Thanos S, Böhm MRR, Meyer Zu Hörste M, Prokosch-Willing V, Hennig M, Bauer D, Heiligenhaus A. Role of crystallins in ocular neuroprotection and axonal regeneration. Prog Retin Eye Res 2014;42:145-61.Abstract
Neuroprotection is an emerging challenge in ophthalmology due to the particularly exposed location of retinal neurons and to the steadily increasing rate of intraocular surgical and pharmacological treatments applied to various eye diseases. Within few decades neuroprotection has developed from strongly contested approaches to being recognized and introduced as a potentially clinical application. One of the groups of putative substances for neuroprotection comprises αA- and αB-crystallins, which are types of heat-shock proteins and are considered to be molecular chaperones. The β/γ-crystallins form their own superfamily and are characterized as proteins with a distinct structure containing four Greek key motifs. Besides being abundant in the ocular lens, crystallins are also expressed in both the developing and mature retina. Crystallins are dramatically up-regulated in numerous retinal pathologies, including mechanical injury, ischemic insults, age-related macular degeneration, uveoretinitis, and diabetic retinopathy. Crystallins of the α family are thought to play a crucial role in retinal neuron survival and inflammation. Crystallins of the β/γ superfamily are also small proteins with a possible emerging role in retinal tissue remodeling and repair. One of the typical retinal diseases associated with crystallins is the experimental glaucomatous neuropathy that is characterized by their expression. Another typical retinal disease is the atrophy that occurs after mechanical injury to the optic nerve, which is associated with the need to regrow retinal axons. We have shown in regenerative models in vivo and in vitro that βB2-crystallin actively supports the regenerative growth of cut retinal axons, thereby offering targets for neuroprotective and regenerative treatments. In this review we discuss the discovery that βB2-crystallin is clearly up-regulated in the regenerating retina in vitro. βB2-Crystallin is produced and secreted during axon elongation, while β/γ-crystallins promote axon growth both in vivo and in vitro by acting either directly by uptake into cells, or indirectly by enhancing the production of ciliary neurotrophic factor from astrocytes to synergistically promote axon regrowth. We also discuss methods to induce the continuous production of crystallins at the site of injury and repair based on the use of transfected neural progenitor cells. This review ultimately leads to the conclusion that the postinjury fate of neurons cannot be seen merely as inevitable, but instead should be regarded as a challenge to shaping the neuroprotective and regenerative conditions that promote cell survival and axon repair.
Swaminathan SS, Oh D-J, Kang MH, Shepard AR, Pang I-H, Rhee DJ. TGF-β2-mediated ocular hypertension is attenuated in SPARC-null mice. Invest Ophthalmol Vis Sci 2014;55(7):4084-97.Abstract
PURPOSE: Transforming growth factor-β2 (TGF-β2) has been implicated in the pathogenesis of primary open-angle glaucoma through extracellular matrix (ECM) alteration among various mechanisms. Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein that regulates ECM within the trabecular meshwork (TM), and is highly upregulated by TGF-β2. We hypothesized that, in vivo, SPARC is a critical regulatory node in TGF-β2-mediated ocular hypertension. METHODS: Empty (Ad.empty) or TGF-β2-containing adenovirus (Ad.TGF-β2) was injected intravitreally into C57BL6-SV129 WT and SPARC-null mice. An initial study was performed to identify a stable period for IOP measurement under isoflurane. The IOP was measured before injection and every other day for two weeks using rebound tonometry. Additional mice were euthanized at peak IOP for immunohistochemistry. RESULTS: The IOP was stable under isoflurane during minutes 5 to 8. The IOP was significantly elevated in Ad.TGF-β2-injected (n = 8) versus Ad.empty-injected WT (n = 8) mice and contralateral uninjected eyes during days 4 to 11 (P < 0.03). The IOPs were not significantly elevated in Ad.TGF-β2-injected versus Ad.empty-injected SPARC-null mice. However, on day 8, the IOP of Ad.TGF-β2-injected SPARC-null eyes was elevated compared to that of contralateral uninjected eyes (P = 0.0385). Immunohistochemistry demonstrated that TGF-β2 stimulated increases in collagen IV, fibronectin, plasminogen activator inhibitor-1 (PAI-1), connective tissue growth factor (CTGF), and SPARC in WT mice, but only PAI-1 and CTGF in SPARC-null mice (P < 0.05). CONCLUSIONS: SPARC is essential to the regulation of TGF-β2-mediated ocular hypertension. Deletion of SPARC significantly attenuates the effects of TGF-β2 by restricting collagen IV and fibronectin expression. These data provide further evidence that SPARC may have an important role in IOP regulation and possibly glaucoma pathogenesis.
