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Ramamirtham R, Akula JD, Curran A-LK, Szczygiel J, Lancos AM, Grytz R, Ferguson DR, Fulton AB. Modelling eye lengths and refractions in the periphery. Ophthalmic Physiol Opt 2023;43(4):815-826.Abstract
PURPOSE: To create a simplified model of the eye by which we can specify a key optical characteristic of the crystalline lens, namely its power. METHODS: Cycloplegic refraction and axial length were obtained in 60 eyes of 30 healthy subjects at eccentricities spanning 40° nasal to 40° temporal and were fitted with a three-dimensional parabolic model. Keratometric values and geometric distances to the cornea, lens and retina from 45 eyes supplied a numerical ray tracing model. Posterior lens curvature (PLC) was found by optimising the refractive data using a fixed lens equivalent refractive index ( n eq ). Then, n eq was found using a fixed PLC. RESULTS: Eccentric refractive errors were relatively hyperopic in eyes with central refractions ≤-1.44 D but relatively myopic in emmetropes and hyperopes. Posterior lens power, which cannot be measured directly, was derived from the optimised model lens. There was a weak, negative association between derived PLC and central spherical equivalent refraction. Regardless of refractive error, the posterior retinal curvature remained fixed. CONCLUSIONS: By combining both on- and off-axis refractions and eye length measurements, this simplified model enabled the specification of posterior lens power and captured off-axis lenticular characteristics. The broad distribution in off-axis lens power represents a notable contrast to the relative stability of retinal curvature.
Ng SMS, Low R, Pak C, Lai SS, Lee B, McCluskey P, Symes R, Invernizzi A, Tsui E, Sitaula RK, Kharel M, Khatri A, Utami AN, Distia Nora RL, Putera I, Sen A, Agarwal M, Mahendradas P, Biswas J, Pavesio C, Cimino L, Sobrin L, Kempen JH, Gupta V, Agrawal R, Agrawal R. The role of a multicentre data repository in ocular inflammation: The Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS). Eye (Lond) 2023;37(15):3084-3096.Abstract
In the current literature, clinical registry cohorts related to ocular inflammation are few and far between, and there are none involving multi-continental international data. Many existing registries comprise administrative databases, data related to specific uveitic diseases, or are designed to address a particular clinical problem. The existing data, although useful and serving their intended purposes, are segmented and may not be sufficiently robust to design prognostication tools or draw epidemiological conclusions in the field of uveitis and ocular inflammation. To solve this, we have developed the Ocular Autoimmune Systemic Inflammatory Infectious Study (OASIS) Clinical Registry. OASIS collects prospective and retrospective data on patients with all types of ocular inflammatory conditions from centers all around the world. It is a primarily web-based platform with alternative offline modes of access. A comprehensive set of clinical data ranging from demographics, past medical history, clinical presentation, working diagnosis to visual outcomes are collected over a range of time points. Additionally, clinical images such as optical coherence tomography, fundus fluorescein angiography and indocyanine green angiography studies may be uploaded. Through the capturing of diverse, well-structured, and clinically meaningful data in a simplified and consistent fashion, OASIS will deliver a comprehensive and well organized data set ripe for data analysis. The applications of the registry are numerous, and include performing epidemiological analysis, monitoring drug side effects, and studying treatment safety efficacy. Furthermore, the data compiled in OASIS will be used to develop new classification and diagnostic systems, as well as treatment and prognostication guidelines for uveitis.
