Effect of connective tissue growth factor gene editing using adeno-associated virus-mediated CRISPR-Cas9 on rabbit glaucoma filtering surgery outcomes.

Suppressing excessive wound healing responses is critical to ensure surgical success in glaucoma filtration surgery (GFS). Currently used adjunctive materials can lead to side effects due to the nonselectivity in cell inhibition and may require repeated applications. The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system may become a compelling opportunity in glaucoma surgery due to its high selectivity and permanent effect. Connective tissue growth factor (CTGF) is one of the most potent stimulators of tissue fibrosis in the eye. Therefore, we tested the effect of CTGF suppression using the CRISPR-Cas9 system on GFS fibrosis. We used an adeno-associated virus (AAV)-CRISPR-Cas9 system and confirmed successful CTGF suppression was achieved in fibroblasts in vitro through western blot analysis and deep sequencing. In the in vivo intereye-comparison rabbit GFS model, CRISPR-CTGF-treated eyes showed significantly better survival of the surgery site, less subconjunctival fibrosis, limited collagen deposition, and reduced cellularity than untreated eyes. Our results suggest a new possibility of CRISPR-Cas9-mediated CTGF suppression to improve human GFS outcomes.

Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome.

Singleton-Merten syndrome (SMS) is an autosomal-dominant multi-system disorder characterized by dental dysplasia, aortic calcification, skeletal abnormalities, glaucoma, psoriasis, and other conditions. Despite an apparent autosomal-dominant pattern of inheritance, the genetic background of SMS and information about its phenotypic heterogeneity remain unknown. Recently, we found a family affected by glaucoma, aortic calcification, and skeletal abnormalities. Unlike subjects with classic SMS, affected individuals showed normal dentition, suggesting atypical SMS. To identify genetic causes of the disease, we performed exome sequencing in this family and identified a variant (c.1118A>C [p.Glu373Ala]) of DDX58, whose protein product is also known as RIG-I. Further analysis of DDX58 in 100 individuals with congenital glaucoma identified another variant (c.803G>T [p.Cys268Phe]) in a family who harbored neither dental anomalies nor aortic calcification but who suffered from glaucoma and skeletal abnormalities. Cys268 and Glu373 residues of DDX58 belong to ATP-binding motifs I and II, respectively, and these residues are predicted to be located closer to the ADP and RNA molecules than other nonpathogenic missense variants by protein structure analysis. Functional assays revealed that DDX58 alterations confer constitutive activation and thus lead to increased interferon (IFN) activity and IFN-stimulated gene expression. In addition, when we transduced primary human trabecular meshwork cells with c.803G>T (p.Cys268Phe) and c.1118A>C (p.Glu373Ala) mutants, cytopathic effects and a significant decrease in cell number were observed. Taken together, our results demonstrate that DDX58 mutations cause atypical SMS manifesting with variable expression of glaucoma, aortic calcification, and skeletal abnormalities without dental anomalies.

Association between the Frequency of Optic Disk Hemorrhage and Progression of NTG Related with the Initial Location of RNFL Defect.

PURPOSE: This study aimed to investigate the association of the frequency of optic disk hemorrhage (DH) and progression of normal tension glaucoma (NTG) between each group based on the location of the initial retinal nerve fiber layer (RNFL) defect. METHODS: In this retrospective, observational cohort study, 142 NTG patients who underwent more than 5 reliable visual field tests with initial superior hemifield (group 2, n = 51), inferior hemifield (group 1, n = 44), or both hemifield (group 3, n = 47) defects were included. The number of DHs was inspected in serial optic disk photographs by 2 different ophthalmologists. Progression rates, which are the slope of mean thresholds from the 52 points, were calculated using a linear mixed effect model. RESULTS: The mean follow-up period was 8.19 ± 3.30 years. DHs related with the initial RNFL defect occurred significantly more frequently in group 2 (35 in inferior hemifield) than in group 1 (6 in superior hemifield) (p = 0.009) or group 3 (6 in inferior hemifield) (p = 0.006). The progression rate in group 2 was significantly faster than in group 1 (p = 0.019) or the superior hemifield of group 3 (p = 0.001). The progression rate of subjects showing recurrent DH was significantly faster than those showing single DH from all groups (-0.5460 vs. -0.2867 dB/year, p = 0.0053). CONCLUSIONS: More careful examination and caution are required when NTG patients show recurrent DH in the inferior hemifield related to the initial RNFL defect.

