Continuous oxygen saturation and risk of retinopathy of prematurity in a Japanese cohort.

BACKGROUND/AIMS: We assessed the associations between retinopathy of prematurity (ROP) and continuous measurements of oxygen saturation (SpO2), and developed a risk prediction model for severe ROP using birth data and SpO2 data. METHODS: This retrospective study included infants who were born before 30 weeks of gestation between August 2009 and January 2019 and who were screened for ROP at a single hospital in Japan. We extracted data on birth weight (BW), birth length, gestational age (GA) and minute-by-minute SpO2 during the first 20 days from the medical records. We defined four SpO2 variables using sequential measurements. Multivariate logistic regression was used to develop a model that combined birth data and SpO2 data to predict treatment-requiring ROP (TR-ROP). The model's performance was evaluated using the area under the receiver operating characteristic curve (AUC). RESULTS: Among 350 infants, 83 (23.7%) required ROP treatment. The SpO2 variables in infants with TR-ROP differed significantly from those with non-TR-ROP. The average SpO2 and high SpO2 showed strong associations with GA (r=0.73 and r=0.70, respectively). The model incorporating birth data and the four SpO2 variables demonstrated good discriminative ability (AUC=0.83), but it did not outperform the model incorporating BW and GA (AUC=0.82). CONCLUSION: Data obtained by continuous SpO2 monitoring demonstrated valuable associations with severe ROP, as well as with GA. Differences in the distribution of average SpO2 and high SpO2 between infants with TR-ROP and non-TR-ROP could be used to establish efficient cut-off values for risk determination.

Effect of polyp regression and reduction on treatment efficacy in polypoidal choroidal vasculopathy treated with aflibercept.

Intravitreal injection of aflibercept (IVA) has successfully treated polypoidal choroidal vasculopathy (PCV), and polyp morphology is an important indicator of treatment efficacy. However, many studies have not reported the presence or absence of polyp regression and treatment outcomes, and few studies have reported polyp reduction and treatment outcomes in cases with residual polyps. We retrospectively measured the polyp area on indocyanine green angiography images before and after the IVA loading phase and investigated the regression and reduction of polyps and treatment outcomes of 81 eyes with PCV treated with IVA. We investigated the relationship between the presence or absence of complete regression of polyps and the percentage change in the polyp area and treatment outcomes. Eyes with complete polyp regression had significantly better visual acuity improvements compared with baseline at 12 months (P = 0.0108), fewer treatments (P = 0.0024), fewer recurrences during 12-months follow-up (P = 0.0010), and more "dry maculas" at 3 months (P = 0.0048) than eyes in which polyp regression did not occur. A significant correlation was seen only between the percentage of polyp regression and visual acuity at 3 months (P = 0.0395). Regarding IVA therapy for PCV, the presence or absence of complete polyp regression at the end of the loading phase affected the treatment outcome, whereas the degree of polyp reduction in cases of residual polyps had no effect.

Comparison of Loading Dose between Aflibercept and Faricimab for Neovascular Age-Related Macular Degeneration.

BACKGROUND: Recently, faricimab was approved as the new drug for neovascular age-related macular degeneration (nAMD). We lack the knowledge to choose between the existing drug and this new drug to use for treatment-naïve nAMD cases. In this study, we compared the functional and morphologic effects in loading dose between patients with treatment-naïve nAMD treated with either intravitreal aflibercept (IVA) or intravitreal faricimab (IVF) injection in a clinical setting. METHOD: This retrospective study included 30 eyes of 28 patients who started treatment with IVA between June and September 2022 and 30 eyes of 29 patients who were administered IVF between October 2022 and March 2023. All patients received three monthly IVA or IVF. The best corrected visual acuity (BCVA), central retinal thickness (CRT), and the proportion of eyes with residual exudative change at baseline and 1,2, and 3 months after initial treatment were compared between the groups. RESULTS: The mean BCVA significantly improved from pre-treatment after the loading dose in the IVA group (0.46 ± 0.46-0.36 ± 0.37, p = 0.0047) but not in the IVF group (0.46 ± 0.41-0.44 ± 0.45, p = 0.60). The mean CRT significantly improved in both groups. The proportion of eyes with residual exudative change was greater in the IVF group than in the IVA group 2 months after the first treatment (p = 0.026). The analysis of cases that achieved complete resolution of exudative changes after the loading dose showed that the IVA group had a significant improvement in the BCVA, whereas the IVF group did not (p = 0.0047 and 0.20, respectively). CONCLUSIONS: Although both IVA and IVF significantly improved CRT, the BCVA improved significantly in the IVA group but not in the IVF group.