Fonda SJ, Bursell S-E, Lewis DG, Clary D, Shahon D, Cavallerano J. Incidence and Progression of Diabetic Retinopathy in American Indian and Alaska Native Individuals Served by the Indian Health Service, 2015-2019. JAMA Ophthalmol 2023;141(4):366-375.Abstract
IMPORTANCE: Estimates of diabetic retinopathy (DR) incidence and progression in American Indian and Alaska Native individuals are based on data from before 1992 and may not be informative for strategizing resources and practice patterns. OBJECTIVE: To examine incidence and progression of DR in American Indian and Alaska Native individuals. DESIGN, SETTING, AND PARTICIPANTS: This was a retrospective cohort study conducted from January 1, 2015, to December 31, 2019, and included adults with diabetes and no evidence of DR or mild nonproliferative DR (NPDR) in 2015 who were reexamined at least 1 time during the 2016 to 2019 period. The study setting was the Indian Health Service (IHS) teleophthalmology program for diabetic eye disease. EXPOSURE: Development of new DR or worsening of mild NPDR in American Indian and Alaska Native individuals with diabetes. MAIN OUTCOMES AND MEASURES: Outcomes were any increase in DR, 2 or more (2+) step increases, and overall change in DR severity. Patients were evaluated with nonmydriatic ultra-widefield imaging (UWFI) or nonmydriatic fundus photography (NMFP). Standard risk factors were included. RESULTS: The total cohort of 8374 individuals had a mean (SD) age of 53.2 (12.2) years and a mean (SD) hemoglobin A1c level of 8.3% (2.2%) in 2015, and 4775 were female (57.0%). Of patients with no DR in 2015, 18.0% (1280 of 7097) had mild NPDR or worse in 2016 to 2019, and 0.1% (10 of 7097) had PDR. The incidence rate from no DR to any DR was 69.6 cases per 1000 person-years at risk. A total of 6.2% of participants (441 of 7097) progressed from no DR to moderate NPDR or worse (ie, 2+ step increase; 24.0 cases per 1000 person-years at risk). Of patients with mild NPDR in 2015, 27.2% (347 of 1277) progressed to moderate NPDR or worse in 2016 to 2019, and 2.3% (30 of 1277) progressed to severe NPDR or worse (ie, 2+ step progression). Incidence and progression were associated with expected risk factors and evaluation with UWFI. CONCLUSIONS AND RELEVANCE: In this cohort study, the estimates of DR incidence and progression were lower than those previously reported for American Indian and Alaska Native individuals. The results suggest extending the time between DR re-evaluations for certain patients in this population, if follow-up compliance and visual acuity outcomes are not jeopardized.
Yang J, Zeng W-X, Cheng J, Kang M, Liao X-L, Ying P, Ling Q, Zou J, Wei H, Wang Y-X, Su T, Shao Y. Fractional amplitude of low-frequency fluctuation changes of specific cerebral regions in patients with toothache: A functional magnetic resonance imaging study. Brain Behav 2023;13(4):e2937.Abstract
BACKGROUND: Previous studies have indicated that pain-related diseases can result in significant functional alterations in the brain. However, differences in spontaneous brain activity in toothache (TA) patients remain unclear. OBJECTIVE: To investigate altered spontaneous brain activity in patients with TA and its underlying mechanisms using the resting-state functional magnetic resonance imaging-fractional amplitude of low-frequency fluctuation (rsfMRI-fALFF) technique. METHODS: Twelve patients with TA and 12 non-toothache controls (NTCs) (matched for sex, age, and level of education) were enrolled. Spontaneous cerebral activity variations were investigated using the rsfMRI-fALFF technique in all individuals. The mean fALFF values of the TA patients and NTCs were classified using receiver operating characteristic (ROC) curves. The correlations between fALFF signals of distinct brain regions and clinical manifestations of TA patients were evaluated using Pearson's correlation analysis. RESULTS: TA patients showed lower fALFF values in the left superior frontal gyrus, medial; right superior frontal gyrus, dorsolateral; and left median cingulate and paracingulate gyri (LDCG) than the NTCs. Moreover, ROC curve analysis indicated that the area under the curve of each cerebral region studied had high accuracy. Besides, in the TA group, the visual analog scale score was negatively correlated with fALFF signal values of the LDCG (r = .962, p < .001). CONCLUSION: Abnormal spontaneous activity was detected in numerous brain regions in patients with TA, which may be valuable for understanding the brain processing mechanism underlying TA. These regional changes in brain activity may serve as effective clinical indicators of TA.