A common variant near TGFBR3 is associated with primary open angle glaucoma.

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Optical coherence tomography measurements in compressive optic neuropathy associated with dysthyroid orbitopathy.

BACKGROUND: The purpose of the study was to assess the influence of optic nerve compression on the peripapillary retinal nerve fiber layer (RNFL) thickness in eyes with acute and chronic dysthyroid optic neuropathy (DON). METHODS: Patients with DON and healthy control subjects underwent peripapillary optical coherence tomography (OCT) scanning with the Cirrus HD-OCT. Patients were classified as acute (within 6 months from the onset of DON) versus chronic (6 months or more from the onset of DON) DON. The thickness of peripapillary RNFL was compared between eyes with acute and chronic DON and control eyes. Baseline factors associated with visual acuity at the last visit were also analyzed. RESULTS: The mean temporal peripapillary RNFL thickness was thinnest in chronic DON at 66 ± 12 µm compared to 76 ± 8 µm in eyes with acute DON and 73 ± 12 µm in control eyes (p = 0.014). In a multivariable analysis, patients with greater inferior peripapillary RNFL thickness and younger age tended to have better visual acuity at the last visit (p = 0.034, odds ratio [OR] = 1.038 and p = 0.007, OR = 0.912, respectively). CONCLUSIONS: Our data revealed a notable difference in temporal peripapillary RNFL thickness in eyes with chronic DON compared to eyes with acute DON and control eyes. We also found a significant association between inferior peripapillary RNFL thickness and visual acuity at the last visit. Thicker inferior peripapillary RNFL thickness was associated with better visual outcome. Further studies with large sample sizes using a prospective design should more clearly reveal the time aspect of the association between the onset of DON and the changes in peripapillary RNFL, and their clinical significance.

Visual and structural prognosis of the untreated fellow eyes of unilateral normal tension glaucoma patients.

PURPOSE: To investigate the visual and structural prognosis of untreated initial non-glaucomatous fellow eyes of unilateral normal tension glaucoma (NTG) patients. METHODS: In this retrospective observational cohort study, 50 NTG patients with unilateral visual field (VF) loss and no VF defect, retinal nerve fiber layer (RNFL) defect or neuroretinal rim (NRR) notching in the fellow eyes, and those who had initial non-glaucomatous fellow eyes untreated were included. For the fellow eyes, the development of VF defect, RNFL defect, and NRR notching was inspected retrospectively by two observers. Baseline clinical characteristics including initial intraocular pressure (IOP), central corneal thickness, and spherical equivalent (SE) were compared between glaucomatous and fellow eyes. RESULTS: During the mean follow-up period of 8.77 ± 2.92 years, five patients (10 %) developed RNFL defect and four patients (8 %) developed NRR notching in the fellow eye. Among six patients (12 %) who had developed either RNFL defect or NRR notching, only three patients (6 %) developed VF loss in 1.81, 3.09, and 9.27 years respectively. The initial IOP was significantly higher (p = 0.031), SE was more myopic (p = 0.025), and the occurrence of disc hemorrhage (p = 0.049) was significantly higher in glaucomatous eyes than that in fellow eyes. CONCLUSIONS: The incidence of glaucoma development in the fellow eye is rather low. Therefore, the initial non-glaucomatous fellow eye of the unilateral NTG patient may be observed without treatment until glaucoma develops.