Stepp MA, Zieske JD, Trinkaus-Randall V, Kyne BM, Pal-Ghosh S, Tadvalkar G, Pajoohesh-Ganji A. Wounding the cornea to learn how it heals. Exp Eye Res 2014;121:178-93.Abstract
Corneal wound healing studies have a long history and rich literature that describes the data obtained over the past 70 years using many different species of animals and methods of injury. These studies have lead to reduced suffering and provided clues to treatments that are now helping patients live more productive lives. In spite of the progress made, further research is required since blindness and reduced quality of life due to corneal scarring still happens. The purpose of this review is to summarize what is known about different types of wound and animal models used to study corneal wound healing. The subject of corneal wound healing is broad and includes chemical and mechanical wound models. This review focuses on mechanical injury models involving debridement and keratectomy wounds to reflect the authors' expertise.
Shao Z, Fu Z, Stahl A, Joyal J-S, Hatton C, Juan A, Hurst C, Evans L, Cui Z, Pei D, Gong Y, Xu D, Tian K, Bogardus H, Edin ML, Lih F, Sapieha P, Chen J, Panigrahy D, Hellstrom A, Zeldin DC, Smith LEH. Cytochrome P450 2C8 ω3-long-chain polyunsaturated fatty acid metabolites increase mouse retinal pathologic neovascularization--brief report. Arterioscler Thromb Vasc Biol 2014;34(3):581-6.Abstract
OBJECTIVE: Regulation of angiogenesis is critical for many diseases. Specifically, pathological retinal neovascularization, a major cause of blindness, is suppressed with dietary ω3-long-chain polyunsaturated fatty acids (ω3LCPUFAs) through antiangiogenic metabolites of cyclooxygenase and lipoxygenase. Cytochrome P450 epoxygenases (CYP2C8) also metabolize LCPUFAs, producing bioactive epoxides, which are inactivated by soluble epoxide hydrolase (sEH) to transdihydrodiols. The effect of these enzymes and their metabolites on neovascularization is unknown. APPROACH AND RESULTS: The mouse model of oxygen-induced retinopathy was used to investigate retinal neovascularization. We found that CYP2C (localized in wild-type monocytes/macrophages) is upregulated in oxygen-induced retinopathy, whereas sEH is suppressed, resulting in an increased retinal epoxide:diol ratio. With a ω3LCPUFA-enriched diet, retinal neovascularization increases in Tie2-driven human-CYP2C8-overexpressing mice (Tie2-CYP2C8-Tg), associated with increased plasma 19,20-epoxydocosapentaenoic acid and retinal epoxide:diol ratio. 19,20-Epoxydocosapentaenoic acids and the epoxide:diol ratio are decreased with overexpression of sEH (Tie2-sEH-Tg). Overexpression of CYP2C8 or sEH in mice does not change normal retinal vascular development compared with their wild-type littermate controls. The proangiogenic role in retina of CYP2C8 with both ω3LCPUFA and ω6LCPUFA and antiangiogenic role of sEH in ω3LCPUFA metabolism were corroborated in aortic ring assays. CONCLUSIONS: Our results suggest that CYP2C ω3LCPUFA metabolites promote retinal pathological angiogenesis. CYP2C8 is part of a novel lipid metabolic pathway influencing retinal neovascularization.