Three cases of macular retinal detachment exacerbated during follow-up with myopic foveoschisis around myopic choroidal neovascularization.

Purpose: Myopic choroidal neovascularization (CNV) and myopic traction maculopathy are major complications of pathologic myopia, and myopic foveoschisis (MF) is one of several symptoms that can be included under the general term "myopic traction maculopathy"; however, only a few cases will have MF around the myopic CNV. We report three cases with MF around myopic CNV that followed different clinical courses observed using swept-source optical coherence tomography. Observations: Case 1 was a 69-year-old woman with an axial length of 29.71 mm, myopic CNV, and MF in the left eye. One month after intravitreal injection of ranibizumab (IVR), a macular retinal detachment (RD) expanded. Vitrectomy and gas tamponade were performed during month 2; the macular RD and MF resolved gradually thereafter. Case 2 was a 54-year-old man with an axial length of 30.59 mm, myopic CNV, and MF in the right eye; after IVR, a macular RD developed and gradually expanded until month 4; the RD and MF resolved spontaneously and resolved during month 8. Case 3 was a 66-year-old woman with an axial length of 28.63 mm, myopic CNV, and MF in the left eye. A macular RD expanded 1 month after a previous vitrectomy for MF; after intravitreal injection of aflibercept, the macular RD and MF resolved gradually in month 12. In all cases, the CNV was accompanied by subretinal fluid, and two of the three cases had outer lamellar holes. Conclusion and Importance: The MF around the myopic CNV may lead to exacerbated MF and RD during follow-up, and the subretinal fluid caused by the CNV might facilitate MF progression. Since this condition is rare, further investigation of this entity is needed to determine appropriate management.

Relationship between Full-Thickness Macular Hole Onset and Posterior Vitreous Detachment: A Temporal Onset Theory.

Purpose: To evaluate the relationship between full-thickness macular hole (FTMH) onset and perifoveal posterior vitreous detachment using OCT data. Design: Retrospective study. Participants: A total of 742 patients with FTMH or impending macular hole (MH) in ≥ 1 eye, as determined by ophthalmoscopy and OCT. Methods: Macular holes were staged using OCT results. Patients with the posterior vitreous membrane clearly detected in the OCT images and vitreoretinal adhesion size ≤ 1500 µm-eyes with MH stages 1-3-were included in the study. The contralateral eyes were also included in the analyses if they showed the focal type of vitreomacular adhesion (VMA) (i.e., vitreoretinal adhesion ≤ 1500 µm). The distance between the posterior vitreous membrane and the surface of the retina was defined as the posterior vitreous separation height (PVSH). Using the OCT images, PVSHs of each eye in 4 directions (nasal, temporal, superior, and inferior) at 1 mm from the center of the MH or fovea were calculated. Main Outcome Measures: The main outcome measures were PVSHs according to the MH stage and VMA, the relationship of the foveal inner tear with PVSH, and the likelihood of a foveal inner tear based on the direction. Results: The PVSH trends in each of the 4 directions were as follows: VMA < MH stage 1 = MH stage 2 < MH stage 3. Initial MH stage 2 (onset of FTMH) was defined as the presence of a gap in only 1 of the 4 directions from the center of the MH. With increased PVSH, the likelihood of a gap increased (P = 0.002), and a temporal gap was more likely to occur than a nasal gap (P = 0.002). Conclusions: At FTMH onset, a foveal inner tear likely appears on the temporal side or the side showing a high PVSH value. Financial Disclosures: The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Microvascular Changes in the Cystic Lesion of Branch Retinal Vein Occlusion Imaged by Swept-Source Optical Coherence Tomography Angiography.

