Myocilin polymorphisms and high myopia in subjects of European origin

Purpose: Three previous studies have tested for an association between high myopia and polymorphisms in the open angle glaucoma gene, myocilin (MYOC), all in subjects of Chinese ethnicity. In two of the studies, a significant association was found while in the third, there was no association. We sought to investigate the association between high myopia and polymorphisms in MYOC in subjects of European ethnicity. Methods: Subjects were recruited from two sites, Cardiff University in the UK and Duke University in the United States. The Cardiff University cohort was comprised of 164 families with high myopia (604 subjects) plus 112 unrelated, highly myopic cases and 114 emmetropic controls. The Duke University cohort was comprised of 87 families with high myopia (362 subjects) plus 59 unrelated, highly myopic cases. Subject DNA was genotyped with a panel of MYOC single nucleotide polymorphisms (SNPs) including those found previously associated with high myopia. The Cardiff cohort was also genotyped for two flanking microsatellite markers analyzed in prior studies. Association between high myopia and MYOC polymorphisms was assessed using the Unphased program. Results: Since there was no evidence of heterogeneity in genotype frequencies between families and singleton samples or between cohorts, both subject groups (families and unrelated subjects) from both recruitment sites were analyzed jointly for those SNPs genotyped in common. Two variants showed significant association before correction for multiple testing. These two variants were rs16864720 (p=0.043) and NGA17 (p=0.026). However, there was no significant association after Bonferroni correction. The estimated relative risk (RR) conferred by each of the MYOC variants was low (RR<1.5). Conclusions: Our results suggest that MYOC polymorphisms have a very low, or possibly negligible, influence on high myopia susceptibility in subjects of European ethnicity

Angiopoietin-1 is required for Schlemm’s canal development in mice and humans

Made available in accordance with publisher's policyPrimary congenital glaucoma (PCG) is a leading cause of blindness in children worldwide and is caused by developmental defects in 2 aqueous humor outflow structures, Schlemm’s canal (SC) and the trabecular meshwork. We previously identified loss-of-function mutations in the angiopoietin (ANGPT) receptor TEK in families with PCG and showed that ANGPT/TEK signaling is essential for SC development. Here, we describe roles for the major ANGPT ligands in the development of the aqueous outflow pathway. We determined that ANGPT1 is essential for SC development, and that Angpt1-knockout mice form a severely hypomorphic canal with elevated intraocular pressure. By contrast, ANGPT2 was dispensable, although mice deficient in both Angpt1 and Angpt2 completely lacked SC, indicating that ANGPT2 compensates for the loss of ANGPT1. In addition, we identified 3 human subjects with rare ANGPT1 variants within an international cohort of 284 PCG patients. Loss of function in 2 of the 3 patient alleles was observed by functional analysis of ANGPT1 variants in a combined in silico, in vitro, and in vivo approach, supporting a causative role for ANGPT1 in disease. By linking ANGPT1 with PCG, these results highlight the importance of ANGPT/TEK signaling in glaucoma pathogenesis and identify a candidate target for therapeutic development

The flipped-classroom approach to teaching horizontal strabismus in ophthalmology residency: a pilot study

PurposeTo compare the flipped classroom (home pre-taped lectures followed by in-class group exercise) to the traditional classroom (home reading assignment followed by in-class lecture) for horizontal strabismus didactics in ophthalmology residency.MethodsAll PGY2-4 residents from four U.S. ophthalmology residencies without prior residency flipped-classroom experience were invited to esotropia and exotropia sessions sequentially, with random order and assignment to flipped and traditional classrooms. Content test scores before and after the two classrooms were compared. Surveys were administered to assess participant experience.ResultsA total of 40 residents attended each session. Likert scale evaluation of preparatory material and classroom activity did not differ between sessions; however, divided by year of training, 70% of senior residents (PGY3-4) and 39% of first-year (PGY2) residents preferred the flipped classroom over the traditional classroom. Pre- and post-test scores for the flipped classroom exceeded those of the traditional classroom for the exotropia course (P&nbsp;=&nbsp;0.01 and P&nbsp;=&nbsp;0.001, resp.) but not for the esotropia course. There was significant improvement between pre- and post-tests for both styles of learning.ConclusionsThe flipped classroom had a favorable effect on test scores for only one of the two strabismus subjects but was preferred over the traditional classroom among PGY3-4 residents

Flipped classroom approach to global outreach: cross-cultural teaching of horizontal strabismus to Chinese ophthalmology residents.