Santiago JG, Walia S, Sun JK, Cavallerano JD, Haddad ZA, Aiello LP, Silva PS. Influence of diabetes and diabetes type on anatomic and visual outcomes following central rein vein occlusion. Eye (Lond) 2014;28(3):259-68.Abstract
PURPOSE: To determine the influence of diabetes and diabetes type on ocular outcomes following central retinal vein occlusion (CRVO). METHODS: Retrospective chart review of all patients evaluated over a 4-year period in a tertiary diabetes eye care center. Ophthalmic findings were recorded including visual acuity and the presence of retinal neovascularization at presentation, after 3-6 months, and at last follow-up. RESULTS: The records of 19,648 patients (13,571 diabetic; 6077 nondiabetic) were reviewed. The prevalence of CRVO in diabetic patients (N=72) and nondiabetic patients (N=27) were 0.5 and 0.4%, respectively. Disc neovascularization (21.3 vs 0.0%, P=0.05) and panretinal photocoagulation (PRP) (48.7 vs 21.4%, P=0.01) were more common in diabetic patients compared with nondiabetic patients. Compared with type 2 diabetic patients, retinal neovascularization (28.6 vs 3.7%, P=0.004) and subsequent PRP (78.6 vs 41.9%, P=0.01) were more likely in type 1 patients. Optic nerve head collateral vessels (CVs) were observed less than half as often (21.4 vs 56.5%, P=0.04) in patients with type 1 diabetes. Presence of optic nerve head CVs at baseline was associated with less likelihood of PRP (14.3 vs 46.1%, P=0.03). CONCLUSIONS: In this cohort, the rates of CRVO in diabetic and nondiabetic patients were similar to previously published population-based studies. Following CRVO, diabetic patients had higher rates of disc neovascularization and were more likely to require subsequent PRP than nondiabetic patients. As compared with CRVO patients with type 2 diabetes, patients with type 1 diabetes and CRVO had worse anatomic outcomes with substantially increased risks of retinal neovascularization and PRP; however, final visual acuity outcomes were similar.
Thornton IM, Bülthoff HH, Horowitz TS, Rynning A, Lee S-W. Interactive multiple object tracking (iMOT). PLoS One 2014;9(2):e86974.Abstract
We introduce a new task for exploring the relationship between action and attention. In this interactive multiple object tracking (iMOT) task, implemented as an iPad app, participants were presented with a display of multiple, visually identical disks which moved independently. The task was to prevent any collisions during a fixed duration. Participants could perturb object trajectories via the touchscreen. In Experiment 1, we used a staircase procedure to measure the ability to control moving objects. Object speed was set to 1°/s. On average participants could control 8.4 items without collision. Individual control strategies were quite variable, but did not predict overall performance. In Experiment 2, we compared iMOT with standard MOT performance using identical displays. Object speed was set to 2°/s. Participants could reliably control more objects (M = 6.6) than they could track (M = 4.0), but performance in the two tasks was positively correlated. In Experiment 3, we used a dual-task design. Compared to single-task baseline, iMOT performance decreased and MOT performance increased when the two tasks had to be completed together. Overall, these findings suggest: 1) There is a clear limit to the number of items that can be simultaneously controlled, for a given speed and display density; 2) participants can control more items than they can track; 3) task-relevant action appears not to disrupt MOT performance in the current experimental context.
Sümbül U, Song S, McCulloch K, Becker M, Lin B, Sanes JR, Masland RH, Seung SH. A genetic and computational approach to structurally classify neuronal types. Nat Commun 2014;5:3512.Abstract
The importance of cell types in understanding brain function is widely appreciated but only a tiny fraction of neuronal diversity has been catalogued. Here we exploit recent progress in genetic definition of cell types in an objective structural approach to neuronal classification. The approach is based on highly accurate quantification of dendritic arbor position relative to neurites of other cells. We test the method on a population of 363 mouse retinal ganglion cells. For each cell, we determine the spatial distribution of the dendritic arbors, or arbor density, with reference to arbors of an abundant, well-defined interneuronal type. The arbor densities are sorted into a number of clusters that is set by comparison with several molecularly defined cell types. The algorithm reproduces the genetic classes that are pure types, and detects six newly clustered cell types that await genetic definition.
Suelves AM, Siddique SS, Schurko B, Foster SC. Anterior chamber intraocular lens implantation in patients with a history of chronic uveitis: five-year follow-up. J Cataract Refract Surg 2014;40(1):77-81.Abstract
PURPOSE: To compare the incidence of long-term complications after cataract surgery with primary anterior chamber intraocular lens (AC IOL) implantation in uveitic patients and patients without a history of intraocular inflammation (control group). SETTING: Single-center private practice. DESIGN: Retrospective clinical study. METHODS: The study comprised patients who between November 2005 and August 2010 had cataract extraction followed by AC IOL implantation because conventional placement was not possible. Outcome measures were the incidence of intraoperative and postoperative complications, preoperative corrected distance visual acuity (CDVA), and CDVA after 1 year. RESULTS: Of the 39 patients identified through electronic medical records, 17 (17 eyes) had a history of chronic uveitis and 22 (23 eyes) had no intraocular inflammatory disease. There were no significant differences in the incidence of intraoperative and postoperative complications between the 2 groups during follow-up (range 12 to 68 months) (P=.702). Although uveitic eyes had a greater risk for epiretinal membrane formation, the incidence of uveitis flareups attributed to the IOL and deposits on IOL surfaces was comparable to that in the control group (P<.001). The CDVA improved significantly in both groups 1 year after surgery (P<.01 and P<.001, respectively). CONCLUSION: In uveitic eyes with inadequate capsule support, AC IOL implantation restored visual function without a significant increase in long-term postoperative complications compared with eyes that had no history of uveitis.