Ichhpujani P, Singh RB, Dhillon HK, Kumar S. Ocular manifestations of COVID-19 in pediatric patients. Ther Adv Ophthalmol 2023;15:25158414221149916.Abstract
The coronavirus disease-19 (COVID-19) infection may remain asymptomatic or may have several different presentations. Although this disease primarily affects the respiratory system, systemic manifestations affecting the gastrointestinal, cardiovascular, neurological, otorhinolaryngologic, and ophthalmic systems have been reported. Ophthalmic signs may be the first and only sign of COVID-19 infection in children. In the current narrative review, we report the ophthalmic manifestations of COVID-19 in the pediatric age cohort. We performed a comprehensive literature search for the publications on ophthalmic manifestations of COVID-19 in children between 1 March 2020 and 1 January 2022 and compiled the ophthalmic manifestations of this entity among the pediatric population. Conjunctivitis is the most common ophthalmic manifestation in children and can develop at any stage of the disease. Ophthalmic manifestations are seen more commonly in children with severe systemic disease. Long-term and indirect consequence of the COVID-19 disease is the rise of myopia among children. Ophthalmic signs may be the first and only sign of COVID-19 infection in children. Pediatricians, as well as ophthalmologists, must keep observing all children with COVID-19 closely for ophthalmic signs.
Zhou A, Babiker F, Philip AM, Anesi SD, Foster SC. Response to "Similarities in clinical course and outcome between juvenile idiopathic arthritis (JIA)-associated and ANA-positive idiopathic anterior uveitis: data from a population-based nationwide study in Germany". Arthritis Res Ther 2023;25(1):41.Abstract
We have read the article entitled "Similarities in clinical course and outcome between juvenile idiopathic arthritis (JIA)-associated and ANA-positive idiopathic anterior uveitis: data from a population-based nationwide study in Germany" by Heiligenhaus et al. While we appreciate the work conducted by the authors, we have several comments we would like to address. First, the follow-up interval of 2 years is too short to conclude that the clinical course between two chronic pathologies is not significantly different. Second, remission status was determined by uveitis inactivity during the 2-year follow-up visit without any mention of flare frequency or length of remission, which is not a reliable measure of uveitis control. Third, ANA-positive idiopathic anterior uveitis is not a classification with a distinct clinical phenotype, and additional reports of serologic investigations would have been helpful.
Patel NA, Hoyek S, Al-Khersan H, Fan KC, Yannuzzi NA, Davila J, Berrocal AM. Retinopathy of Prematurity Outcomes of Neonates Meeting Only a Single Screening Criterion: Proposal of the TWO-ROP Algorithm. Am J Ophthalmol 2023;252:147-152.Abstract
PURPOSE: To assess the rates of retinopathy of prematurity (ROP) and treatment-warranted ROP in a modern set of patients meeting 0 or 1 of the current ROP screening criteria. DESIGN: Retrospective cohort study. METHODS: Single-center study of 9350 infants screened for ROP from 2009 to 2019. Rates of ROP and treatment-warranted ROP were evaluated in group 1 (birth weight [BW] <1500 g and gestational age [GA] ≥30 weeks), group 2 (BW ≥1500 g and GA <30 weeks), and group 3 (BW ≥1500 g and GA ≥30 weeks). RESULTS: Of 7520 patients with reported BW and GA, 1612 (21.4%) patients met the inclusion criteria. The number of patients in groups 1, 2, and 3 was 466 (6.19%), 23 (0.31%), and 1123 (14.93%), respectively. The number of patients diagnosed with ROP was 20 (4.29%) in group 1, 1 (4.35%) in group 2, and 12 (1.07%) in group 3 (P < .001). The mean interval between birth and ROP diagnosis was 36.25 days (range 12-75 days) in group 1, 47 days in group 2, and 23.33 days (range 10-39 days) in group 3 (P = .05). No cases of stage 3, zone 1, or plus disease were recorded. No patients met the treatment criteria. CONCLUSIONS: Patients meeting 1 screening criterion had a low rate of ROP (<5%), with no stage 3, zone 1, or plus disease. No patients required treatment. We propose a possible algorithm (TWO-ROP) in appropriate neonatal intensive care units, with an amendment in screening protocol for this low-risk population to include only an outpatient screening examination within 1 week of discharge, or at 40 weeks if inpatient, to decrease the inpatient ROP screening burden while maintaining safety. Further external validation of this protocol would be required.