Introduction: This study aimed to describe the quantitative features of the microvasculature in the cystic lesions of branch retinal vein occlusion (BRVO). Methods: A total of 43 eyes with BRVO, treated with anti-vascular endothelial growth factor therapy, were analyzed. Using wide-field swept-source optical coherence tomography angiography (OCTA), en face OCT images were obtained by depth-integrated reflectivity of the retina, and vascular density (VD), vascular length (VL), vascular lacunarity, and fractal dimension (FD) were evaluated in a 12 × 12-mm area of retinal nonperfusion. Results: The mean area of affected lesions was 38.7 ± 19.8 mm2, and cystic lesions were 8.5 ± 10.1 mm2. VD, VL, and FD were significantly decreased in the cystic lesions compared to other affected lesions in the same eyes (p = 0.0010, p = 0.0001, and p = 0.0003, respectively) and in all eyes (p = 0.0281, p = 0.0050, and p < 0.0001, respectively). VD in cystic lesions within the vascular arcade (25 eyes) correlated with best-corrected visual acuity on OCTA (r = -0.433, and p = 0.0492). Conclusions: Vascular structure in the cystic lesions was unpreserved compared to the other lesions in BRVO. These findings may help in understanding the pathophysiology of retinal edema in BRVO.

The Caliber of Optociliary Shunt Vessels Is Associated with Macular Blood Flow and Visual Acuity in Central Retinal Vein Occlusion.

Purpose: To define the role of optociliary shunt vessels (OSVs) in eyes with central retinal vein occlusion (CRVO) using OCT angiography (OCTA) with macular parameters. Design: Retrospective, observational, consecutive case series. Participants: Forty-one eyes in 38 consecutive patients with CRVO were analyzed in this study. Methods: Optic disc and macula were imaged by swept-source OCTA (3 × 3 mm) as well as by high-quality fundus photography. Main Outcome Measures: We compared macular vessel density (VD) and visual acuity between eyes in which OSVs developed and those in which they did not. Furthermore, we measured the diameter of the OSVs and analyzed the correlation with macular VD and visual acuity. Results: Optociliary shunt vessels were found in 25 eyes (61%). Central retinal vein occlusion with OSVs did not show any statistical difference compared with CRVO without OSVs in either macular VD of the total retina (0.31 ± 0.07 and 0.26 ± 0.09, respectively; P = 0.0937) or final best-corrected visual acuity (BCVA) (0.30 ± 0.43 logarithm of the minimum angle of resolution [logMAR] and 0.59 ± 0.54 logMAR, respectively; P = 0.0705). The mean OSV diameter was 71 ± 30 µm in CRVO with OSV. The diameter of the OSVs was correlated positively with superficial VD (r = 0.443; P = 0.027), deep VD (r = 0.494; P = 0.012), and total VD (r = 0.491; P = 0.013). Furthermore, the OSV diameter was also negatively correlated with BCVA (logMAR) at the final visit (r = -0.531; P = 0.006). Conclusions: The results demonstrated that the diameter of the OSVs was associated with macular VD and visual acuity in patients with CRVO. The development of large OSVs on the optic disc may be a good indicator of the maintenance of blood flow in the macula.

Characteristics of choroidal neovascularization in elderly eyes with high myopia not meeting the pathologic myopia definition.

The META-Analysis of Pathologic Myopia Study group proposed a new classification system for myopic maculopathy (MM) with pathologic myopia (PM) defined as MM equal to/more serious than diffuse atrophy or the presence of plus lesions and myopic choroidal neovascularization (mCNV) defined as CNV in the eye with PM. However, CNV in elderly eyes with high myopia (HM) not meeting the PM definition (high-myopia CNV) are not classified as age-related macular degeneration (nAMD) or mCNV. This retrospective study included 39 eyes with high-myopia CNV, 20 eyes with mCNV, and 20 eyes with AMD. All patients were at least 40 years old. We compared the clinical characteristics and treatment outcomes among three groups. The high-myopia CNV group had significantly more CNV types, shorter axial length and fewer lacquer cracks (P < 0.0001, respectively); larger baseline greatest linear dimension (P = 0.0002), more fellow-eye drusen (P = 0.0106), more men (P = 0.0029), and more treatments (24 months, P = 0.0098) compared to the mCNV group. Compared with the nAMD group, the high-myopia CNV group was significantly younger (P = 0.0041), and had fewer CNV types (P = 0.0316), more lacquer cracks (P = 0.0079) and fewer drusen (affected-eye, P = 0.0006 and fellow-eye, P = 0.0222), and fewer treatments (24 months, P = 0.0030). Because the CNV in elderly eyes with HM not meeting the PM definition is classified as combined mCNV and nAMD, the clinical and angiographic findings are critical to determine the treatment strategy.

Adiponectin accumulation in the retinal vascular endothelium and its possible role in preventing early diabetic microvascular damage.