Long-term outcomes of argon laser photocoagulation in small size cyclodialysis cleft.

BACKGROUND: To evaluate the long-term outcomes of Argon laser photocoagulation compared to surgical direct cyclopexy in small-size cyclodialysis cleft patients. METHODS: This is a retrospective study. Small-size cyclodialysis cleft patients who underwent Argon laser photocoagulation and surgical direct cyclopexy were reviewed. The mean follow-up period were 82.4 (range, 61 - 145) months and 99.9 (range, 62 - 184) months in both groups. The comparison of best corrected visual acuity (BCVA), intraocular pressure (IOP), postoperative peak IOP and time to normalization of IOP before and after the treatment. RESULTS: The causes of all included 15 cyclodialysis cleft cases were blunt trauma. seven patients underwent Argon laser photocoagulation and eight patients underwent surgical direct cyclopexy. The mean age of included patients was not significantly different (p = 0.38). Preoperatively, the mean logMAR BCVA (standard deviation, SD) was 0.7 (0.2) and 1.1 (0.9) and mean IOP was 4.4 (2.4) mmHg and 3.0 (1.5) mmHg in Argon laser group and surgical direct cyclopexy group (p = 0.24 and p = 0.18, respectively). The extension of cyclodialysis and duration of cyclodialysis cleft were not significantly different between the two groups (p = 0.08 and p = 0.24, respectively). The mean follow-up period were 82.4 (range, 61 - 145) months and 99.9 (range, 62 - 184) months in both groups (p = 0.41). Postoperatively, the mean logMAR BCVA was 0.0 (0.1) and 0.2 (0.3) and mean IOP was 14.5 (3.1) mmHg and 16.8 (2.5) mmHg (p = 0.15 and p = 0.16, respectively). Postoperative peak IOP and time to normalization of IOP were not different between the two groups (p = 0.75 and p = 0.91, respectively). DISCUSSION: It is necessary to use invasive treatment such as cryotherapy or surgical direct cyclopexy in cyclodialysis cleft with hypotonic maculopathy. In the present study, Argon laser photocoagulation showed good prognosis in a small-size cyclodialysis cleft below 1.5 clock-hours. Considering possible complications and cost of surgical direct cyclopexy, Argon laser can be more beneficial than surgical direct cyclopexy in small-size cyclodialysis cleft below 1.5 clock-hours. CONCLUSIONS: The clinical ourcome of Argon laser photocoagulation seems to be as good as surgical direct cyclopexy in small-size cyclodialysis cleft below 1.5 clock-hours.

Longitudinal Rates of Change in Structural Parameters of Optical Coherence Tomography in Primary Angle Closure Glaucoma following Laser Iridotomy along with Peripheral Iridoplasty.

Background: This study aimed to investigate longitudinal rates of change (LRCs) of structural parameters from optical coherence tomography (OCT) in patients with primary angle closure glaucoma (PACG) after laser iridotomy (LI) along with laser peripheral iridoplasty (PI). Methods: Among 146 patients diagnosed with PACG, thirty-two subjects (32 eyes) who underwent LI plus PI and accomplished more than five times of reliable OCT tests were included in the current retrospective study. Retinal nerve fiber layer (RNFL) and Bruch's membrane opening-minimum rim width (BMO-MRW) were measured by spectral-domain OCT with three month interval. LRCs of global and six Garway-Heath sectors were investigated using the linear mixed-effects model which adjusted BMO area, sex, and age. Imaging of dual Scheimpflug analyzer was performed before and at 1 week after LI with PI and yearly thereafter. Results: The mean follow-up period was 32.28 ± 13.34 months with a mean number of 10.18 ± 3.33 OCT images. Baseline characteristics are as follows: age, 63 ± 7.9 years; female, 62.5%; intraocular pressure(IOP), 15.48 ± 4.79 mmHg; anterior chamber depth, 2.09 ± 0.18 mm; and mean deviation, -7.97 ± 8.48 dB. Global LRC of BMO-MRW was 0.86 ± 1.34 µm/yr and RNFL was -0.64 ± 0.22 µm/yr. IOP decreased significantly to 13.06 ± 2.21 mmHg (p=0.001) while anterior chamber volume (p=0.011) and mean anterior chamber angle (p=0.022) increased significantly after LI along with PI compared to the baseline at the final visit. Conclusions: LRC of a new parameter, BMO-MRW, and LRC of RNFL were relatively low in patients with PACG, following LI along with PI. After widening of the anterior chamber angle and decrease of IOP due to LI plus PI, PACG might show stable structural prognosis assessed by OCT.

