Metabolic and proteomic indications of diabetes progression in human aqueous humor.

Diabetes mellitus is a multiorgan systemic disease impacting numerous ocular structures that results in significant ocular morbidity and often results in more frequent corneal and glaucoma surgeries for affected individuals. We hypothesize that the systemic metabolic and proteomic derangement observed in the progression of diabetes influences the composition of the aqueous humor (AH), which ultimately impacts the anterior segment health of the eye. To identify changes associated with diabetes progression, we mapped the metabolite profile and proteome of AH samples from patients with varying severities of type II diabetes (T2DM). Patients were classified as nondiabetic (ND or control), non-insulin-dependent diabetic without advanced features of disease (NAD-ni), insulin-dependent diabetic without advanced features (NAD-i), or diabetic with advanced features (AD). AH samples collected from the anterior chamber during elective ophthalmic surgery were evaluated for metabolite and protein expression changes associated with diabetic severity via gas chromatography/mass spectrometry and ultra-high performance liquid chromatography tandem mass spectrometry, respectively. Metabolic and proteomic pathway analyses were conducted utilizing MetaboAnalyst 4.0 and Ingenuity Pathway Analysis. A total of 14 control, 12 NAD-ni, 4 NAD-I, and 14 AD samples were included for analysis. Elevated levels of several branched amino acids (e.g., valine, leucine, isoleucine), and lipid metabolites (e.g., palmitate) were found only with increasing diabetic severity (i.e., the AD group). Similar proteomic trends were noted in amino acid and fatty acid metabolism and the unfolded protein/stress response. These results represent the first report of both metabolomic and proteomic evaluation of aqueous humor. Diabetes results in metabolic and proteomic perturbations detectable in the AH, and unique changes become manifest as T2DM severity worsens. Changes in AH composition may serve as an indicator of disease severity, risk assessment of anterior segment cells and structures, and potential future therapies.

Descemet membrane endothelial keratoplasty for corneal decompensation due to iridoschisis.

PURPOSE: To report a case of bilateral iridoschisis with cataracts and corneal decompensation in a patient who underwent cataract extraction and superficial iridectomy followed by Descemet membrane endothelial keratoplasty (DMEK). OBSERVATIONS: A 58-year-old man with previously diagnosed iridoschisis, cataracts, and diabetes mellitus experienced progressive vision loss bilaterally due to corneal decompensation. Slit lamp examination revealed iridoschisis with iris fibrils contacting the corneal endothelium, stromal edema, and mild guttate changes bilaterally. Corneal findings were more severe in the right eye, including the presence of bullous keratopathy at the time of presentation. Cataract extraction with intraocular lens implantation and superficial iridectomy were performed in the right eye, followed by DMEK. These same procedures were performed subsequently in the left eye. Postoperatively, the patient had significant improvement in visual acuity and corneal edema. CONCLUSIONS AND IMPORTANCE: DMEK can be performed safely and successfully after staged cataract surgery with superficial iridectomy in eyes with endothelial decompensation caused by iridoschisis.

Impact of a structured surgical curriculum on ophthalmic resident cataract surgery complication rates.

PURPOSE: To determine whether institution of a structured surgical curriculum for ophthalmology residents decreased the rate of sentinel surgical complications. SETTING: Veterans Affairs Medical Center, Des Moines, Iowa, USA. METHODS: A retrospective review was performed of third-year ophthalmic resident quality-assurance surgical outcomes data at a single residency-training site from 1998 to 2008. The primary outcome measure was defined as a sentinel event; that is, a posterior capsule tear (with or without vitreous loss) or vitreous loss (from any cause) occurring during a resident-performed case. The study population was divided into 2 groups. Group 1 comprised surgical cases of residents trained before the surgical curriculum change (academic years 1998 to 2003) and Group 2, surgical cases of residents trained with the enhanced curriculum (academic years 2004 to 2008). Data from 1 year (academic year 2003 to 2004) were excluded because the transition to the enhanced curriculum occurred during that period. The data were analyzed and adjusted for surgical experience. RESULTS: In Group 1 (before institution of surgical curriculum), there were 823 cases with 59 sentinel complications. In Group 2 (after institution of surgical curriculum), there were 1009 cases with 38 sentinel complications. There was a statistically significant reduction in the sentinel complication rate, from 7.17% before the curriculum changes to 3.77% with the enhanced curriculum (P = .001, unpaired 2-tailed t test). CONCLUSION: Implementation of a structured surgical curriculum resulted in a statistically significant reduction in sentinel event complications, even after adjusting for surgical experience.