Adiponectin (APN), a protein abundantly secreted from adipocytes, has been reported to possess beneficial effects on cardiovascular diseases in association with its accumulation on target organs and cells by binding to T-cadherin. However, little is known about the role of APN in the development of diabetic microvascular complications, such as diabetic retinopathy (DR). Here we investigated the impact of APN on the progression of early retinal vascular damage using a streptozotocin (STZ)-induced diabetic mouse model. Our immunofluorescence results clearly showed T-cadherin-dependent localization of APN in the vascular endothelium of retinal arterioles, which was progressively decreased during the course of diabetes. Such reduction of retinal APN accompanied the early features of DR, represented by increased vascular permeability, and was prevented by glucose-lowering therapy with dapagliflozin, a selective sodium-glucose co-transporter 2 inhibitor. In addition, APN deficiency resulted in severe vascular permeability under relatively short-term hyperglycemia, together with a significant increase in vascular cellular adhesion molecule-1 (VCAM-1) and a reduction in claudin-5 in the retinal endothelium. The present study demonstrated a possible protective role of APN against the development of DR.

Analysis of Progressive Neovascularization in Diabetic Retinopathy Using Widefield OCT Angiography.

PURPOSE: To document enlarged neovascularization elsewhere (NVE) quantitatively and morphologically using widefield swept-source (SS) OCT angiography (OCTA) with vitreoretinal interface (VRI) slab images. DESIGN: Retrospective, observational imaging study. PARTICIPANTS: The study included 46 NVE examples in 25 eyes of 21 consecutive patients who demonstrated severe proliferative diabetic retinopathy with NVE between March 2018 and June 2020 at Osaka University Hospital. METHODS: All patients underwent ophthalmologic examination, including ultra-widefield fluorescein angiography and widefield SS OCTA scans. MAIN OUTCOME MEASURES: We evaluated the area and the vascular density (VD) of NVE lesions detected on five 12 × 12-mm2 or two 15 × 9-mm2 SS OCTA panoramic VRI slab images obtained at the first and final visits. RESULTS: At baseline, the mean NVE area on OCTA was 1.85 ± 2.81 mm2, and the VD of the NVE lesions was 73.9 ± 14.6%. At the final visit, the mean NVE area on OCTA was 2.14 ± 3.14 mm2, and the mean VD of the NVE lesions was 65.3 ± 17.1%. The average NVE size change (square millimeters per month) was associated significantly with the ischemic index (P = 0.009). Growth of NVE area was classified into 2 patterns: round (61.8%) and ramified (38.2%). The round group tended to have a larger ischemic index at baseline than the ramified group (P = 0.0375). CONCLUSIONS: We quantified the size and density of NVE lesions over time. The NVE size increase was associated significantly with the severity of ischemic changes. Furthermore, the round growth pattern was correlated significantly with the ischemic index. These findings suggest that the morphologic features of NVE are associated with more severe ischemia.

Association between choriocapillaris flow deficit and choroidal neovascularization activity in eyes with myopic choroidal neovascularization.

Although choriocapillaris flow deficit (CFD) around choroidal neovascularization (CNV) is less associated with CNV activity in myopic eyes, no reports are investigating its size as an indicator of CNV activity. We investigated the relationship between CFD and high myopia-related CNV. In this retrospective, observational study, patients underwent optical coherence tomography angiography (OCTA) with split-spectrum amplitude-decorrelation angiography for diagnosing pathological myopic CNV (mCNV); CFD features around CNV margins were evaluated. Of the 33 eyes (30 patients), 11 (33.3%) had active mCNV, and 22 (66.7%) had inactive CNV. Six eyes (18.2%) were treatment-naïve, while the remainder previously underwent anti-vascular endothelial growth factor therapy. On OCTA, blood flow signals were detected in CNV in the outer retinal layer in 28 (84.8%) eyes, including all active cases (11 cases) and 17 (77.3%) of 22 inactive cases. CNV flow signal size correlated significantly with activity (P < 0.001). CFD around CNV was observed in 24 eyes (72.7%), including all active cases (11 cases) and 13 (59.1%) of 22 inactive cases. CFD size correlated significantly with CNV activity (P < 0.001). The size of both the CFD area around CNV and CNV flow signal area are useful indicators of CNV activity in eyes with mCNV, which may help determine treatment timing.

