year risk of progression to the severe form of AMD. Here we review these developments, the main tasks that were addressed, and the main methods that were carried out.

Internationally, a significant number of secondary school students present signs of disengagement in the classroom, having consequences for learning, achievement, and school completion. The instructional environment is a powerful vehicle to stimulate student engagement in the classroom. It can mitigate more distal bioecological influences such as gender, age, socioeconomic status, and cultural background. In this chapter, we discuss the key characteristics of instructional environments that support behavioral, emotional, and cognitive student engagement. These characteristics include meaningful classwork, the development of student competence, the support of student agency, the promotion of positive peer relationships, and the establishment of positive teacher–student relationships. We then conduct an international literature review identifying studies of interventions influencing student engagement, and profile selected intervention studies in more depth. The chapter concludes by discussing questions that emerge from our review and suggesting directions for future research.

The advent of computer graphic processing units, improvement in mathematical models and availability of big data has allowed artificial intelligence (AI) using machine learning (ML) and deep learning (DL) techniques to achieve robust performance for broad applications in social-media, the internet of things, the automotive industry and healthcare. DL systems in particular provide improved capability in image, speech and motion recognition as well as in natural language processing. In medicine, significant progress of AI and DL systems has been demonstrated in image-centric specialties such as radiology, dermatology, pathology and ophthalmology. New studies, including pre-registered prospective clinical trials, have shown DL systems are accurate and effective in detecting diabetic retinopathy (DR), glaucoma, age-related macular degeneration (AMD), retinopathy of prematurity, refractive error and in identifying cardiovascular risk factors and diseases, from digital fundus photographs. There is also increasing attention on the use of AI and DL systems in identifying disease features, progression and treatment response for retinal diseases such as neovascular AMD and diabetic macular edema using optical coherence tomography (OCT). Additionally, the application of ML to visual fields may be useful in detecting glaucoma progression. There are limited studies that incorporate clinical data including electronic health records, in AL and DL algorithms, and no prospective studies to demonstrate that AI and DL algorithms can predict the development of clinical eye disease. This article describes global eye disease burden, unmet needs and common conditions of public health importance for which AI and DL systems may be applicable. Technical and clinical aspects to build a DL system to address those needs, and the potential challenges for clinical adoption are discussed. AI, ML and DL will likely play a crucial role in clinical ophthalmology practice, with implications for screening, diagnosis and follow up of the major causes of vision impairment in the setting of ageing populations globally.

We look at the recent application of deep learning (DL) methods in automated fine-grained segmentation of spectral domain optical coherence tomography (OCT) images of the retina. We describe a new method combining fully convolutional networks (FCN) with Gaussian Processes for post processing. We report performance comparisons between the proposed approach, human clinicians, and other machine learning (ML) such as graph based approaches. The approach is demonstrated on an OCT dataset consisting of mild non-proliferative diabetic retinopathy from the University of Miami. The method is shown to have performance on par with humans, also compares favorably with the other ML methods, and appears to have as small or smaller mean unsigned error (equal to 1.06), versus errors ranging from 1.17 to 1.81 for other methods, and compared with human error of 1.10.

Purpose Geographic atrophy (GA) is an advanced form of age-related macular degeneration. GA often initially spares the center of the fovea, leading to a functional disconnect between reading speed and distance visual acuity. This study was designed to determine the correlation between baseline GA lesion size, change in lesion size, and maximum reading speed (MRS) over 18 months. Methods Post hoc analysis included US patients from the phase 2 Mahalo study of intravitreal lampalizumab with Minnesota low-vision reading (MNREAD) assessments at baseline and 6, 12, and 18 months. Binocular MRS was assessed using MNREAD Acuity Charts and GA lesion size by fundus autofluorescence. Correlations were estimated using Spearman's rank correlation coefficient. Results Seventy-seven patients were included in the analysis. Baseline MRS correlated with baseline GA lesion size (correlation coefficient, -0.47; 95% confidence interval, -0.63 to -0.28; P < 0.0001). In patients with lesions ≥10 mm2 (four disc areas), the proportion reading below a nonfluent level (MRS