Re-engineering the resident applicant selection process in ophthalmology: a literature review and recommendations for improvement.

The current resident selection process for ophthalmology has undergone little change over the last several years and remains highly dependent on the traditional selection factors (i.e., grades, honors, letters of recommendation, and an interview). Unfortunately, these selection factors have not been shown to be consistently predictive of future resident performance. In addition, the Accreditation Council for Graduate Medical Education (ACGME) has mandated implementation of six new competencies in resident training in the USA and the current selection process does not directly recruit for these competencies. We propose an implementation strategy to re-engineer and improve the resident selection process in ophthalmology and potentially develop assessments that would be predictive of actual downstream resident performance that would encompass the ACGME related competencies. An intra-departmental Task Force for the ACGME Competencies reviewed a PubMed literature search regarding resident selection. A content expert (AGL) gleaned selected "good practices" from the literature review and summarized the results. Specific recommendations were reviewed for topicality to ophthalmology and where possible for feasibility, reliability, and validity. We summarize several good practices identified from the literature review and propose an implementation matrix for aligning the resident application process with the ACGME competencies that might include: using a standardized and consolidated academic score for the cognitive domains; converting the letter of recommendation format into a letter of evaluation; standardizing the letters of evaluation, including the "Dean's letter"; using behavior specific interview techniques with standardized questions; and developing a specialty based consensus for the selection of traits specific to ophthalmology that might predict success. The resident selection process for ophthalmology might be improved by implementation of specific good practices from the literature. Ophthalmology should strive to develop applicant selection tools that might be useful for predicting residency performance and that would align with the ACGME competency mandate for tools to predict future performance as a physician.

The Iowa ophthalmology wet laboratory curriculum for teaching and assessing cataract surgical competency.

PURPOSE: To describe an ophthalmology wet laboratory (OWL) curriculum for residents in training. METHODS: Systematic literature review and selection of best practices for use in the OWL learning plan from a single academic ophthalmology program. RESULTS: A pretest and posttest of cognitive skills, objective wet laboratory structured assessment of skill and technique, and summative global evaluation form were developed as part of a systematic OWL curriculum. CONCLUSION: The Iowa OWL curriculum may form the basis for successfully utilizing the wet laboratory to teach and assess aspects of resident surgical competence in cataract surgery.

Variation in optineurin (OPTN) allele frequencies between and within populations.

PURPOSE: To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in different populations. METHODS: Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma, 33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons were resequenced and case frequencies were compared to frequencies in controls matched for ancestry. RESULTS: The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the 691_692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports, we also present information for populations of Hispanic and black African ancestries. CONCLUSIONS: Our study contributes additional evidence to support the previously reported association of the OPTN E50K mutation with glaucoma. After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations. It is currently not possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies.

Teaching and assessing surgical competency in ophthalmology training programs.

BACKGROUND AND OBJECTIVE: The Accreditation Council for Graduate Medical Education (ACGME) has mandated implementation of six new competencies in resident training in the United States. An implementation strategy is proposed to teach and assess cataract surgical competence. PATIENTS AND METHODS: An intradepartmental Task Force for the ACGME competencies reviewed the literature for assessment tools to develop an implementation matrix for assessing surgical competence. RESULTS: "Good practices" (gleaned from the literature) were adapted for the institution's needs and tested, including (1) written and explicit goals or objectives for each stage of training; (2) substitution of a criterion-referenced (Dreyfus model) scoring rubric for a norm-referenced, peer-benchmarked global evaluation; (3) use of formative rather than summative feedback; (4) incorporation of deliberate practice (Ericsson model); and (5) portfolio-based documentation of sentinel event markers and remediation. CONCLUSION: An implementation matrix for teaching and assessing surgical competence might be useful for local compliance with the ACGME mandate.

Interim results of the United States investigational device study of the Ophtec capsular tension ring.

