James Reynolds - Academia.edu (original) (raw)

Papers by James Reynolds

Archives of Ophthalmology, 1984

The international classification of acute retinopathy of prematurity (ROP) appearing in this issu... more The international classification of acute retinopathy of prematurity (ROP) appearing in this issue 1 is a timely and important contribution to the ocular examination and management of the retinopathy in these premature infants. See also p 1130. During the epidemic period of ROP, generally designated then as retrolental fibroplasia, the survival rate of small premature neonates with birthweights under 1,000 g was less than 10%. By the 1980s, due to improved neonatal care, that survival rate has increased by fourfold or greater. These low-birthweight infants, who are at the highest risk of ROP, are surviving today, but in the early 1950s would not have lived long enough for the disease to develop. Cases of ROP are occurring today despite the most meticulous monitoring of arterial blood gases. The extreme prematurity, combined with factors other than excess oxygen, may be responsible for current cases. With a substantial number of new cases

Ophthalmology, Nov 1, 2016

Objective-To identify patterns of inter-expert discrepancy in plus disease diagnosis in retinopat... more Objective-To identify patterns of inter-expert discrepancy in plus disease diagnosis in retinopathy of prematurity (ROP). Design-We developed two datasets of clinical images of varying disease severity (100 images and 34 images) as part of the Imaging and Informatics in ROP study, and determined a consensus reference standard diagnosis (RSD) for each image, based on 3 independent image graders and the clinical exam. We recruited 8 expert ROP clinicians to classify these images and compared the distribution of classifications between experts and the RSD. Subjects, Participants, and/or Controls-Images obtained during routine ROP screening in neonatal intensive care units. 8 participating experts with >10 years of clinical ROP experience and >5 peer-reviewed ROP publications. Methods, Intervention, or Testing-Expert classification of images of plus disease in ROP. Main Outcome Measures-Inter-expert agreement (weighted kappa statistic), and agreement and bias on ordinal classification between experts (ANOVA) and the RSD (percent agreement). Results-There was variable inter-expert agreement on diagnostic classifications between the 8 experts and the RSD (weighted kappa 0-0.75, mean 0.30). RSD agreement ranged from 80-94% agreement for the dataset of 100 images, and 29-79% for the dataset of 34 images. However, when images were ranked in order of disease severity (by average expert classification), the pattern of expert classification revealed a consistent systematic bias for each expert consistent with unique cut points for the diagnosis of plus disease and pre-plus disease. The two-way ANOVA model suggested a highly significant effect of both image and user on the average score (P<0.05, adjusted R 2 =0.82 for dataset A, and P< 0.05 and adjusted R 2 =0.6615 for dataset B). Conclusions and Relevance-There is wide variability in the classification of plus disease by ROP experts, which occurs because experts have different "cut-points" for the amounts of vascular abnormality required for presence of plus and pre-plus disease. This has important implications for research, teaching and patient care for ROP, and suggests that a continuous ROP plus disease severity score may more accurately reflect the behavior of expert ROP clinicians, and may better standardize classification in the future.

The Lancet, 2019

Background: Current therapy does not eradicate ocular morbidity and visual disability following r... more Background: Current therapy does not eradicate ocular morbidity and visual disability following retinopathy of prematurity. Anti-vascular endothelial growth factor treatment provides a potentially new treatment. Methods: Infants with birth weight <1,500g meeting established criteria for ROP treatment were recruited in 87 neonatal and ophthalmology centres in 26 countries. We performed a randomised, multicentre, open-label, 3arm, parallel-group study evaluating efficacy and safety of intravitreal injection of ranibizumab 0•2mg or ranibizumab 0•1mg against laser therapy. The primary outcome was treatment success, defined as survival with no active retinopathy, unfavourable structural outcomes or the need for an additional treatment modality at or before 24 weeks. Findings: Treatment success occurred in 56/70 (80%) infants receiving ranibizumab 0•2mg compared with 57/76 (75%) receiving ranibizumab 0•1mg and 45/68 (66%) infants following laser therapy. The odds ratio of a successful outcome following ranibizumab 0•2mg compared with laser therapy was 2•19 (95% confidence interval 0•99-4•82; p=0•051). One infant had an unfavourable structural outcome following ranibizumab 0•2mg, compared to five following ranibizumab 0•1mg and seven after laser therapy. Ranibizumab 0•2mg was effective in both Zone I and Zone II disease. Ranibizumab 0•1mg offered no advantage over 0•2 mg. Death, serious and non-serious systemic and ocular adverse events were evenly distributed between the three groups. Interpretation: In the treatment of retinopathy of prematurity, ranibizumab 0•2mg was effective with fewer unfavourable ocular outcomes than laser therapy and with an acceptable short-term safety profile. Funding: Novartis Pharma; RAINBOW ClinicalTrials.gov number, NCT02375971.