Different glaucoma progression rates by age groups in young myopic glaucoma patients.

We aimed to investigate the age-related glaucoma progression rates in myopic normal tension glaucoma (NTG). In this long-term retrospective cohort (7.2 ± 3.5 years), we grouped patients based on their age at initial presentation: group A (age < 30 years, 60 eyes), group B (30 ≤ age < 40, 66 eyes), and group C (40 ≤ age < 50 years, 63 eyes). We used a linear mixed-effects model to estimate retinal nerve fiber layer (RNFL) defect width enlargement rates. Group A showed a significantly faster rate of RNFL defect progression (3.01 ± 1.74°/year) than those of groups B and C (2.05 ± 1.55°/year and 2.06 ± 1.29°/year, P = 0.004 and 0.002). The difference was more marked when calculated for the first 10 years of follow-up in group A, B, and C (3.95 ± 2.70°/year, 2.39 ± 1.64°/year, and 1.98 ± 1.31°/year), and between the periods of age < 30 years, 30 ≤ age < 40 years, and 40 ≤ age < 50 years within group A. This is the first evidence of rapid glaucoma progression in the young adulthood and stabilization in older age in myopic NTG. Clinicians should consider the potentially aggressive course of glaucoma, especially in younger patients with myopic NTG, in contrast to the general slow progression in adulthood.

Longitudinal changes in optic disc cupping from the baseline in chiasmal lesion optic neuropathy and glaucoma.

We aimed to investigate the changes in cupping in chiasmal lesion optic neuropathy (chON) compared to baseline optic disc and glaucoma. We used a novel study design to enroll patients who had fundus photographs incidentally taken during routine health check-ups prior to the onset of optic neuropathy. In 31 eyes (21 patients) with chON and 33 eyes (30 patients) with glaucoma, we investigated the change in cup-to-disc (C/D) area from the baseline to overt cupping using flicker analysis. Compared to the baseline, 23 eyes (74.2%) had increased cup size and 3 (9.7%) had vascular configuration changes in the chONgroup; in contrast, all glaucoma eyes exhibited changes in cup size and vascular configuration. The increase in C/D area ratio was significantly smaller in chON (0.04 ± 0.04) compared to glaucoma (0.10 ± 0.04, P < 0.001); the minimum residual neuroretinal rim width showed a more pronounced difference (29.7 ± 8.2% vs 7.1 ± 3.9%, P < 0.001). The changes distributed predominantly towards the nasal direction in chON, contrasting the changes to the arcuate fibers in glaucoma. In conclusion, our results provide the first longitudinal evidence of true pathological cupping in chONcompared to photographically disease-free baseline. The marked difference in the residual minimum rim width reaffirms the importance of rim obliteration in the differential diagnosis between the two diseases.

Deep learning-based optic disc classification is affected by optic-disc tilt.

