Effect of peripheral iridectomy on VEGF-A and TGF-ß levels in rabbit aqueous humour.

BACKGROUND: Peripheral iridectomy (PI), routinely performed during glaucoma filtration surgery, may contribute to scarring. This study aims to determine whether PI alters the concentrations of VEGF-A and TGF-ß isoforms in the rabbit aqueous humour. METHODS: Anterior chamber paracentesis (ACP) was performed in both eyes of six New Zealand white rabbits, with additional surgical PI performed in the right eyes. Eyes were examined on postoperative days (PODs) 1, 7, 30 and 60 by means of the tonopen, slit-lamp biomicroscopy, and bead-based cytokine assays for TGF-ß and VEGF-A concentrations in the aqueous humor. RESULTS: ACP caused a significant reduction in intraocular pressure (IOP) from mean preoperative 11.47 ± 1.01 mmHg to 5.67 ± 1.63 mmHg on POD 1 while PI did not cause further IOP reduction. Limbal conjunctival vasculature appeared slightly increased on POD 1 in both ACP and PI eyes with PI also causing mild bleeding from damaged iris vessels. Two PI eyes developed fibrinous anterior chamber reaction and/ or peripheral anterior synechiae. Aqueous VEGF-A levels were not significantly different between eyes treated with ACP and PI. Aqueous TGF-ß concentrations distributed in the ratio of 4:800:1 for TGF-ß1:TGF-ß2:TGF-ß3 respectively. While aqueous TGF-ß2 was not significantly induced by either procedure at any time point, TGF-ß1 and TGF-ß3 were significantly induced above baseline levels by PI on POD 1. CONCLUSION: PI increases the risk of inflammation. The combined induction of aqueous TGF-ß1 and TGF-ß3 by PI in glaucoma surgery may impact surgery success in glaucoma subtypes sensitive to these isoforms.

Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci for Estimating Angle Closure Disease Severity.

PURPOSE: To investigate whether recently identified genetic loci for primary angle-closure glaucoma (PACG) are associated with disease severity. DESIGN: Case-control study. PARTICIPANTS: Eight hundred four PACG patients and 943 control participants of Chinese ethnicity from Singapore. METHODS: The 8 PACG-associated single nucleotide polymorphisms (SNPs; rs11024102 at PLEKHA7, rs3753841 at COL11A1, rs1015213 located between PCMTD1 and ST18 on chromosome 8q, rs3816415 at EPDR1, rs1258267 at CHAT, rs736893 at GLIS3, rs7494379 at FERMT2, and rs3739821 mapping in between DPM2 and FAM102A) identified from genome-wide association studies were tested for association with disease severity using logistic regression adjusted for age and gender. A P value of 0.006 was set as significant after Bonferroni correction for testing of 8 loci. We also calculated the weighted genetic risk score (GRS) weighted by the estimated individual SNP effect size on PACG calculated as logarithm of the odds ratio (OR). Disease severity was based on the visual field mean deviation (MD) and classified as early to moderate (MD, >-12 dB) and severe (MD, <-20 dB). MAIN OUTCOME MEASURES: Association of PACG loci with severe disease. RESULTS: Of the 804 PACG patients, genotyping data were available for 768 individuals and included 436 with mild-to-moderate PACG and 206 with severe PACG. The PACG patients were significantly older (mean age, 64.3 ± 9.1 years vs. 56.4 ± 8.9 years; P < 0.001) and there were proportionately more women compared with control participants (58.4% vs. 49.0%; P < 0.001). Of the 8 loci investigated, we observed significant evidence of association with severe PACG at 1 SNP, namely rs3816415 in EPDR1 (OR, 2.03; 95% confidence interval [CI], 1.49-2.78; P = 1 × 10-5). A higher-weighted GRS was associated significantly with severe PACG, with an OR of 3.11 (95% CI, 1.95-4.96) comparing the lowest quartile with the highest quartile. CONCLUSIONS: Our results show that EPDR1 is associated significantly with severe PACG, suggesting that it may predispose patients to more aggressive disease development. Individuals with PACG with a higher GRS were associated with a higher risk of severe PACG.

Functional, structural, and molecular identification of lymphatic outflow from subconjunctival blebs.