Translational Vision Science & Technology, 2020

To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with r... more To develop a population pharmacokinetic (PK) model for intravitreal ranibizumab in infants with retinopathy of prematurity (ROP) and assess plasma free vascular endothelial growth factor (VEGF) pharmacodynamics (PD). Methods: The RAnibizumab compared with laser therapy for the treatment of INfants BOrn prematurely With retinopathy of prematurity (RAINBOW) trial enrolled 225 infants to receive a bilateral intravitreal injection of ranibizumab 0.1 mg, ranibizumab 0.2 mg, or laser in a 1:1:1 ratio and included sparse sampling of blood for population PK and PD analysis. An adult PK model using infant body weight as a fixed allometric covariate was re-estimated using the ranibizumab concentrations in the preterm population. Different variability, assumptions, and covariate relationships were explored. Model-based individual predicted concentrations of ranibizumab were plotted against observed free VEGF concentrations. Results: Elimination of ranibizumab had a median half-life of 5.6 days from the eye and 0.3 days from serum, resulting in an apparent serum half-life of 5.6 days. Time to reach maximum concentration was rapid (median: 1.3 days). Maximum concentration (median 24.3 ng/mL with ranibizumab 0.2 mg) was higher than that reported in adults. No differences in plasma free VEGF concentrations were apparent between the groups or over time. Plotted individual predicted concentrations of ranibizumab against observed free VEGF concentrations showed no relationship. Conclusions: In preterm infants with ROP, elimination of ranibizumab from the eye was the rate-limiting step and was faster compared with adults. No reduction in plasma free VEGF was observed. The five-year clinical safety follow-up from RAINBOW is ongoing. Translational Relevance: Our population PK and VEGF PD findings suggest a favorable ocular efficacy: systemic safety profile for ranibizumab in preterm infants.

Archives of Ophthalmology, 2010

To examine the frequency and timing of progression from type 2 to type 1 retinopathy of prematuri... more To examine the frequency and timing of progression from type 2 to type 1 retinopathy of prematurity (ROP) in the Early Treatment for Retinopathy of Prematurity Study. Methods: Infants with prethreshold ROP that was no worse than low risk in 1 or both eyes, based on the RM-ROP2 model, were examined every 2 to 4 days for at least 2 weeks. Using the Early Treatment for Retinopathy of Prematurity Study-defined classification of eyes as having type 1 or type 2 prethreshold ROP, we analyzed the time to conversion from type 2 to type 1. Data were analyzed for 1 randomly selected eye for each child. Results: Of 294 eyes at first diagnosis of type 2 ROP, 65 (22.1%) progressed to type 1 (mean [SD] interval, 9.0 [6.6] days; median, 7.0 days). Of 217 eyes with type 2 ROP that had an examination in less than 7 days, 25 Author Affiliations are listed at the end of this article. Group Information: A list of the Early Treatment for Retinopathy of Prematurity Cooperative Group members was published in

JAMA ophthalmology, Jan 14, 2016

Published definitions of plus disease in retinopathy of prematurity (ROP) reference arterial tort... more Published definitions of plus disease in retinopathy of prematurity (ROP) reference arterial tortuosity and venous dilation within the posterior pole based on a standard published photograph. One possible explanation for limited interexpert reliability for a diagnosis of plus disease is that experts deviate from the published definitions. To identify vascular features used by experts for diagnosis of plus disease through quantitative image analysis. A computer-based image analysis system (Imaging and Informatics in ROP [i-ROP]) was developed using a set of 77 digital fundus images, and the system was designed to classify images compared with a reference standard diagnosis (RSD). System performance was analyzed as a function of the field of view (circular crops with a radius of 1-6 disc diameters) and vessel subtype (arteries only, veins only, or all vessels). Routine ROP screening was conducted from June 29, 2011, to October 14, 2014, in neonatal intensive care units at 8 academic i...