We aimed to determine the effect of optic disc tilt on deep learning-based optic disc classification. A total of 2507 fundus photographs were acquired from 2236 eyes of 1809 subjects (mean age of 46 years; 53% men). Among all photographs, 1010 (40.3%) had tilted optic discs. Image annotation was performed to label pathologic changes of the optic disc (normal, glaucomatous optic disc changes, disc swelling, and disc pallor). Deep learning-based classification modeling was implemented to develop optic-disc appearance classification models with the photographs of all subjects and those with and without tilted optic discs. Regardless of deep learning algorithms, the classification models showed better overall performance when developed based on data from subjects with non-tilted discs (AUC, 0.988 ± 0.002, 0.991 ± 0.003, and 0.986 ± 0.003 for VGG16, VGG19, and DenseNet121, respectively) than when developed based on data with tilted discs (AUC, 0.924 ± 0.046, 0.928 ± 0.017, and 0.935 ± 0.008). In classification of each pathologic change, non-tilted disc models had better sensitivity and specificity than the tilted disc models. The optic disc appearance classification models developed based all-subject data demonstrated lower accuracy in patients with the appearance of tilted discs than in those with non-tilted discs. Our findings suggested the need to identify and adjust for the effect of optic disc tilt on the optic disc classification algorithm in future development.

Myocilin interacts with syntrophins and is member of dystrophin-associated protein complex.

Genetic studies have linked myocilin to open angle glaucoma, but the functions of the protein in the eye and other tissues have remained elusive. The purpose of this investigation was to elucidate myocilin function(s). We identified α1-syntrophin, a component of the dystrophin-associated protein complex (DAPC), as a myocilin-binding candidate. Myocilin interacted with α1-syntrophin via its N-terminal domain and co-immunoprecipitated with α1-syntrophin from C2C12 myotubes and mouse skeletal muscle. Expression of 15-fold higher levels of myocilin in the muscles of transgenic mice led to the elevated association of α1-syntrophin, neuronal nitric-oxide synthase, and α-dystroglycan with DAPC, which increased the binding of laminin to α-dystroglycan and Akt signaling. Phosphorylation of Akt and Forkhead box O-class 3, key regulators of muscle size, was increased more than 3-fold, whereas the expression of muscle-specific RING finger protein-1 and atrogin-1, muscle atrophy markers, was decreased by 79 and 88%, respectively, in the muscles of transgenic mice. Consequently, the average size of muscle fibers of the transgenic mice was increased by 36% relative to controls. We suggest that intracellular myocilin plays a role as a regulator of muscle hypertrophy pathways, acting through the components of DAPC.

Evaluation of lysyl oxidase-like 1 gene polymorphisms in pseudoexfoliation syndrome in a Korean population.

PURPOSE: The purpose of this study was to evaluate association profiles of lysyl oxidase-like 1 (LOXL1) gene polymorphisms with pseudoexfoliation syndrome (XFS) in a Korean population. METHODS: A total of 110 Korean patients with XFS and 127 control subjects were included in this study. Genotypes of three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs3825942, and rs2165241) were analyzed with direct sequencing, and a case-control association study was performed. Genotype frequencies of each SNP were compared according to the XFS phenotypes. RESULTS: All three SNPs were significantly associated with XFS. The T allele at rs1048661 (odds ratio [OR] = 14.29, 95% confidence interval [CI] = 6.25-33.3) and the C allele at rs2165241 (OR = 7.14, 95% CI = 1.59-33.3) were risk alleles in Korean subjects, which was consistent with findings in other Asian populations. However, our findings were opposite to results from Caucasian populations in which the risk alleles at rs1048661 and rs2165241 were G and T, respectively. At the rs3825942, the G allele (OR = 12.50, 95% CI = 2.94-50.0) was a risk allele for XFS, which was similar to results from most other ethnic groups except black South Africans in whom the A allele increased the risk. In the haplotype analysis, the T-G-C haplotype composed of all three risk alleles was significantly overrepresented in XFS and conferred an 11.36 fold (95% CI = 5.97-23.49) increased likelihood of XFS. There was no significant association between the genotype frequencies of the three SNPs and the XFS phenotypes. CONCLUSIONS: Three SNPs of LOXL1 (rs1048661, rs3825942, and 2,165,241) are highly associated with XFS in a Korean population. The risk alleles of these SNPs were similar to those of other Asian populations, such as Japanese or Chinese, but differed from non-Asian populations, suggesting that still unidentified genetic or environmental factors may contribute to disease expression.