Importance Moderate to substantial agreement between Early Treatment Diabetic Retinopathy Study (ETDRS) 7-field imaging and ultrawide-field (UWF) imaging has been suggested in single-center studies. Comparing images obtained by multiple centers could increase confidence that UWF images can be used reliably in place of ETDRS imaging in future clinical trials. Objective To compare diabetic retinopathy (DR) severity from modified ETDRS 7-field imaging and UWF imaging. Design, Setting, and Participants This preplanned, cross-sectional analysis included modified ETDRS 7-field images obtained using the Diabetic Retinopathy Clinical Research Network acquisition protocol and UWF images obtained captured with the Optos 200Tx system (Optos, PLC) from adult participants (≥18 years old) with type 1 or type 2 diabetes. Both image types were evaluated by trained graders masked to clinical data. Data collection occurred from February 2015 to December 2015, and data analysis from June 2016 to December 2017. Main Outcomes and Measures Agreement between UWF images, UWF images masked to include only the ETDRS 7-field area, and ETDRS 7-field images were calculated using κ statistics. Results A total of 764 eyes from 385 participants were included; participants had a median (IQR) age of 62.2 (53.6-69.2) years, 194 (50.4%) were women, and 256 (66.5%) were white. Of 742 eyes with both ETDRS 7-field images and UWF masked images graded, 359 (48.4% [95% CI, 44.4%-52.4%]) eyes had exact agreement, and 653 eyes (88.0% [95% CI, 85.2%-90.3%]) agreed within 1 step (weighted κ, 0.51 [95% CI, 0.44-0.58]). After open adjudication by an independent senior grader of all images with more than a 2-step discrepancy, perfect agreement was found in 435 eyes (59.0% [95% CI, 55.1%-62.8%]) and agreement within 1 step in 714 eyes (96.9% [95% CI, 95.1%-98.0%]; κ, 0.77 [95% CI, 0.73-0.82]). Ability of the imaging modalities to detect retinopathy severity in an individual eye was considered similar in 59 eyes (50.9% [95% CI, 41.3%-60.4%]), better for ETDRS 7-field imaging in 22 eyes (19.0% [95% CI, 12.5%-27.7%]), and better for UWF-masked images in 31 eyes (26.7% [95% CI 18.8%-36.5%]). Comparing UWF masked and unmasked images, 94 of 751 eyes (12.5%) had DR graded as at least 1 step more severe on UWF unmasked images vs UWF masked images. Predominantly peripheral DR lesions were present in 308 of 751 eyes (41.0%); this suggested increased DR severity by 2 or more steps in 34 eyes (11.0%). Conclusions and Relevance Imaging by the ETDRS 7-field and UWF imaging systems have moderate to substantial agreement when determining the severity of DR within the 7 standard fields. Disparities in an individual eye are equivalently distributed between imaging modalities and can be better or worse on 1 or the other. Longitudinal follow-up will evaluate the primary outcome of this study to determine if peripheral retinal findings are associated with future retinopathy outcomes.

Purpose This study evaluated generative methods to potentially mitigate artificial intelligence (AI) bias when diagnosing diabetic retinopathy (DR) resulting from training data imbalance or domain generalization, which occurs when deep learning systems (DLSs) face concepts at test/inference time they were not initially trained on. Methods The public domain Kaggle EyePACS dataset (88,692 fundi and 44,346 individuals, originally diverse for ethnicity) was modified by adding clinician-annotated labels and constructing an artificial scenario of data imbalance and domain generalization by disallowing training (but not testing) exemplars for images of retinas with DR warranting referral (DR-referable) from darker-skin individuals, who presumably have greater concentration of melanin within uveal melanocytes, on average, contributing to retinal image pigmentation. A traditional/baseline diagnostic DLS was compared against new DLSs that would use training data augmented via generative models for debiasing. Results Accuracy (95% confidence intervals [CIs]) of the baseline diagnostics DLS for fundus images of lighter-skin individuals was 73.0% (66.9% to 79.2%) versus darker-skin of 60.5% (53.5% to 67.3%), demonstrating bias/disparity (delta = 12.5%; Welch t-test t = 2.670, P = 0.008) in AI performance across protected subpopulations. Using novel generative methods for addressing missing subpopulation training data (DR-referable darker-skin) achieved instead accuracy, for lighter-skin, of 72.0% (65.8% to 78.2%), and for darker-skin, of 71.5% (65.2% to 77.8%), demonstrating closer parity (delta = 0.5%) in accuracy across subpopulations (Welch t-test t = 0.111, P = 0.912). Conclusions Findings illustrate how data imbalance and domain generalization can lead to disparity of accuracy across subpopulations, and show that novel generative methods of synthetic fundus images may play a role for debiasing AI. Translational relevance New AI methods have possible applications to address potential AI bias in DR diagnostics from fundus pigmentation, and potentially other ophthalmic DLSs too.