Owen LA, Morrison MA, Ahn J, Woo SJ, Sato H, Robinson R, Morgan DJ, Zacharaki F, Simeonova M, Uehara H, Chakravarthy U, Hogg RE, Ambati BK, Kotoula M, Baehr W, Haider NB, Silvestri G, Miller JW, Tsironi EE, Farrer LA, Kim IK, Park KH, Deangelis MM. FLT1 genetic variation predisposes to neovascular AMD in ethnically diverse populations and alters systemic FLT1 expression. Invest Ophthalmol Vis Sci 2014;55(6):3543-54.Abstract
PURPOSE: Current understanding of the genetic risk factors for age-related macular degeneration (AMD) is not sufficiently predictive of the clinical course. The VEGF pathway is a key therapeutic target for treatment of neovascular AMD; however, risk attributable to genetic variation within pathway genes is unclear. We sought to identify single nucleotide polymorphisms (SNPs) associated with AMD within the VEGF pathway. METHODS: Using a tagSNP, direct sequencing and meta-analysis approach within four ethnically diverse cohorts, we identified genetic risk present in FLT1, though not within other VEGF pathway genes KDR, VEGFA, or VASH1. We used ChIP and ELISA in functional analysis. RESULTS: The FLT1 SNPs rs9943922, rs9508034, rs2281827, rs7324510, and rs9513115 were significantly associated with increased risk of neovascular AMD. Each association was more significant after meta-analysis than in any one of the four cohorts. All associations were novel, within noncoding regions of FLT1 that do not tag for coding variants in linkage disequilibrium. Analysis of soluble FLT1 demonstrated higher expression in unaffected individuals homozygous for the FLT1 risk alleles rs9943922 (P = 0.0086) and rs7324510 (P = 0.0057). In silico analysis suggests that these variants change predicted splice sites and RNA secondary structure, and have been identified in other neovascular pathologies. These data were supported further by murine chromatin immunoprecipitation demonstrating that FLT1 is a target of Nr2e3, a nuclear receptor gene implicated in regulating an AMD pathway. CONCLUSIONS: Although exact variant functions are not known, these data demonstrate relevancy across ethnically diverse genetic backgrounds within our study and, therefore, hold potential for global efficacy.
Nassi JJ, Gómez-Laberge C, Kreiman G, Born RT. Corticocortical feedback increases the spatial extent of normalization. Front Syst Neurosci 2014;8:105.Abstract
Normalization has been proposed as a canonical computation operating across different brain regions, sensory modalities, and species. It provides a good phenomenological description of non-linear response properties in primary visual cortex (V1), including the contrast response function and surround suppression. Despite its widespread application throughout the visual system, the underlying neural mechanisms remain largely unknown. We recently observed that corticocortical feedback contributes to surround suppression in V1, raising the possibility that feedback acts through normalization. To test this idea, we characterized area summation and contrast response properties in V1 with and without feedback from V2 and V3 in alert macaques and applied a standard normalization model to the data. Area summation properties were well explained by a form of divisive normalization, which computes the ratio between a neuron's driving input and the spatially integrated activity of a "normalization pool." Feedback inactivation reduced surround suppression by shrinking the spatial extent of the normalization pool. This effect was independent of the gain modulation thought to mediate the influence of contrast on area summation, which remained intact during feedback inactivation. Contrast sensitivity within the receptive field center was also unaffected by feedback inactivation, providing further evidence that feedback participates in normalization independent of the circuit mechanisms involved in modulating contrast gain and saturation. These results suggest that corticocortical feedback contributes to surround suppression by increasing the visuotopic extent of normalization and, via this mechanism, feedback can play a critical role in contextual information processing.