Impact of photoreceptor density in a 3D simulation of panretinal laser photocoagulation.

BACKGROUND: During panretinal photocoagulation (PRP), the outer retina, especially the photoreceptors, are destroyed. During such procedures, the impact of the retinal photocoagulation, which is performed in the same photocoagulated area, may change if it is applied to different locations with different photoreceptor densities. Thus, we aimed to evaluate the influence of photoreceptor density on PRP. METHODS: We constructed a three-dimensional (3D) average distribution of photoreceptors with 3D computer-aided design (CAD) software using previously derived photoreceptor density data and calculated the number of photoreceptors destroyed by scatter PRP and full-scatter PRP (size 400-µm on the retina, spacing 1.0 spot) using a geometry-based simulation. To investigate the impact of photoreceptor density on PRP, we calculated the ratio of the number of photoreceptors destroyed to the total number of photoreceptors, termed the photoreceptor destruction index. RESULTS: In this 3D simulation, the total number of photoreceptors was 96,571,900. The total number of photoreceptors destroyed by scatter PRP and full-scatter PRP were 15,608,200 and 19,120,600, respectively, and the respective photoreceptor destruction indexes were 16.2 and 19.8%, respectively. CONCLUSIONS: Scatter PRP is expected to have 4/5 of the number of photoreceptors destroyed by full-scatter PRP.

Long-term outcomes of intravitreal activated protein C injection for ischemic central retinal vein occlusion: an extension trial.

PURPOSE: Our previous 1-year pilot study evaluated the efficacy of intravitreally injected activated protein C (APC) in 10 eyes with ischemic central retinal vein occlusion (CRVO). The reperfusion of the areas of retinal nonperfusion (RNP) exceeded 50% of the baseline in five (50%) eyes 1 year after the APC injection. The current study evaluated the long-term efficacy and safety of intravitreal APC. METHODS: The 10 eyes in the pilot study were included in this study. Other treatments were administered at the physicians' discretion after the pilot study. We evaluated visual acuity (VA), central retinal thickness (CRT) and perfusion status, and adverse events and severity over the long term. RESULTS: The median follow-up was 60 months (range, 48-68 months). Compared with baseline, the post-treatment VA improved significantly (P < 0.001) from 1.39 to 1.06 logarithm of the minimum angle of resolution. The CRT improved significantly (P < 0.001) from 1090 to 195 µm at the last visit. The RNP areas decreased from an average 29.7 disc areas (DAs) at baseline to an average 16.5 DAs at the last examination (mean, 40 ± 6.5 months after the first APC treatment). No adverse events were related to intravitreal APC. CONCLUSION: No complications were associated with intravitreal APC, the clinical course improved, and improved RNP was maintained for the long term, suggesting that intravitreal APC may be an alternative treatment for CRVO.

Rho GTPases in Retinal Vascular Diseases.

The Rho family of small GTPases (Rho GTPases) act as molecular switches that transduce extrinsic stimuli into cytoskeletal rearrangements. In vascular endothelial cells (ECs), Cdc42, Rac1, and RhoA control cell migration and cell-cell junctions downstream of angiogenic and inflammatory cytokines, thereby regulating vascular formation and permeability. While these Rho GTPases are broadly expressed in various types of cells, RhoJ is enriched in angiogenic ECs. Semaphorin 3E (Sema3E) releases RhoJ from the intracellular domain of PlexinD1, by which RhoJ induces actin depolymerization through competition with Cdc42 for their common effector proteins. RhoJ further mediates the Sema3E-induced association of PlexinD1 with vascular endothelial growth factor receptor (VEGFR) 2 and the activation of p38. Upon stimulation with VEGF-A, RhoJ facilitates the formation of a holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, leading to the prevention of VEGFR2 degradation and the maintenance of intracellular signal transduction. These pleiotropic roles of RhoJ are required for directional EC migration in retinal angiogenesis. This review highlights the latest insights regarding Rho GTPases in the field of vascular biology, as it will be informative to consider their potential as targets for the treatment of aberrant angiogenesis and hyperpermeability in retinal vascular diseases.

Flow pattern and perforating vessels in three different phases of myopic choroidal neovascularization seen by swept-source optical coherence tomography angiography.