Hsu Y, Bhattarai S, Thompson JM, Mahoney A, Thomas J, Mayer SK, Datta P, Garrison J, Searby CC, Vandenberghe LH, Seo S, Sheffield VC, Drack AV. Subretinal gene therapy delays vision loss in a Bardet-Biedl Syndrome type 10 mouse model. Mol Ther Nucleic Acids 2023;31:164-181.Abstract
Blindness in Bardet-Biedl syndrome (BBS) is caused by dysfunction and loss of photoreceptor cells in the retina. BBS10, mutations of which account for approximately 21% of all BBS cases, encodes a chaperonin protein indispensable for the assembly of the BBSome, a cargo adaptor important for ciliary trafficking. The loss of BBSome function in the eye causes a reduced light sensitivity of photoreceptor cells, photoreceptor ciliary malformation, dysfunctional ciliary trafficking, and photoreceptor cell death. Cone photoreceptors lacking BBS10 have congenitally low electrical function in electroretinography. In this study, we performed gene augmentation therapy by injecting a viral construct subretinally to deliver the coding sequence of the mouse Bbs10 gene to treat retinal degeneration in a BBS10 mouse model. Long-term efficacy was assessed by measuring the electrical functions of the retina over time, imaging of the treated regions to visualize cell survival, conducting visually guided swim assays to measure functional vision, and performing retinal histology. We show that subretinal gene therapy slowed photoreceptor cell death and preserved retinal function in treated eyes. Notably, cone photoreceptors regained their electrical function after gene augmentation. Measurement of functional vision showed that subretinal gene therapy provided a significant benefit in delaying vision loss.
Niaudet C, Jung B, Kuo A, Swendeman S, Bull E, Seno T, Crocker R, Fu Z, Smith LEH, Hla T. Therapeutic activation of endothelial sphingosine-1-phosphate receptor 1 by chaperone-bound S1P suppresses proliferative retinal neovascularization. EMBO Mol Med 2023;15(5):e16645.Abstract
Sphingosine-1-phosphate (S1P), the circulating HDL-bound lipid mediator that acts via S1P receptors (S1PR), is required for normal vascular development. The role of this signaling axis in vascular retinopathies is unclear. Here, we show in a mouse model of oxygen-induced retinopathy (OIR) that endothelial overexpression of S1pr1 suppresses while endothelial knockout of S1pr1 worsens neovascular tuft formation. Furthermore, neovascular tufts are increased in Apom-/- mice which lack HDL-bound S1P while they are suppressed in ApomTG mice which have more circulating HDL-S1P. These results suggest that circulating HDL-S1P activation of endothelial S1PR1 suppresses neovascular pathology in OIR. Additionally, systemic administration of ApoM-Fc-bound S1P or a small-molecule Gi-biased S1PR1 agonist suppressed neovascular tuft formation. Circulating HDL-S1P activation of endothelial S1PR1 may be a key protective mechanism to guard against neovascular retinopathies that occur not only in premature infants but also in diabetic patients and aging people.
