University of Toronto's redesigned ophthalmology curriculum and eye dissection lab.

OBJECTIVE: To present a multifaceted approach to ophthalmology undergraduate medical education and to assess the efficacy of an eye dissection laboratory in enhancing medical student learning. DESIGN: Curriculum review, validation, and student feedback evaluations. PARTICIPANTS: Year 2 medical students enrolled in the University of Toronto's Doctor of Medicine Program. METHODS: Student feedback evaluations were compiled from the University of Toronto undergraduate medical education student surveys before 2012-2016 and following introduction of the redesigned foundations ophthalmology curriculum at the University of Toronto (2017-2018). Students who participated in the Eye Dissection Lab as part of the newly designed curriculum completed the pre- and postsession satisfaction and overall interest in ophthalmology questionnaires and a knowledge-based test. RESULTS: Analysis of 1640 student evaluations demonstrated an increase in ophthalmology curriculum rating following the launch of the foundations ophthalmology curriculum (p = 0.015). Among the 335 students who completed the eye dissection lab, there was a significant increase in the average scores for the satisfaction questionnaire, knowledge-based test, and level of interest in the field of ophthalmology from before and after the session, with improvements in scores noted in 91%, 42%, and 36% of the educational parameters of the participants, respectively (p < 0.001). CONCLUSIONS: The newly designed foundations ophthalmology curriculum and the eye dissection lab at the University of Toronto serve as effective means for enhancing ophthalmology teaching in medical schools across Canada.

Synthesis and SAR of novel benzoxaboroles as a new class of ß-lactamase inhibitors.

A new class of benzoxaborole ß-lactamase inhibitors were designed and synthesized. 6-Aryloxy benzoxaborole 22 inhibited AmpC P99 and CMY-2 with K(i) values in the low nanomolar range. Compound 22 restored antibacterial activity of ceftazidime against Enterobacter cloacae P99 expressing AmpC, a class C ß-lactamase enzyme. The SAR around the arylbenzoxaboroles, which included the influence of linker and substitutions was also established.

Discovery of a potent and highly selective PDK1 inhibitor via fragment-based drug discovery.

We report the use of a fragment-based lead discovery method, Tethering with extenders, to discover a pyridinone fragment that binds in an adaptive site of the protein PDK1. With subsequent medicinal chemistry, this led to the discovery of a potent and highly selective inhibitor of PDK1, which binds in the 'DFG-out' conformation.

Discovery of an Aurora kinase inhibitor through site-specific dynamic combinatorial chemistry.

We demonstrate a fragment-based lead discovery method that combines site-directed ligand discovery with dynamic combinatorial chemistry. Our technique targets dynamic combinatorial screening to a specified region of a protein by using reversible disulfide chemistry. We have used this technology to rapidly identify inhibitors of the drug target Aurora A that span the purine-binding site and the adaptive pocket of the kinase. The binding mode of a noncovalent inhibitor has been further characterized through crystallography.

Primary piggyback implantation of 3 intraocular lenses in nanophthalmos.

We present a patient with bilateral nanophthalmos who had uneventful cataract extraction in the right eye with primary implantation of 3 intraocular lenses (IOLs) of 2 different materials: a 30 diopter (D) acrylic IOL and a 9 D silicone IOL in the capsular bag and a 30 D silicone IOL in the ciliary sulcus. Subsequently, cataract extraction was done in the left eye with bag-sulcus implantation of two 30 D silicone IOLs. The use of 3 IOLs in 1 eye was necessary because the highest available power of acrylic and silicone IOLs at our institution was 30 D. The only short-term complications were temporary corneal edema and partial displacement of the sulcus IOL anterior to the iris in the right eye and bilateral posterior capsule opacification. The late complication of interlenticular opacification was not present 1 year after piggyback IOL implantation.

Indications for penetrating keratoplasty in a tertiary referral centre in Canada, 1996-2004.

BACKGROUND: The leading indications for penetrating keratoplasty (PKP) have changed over recent years. This study examined the leading indications for PKP and their trends, comparing these with recently published data from other studies, including a report from our centre examining indications from 1986 through 1995. METHODS: A retrospective chart review was conducted of all patients who underwent PKP in a single practice at the University Health Network, Toronto Western Hospital, between July 1, 1996, and June 30, 2004. RESULTS: A total of 617 patients underwent 794 PKP operations during the 8-year study period. Sufficient documentation was available to include 777 surgeries from 600 patients in this study. Specific indications for PKP were reported and grouped into 16 categories. The leading indication categories for PKP were regraft (209 cases, 26.9%), pseudophakic bullous keratopathy (PBK) (193 cases, 24.8%), primary corneal endotheliopathies including Fuchs' endothelial dystrophy (101 cases, 13.0%), anterior keratoconus (93 cases, 12.0%), and viral or postviral causes (41 cases, 5.3%). Regraft, keratoconus, and Fuchs' endothelial dystrophy each displayed a nonsignificant decreasing trend from 1996 to 2004, and PBK, herpes simplex virus, and mechanical trauma each displayed a nonsignificant increasing trend (p > 0.05 for all). INTERPRETATION: Regraft was the leading indication for PKP at our centre, followed by PBK; these findings were in agreement with data reported in recent literature. The frequency of regraft had increased since a previous study from our centre (1986-1995), and the frequency of PBK had decreased.