Journal of American Association for Pediatric Ophthalmology and Strabismus, 2012

The purpose of this presentation is to explain norms and ranges of critical practice performance ... more The purpose of this presentation is to explain norms and ranges of critical practice performance metrics. Participants may use this data to make their practices more efficient, allowing them to continue delivering clinical services by becoming running a more sustainable practice. Target Audience: The target audience is pediatric ophthalmologists and their practice administrators. Current Outcomes: Currently, all pediatric ophthalmologistswhether in private or academic practice-face challenges navigating changes in practice economics and they do so without established reference points. Results: At the conclusion of this presentation, attendees will be able to: assess whether their costs of operation deviate from the norm (and to what degree); understand where they fall in the range of profitability; compare their net income to their peers, as a group; have a better understanding of various methods for enhancing practice profitability. Format: Based on a survey of the AAPOS membership conducted in January 2012, data pertaining to fiscal year 2010 will be analyzed and presented. Summary: Following a brief data and analysis presentation, a series of didactic presentations will address performance improvements in the following areas: enhancing revenue, reducing costs and challenges of collecting fiscal data in an academic setting. A brief question-and-answer period will follow each section, with an open-ended question period at the end.

British Journal of Ophthalmology, 2006

To determine whether earlier treatment of high-risk, prethreshold retinopathy of prematurity (ROP... more To determine whether earlier treatment of high-risk, prethreshold retinopathy of prematurity (ROP) improves retinal structural outcome at 2 years of age. Methods: Infants with bilateral high-risk prethreshold ROP had one eye randomly assigned to treatment with peripheral retinal ablation. The fellow eye was managed conventionally, and either treated at threshold ROP or observed if threshold was never reached. In patients with asymmetrical disease, the highrisk, prethreshold eye was randomised to earlier treatment or to conventional management. At 2 years of age, children were examined comprehensively by certified ophthalmologists to determine structural outcomes for their eyes. For the purposes of this study, an unfavourable structural outcome was defined as (1) a posterior retinal fold involving the macula, (2) a retinal detachment involving the macula or (3) retrolental tissue or ''mass'' obscuring the view of the posterior pole. Results of the 2-year examination were compared with those from the 9 months examination. Results: Data were available on 339 of 374 (90.6%) surviving children. Unfavourable structural outcomes were reduced from 15.4% in conventionally managed eyes to 9.1% in earlier-treated eyes (p = 0.002) at 2 years of age. Ophthalmic side effects (excluding retinal structure) from the ROP or its treatment were similar in the earlier-treated eyes and the conventionally managed eyes. Conclusion: The benefit of earlier treatment of high-risk prethreshold ROP on retinal structure endures to 2 years of age, and is not counterbalanced by any known side effect caused by earlier intervention. Earlier treatment improves the chance for long-term favourable retinal structural outcome in eyes with high-risk prethreshold ROP. Long-term follow-up is planned to determine structural and functional outcomes at 6 years of age.

American Journal of Ophthalmology, 2010

Purpose-To examine the relationship between rate of vascular change and plus disease diagnosis. D... more Purpose-To examine the relationship between rate of vascular change and plus disease diagnosis. Design-Retrospective observational case-control study. Methods-Wide-angle images were taken bilaterally from 37 infants at 31-33 and 35-37 weeks post-menstrual age (PMA). The semi-automated Retinal Image multiScale Analysis system was used to measure parameters for all arteries and veins: integrated curvature, diameter, and tortuosity index. A reference standard diagnosis (plus vs. not plus) was defined for each eye by consensus of five

Archives of Ophthalmology, 2002

Background: The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) demons... more Background: The Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (CRYO-ROP) demonstrated the efficacy of treatment for threshold ROP and indicated the need for worldwide ROP screening. Previous guidelines for ROP screening have been largely based on clinical impression; we can now develop evidencebased screening recommendations. Objective: To define the appropriate ages and retinal ophthalmoscopic signs that determine when to commence and conclude acute phase ROP screening.