AimTo evaluate the flipped classroom model for teaching horizontal strabismus didactics in an ophthalmology residency program in China as part of a visiting professorship from the United States.MethodsResidents from an ophthalmology residency program in China were invited to participate in flipped classroom sessions taught by an experienced American ophthalmology faculty in 2018. Residents were instructed to watch a pre-class video lecture prior to the in-class-case-based activity. Content tests (5 Ophthalmic Knowledge Assessment Program style questions) and surveys were administered before and after the classroom sessions (100% response rate). These results were compared to that of an American cohort who were taught the same content.ResultsThe Chinese cohort of 12 residents preferred the flipped classroom to the traditional classroom at higher rates than the American cohort of 40 residents (92% vs 55%, P=0.04) and felt that all ophthalmology topics would be appropriate for the flipped classroom teaching style (P-values between 0.008 and &lt;0.001). In both Chinese and American cohorts, we found that the exotropia curriculum saw a small but significant improvement in performance following the flipped classroom session (P=0.025 for Chinese residents; P=0.001 for US residents), whereas scores in both groups for the esotropia course did not significantly improve.ConclusionThis is the first study to evaluate the flipped classroom model implemented by a visiting ophthalmology professor in a global outreach setting. The flipped classroom sessions are viewed favorably by the Chinese residents relative to the US cohort with a modest impact on knowledge. Decreased in-person interpreter requirement and increased student engagement make this model valuable in cross-cultural visiting professorship settings. Finally, the flipped classroom may lend itself well to a virtual format to prevent the transmission of COVID-19, although such a format requires further study

The flipped-classroom approach to teaching horizontal strabismus in ophthalmology residency: a multicentered randomized controlled study

BackgroundThe flipped-classroom involves watching prerecorded lectures at home followed by group learning exercises within the classroom. This study compares the flipped classroom approach with the traditional classroom for teaching horizontal strabismus didactics in ophthalmology residency.MethodsIn this multicenter, randomized controlled survey study from October 2017 to July 2018, 110 ophthalmology residents were taught esotropia and exotropia sequentially, randomized by order and classroom style. Flipped classroom participants were assigned a preclass video lecture prior to the in-class case-based activity. The traditional classroom included a preparatory reading assignment and an in-person lecture. Residents completed three identical 5-question assessments (pretest, post-test, and 3-month retention) and surveys for each classroom. The primary outcome measured residents' preferences for classroom styles; the secondary outcome compared knowledge acquisition.ResultsIn our study cohort, the flipped classroom resulted in greater at-home preparation than the traditional classroom (P&nbsp;=&nbsp;0.001) and was preferred by 33 of 53 residents (62%); 45 of 53 (85%) wished to see the flipped classroom used at least 25% of the time. The exotropia flipped classroom scored higher than traditional classroom on the pretest (3.71/5 [74%] vs 2.87/5 [57%]; P&nbsp;&lt;&nbsp;0.001) and post-test (4.53/5 [91%] vs 4.13/5 [83%]; P&nbsp;=&nbsp;0.01) but not the 3-month retention test (3.53/5 [71%] vs 3.37/5 [67%]; P&nbsp;=&nbsp;0.48). The esotropia classroom styles did not differ on pre- or post-test but demonstrated higher scores for the traditional classroom at 3-month retention (3.43/5 [69%] vs 2.92/5 [58%]; P&nbsp;=&nbsp;0.03). Advantages cited for flipped classroom include being interactive and engaging while incentivizing better classroom preparation.ConclusionsThe flipped classroom method was received favorably by trainees and may complement traditional methods of teaching

Reduced penetrance in a large Caucasian pedigree with Stickler syndrome

<p><i>Background</i>: In a four-generation Caucasian family variably diagnosed with autosomal dominant (AD) Stickler or Wagner disease, commercial gene screening failed to identify a mutation in <i>COL2A1</i> or <i>VCAN</i>. We utilized linkage mapping and exome sequencing to identify the causal variant.</p> <p><i>Materials and methods</i>: Genomic DNA samples collected from 40 family members were analyzed. A whole-genome linkage scan was performed using Illumina HumanLinkage-24 BeadChip followed by two-point and multipoint linkage analyses using FASTLINK and MERLIN. Exome sequencing was performed on two affected individuals, followed by co-segregation analysis.</p> <p><i>Results</i>: Parametric multipoint linkage analysis using an AD inheritance model demonstrated HLOD scores > 2.00 at chromosomes 1p36.13-1p36.11 and 12q12-12q14.1. SIMWALK multipoint analysis replicated the peak in chromosome 12q (peak LOD = 1.975). FASTLINK two-point analysis highlighted several clustered chromosome 12q SNPs with HLOD > 1.0. Exome sequencing revealed a novel nonsense mutation (c.115C>T, p.Gln39*) in exon 2 of <i>COL2A1</i> that is expected to result in nonsense-mediated decay of the RNA transcript. This mutation co-segregated with all clinically affected individuals and seven individuals who were clinically unaffected.</p> <p><i>Conclusions</i>: The utility of combining traditional linkage mapping and exome sequencing is highlighted to identify gene mutations in large families displaying a Mendelian inheritance of disease. Historically, nonsense mutations in exon 2 of <i>COL2A1</i> have been reported to cause a fully penetrant ocular-only Stickler phenotype with few or no systemic manifestations. We report a novel nonsense mutation in exon 2 of <i>COL2A1</i> that displays incomplete penetrance and/or variable age of onset with extraocular manifestations.</p