Demographics of corneal transplantation in Canada in 2004.

BACKGROUND: Penetrating keratoplasty (PKP) is the most frequently performed transplant surgery, and one of the most successful, yet no national study on the demographics of corneal transplantation in Canada has been published to date. The objectives of this study were to determine demographics of Canadian corneal transplant surgeons, donor tissue availability and waitlist length for each province, and limiting factors for the number of PKPs performed in Canada. METHODS: An anonymous voluntary survey of all Canadian corneal transplant surgeons was conducted between June and September 2004, with a concurrent voluntary survey of all eye banks in Canada. RESULTS: In 2004, there were 76 corneal transplant surgeons distributed as follows: British Columbia 17.1%, Alberta 11.8%, Saskatchewan 3.9%, Manitoba 7.9%, Ontario 36.8%, Quebec 17.1% and the Atlantic provinces 5.3%. The response rate of the Canadian corneal transplant surgeon survey was 69.7%. On average, each respondent performed 1 (SD 1) PKP/week, 40 (33) PKPs/year, and had a waitlist of 50 (63) patients. The mean wait time from date of referral to initial consultation was 10 (SD 7) weeks and from time of diagnosis to PKP was 51 (32) weeks. The most significant contributing factor to PKP waitlist selected by respondents in all provinces except Ontario was donor tissue shortage (64.7%); Ontario respondents (81.0%) believed that insufficient operating room time was the main factor. Ontario was the only province where all corneal transplant surgeons scheduled PKP electively and where surplus corneal tissue was regularly exported. INTERPRETATION: Recommendations include standardizing the criteria for acceptable donor tissue across all eye banks in Canada to increase efficiency of distribution, introducing and properly implementing mandatory referral and request legislation to increase donor rates, and increasing availability of operating room time for corneal transplant surgeons, especially in Ontario.

A survey for the need of translational aids among Canadian ophthalmologists.

OBJECTIVE: To conduct a needs assessment survey of Canadian ophthalmologists to determine whether there is a requirement for translational aids in ophthalmology, and if so, the content, format, and languages to include. DESIGN: Anonymous voluntary online needs assessment questionnaire. PARTICIPANTS: A total of 139 ophthalmologists completed the online needs assessment questionnaire. METHODS: An anonymous voluntary online survey in English and French was distributed to 700 active members (practicing Canadian ophthalmologists) of the Canadian Ophthalmological Society. Data were collected regarding the potential utility of translational aids, as well as the contents and languages that should be included if such aids were to be created. Level of support for translational aids, as well as the contents and languages of potential translational aids, was assessed. RESULTS: The survey response rate was 19.9% (139/700). The majority of the respondents (130/139, 93.5%) have encountered difficulty in communicating with patients because of language barrier, and 88.5% (123/139) would benefit from having a list of ophthalmologic terms translated into several of Canada's most popular languages. The top 10 languages that the respondents indicated would be most beneficial are (in descending order): Chinese, Hindi, Spanish, Punjabi, Italian, Portuguese, Arabic, Greek, Cree, and Vietnamese. The survey responses provided a comprehensive list of the most useful ophthalmologic symptoms, instructions to patients, and diagnoses to be translated. Most respondents (120/139, 86.3%) believed that having basic information pamphlets on specific ocular conditions translated into several languages would benefit their practice; the top 3 conditions were cataract, glaucoma, and age-related macular degeneration. Producing the translational aids in both paper and electronic format was found to be the most favoured (89/139, 64.0%). CONCLUSIONS: Canadian ophthalmologists believe they would benefit from translational aids. The results of this survey provide a framework for the creation of such aids.

Residual stereopsis in age-related macular degeneration patients and its impact on vision-related abilities: a pilot study.