Measurement of macular ganglion cell layer and circumpapillary retinal nerve fiber layer to detect paracentral scotoma in early glaucoma.

BACKGROUND: Glaucoma patients with paracentral scotoma are at higher risk of losing central vision than those without glaucoma. The purpose of this study was to determine whether macular inner retinal layer (MIRL) measurements with spectral-domain optical coherence tomography (SD-OCT) outperform circumpapillary retinal nerve fiber layer (cpRNFL) measurements in discriminating between eyes with and without paracentral scotoma. METHODS: This retrospective study included 63 early glaucomatous eyes of 63 patients with (PSI group) or without (PSF group) paracentral visual field (VF) defects. MIRL thicknesses, including macular ganglion cell complex (mGCC), macular ganglion cell layer + inner plexiform layer (mGCL+), macular RNFL (mRNFL), and cpRNFL thickness were measured using a SD-OCT instrument (3D OCT-2000). The MIRL and cpRNFL were divided into 50 grid cells and 36 sectors, respectively, which were numbered from center/temporal to periphery/nasal. Discriminating ability of the methods for number of cells/sectors with abnormal thickness (<5% of normal) and average thickness in the hemisphere corresponding to the VF defects (termed hemi-thickness) was compared by area under the receiver operating characteristics curves (AROCs). RESULTS: The number of abnormal nearest sectors of cpRNFL and all MIRL parameters were significantly smaller in the PSI group than in the PSF group (P ≤ 0.001-0.047), whereas no significant differences were found for average or hemi-cpRNFL thickness. The AROCs of the number of abnormal nearest cells for mGCC and mGCL+ and average hemi-thickness for mGCC, mGCL+, and mRNFL were comparable and significantly higher than those of the number of abnormal nearest sectors/cells for cpRNFL (P = 0.0002-0.0063) and mRNFL (P = 0.0003-0.0267) parameters. CONCLUSIONS: Regional assessment of MIRL thickness as measured by SD-OCT may potentially be an effective method for predicting central involvement of VF defects in early glaucoma.

Evaluation of an e-PBL model to promote individual reasoning.

AIM: Medical educators should promote the development of student clinical reasoning toward independence in clinical settings. The objective of this study was to evaluate an online problem-based learning (e-PBL) model designed to promote student individual reasoning in supplement to traditional PBL. METHODS: Twelve e-PBL modules were added to the fully problem-based curriculum for Year 2 at Sungkyunkwan University School of Medicine (SKKUSOM). In this e-PBL, students worked on the problems individually in an online setting, followed by face-to-face discussions in a colloquium. The cases were presented using interactive multimedia to enhance the authenticity of the case and stimulate student interest in learning. A formative evaluation study was conducted to determine student satisfaction with e-PBL and its effectiveness as perceived by the students using both quantitative and qualitative methods. A cohort of Year 2 students at SKKUSOM (n = 38) took part in this study. RESULTS: Students perceived e-PBL significantly more positively after they had taken a module in terms of its ability to foster problem-solving skills and its ability to allow them to learn in ways suited to individual learning styles. Additionally, student survey and interview revealed that a vast majority of students were satisfied with the overall learning process in e-PBL and perceived it positively in fostering knowledge acquisition and clinical reasoning. Moreover, students found the cases realistic and engaging. CONCLUSIONS: The results show the potential of e-PBL to enhance traditional PBL by promoting the development of individual reasoning in a flexible online-learning environment and offering cases in an interactive multimedia format, which warrants further investigation into its impact on student learning outcomes.

Ancillary PanoMap OCT shows the progression of glaucomatous papillomacular bundle defect with disc haemorrhage on the fovea-disc axis.