The purpose of this study is to evaluate outflow pathways from subconjunctival blebs and to identify their identity. Post-mortem porcine (n = 20), human (n = 1), and bovine (n = 1) eyes were acquired, and tracers (fluorescein, indocyanine green, or fixable/fluorescent dextrans) were injected into the subconjunctival space to create raised blebs where outflow pathways were visualized qualitatively and quantitatively. Rodents with fluorescent reporter transgenes were imaged for structural comparison. Concurrent optical coherence tomography (OCT) was obtained to study the structural nature of these pathways. Using fixable/fluorescent dextrans, tracers were trapped to the bleb outflow pathway lumen walls for histological visualization and molecular identification using immunofluorescence against lymphatic and blood vessel markers. Bleb outflow pathways could be observed using all tracers in all species. Quantitative analysis showed that the nasal quadrant had more bleb-related outflow pathways compared to the temporal quadrant (nasal: 1.9±0.3 pathways vs. temporal: 0.7±0.2 pathways; p = 0.003). However, not all blebs resulted in an outflow pathway (0-pathways = 18.2%; 1-pathway = 36.4%; 2-pathways = 38.6%; and 3-pathways = 6.8%). Outflow signal was validated as true luminal pathways using optical coherence tomography and histology. Bicuspid valves were identified in the direction of flow in porcine eyes. Immunofluorescence of labeled pathways demonstrated a lymphatic (Prox-1 and podoplanin) but not a blood vessel (CD31) identity. Therefore, subconjunctival bleb outflow occurs in discrete luminal pathways. They are lymphatic as assessed by structural identification of valves and molecular identification of lymphatic markers. Better understanding of lymphatic outflow may lead to improved eye care for glaucoma surgery and ocular drug delivery.

Asian-specific vertical cup-to-disc ratio cut-off for glaucoma screening: An evidence-based recommendation from a multi-ethnic Asian population.

IMPORTANCE: Evidence-based guidelines are essential for glaucoma screening to work effectively. BACKGROUND: To derive a vertical cup-to-disc ratio (VCDR) cut-off for glaucoma screening in a multi-ethnic Asian population. DESIGN: The Singapore Epidemiology of Eye Diseases (SEED) study is a population-based study conducted from 2004 to 2011 in a single tertiary care research institute. PARTICIPANTS: SEED comprised of 10 033 Chinese, Malay and Indian adults aged ≥40 (response rate 75.6%). After excluding participants with a history of glaucoma medication or surgery, 9673 participants were included for analysis. METHODS: A systematic eye examination, which included applanation tonometry, visual field testing, gonioscopy and dilated fundus examination was conducted. MAIN OUTCOME MEASURE: Diagnosis of glaucoma. RESULTS: The distribution of VCDR and VCDR asymmetry were relatively homogenous in this multi-ethnic Asian population, with a 97.5th percentile value of 0.67 and 0.17, respectively. In the absence of more definite signs of glaucoma, VCDR ≥0.60 and VCDR asymmetry ≥0.20 provided the best balance between sensitivity (95.1%) and specificity (90.9%) in detecting glaucoma. For larger optic disc (≥2.0 mm), VCDR ≥0.65 with VCDR asymmetry ≥0.20 provided the best balance between sensitivity (84.8%) and specificity (93.2%). CONCLUSION AND RELEVANCE: Overall, VCDR ≥0.60 with VCDR ≥0.20 asymmetry provides a good balance between sensitivity and specificity in detecting glaucoma. For larger optic disc, VCDR ≥0.65 should be considered instead to mitigate against false-referrals due to larger physiological disc cupping. Our findings may act as a reference to populations with similar VCDR distribution.

Evaluation of Primary Angle-Closure Glaucoma Susceptibility Loci in Patients with Early Stages of Angle-Closure Disease.

PURPOSE: To investigate whether newly identified genetic loci for primary angle-closure glaucoma (PACG) are associated with early stage angle-closure disease defined as primary angle closure suspect (PACS). DESIGN: Case-control study. PARTICIPANTS: A total of 1397 PACS patients and 943 controls of Chinese ethnicity from Singapore and 604 PACS patients and 287 controls of Indian ethnicity. METHODS: The 8 PACG single nucleotide polymorphisms (SNPs; rs11024102 at PLEKHA7, rs3753841 at COL11A1, rs1015213 located between PCMTD1 and ST18 son chromosome 8q, rs3816415 at EPDR1, rs1258267 at CHAT, rs736893 at GLIS3, rs7494379 at FERMT2, and rs3739821 mapping in between DPM2 and FAM102A) were genotyped by Taqman assays. The association between SNP genotypes and PACS status was measured using logistic regression. A P value of 0.006 was set to account for the testing of 8 genetic loci using a Bonferroni correction. A meta-analysis was conducted to calculate the overall P value and accompanying per-allele odds ratios for each SNP analyzed. MAIN OUTCOME MEASURES: Association of PACG loci with PACS status. RESULTS: The PACS patients were significantly older in both cohorts (Chinese, P < 0.001; Indian, P = 0.002), and there were also more women (P < 0.001, both Chinese and Indian cohorts). In the Chinese cohort, significant evidence of association was noted at 3 SNPs: rs1015213 [A] in PCMTD1-ST18 (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.36-4.11; P = 0.002), rs3816415 [A] in EPDR1 (OR, 1.49; 95% CI, 1.19-1.85; P < 0.001), and rs3739821 [G] in DPM2-FAM102A (OR, 1.40; 95% CI, 1.18-1.65; P < 0.001). Only PCMTD1-ST-18 was replicated modestly in the Indian population (P = 0.056). Meta-analysis showed significant evidence of association for PCMTD1-ST-18 (OR, 1.55; 95% CI, 1.18-2.04; P = 0.002) and DPM2-FAM102A (OR, 1.27; 95% CI, 1.12-1.45; P = 0.0002). CONCLUSIONS: In this study, 2 of 8 PACG-associated loci were associated significantly with PACS status, the earliest stage in the angle-closure glaucoma disease course. The association of these PACG loci with PACS status suggests that these loci may confer susceptibility to a narrow angle configuration.