Pediatric Ophthalmology and Strabismus, 2003

American Journal of Medical Genetics, 1996

Strabismus is a frequently recognized manifestation of Williams syndrome [Greenberg and Lewis, 19... more Strabismus is a frequently recognized manifestation of Williams syndrome [Greenberg and Lewis, 1988: Ophthalmology 95:1608-1612; Kapp et al., 1995: Am J Ophthalmol 119:355-360]. We recently evaluated the ophthalmologic function of 12 patients with Williams syndrome (WS), with an emphasis on binocularity. Four of 12 patients (33%) had measurable strabismus. Of the 8 remaining patients, examination of binocular function was possible in 6, all of whom demonstrated reduced stereoacuity. We speculate that subnormal binocular vision and the poor visuospatial performance observed in patients with WS may be related to abnormal brain morphogenesis in the region of the occipitoparietal cortex.

Journal of American Association for Pediatric Ophthalmology and Strabismus, 1998

Journal of Pediatric Ophthalmology & Strabismus, 1997

Patients with Williams syndrome have been found to have a high prevalence of strabismus. This may... more Patients with Williams syndrome have been found to have a high prevalence of strabismus. This may be due to a primary sensory abnormality. The purpose of this study was to determine the prevalence of subnormal binocular vision in patients with Williams syndrome. Patients being followed in an interdisciplinary Williams syndrome clinic were prospectively evaluated to determine their binocular status. Eleven patients with Williams syndrome underwent an ophthalmologic evaluation. Twenty-seven percent of patients had strabismus (3/11). Eight patients demonstrated no measurable strabismus. Six of these patients were found to have monofixation syndrome. There is a high prevalence of subnormal binocular vision in Williams syndrome. This subnormal binocular vision may explain the high prevalence of strabismus in this syndrome.

Journal of Pediatric Ophthalmology and Strabismus, 2004

The American orthoptic journal, 2017

To assess the possibility of determining the insertion distance from the limbus of previously ope... more To assess the possibility of determining the insertion distance from the limbus of previously operated extraocular rectus muscles (EOM) with the Heidelberg Spectralis anterior segment optical coherence tomography (AS-OCT). Subjects with a history of previous strabismus surgery underwent AS-OCT of the EOM before planned additional strabismus surgery. The EOM insertion distances from the limbus were measured pre-operatively on the AS-OCT and compared to the caliper distance measured during the strabismus surgery. Ten previously operated muscles on nine subjects underwent AS-OCT before subsequent additional strabismus surgery. Four additional un-operated muscles subsequently operated on, were also imaged with the AS-OCT pre-operatively. Subject ages ranged from 13-52 years old (mean ± SD; 27.9 ± 13.2). The muscle insertion could be definitely identified in 6/10 muscles previously operated and 4/4 un-operated muscles. The difference between the two measurements of limbus to insertion in...

Seminars in Neonatology, 2001

There have been many major advances recently that have improved the identification and management... more There have been many major advances recently that have improved the identification and management of retinopathy of prematurity (ROP). This chapter describes the clinical features of ROP and then considers briefly the incidence and epidemiology of acute phase disease. This is followed by a discussion of the two ROP epidemics and ROP-induced disability in high, low and middle income countries, and how this has been impacted by treatment. The principles and specifics of screening for ROP are considered, focusing on certain topical issues such as whether one screening guideline suits all populations. Treatment has undergone several advances, so that now laser therapy has overtaken cryotherapy as the preferred mode of treatment, and treatment at an earlier stage is now being considered. Finally, the authors attempt to look into the future and wonder how the criteria for treatment will change, and whether innovations in ocular imaging will impact ROP screening in both high and middle income countries.

The American orthoptic journal, 2014

Retinopathy of prematurity (ROP) is a complex disease. We have established much of the pathophysi... more Retinopathy of prematurity (ROP) is a complex disease. We have established much of the pathophysiology of this disease including the critical roles of retinal metabolic demand and vascular endothelial growth factor (VEGF). The purpose of this paper is to provide some background material and specifically highlight issues that are new, controversial, or underappreciated. ROP is subdivided into classification, incidence, screening, treatment, and co-morbidities. A brief background is given for each followed by highlighting specific problems attendant with current practices. Disease classification is accurate, reliable, and extremely useful, and can be consistently applied. However, disease behavior can occasionally confound the classification system, such as Zone III ROP with previous Zone II disease as well as the temporal wedge seen in posterior ROP. Incidences of various ROP states are well known and consistent, but the true incidence of Zone I disease and plus disease are currently...