Transparency in the Ophthalmology Residency Match: Background, Study, and Implications.

Background Medical students are applying to dramatically more ophthalmology residency programs than in the past, causing an increased administrative burden for programs and financial harm to students. This study considers the background of this situation and looks at how a lack of transparency surrounding potential residency match filters contributes. Furthermore, this study raises several potential solutions to this lack of transparency that may increase the functionality of the ophthalmology residency match. Objective The purpose of this study was to determine the availability and consistency of potential ophthalmology residency match filters through training program websites and the American Medical Association's (AMA) Residency & Fellowship Database (FREIDA). Methods This study was a cross-sectional observational study of ophthalmology residency program websites and AMA's FREIDA database entries. For 119 ophthalmology residency programs, five potential filters were evaluated for both availability and consistency on individual residency websites and FREIDA. These filters were: (1) whether a program required a minimum United States Medical Licensing Examination (USMLE) Step 1 score; (2) minimum number of letters of recommendation required; 3) whether a minimum USMLE Step 2 score was required; (4) if the program accepts the Comprehensive Osteopathic Medical Licensing Examination (COMLEX) sequence in lieu of the USMLE; and (5) ability of the residency to sponsor a visa (J-1, H-1B, or F-1). Each program's website and FREIDA entry were independently evaluated by two authors to increase validity, with a third author brought in to break the tie in case of a disagreement. Results Only two ophthalmology residency programs had information about all five filters both available and consistent on their website and FREIDA. Inter-reviewer reliability was 92.5%. Conclusions Information about potential filters used in the ophthalmology residency match is neither publicly available nor consistent. This lack of transparency may contribute to the phenomenon of medical students applying to dramatically more ophthalmology residency programs. A standardized database of these filters is needed to increase transparency to applicants, which may reduce the expenses of medical students and the workload of program directors.

Rank Order of Small Molecule Induced Hypoxiamimesis to Prevent Retinopathy of Prematurity.

Here we rank order small molecule inhibitors of hypoxia inducible factor (HIF) prolyl hydroxylases (PHDs) using severity of oxygen induced retinopathy (OIR) as an outcome measure. Dose response analyses in cell cultures of hepatoma (Hep3B), retinal Müller cells (MIO-M1) and primary retinal endothelial cells were conducted to evaluate potency by comparing dose to HIF-1,2 protein levels by western blotting. In vivo dose response was determined using the luciferase-transgene HIF reporter (luc-ODD). Each compound was placed in rank order by their ability to reduce neovascularization and capillary drop out in the OIR mouse model. An Epas1 KO confined to retinal Müller cells was used to determine whether successful protection by HIF stabilization requires HIF-2. Two candidate small molecules can prevent OIR by stabilizing HIF-1 to prevent oxygen induced growth attenuation and vascular obliteration. Müller cell HIF-2, the mediator of pathologic retinal angiogenesis, is not required for protection. The lack of dependence on Müller cell HIF-2 predicts that inhibition of HIF PHD will not drive pathological angiogenesis.

Hyperoxia induces glutamine-fuelled anaplerosis in retinal Müller cells.

Although supplemental oxygen is required to promote survival of severely premature infants, hyperoxia is simultaneously harmful to premature developing tissues such as in the retina. Here we report the effect of hyperoxia on central carbon metabolism in primary mouse Müller glial cells and a human Müller glia cell line (M10-M1 cells). We found decreased flux from glycolysis entering the tricarboxylic acid cycle in Müller cells accompanied by increased glutamine consumption in response to hyperoxia. In hyperoxia, anaplerotic catabolism of glutamine by Müller cells increased ammonium release two-fold. Hyperoxia induces glutamine-fueled anaplerosis that reverses basal Müller cell metabolism from production to consumption of glutamine.

Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity.

We determined which metabolic pathways are activated by hypoxia-inducible factor 1-mediated (HIF-1-mediated) protection against oxygen-induced retinopathy (OIR) in newborn mice, the experimental correlate to retinopathy of prematurity, a leading cause of infant blindness. HIF-1 coordinates the change from oxidative to glycolytic metabolism and mediates flux through serine and 1-carbon metabolism (1CM) in hypoxic and cancer cells. We used untargeted metabolite profiling in vivo to demonstrate that hypoxia mimesis activates serine/1CM. Both [13C6] glucose labeling of metabolites in ex vivo retinal explants as well as in vivo [13C3] serine labeling of metabolites followed in liver lysates strongly suggest that retinal serine is primarily derived from hepatic glycolytic carbon and not from retinal glycolytic carbon in newborn pups. In HIF-1α2lox/2lox albumin-Cre-knockout mice, reduced or near-0 levels of serine/glycine further demonstrate the hepatic origin of retinal serine. Furthermore, inhibition of 1CM by methotrexate blocked HIF-mediated protection against OIR. This demonstrated that 1CM participates in protection induced by HIF-1 stabilization. The urea cycle also dominated pathway enrichment analyses of plasma samples. The dependence of retinal serine on hepatic HIF-1 and the upregulation of the urea cycle emphasize the importance of the liver to remote protection of the retina.

3-Hydroxypyruvate Destabilizes Hypoxia Inducible Factor and Induces Angiostasis.

Purpose: Transcriptional analysis of retina protected by hypoxia-inducible factor (HIF) stabilization demonstrates an increase in genes associated with aerobic glycolysis. We hypothesized that since protection is associated with a change in metabolism, oxygen-induced metabolites might transduce oxygen toxicity. We used global metabolic profiling to identify retinal metabolites increased in hyperoxia compared to normoxia. Methods: Untargeted gas chromatography mass spectroscopy (GC-MS) was performed on both mouse retina samples collected in hyperoxia and on primary human retinal endothelial cells, each with and without HIF stabilization. After identifying 3-hydropxypyruvate (3OH-pyruvate) as a unique hyperoxic metabolite, endothelial cells in culture and choroidal explants were challenged with 3OH-pyruvate in order to determine how this glycolytic intermediate was metabolized, and whether it had an effect on angiogenesis. Results: 3OH-pyruvate was one of five metabolites at least 2.0-fold elevated in hyperoxia with a P value < 0.1. Once metabolized by endothelial cells, 3OH-pyruvate led to a 20-fold increase in 3-phosphoglycerate and a 4-fold increase in serine when cells were treated with Roxadustat to induce HIF stabilization. 3OH-pyruvate, but not pyruvate, destabilized HIF in endothelial cells with an increase in proline hydroxylation. 3OH-pyruvate was angiostatic in choroidal explant assays. Conclusions: 3OH-pyruvate is a unique metabolite induced by hyperoxia that destabilizes HIF at least in part by a canonical pathway. 3OH-pyruvate induces angiostasis in vitro. HIF stabilization increases serine biosynthesis in vitro and in vivo.