PURPOSE: To compare the choroidal neovascularization (CNV) flow patterns and the relationship between perforating vessels (PVs) and CNV in the three different stages of networks in myopic CNV (mCNV) using swept-source optical coherence tomography angiography (SS-OCTA). METHODS: This retrospective study included 28 eyes with mCNV that was divided into three phases (active, scar, and atrophic) and observed by SS-OCTA. SS-OCTA findings, with special focus on the relationship between the PVs and CNV, were compared among the three phases. RESULTS: Overall, the CNV signal was detected in 31 of the 34 areas of CNV (91%); in the active, scar, and atrophic phases, respectively, CNV signals were detected in eight of eight areas of CNV (100%), 10 of 11 areas of CNV (91%), and 13 of 15 areas of CNV (86%). Two signal patterns were observed in each phase, i.e., dense and loop; in the atrophic phase, seven eyes were unclassifiable. The ratio between the dense and loop patterns did not differ significantly among the phases. In 30 of 34 areas of CNV for which clear images were obtained, the PVs and CNV were connected directly or indirectly in 19 area of CNV, and in five areas of CNV, trunk-like vessels were connected to the PVs within the CNV. The numbers of foveal or parafoveal CNVs accompanied by PVs were significantly (p=0.0048) greater than those of the extrafoveal CNV. CONCLUSIONS: OCTA provides detailed observation of mCNV and the relationship between CNV and PVs. Although the CNV signal pattern does not differ depending on the degree of atrophy, there are cases in which only the trunk-like vessels connect to the PVs within the CNV in the atrophic phase without CNV flow signal.

Automated detection of early-stage ROP using a deep convolutional neural network.

BACKGROUND/AIM: To automatically detect and classify the early stages of retinopathy of prematurity (ROP) using a deep convolutional neural network (CNN). METHODS: This retrospective cross-sectional study was conducted in a referral medical centre in Taiwan. Only premature infants with no ROP, stage 1 ROP or stage 2 ROP were enrolled. Overall, 11 372 retinal fundus images were compiled and split into 10 235 images (90%) for training, 1137 (10%) for validation and 244 for testing. A deep CNN was implemented to classify images according to the ROP stage. Data were collected from December 17, 2013 to May 24, 2019 and analysed from December 2018 to January 2020. The metrics of sensitivity, specificity and area under the receiver operating characteristic curve were adopted to evaluate the performance of the algorithm relative to the reference standard diagnosis. RESULTS: The model was trained using fivefold cross-validation, yielding an average accuracy of 99.93%±0.03 during training and 92.23%±1.39 during testing. The sensitivity and specificity scores of the model were 96.14%±0.87 and 95.95%±0.48, 91.82%±2.03 and 94.50%±0.71, and 89.81%±1.82 and 98.99%±0.40 when predicting no ROP versus ROP, stage 1 ROP versus no ROP and stage 2 ROP, and stage 2 ROP versus no ROP and stage 1 ROP, respectively. CONCLUSIONS: The proposed system can accurately differentiate among ROP early stages and has the potential to help ophthalmologists classify ROP at an early stage.

RhoJ integrates attractive and repulsive cues in directional migration of endothelial cells.

During angiogenesis, VEGF acts as an attractive cue for endothelial cells (ECs), while Sema3E mediates repulsive cues. Here, we show that the small GTPase RhoJ integrates these opposing signals in directional EC migration. In the GTP-bound state, RhoJ interacts with the cytoplasmic domain of PlexinD1. Upon Sema3E stimulation, RhoJ released from PlexinD1 induces cell contraction. PlexinD1-bound RhoJ further facilitates Sema3E-induced PlexinD1-VEGFR2 association, VEGFR2 transphosphorylation at Y1214, and p38 MAPK activation, leading to reverse EC migration. Upon VEGF stimulation, RhoJ is required for the formation of the holoreceptor complex comprising VEGFR2, PlexinD1, and neuropilin-1, thereby preventing degradation of internalized VEGFR2, prolonging downstream signal transductions via PLCγ, Erk, and Akt, and promoting forward EC migration. After conversion to the GDP-bound state, RhoJ shifts from PlexinD1 to VEGFR2, which then terminates the VEGFR2 signals. RhoJ deficiency in ECs efficiently suppressed aberrant angiogenesis in ischemic retina. These findings suggest that distinct Rho GTPases may act as context-dependent integrators of chemotactic cues in directional cell migration and may serve as candidate therapeutic targets to manipulate cell motility in disease or tissue regeneration.