OBJECTIVE: To determine the effect of residual stereopsis on vision-related abilities of low vision (LV) patients with age-related macular degeneration (AMD). METHODS: Prospective non-randomized observational case series. Inclusion criteria included documented AMD, LV with best corrected visual acuity (BCVA) of 20/50-20/400 in the better eye, and ages between 50 and 90 years. Stereoacuity was measured using the near Frisby Stereotest. Vision related abilities were documented with the VA LV VFQ-48 questionnaire. RESULTS: Twenty-seven subjects with mean age of 84±6 years old were recruited, of which 59.3% (16/27) were female. 59.3% (16/27) of the subjects were not able to see any stereoacuity plate, 25.9% (7/27) had stereoacuity of 340s of arc (SOA), 11.1% (3/27) had stereoacuity of 170 SOA and 3.7% (1/27) had stereoacuity of 85 SOA. The mean Overall Functional Visual Abilities (OFVA) score was significantly higher in those with stereopsis (2.25±0.99) than those without stereopsis (1.50±0.92) (P=0.028). CONCLUSIONS: LV patients with stereopsis have better OFVA than those without. Stereopsis should be considered as a component of LV rehabilitation and considered as an outcome measure in research and clinical practice.

Relationship between central corneal thickness and progression of visual field loss in patients with open-angle glaucoma.

OBJECTIVE: To determine whether a relationship exists between central corneal thickness (CCT) and visual field (VF) progression in treated patients with open-angle glaucoma and asymmetric corneal thickness. DESIGN: Retrospective chart review. PARTICIPANTS: We studied 100 charts of patients with open-angle glaucoma and also bilateral CCT and VF data. METHODS: Charts from 2 glaucoma subspecialty practices were reviewed. The CCT and the rate of progression and event analysis of visual field data were assessed in all subjects. Subanalysis was performed for subjects whose CCT asymmetry was ≥ 16 µm. RESULTS: The mean CCT was 544 ± 40 µm OD and 541 ± 40 µm OS. The mean CCT difference between fellow eyes was 15 ± 11 µm (range, 1 to 52 µm). There was no significant intrasubject difference in the mean deviation (MD) and the pattern standard deviation (PSD) (p =0.917 and p = 0.704, respectively; paired t test). The more advanced VF MDs and PSDs were found in the thin eyes of 47 and 50 subjects, respectively (p = 0.459 and p = 0.317, respectively; χ(2)). Of the 65 subjects whose visual field indexes were available, 34 had the more rapid visual field index rates of progression in the thin eye (p = 0.400; χ(2)). Of the 27 subjects for whom event analysis was available, 15 had the worse progression category in the thin eye (p = 0.453, χ2). Subgroup analysis of 48 subjects with ≥ 16 µm CCT asymmetry did not find any significant difference in analyses of field progression between fellow eyes. CONCLUSIONS: No relationship was found between CCT and VF loss in treated patients with primary open-angle glaucoma or normal-tension glaucoma with asymmetrical CCT. Specifically, the thin eye did not have the more advanced VF loss or more rapid VF progression.

The apolipoprotein(a) component of lipoprotein(a) stimulates actin stress fiber formation and loss of cell-cell contact in cultured endothelial cells.

Elevated plasma concentrations of lipoprotein(a) (Lp(a)) are a risk factor for a variety of atherosclerotic disorders including coronary heart disease. In the current study, we report that incubation of cultured human umbilical vein or coronary artery endothelial cells with Lp(a) elicits a dramatic rearrangement of the actin cytoskeleton characterized by increased central stress fiber formation and redistribution of focal adhesions. These effects are mediated by the apolipoprotein(a) (apo(a)) component of Lp(a) since incubation of apo(a) with the cells evoked similar cytoskeletal rearrangements, while incubation with low density lipoprotein had no effect. Apo(a) also produced a time-dependent increase in transendothelial permeability. The cytoskeletal rearrangements evoked by apo(a) were abolished by C3 transferase, which inhibits Rho, and by Y-27632, an inhibitor of Rho kinase. In addition to actin cytoskeleton remodeling, apo(a) was found to cause VE-cadherin disruption and focal adhesion molecule reorganization in a Rho- and Rho kinase-dependent manner. Cell-cell contacts were found to be regulated by Rho and Rac but not Cdc42. Apo(a) caused a transient increase in the extent of myosin light chain phosphorylation. Finally apo(a) did not evoke increases in intracellular calcium levels, although the effects of apo(a) on the cytoskeleton were found to be calcium-dependent. We conclude that the apo(a) component of Lp(a) activates a Rho/Rho kinase-dependent intracellular signaling cascade that results in increased myosin light chain phosphorylation with attendant rearrangements of the actin cytoskeleton. We propose that the resultant increase in endothelial permeability caused by Lp(a) may help explain the atherosclerotic risk posed by elevated concentrations of this lipoprotein.