Matsumoto H, Kataoka K, Tsoka P, Connor KM, Miller JW, Vavvas DG. Strain difference in photoreceptor cell death after retinal detachment in mice. Invest Ophthalmol Vis Sci 2014;55(7):4165-74.Abstract
PURPOSE: To evaluate the potential for mouse genetic background to effect photoreceptor cell death in response to experimental retinal detachment (RD). METHODS: Retinal detachment was induced in three inbred mouse strains (C57BL/6, BALB/c, and B6129SF2) by subretinal injection of sodium hyaluronate. A time course of photoreceptor cell death was assessed by TUNEL assay. Total photoreceptor cell death was analyzed through comparing the outer nuclear layer (ONL)/inner nuclear layer (INL) ratio 7 days post RD. Western blot analysis or quantitative real-time PCR (qPCR) were performed to assess cell death signaling, expression of endogenous neurotrophin, and levels of apoptosis inhibitors 24 hours after RD. Inflammatory cytokine secretion and inflammatory cell infiltration were quantified by ELISA and immunostaining, respectively. RESULTS: The peak of photoreceptor cell death after RD was at 24 hours in all strains. Photoreceptor cell death as well as monocyte chemoattractant protein 1 and interleukin 6 secretion at 24 hours after RD was the highest in BALB/c, followed in order of magnitude by C57BL/6 and B6129SF2. Conversely, nerve growth factor expression and ONL/INL ratio were the lowest in BALB/c. Apoptosis signaling was higher in C57BL/6, whereas necroptosis signaling was higher in C57BL/6 and BALB/c. Autophagic signaling was higher in BALB/c. X-linked inhibitor of apoptosis (XIAP) and survivin protein levels were lower in C57BL/6 and BALB/c, respectively. Macrophage/microglia infiltration was higher in C57BL/6 and BALB/c at 24 hours after RD. CONCLUSIONS: Photoreceptor cell death after RD was significantly different among the three strains, suggesting the presence of genetic factors that affect photoreceptor cell death after RD.
Levin MH, Pistilli M, Daniel E, Gangaputra SS, Nussenblatt RB, Rosenbaum JT, Suhler EB, Thorne JE, Foster SC, Jabs DA, Levy-Clarke GA, Kempen JH. Incidence of visual improvement in uveitis cases with visual impairment caused by macular edema. Ophthalmology 2014;121(2):588-95.e1.Abstract
PURPOSE: Among cases of visually significant uveitic macular edema (ME), to estimate the incidence of visual improvement and identify predictive factors. DESIGN: Retrospective cohort study. PARTICIPANTS: Eyes with uveitis, seen at 5 academic ocular inflammation centers in the United States, for which ME was documented to be currently present and the principal cause of reduced visual acuity (<20/40). METHODS: Data were obtained by standardized chart review. MAIN OUTCOME MEASURES: Decrease of ≥ 0.2 base 10 logarithm of visual acuity decimal fraction-equivalent; risk factors for such visual improvement. RESULTS: We identified 1510 eyes (of 1077 patients) with visual impairment to a level <20/40 attributed to ME. Most patients were female (67%) and white (76%), and had bilateral uveitis (82%). The estimated 6-month incidence of ≥ 2 lines of visual acuity improvement in affected eyes was 52% (95% confidence interval [CI], 49%-55%). Vision reduced by ME was more likely to improve by 2 lines in eyes initially with poor visual acuity (≤ 20/200; adjusted hazard ratio [HR] 1.5; 95% CI, 1.3-1.7), active uveitis (HR, 1.3; 95% CI, 1.1-1.5), and anterior uveitis as opposed to intermediate (HR, 1.2), posterior (HR, 1.3), or panuveitis (HR, 1.4; overall P = 0.02). During follow-up, reductions in anterior chamber or vitreous cellular activity or in vitreous haze each led to significant improvements in visual outcome (P <0.001 for each). Conversely, snowbanking (HR, 0.7; 95% CI, 0.4-0.99), posterior synechiae (HR, 0.8; 95% CI, 0.6-0.9), and hypotony (HR, 0.2; 95% CI, 0.06-0.5) each were associated with lower incidence of visual improvement with respect to eyes lacking each of these attributes at a given visit. CONCLUSIONS: These results suggest that many, but not all, patients with ME causing low vision in a tertiary care setting will enjoy meaningful visual recovery in response to treatment. Evidence of significant ocular damage from inflammation (posterior synechiae and hypotony) portends a lower incidence of visual recovery. Better control of anterior chamber or vitreous activity is associated with a greater incidence of visual improvement, supporting an aggressive anti-inflammatory treatment approach for ME cases with active inflammation.