BACKGROUND/AIMS: To identify the spatial relationship between disc haemorrhage (DH) on the fovea-disc axis and retinal nerve fibre layer (RNFL) defect in the papillomacular bundle (PMB) using ancillary PanoMap optical coherence tomography (OCT). METHODS: We investigated the presence and progression of spatially corresponding PMB defects in glaucomatous eyes with temporally located DH on the fovea-disc axis (FoDi-DH). We identified PMB defects using ancillary PanoMap OCT with guided progression analysis, in addition to red-free photographs. RESULTS: We studied 36 eyes of 35 glaucoma patients with FoDi-DH, pre-existing PMB defects were observed in 18 eyes (50.0%) at the time and location of the initial FoDi-DH occurrence, 14 (38.9%) of which progressed during the follow-up period. New development of PMB defects occurred in 15 (41.7%) of 18 eyes without pre-existing PMB defects. Overall, FoDi-DH was associated with PMB defects in 33 (91.7%) eyes at locations spatially overlapping the PMB defect. Red-free photography and OCT were complementary in detecting PMB defects and progression. Among 47 cases, 20 were concordant, while 10 and 17 were detected only in photography and OCT, respectively. The central visual field defect increased significantly throughout the follow-up period (p=0.006). CONCLUSION: Most FoDi-DH cases were related to the presence and progression of glaucomatous PMB defects at locations spatially overlapping the defect. OCT helped clarify changes in PMB defects detected by red-free photograph and the detection of photo-negative PMB defects as well. Similar to inferotemporal and superotemporal-direction DH, temporal DH on the PMB may be an indicator of ongoing RNFL damage that deserves close attention.

Deep Optic Nerve Head Morphology in Tilted Disc Syndrome and Its Clinical Implication on Visual Damage.

Purpose: To study deep optic nerve head (ONH) morphology in tilted disc syndrome (TDS) and identify factors associated with retinal nerve fiber layer (RNFL) defect. Methods: In patients with TDS, we evaluated the optic disc shape using the Bruch's membrane opening (BMO)-anterior scleral canal opening (ASCO) offset and measured the border tissue (BT) length, depth, and angle in the direction of the tilt, using radial ONH optical coherence tomography (OCT). We compared the parameters between the TDS groups with and without RNFL defects. Results: Twenty-one eyes had no glaucomatous RNFL defect, and 38 eyes had a glaucomatous RNFL defect. The group with RNFL defects had a higher baseline IOP, larger tilt axis of BMO-ASCO optic disc margin (76.4° ± 14.5° vs. 87.9° ± 15.4°, P = 0.012), larger BMO-lamina cribrosa insertion (LCI) angle (25.6° ± 9.3° vs. 43.6° ± 15.2°, P < 0.001), and more lamina cribrosa (LC) defects (4.3% vs. 30.6%, P = 0.028) than without RNFL defects. The tilt axis and BMO-LCI angle were significant factors after adjusting for baseline IOP and LC defect. The BMO-LCI angle had excellent diagnostic power for glaucomatous RNFL defect in TDS, similar to the visual field mean deviation. Conclusions: OCT-based large deep ONH BT angle and tilt axis were factors associated with the presence of RNFL defects in TDS. The results suggest a mechanism of RNFL defect associated with structural ONH deformation. Further investigations are warranted to understand the role of ONH structures in a general population with and without optic disc tilt.

Peripapillary Vascular Density in Compressive Optic Neuropathy and Normal-Tension Glaucoma: A Severity-Controlled Comparison.