Mahjoub H, Ssekasanvu J, Yonekawa Y, Justin GA, Cavuoto KM, Lorch A, Madan V, Sivakumar I, Zhao X, Quintero M, Simeon OF, Salabati M, Wu CM, Woreta FA. Most Common Ophthalmic Diagnoses in Eye Emergency Departments: A Multicenter Study. Am J Ophthalmol 2023;254:36-43.Abstract
PURPOSE: To characterize the most common ophthalmic conditions seen in the emergency department (ED) DESIGN: Cross-sectional study METHODS: This is a multicenter study of 64,988 patients who visited the Bascom Palmer Eye Institute, Massachusetts Eye and Ear, Wills Eye Hospital, and Johns Hopkins Hospital/Wilmer Eye Institute from January 1, 2019, until December 31, 2019. Demographic and primary diagnosis data were extracted including gender, age, race, ethnicity, insurance type, and ophthalmology consult status. Descriptive statistics were performed on all data using STATA IC 14 (64-bit). RESULTS: A total of 64,988 patients with primary ocular diagnoses were seen across all 4 EDs. The majority of patients were White (63.1%), non-Hispanic/Latino (64.8%), and female (52.3%). The most frequently seen age group was 50-64 years (28.6%). The most common diagnoses across all institutions were conjunctivitis (7.91%), corneal abrasions (5.61%), dry eye (4.49%), posterior vitreous detachments (4.15%), chalazions (3.71%), corneal ulcers (3.01%), subconjunctival hemorrhages (2.96%), corneal foreign bodies (2.94%), retinal detachments (2.51%), and glaucoma (2.12%). Specifically, viral conjunctivitis (2283 of 5139, 44.4%) and primary open-angle glaucoma (382 of 1379, 27.7%) were the most frequently seen subtypes of conjunctivitis and glaucoma. CONCLUSIONS: The most regularly treated ophthalmic conditions in high-volume EDs tend to be lower acuity diagnoses. To combat ED overcrowding and rising health care costs in the United States, we suggest diverting eye-related ED visits to a specialized eye ED service or same-day eye clinic appointment in addition to expanding education for patients and primary care clinicians.
Florea M, Nicolaou F, Pacouret S, Zinn EM, Sanmiguel J, Andres-Mateos E, Unzu C, Wagers AJ, Vandenberghe LH. High-efficiency purification of divergent AAV serotypes using AAVX affinity chromatography. Mol Ther Methods Clin Dev 2023;28:146-159.Abstract
The adeno-associated viral vector (AAV) provides a safe and efficient gene therapy platform with several approved products that have marked therapeutic impact for patients. However, a major bottleneck in the development and commercialization of AAV remains the efficiency, cost, and scalability of AAV production. Chromatographic methods have the potential to allow purification at increased scales and lower cost but often require optimization specific to each serotype. Here, we demonstrate that the POROS CaptureSelect AAVX affinity resin efficiently captures a panel of 15 divergent AAV serotypes, including the commonly used AAV2, AAV8, AAV9, PHP.B, and Anc80. We also find that AAVX resin can be regenerated repeatedly without loss of efficiency or carry-over contamination. While AAV preps purified with AAVX showed a higher fraction of empty capsids than preps purified using iodixanol ultracentrifugation, the potency of the AAVX purified vectors was comparable with that of iodixanol purified vectors both in vitro and in vivo. Finally, optimization of the purification protocol resulted in a process with an overall efficiency of 65%-80% across all scales and AAV serotypes tested. These data establish AAVX affinity chromatography as a versatile and efficient method for purification of a broad range of AAV serotypes.
Dohlman JC, Elliott AT. Severe Eyelid Malformation With Facial Clefting and Amniotic Bands. Ophthalmic Plast Reconstr Surg 2023;39(4):e117-e119.Abstract
Amniotic bands can lead to eyelid colobomas contiguous with facial clefts, resulting in severe and highly variable eyelid malformations. There is no known underlying genetic cause of amniotic band sequence. Here, the authors review the case of an infant born with large, 4-eyelid colobomatous defects in the setting of facial clefts, amniotic bands and an underlying SMOC1 mutation, which has not previously been linked to amniotic band sequence or eyelid colobomas. Reconstructive technique and the postoperative course are described, and underlying etiologic theories of amniotic band sequence are reviewed and expanded upon. Although amblyopia prevention in this patient with poor visual potential was not a consideration, the goals of improving the patient's ocular surface and maintaining eye contact were achieved.