Nguyen J, Fay A, Yadav P, MacIntosh PW, Metson R. Stereotactic microdebrider in deep lateral orbital decompression for patients with thyroid eye disease. Ophthalmic Plast Reconstr Surg 2014;30(3):262-6.Abstract
PURPOSE: Stereotactic navigation systems have been used in neurosurgery and otolaryngology with great success. The current investigation illustrates the novel use of a microdebrider with built-in stereotactic guidance in a series of thyroid orbitopathy patients who underwent deep lateral orbital wall decompression surgery. METHODS: A noncomparative, interventional, retrospective case series of patients who underwent deep lateral deep orbital wall decompression from 2006 to 2013 was conducted in accordance with Institutional Review Board policy and the Declaration of Helsinki. Patient demographics, indications for surgery, pre-, intra-, and postoperative findings along with complications were recorded. RESULTS: One hundred eight deep lateral orbital decompression surgeries were performed in 69 patients using the Straightshot M4 Microdebrider with built-in stereotactic guidance (Medtronics). Seventy-eight cases were in women and 30 cases were in men. The average age was 50.4 years (SD = 11.9 years). Indications for surgery included proptosis, exposure keratopathy, or compressive optic neuropathy. No patient experienced intraoperative complications. Specifically, cerebrospinal fluid leak, visual loss, infection, or unanticipated inflammation were not encountered. The average postoperative follow-up time was 5.35 months. Mean reduction in proptosis was 3.72 mm (SD = 2.1). Visual acuity improved in 32.4% (35/108) of cases. CONCLUSIONS: This surgical instrument combines a single handpiece locator, microdebrider, irrigator, retractor, and suction device into one. It enhances anatomical localization during orbital decompression and, with an integrated tissue guard, may decrease the risk of injury to orbital soft tissues. Stereotactic navigation enhances the surgeon's ability to determine the maximal limits of decompression in real time by confirming depth of bone removal and may potentially increase surgeons' confidence in orbital decompression surgery.
Miller JW. The Harvard angiogenesis story. Surv Ophthalmol 2014;59(3):361-4.Abstract
I shall discuss the work of researchers at Harvard Medical School who came together in the early 1990s. Scattered across various Harvard-affiliated hospitals and research centers, these individuals were unified by their interest in ocular neovascularization. Together and separately, they investigated models of ocular neovascularization, exploring tumor angiogenesis in eye development and disease.
Lundgren P, Kistner A, Andersson EM, Hansen Pupp I, Holmström G, Ley D, Niklasson A, Smith LEH, Wu C, Hellström A, Löfqvist C. Low birth weight is a risk factor for severe retinopathy of prematurity depending on gestational age. PLoS One 2014;9(10):e109460.Abstract
OBJECTIVE: To evaluate the impact of low birth weight as a risk factor for retinopathy of prematurity (ROP) that will require treatment in correlation with gestational age at birth (GA). STUDY DESIGN: In total, 2941 infants born <32 weeks GA were eligible from five cohorts of preterm infants previously collected for analysis in WINROP (Weight IGF-I Neonatal ROP) from the following locations: Sweden (EXPRESS) (n = 426), North America (n = 1772), Boston (n = 338), Lund (n = 52), and Gothenburg (n = 353). Data regarding GA at birth, birth weight (BW), gender, and need for ROP treatment were retrieved. Birth weight standard deviation scores (BWSDS) were calculated with Swedish as well as Canadian reference models. Small for gestational age (SGA) was defined as BWSDS less than -2.0 SDS using the Swedish reference and as BW below the 10th percentile using the Canadian reference charts. RESULTS: Univariate analysis showed that low GA (p<0.001), low BW (p<0.001), male gender (p<0.05), low BWSDSCanada (p<0.001), and SGACanada (p<0.01) were risk factors for ROP that will require treatment. In multivariable logistic regression analysis, low GA (p<0.0001), male gender (p<0.01 and p<0.05), and an interaction term of BWSDS*GA group (p<0.001), regardless of reference chart, were risk factors. Low BWSDS was less important as a risk factor in infants born at GA <26 weeks compared with infants born at GA ≥26 weeks calculated with both reference charts (BWSDSSweden, OR = 0.80 vs 0.56; and BWSDSCanada, OR = 0.72 vs 0.41). CONCLUSIONS: Low BWSDS as a risk factor for vision-threatening ROP is dependent on the infant's degree of immaturity. In more mature infants (GA ≥26 weeks), low BWSDS becomes a major risk factor for developing ROP that will require treatment. These results persist even when calculating BW deficit with different well-established approaches.