RhoJ Regulates α5ß1 Integrin Trafficking to Control Fibronectin Remodeling during Angiogenesis.

Rho guanosine triphosphatases (GTPases) are master regulators of cell shape and cell movement [1]. The archetypal family members RhoA, Rac1, and Cdc42 arose early in eukaryotic evolution and coordinate a diverse range of cell morphologies and migrations. Evolution of the vertebrates was paralleled by expansion of this family through gene duplication. Emergence of an adaptive immune system and more complex neural systems presented new roles for Rho GTPases, filled by new family members. Cdc42 underwent gene duplication to produce two related proteins-RhoQ and RhoJ [2]. RhoQ is active in neural dynamics; however, RhoJ is highly expressed in endothelial cells under control of the endothelial-specific promoter ERG [3, 4]. RhoJ is required for angiogenesis [5, 6] and has multiple roles in this process [7, 8]. We recently demonstrated that RhoJ regulates the endosomal trafficking of podocalyxin during angiogenesis to control lumen formation [9]. Here, we use vesicle purification and proteomic analysis to identify the endothelial targets of RhoJ-mediated trafficking. We identify α5ß1 integrin as a major RhoJ cargo and show that RhoJ regulates the intracellular trafficking of active α5ß1 integrin in endothelial cells to repress fibronectin fibrillogenesis. Accordingly, mice lacking RhoJ show deregulated deposition of fibronectin around vessels during developmental angiogenesis. Intriguingly, we show that RhoJ acts in opposition to Cdc42 in this process through competition for a shared partner, PAK3. These studies identify a critical role for RhoJ in matrix remodeling during blood vessel formation and demonstrate a functional interrelationship between RhoJ and its evolutionary parent.

Characterization of the Progression Pattern in Retinopathy of Prematurity Subtypes.

PURPOSE: To evaluate differences in the progression pattern among subtypes of retinopathy of prematurity (ROP). DESIGN: Retrospective cohort study. PARTICIPANTS: Premature infants screened for ROP. METHODS: Medical records of 578 premature infants who were screened at the neonatal intensive care unit from September 2009 through March 2016 were reviewed. We matched for the number of patients, gestational age at birth, and postmenstrual age at the first examination between infants with spontaneously regressed ROP and those with treated ROP. A total of 133 premature infants who were born before 27 weeks' gestation were included. MAIN OUTCOME MEASURES: The mean age at onset of any ROP and the duration from the initial examination to onset were compared between infants with regressed ROP and those with treated ROP. The mean age at treatment and the duration from onset to treatment were compared between infants with type 1 ROP and those with aggressive posterior ROP (AP-ROP). Data were analyzed for 1 randomly selected eye for each infant. RESULTS: Of 133 premature infants with any ROP, 67 regressed spontaneously, 43 demonstrated type 1 ROP, and 23 demonstrated AP-ROP. Individual trajectories of ROP progression over time showed that AP-ROP progressed through the stages in a steep linear manner in most cases. In contrast, the type 1 ROP and regressed ROP developed in a slower, stepwise manner. CONCLUSIONS: In infants with ROP, the disease trajectories across ROP stages are different based on the ROP subtype, despite postmenstrual age at onset being comparable across subtypes. Our findings could be useful for managing follow-up screening.

Effect of fluctuation of oxygenation on the development of severe retinopathy of prematurity in extremely preterm infants.

OBJECTIVE: To investigate factors associated with development of severe retinopathy of prematurity (ROP) in extremely preterm (EP) infants. STUDY DESIGN: This retrospective cohort study included 213 EP infants (22 + 0 to 27 + 6 weeks gestation) who were admitted to the neonatal intensive care unit of Osaka Women's and Children's Hospital between 2009 and 2017. Multivariable logistic regression analysis was used to identify neonatal factors associated with severe ROP requiring treatment. RESULT: After adjustments for gestational age (GA), birth weight, sex, red blood cell transfusion, average SpO2, and fluctuations of SpO2 from birth to 32 weeks postmenstrual age, fluctuations of SpO2 (odds ratio [OR]: 2.10, 95% confidence interval [CI]: 1.03-4.27), and low GA (OR: 0.95, 95% CI: 0.91-0.98) were significantly associated with severe ROP. CONCLUSIONS: Fluctuations of SpO2 from birth to 32 weeks postmenstrual age and low GA were significantly associated with development of severe ROP requiring treatment in EP infants.