Purpose: To investigate the differences in peripapillary vessel density (VD) between compressive optic neuropathy (CON) and normal-tension glaucoma (NTG). Methods: We compared patients with chronic CON and NTG, particularly after strictly controlling the mean extent of macular damage by the area of the ganglion cell-inner plexiform layer (GCIPL) loss in optical coherence tomography (OCT). We compared retinal nerve fiber layer (RNFL) and GCIPL thickness from OCT and peripapillary and macular VD from OCT angiography (OCTA) between the CON and NTG groups. Results: From the initial 184 patients with CON and 443 patients with OAG, we included 41 patients with CON (57 eyes) and 64 patients with NTG (75 eyes) with a comparable extent of macular GCIPL thinning. Under similar mean macular involvement, the peripapillary VD was significantly lower in the CON group than in the NTG group after considering the effects of age, spherical equivalent, visual field sensitivity, peripapillary RNFL (pRNFL) thickness, GCIPL thickness, and image quality scores (P < 0.001). Marked loss of VD in the temporal and nasal sectors in CON was notable, attributing to the significantly lower peripapillary VD compared to NTG. Conclusions: Patients with CON had a significantly lower peripapillary VD than those with NTG under similar mean degrees of pRNFL thickness and GCIPL damage. Our results reveal the potential utility of OCTA VD besides OCT pRNFL thickness, in relation to different topographic patterns of pRNFL loss, and possible differences in the pathogenesis of microvascular compromise between CON and NTG.

Gifted students' academic performance in medical school: a study of Olympiad winners.

BACKGROUND: The present study examines the performance of academically talented students (i.e., those who received awards in Olympiads, the international competitions for gifted students in science or mathematics) in medical school. PURPOSE: The goal is to investigate whether students exceptionally talented in science and mathematics excel in medical school. METHODS: A retrospective analysis of 13 cohorts of medical students (N = 475) was conducted to compare learning outcomes of academically talented students (ATS) with their peers in terms of their grade point averages (GPAs) and national licensing exam (KMLE) scores. RESULTS: ATS outperformed their peers in total GPAs (p < .001); yet there was a statistical trend of gradually diminishing performance gap between the groups as they progressed into the later years of the program. KMLE scores were comparable between the groups (p = .89). In addition, there was no significant difference in GPAs and KLME scores among ATS regardless of their areas of excellence. CONCLUSIONS: Academic merit alone is not a strong predictor of success in medical school, even among those with exceptional talent. Better understanding of nonacademic factors associated with medical school performance is warranted to improve our selection processes and to better help academically talented students succeed in medical school.

Parapapillary deep-layer microvasculature dropout is only found near the retinal nerve fibre layer defect location in open-angle glaucoma.

PURPOSE: We aimed to investigate the topographic correspondence between deep-layer microvasculature dropout (MvD) and retinal nerve fibre layer (RNFL) defects in eyes with open-angle glaucoma (OAG) using spectral-domain optical coherence tomography (SD-OCT) and optical coherence tomography angiography (OCT-A). METHODS: Microvasculature dropout width and location were determined using OCT-A, RNFL thickness, RNFL defect width and location were revealed using SD-OCT. The association between MvD and RNFL widths and that between the location of the MvD and RNFL defects were investigated. In addition, patients with OAG were divided into two groups: the RNFL defect in one hemiretina (RNFLD-HR) group (n = 24 eyes) and the RNFL defects in both hemiretinas (RNFLD-BR) group (n = 25 eyes). The presence, width and location of MvDs were compared between the two groups. RESULTS: Forty-nine eyes were included. In 24 RNFLD-HR eyes, all MvDs were found in the inferior area, corresponding with the location of the RNFL defect. Meanwhile, in 25 RNFLD-BR eyes, 18 MvDs (72%) were found in the inferior hemiretina, two (8%) were found in the superior hemiretina, and five (20%) were found in both hemiretinas. In RNFLD-BR eyes, the average RNFL thickness was thinner in a location with MvD than a location without MvD. CONCLUSION: Considering that MvD is only observed at the location of the RNFL defect in RNFLD-HR eyes and is usually found in the location of more severe RNFL defects in RNFLD-BR eyes, MvD seems to be a sign that accompanies glaucomatous damage in OAG eyes.