Importance Neovascular age-related macular degeneration is the leading cause of blindness in individuals 50 years or older. The availability of a ranibizumab biosimilar product (SB11) may facilitate access to an effective alternative to this treatment. Objective To demonstrate equivalence of efficacy, similar safety, and similar immunogenicity of SB11 compared with the reference ranibizumab. Design, Setting, and Participants This randomized, double-masked, parallel-group phase 3 equivalence study was conducted in 75 centers in 9 countries from March 14, 2018, to December 9, 2019, among 705 participants 50 years or older with neovascular age-related macular degeneration with active subfoveal choroidal neovascularization lesions. Analysis was performed on an intent-to-treat basis. Interventions Intravitreous injection of SB11 or ranibizumab, 0.5 mg, every 4 weeks through week 48. Main Outcomes and Measures Preplanned interim analysis after all participants completed the week 24 assessment of primary efficacy end points at week 8 for change from baseline in best-corrected visual acuity (BCVA) and week 4 for central subfield thickness (CST), with predefined equivalence margins for adjusted treatment differences of −3 letters to 3 letters for BCVA and −36 μm to 36 μm for CST. Results Baseline and disease characteristics among 705 randomized participants (403 women [57.2%]; mean [SD] age, 74.1 [8.5] years) were comparable between treatment groups (SB11, 351; ranibizumab, 354). Least-squares mean (SE) changes in BCVA from baseline at week 8 were 6.2 (0.5) letters in the SB11 group vs 7.0 (0.5) letters in the ranibizumab group, with an adjusted treatment difference of −0.8 letter (90% CI, −1.8 to 0.2 letters). Least-squares mean (SE) changes in CST from baseline at week 4 were −108 (5) μm in the SB11 group vs −100 (5) μm in the ranibizumab group, with an adjusted treatment difference of −8 μm (95% CI, −19 to 3 μm). Incidences of treatment-emergent adverse events (231 of 350 [66.0%] vs 237 of 354 [66.9%]), including serious treatment-emergent adverse events (44 of 350 [12.6%] vs 44 of 354 [12.4%]) and treatment-emergent adverse events leading to study drug discontinuation (8 of 350 [2.3%] vs 5 of 354 [1.4%]), were similar in the SB11 and ranibizumab groups. Immunogenicity was low, with a cumulative incidence of antidrug antibodies up to week 24 of 3.0% (10 of 330) in the SB11 group and 3.1% (10 of 327) in the ranibizumab group. Conclusions and Relevance These findings of equivalent efficacy and similar safety and immunogenicity profiles compared with ranibizumab support the use of SB11 for patients with neovascular age-related macular degeneration. Trial Registration ClinicalTrials.gov Identifier:NCT03150589

Importance Recent studies have demonstrated the successful application of artificial intelligence (AI) for automated retinal disease diagnostics but have not addressed a fundamental challenge for deep learning systems: the current need for large, criterion standard–annotated retinal data sets for training. Low-shot learning algorithms, aiming to learn from a relatively low number of training data, may be beneficial for clinical situations involving rare retinal diseases or when addressing potential bias resulting from data that may not adequately represent certain groups for training, such as individuals older than 85 years. Objective To evaluate whether low-shot deep learning methods are beneficial when using small training data sets for automated retinal diagnostics. Design, Setting, and Participants This cross-sectional study, conducted from July 1, 2019, to June 21, 2020, compared different diabetic retinopathy classification algorithms, traditional and low-shot, for 2-class designations (diabetic retinopathy warranting referral vs not warranting referral). The public domain EyePACS data set was used, which originally included 88 692 fundi from 44 346 individuals. Statistical analysis was performed from February 1 to June 21, 2020. Main Outcomes and Measures The performance (95% CIs) of the various AI algorithms was measured via receiver operating curves and their area under the curve (AUC), precision recall curves, accuracy, and F1 score, evaluated for different training data sizes, ranging from 5120 to 10 samples per class. Results Deep learning algorithms, when trained with sufficiently large data sets (5120 samples per class), yielded comparable performance, with an AUC of 0.8330 (95% CI, 0.8140-0.8520) for a traditional approach (eg, fined-tuned ResNet), compared with low-shot methods (AUC, 0.8348 [95% CI, 0.8159-0.8537]) (using self-supervised Deep InfoMax [our method denoted as DIM]). However, when far fewer training images were available (n = 160), the traditional deep learning approach had an AUC decreasing to 0.6585 (95% CI, 0.6332-0.6838) and was outperformed by a low-shot method using self-supervision with an AUC of 0.7467 (95% CI, 0.7239-0.7695). At very low shots (n = 10), the traditional approach had performance close to chance, with an AUC of 0.5178 (95% CI, 0.4909-0.5447) compared with the best low-shot method (AUC, 0.5778 [95% CI, 0.5512-0.6044]). Conclusions and Relevance These findings suggest the potential benefits of using low-shot methods for AI retinal diagnostics when a limited number of annotated training retinal images are available (eg, with rare ophthalmic diseases or when addressing potential AI bias).