Liebman DL, Wen JC, Shen LQ. Detecting disease progression in mild, moderate and severe glaucoma. Curr Opin Ophthalmol 2023;34(2):168-175.Abstract
PURPOSE OF REVIEW: The purpose of this review is to examine contemporary techniques for detecting the progression of glaucoma. We provide a general overview of detection principles and review evidence-based diagnostic strategies and specific considerations for detecting glaucomatous progression in patients with mild, moderate and severe disease. RECENT FINDINGS: Diagnostic techniques and technologies for glaucoma have dramatically evolved in recent years, affording clinicians an expansive toolkit with which to detect glaucoma progression. Each stage of glaucoma, however, presents unique diagnostic challenges. In mild disease, either structural or functional changes can develop first in disease progression. In moderate disease, structural or functional changes can occur either in tandem or in isolation. In severe disease, standard techniques may fail to detect further disease progression, but such detection can still be measured using other modalities. SUMMARY: Detecting disease progression is central to the management of glaucoma. Glaucomatous progression has both structural and functional elements, both of which must be carefully monitored at all disease stages to determine when interventions are warranted.
Sun JA, Manz SN, Shen LQ. Glaucoma management in patients with penetrating keratoplasty or keratoprosthesis. Curr Opin Ophthalmol 2023;34(2):95-102.Abstract
PURPOSE OF REVIEW: Advances in surgical techniques and postoperative care have significantly improved rates of short-term complications following keratoplasty; however, glaucoma remains a highly prevalent long-term and potentially devastating complication for postkeratoplasty patients. In this review, we provide an overview of recent literature on glaucoma management in patients who have undergone penetrating keratoplasty or the Boston keratoprosthesis type I (KPro) implantation. RECENT FINDINGS: New research suggests an inflammatory cause underlying glaucoma following KPro. Accurate IOP measurement is difficult in patients postkeratoplasty; study of objective techniques such as PDCT or Tono-Pen in penetrating keratoplasty eyes and trans-palpebral Diaton tonometry in KPro eyes have shown promising results. Early glaucoma surgical intervention should be considered for patients undergoing penetrating keratoplasty and KPro. SUMMARY: Patients who have undergone penetrating keratoplasty or implantation of the Boston keratoprosthesis type I should be monitored frequently for elevated intraocular pressure and for other signs of glaucomatous optic nerve damage. Intraocular pressure elevation should be treated promptly either medically or surgically while minimizing risk to the corneal graft. Further research into inflammatory causes and other treatment modalities is promising for the long-term visual success in these patients.
Fu Z, Lundgren P, Pivodic A, Yagi H, Harman JC, Yang J, Ko M, Neilsen K, Talukdar S, Hellström A, Smith LEH. FGF21 via mitochondrial lipid oxidation promotes physiological vascularization in a mouse model of Phase I ROP. Angiogenesis 2023;26(3):409-421.Abstract
Hyperglycemia in early postnatal life of preterm infants with incompletely vascularized retinas is associated with increased risk of potentially blinding neovascular retinopathy of prematurity (ROP). Neovascular ROP (Phase II ROP) is a compensatory but ultimately pathological response to the suppression of physiological postnatal retinal vascular development (Phase I ROP). Hyperglycemia in neonatal mice which suppresses physiological retinal vascular growth is associated with decreased expression of systemic and retinal fibroblast growth factor 21 (FGF21). FGF21 administration promoted and FGF21 deficiency suppressed the physiological retinal vessel growth. FGF21 increased serum adiponectin (APN) levels and loss of APN abolished FGF21 promotion of physiological retinal vascular development. Blocking mitochondrial fatty acid oxidation also abolished FGF21 protection against delayed physiological retinal vessel growth. Clinically, preterm infants developing severe neovascular ROP (versus non-severe ROP) had a lower total lipid intake with more parenteral and less enteral during the first 4 weeks of life. Our data suggest that increasing FGF21 levels in the presence of adequate enteral lipids may help prevent Phase I retinopathy (and therefore prevent neovascular disease).

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