PURPOSE: To evaluate the safety and efficacy of the Ophtec capsular tension ring (CTR) in providing capsular support during and/or after cataract extraction in cases of a weak or partially broken ciliary zonule. DESIGN: Phase III multicenter, nonrandomized, investigational device study. PARTICIPANTS: Twelve investigators at 9 sites enrolled 224 subjects and placed 255 CTRs. METHODS: Capsular tension rings were placed in patients who were found to have a weakened or partially broken ciliary zonule comprising <34% of the circumference of the lens capsule. Two CTR models were evaluated, with noncompressed diameters of 12 mm and 13 mm. Patients were examined preoperatively, intraoperatively, and postoperatively at day 1 and months 1, 3, 6, and 12. MAIN OUTCOME MEASURES: Rate of successful stabilization of the capsular bag and intraocular lens (IOL) centration, complications, and adverse events. RESULTS: Interim results from this ongoing study indicate that immediately after surgery 98.8% of IOLs were centered and 1.2% of the IOLs implanted (3/251) were not centered. Subsequently, the prevalence of decentered IOLs was 1.7% (4/236) 3 months after surgery, 3.8% (8/211) 6 months after surgery, and 2.3% (4/172) 12 months after surgery. The primary complication was posterior capsular opacification, which is unlikely to be a complication of CTR insertion. Neodymium:yttrium-aluminum-garnet laser capsulotomies have been performed in 12.8% of eyes by 12 months (22/172). CONCLUSIONS: Ophtec CTR models 275 and 276 safely provided capsular support during and after cataract surgery in cases where the zonule was weak or partially broken.

Evaluation of optineurin sequence variations in 1,048 patients with open-angle glaucoma.

PURPOSE: To investigate the association of sequence variations in the optineurin (OPTN) gene in patients with open-angle glaucoma. DESIGN: Prospective case control study. METHODS: The OPTN gene was screened for sequence variations using a combination of single-strand conformational polymorphism analysis and automated DNA sequencing. A total of 1,299 subjects (1048 glaucoma patients and 251 controls) were screened for variations in the four portions of the gene that had been previously associated with glaucoma. A subset of these subjects (376 patients and 176 controls) was screened for variations in the entire coding sequence. Twenty-four percent of the patients and 35% of the controls were Japanese, whereas the remainder were predominantly Caucasian. Allele frequencies were compared with the Fisher exact test. RESULTS: The OPTN sequence variations were not significantly associated with any form of high-tension open-angle glaucoma. One proband with familial normal-tension glaucoma was found to harbor the previously reported Glu50Lys variation. Another previously reported change, Met98Lys, was associated with normal-tension glaucoma in Japanese but not in Caucasian patients. CONCLUSIONS: This study provides some additional evidence for the association of the Glu50Lys OPTN sequence variation with familial normal tension glaucoma. However, because familial normal-tension glaucoma is so rare, this change seems to be responsible for less than 0.1% of all open-angle glaucoma. The Arg545Gln variation is likely to be a nondisease-causing polymorphism. The Met98Lys change may be associated with a fraction of normal-tension glaucoma in patients of Japanese ethnicity.

Variations in the myocilin gene in patients with open-angle glaucoma.

OBJECTIVE: To determine the prevalence and associated phenotype of myocilin (MYOC) coding sequence variations and a specific promoter polymorphism (MYOC.mt1) in patients with glaucoma and glaucoma suspects. METHODS: A consecutive, unselected series of 779 patients (652 with open-angle glaucoma and 127 glaucoma suspects) were recruited from a university medical center and clinically characterized. The coding sequences of the MYOC gene and the MYOC.mt1 locus in the promoter region were screened for sequence variations. We determined the prevalence of MYOC coding sequence mutations and the MYOC.mt1 promoter polymorphism. We also compared the clinical features of individuals with and without mutations and the MYOC.mt1 promoter polymorphism. RESULTS: Plausible disease-causing sequence variations (DCVs) in the MYOC gene were found in 3.0% of the entire group. Such variations were found in patients with most forms of open-angle glaucoma studied. Patients with primary open-angle glaucoma (POAG) who harbored coding sequence DCVs were clinically similar to patients without them. Patients who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different in any measure of disease severity from those who harbored the more common allele. CONCLUSIONS: MYOC DCVs were found in approximately 3% of patients with glaucoma and glaucoma suspects. The 2 alleles of the MYOC.mt1 promoter polymorphism were equally distributed among patients with POAG and healthy control subjects. Patients with POAG who harbored the rarer allele of the MYOC.mt1 promoter polymorphism were no different from those with the more common variant in any measure of disease severity. CLINICAL RELEVANCE: Testing for the MYOC.mt1 promoter polymorphism appears to be of no value in the evaluation of patients with glaucoma.