Ocular surface status in glaucoma and ocular hypertension patients with existing corneal disorders switched from latanoprost 0.005% to tafluprost 0.0015%: comparison of two prostaglandin analogues with different concentrations of benzalkonium chloride.

IMPORTANCE: Glaucoma treatment has often been associated with adverse side-effects from preservatives that are included in the used eye drops. BACKGROUND: To evaluate changes in the ocular surface and the presence of prostaglandin-induced corneal disorders after being switched from latanoprost 0.005% to low preservative tafluprost 0.0015% ophthalmic solution. DESIGN: Single centre, prospective study. PARTICIPANTS: Patients with primary open-angle glaucoma or ocular hypertension that had received treatment with once daily latanoprost 0.005% ophthalmic solution for control of intraocular pressure (IOP) for 3 months, with a score of above 1 on the National Eye Institute (NEI) ocular surface staining scale. METHODS: Following the ≥3 month latanoprost treatment period, patients were switched to once daily low preservative tafluprost 0.0015% ophthalmic solution. Patients were followed for a minimum of 3 months. MAIN OUTCOME MEASURES: Ocular surface changes were assessed by fluorescein staining score (NEI scale). Additional evaluations included tear break-up time, hyperaemia score, subjective symptoms, changes in intraocular pressure and presence of adverse reactions. RESULTS: Out of 59 patients enrolled, 51 were included in the final analysis. Fluorescein staining scores at baseline, prior to treatment switch, were 6.9 ± 3.1 and 3.3 ± 2.7 at the end of the study period (change in scores was -3.6 ± 2.2 [P < 0.001]). At last follow-up, significant improvements were observed in tear break-up time, hyperaemia score and subjective symptoms (all P < 0.05). CONCLUSIONS AND RELEVANCE: The clinical signs of ocular surface disease and subjective symptoms of dry eyes improved following the switch to low preservative tafluprost and demonstrated comparable IOP lowering effectiveness.

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.

Pattern of Visual Field Loss in Primary Angle-Closure Glaucoma Across Different Severity Levels.

PURPOSE: To investigate the patterns of visual field (VF) defects in primary angle-closure glaucoma (PACG) across different severity levels and to assess hemifield differences within each severity level. DESIGN: Cross-sectional study. PARTICIPANTS: Three hundred four patients diagnosed with PACG were recruited from glaucoma clinics at a Singapore hospital. METHODS: Point-wise total deviation values were recorded from the static automated perimetry (Swedish interactive threshold algorithm standard program 24-2; Humphrey model 750 [Carl Zeiss Meditec, Dublin, CA]) printouts. Patients were excluded if they had unreliable VFs (fixation losses >33% and false-positive responses >15%), had undergone only 10-2 VF testing, had VF defects not typical of glaucoma, or had undergone cataract extraction. Mild, moderate, and severe VF loss were defined by a mean deviation of -6.00 dB or more, -6.01 to -12.00 dB, and -12.01 dB or less, respectively. Each hemifield was divided into regions according to glaucoma hemifield test sectors. The average mean deviation (MD) of each region was obtained using total deviation values. MAIN OUTCOME MEASURES: Between- and within-hemifield differences of the regions across the severity levels. RESULTS: After excluding ineligible cases, 249 patients with PACG were included in the analysis. Mean age of the patients was 65.7±8.6 years, with a 1:1 gender ratio. The number of patients who had mild, moderate, and severe VFs was 72 (28.9%), 78 (31.3%), and 99 (39.8%), respectively. For between-hemifield comparisons, all regions in the superior hemifield had worse MDs compared with their counterparts in the inferior hemifield across the severity spectrum. Likewise, for within-hemifield comparisons, MDs of the regions gradually worsened with increasing distance from the fixation point. CONCLUSIONS: In this group of clinic-based PACG patients, the superior hemifield was found to be affected more severely than the inferior hemifield, and the differences between them increased with worsening disease severity. The damage was consistently more pronounced in the nasal area.

Argon Laser Peripheral Iridoplasty for Primary Angle-Closure Glaucoma: A Randomized Controlled Trial.

PURPOSE: To determine the effectiveness of argon laser peripheral iridoplasty (ALPI) in primary angle closure (PAC) and primary angle-closure glaucoma (PACG). DESIGN: Randomized controlled trial. PARTICIPANTS: Eighty PAC or PACG subjects who underwent laser iridotomy (LI) and had at least 180° of persistent appositional angle closure and intraocular pressure (IOP) of more than 21 mmHg were enrolled. METHODS: Subjects were randomized to receive either 360° ALPI (Visulas 532s; Carl Zeiss Meditec, Jena, Germany) or medical therapy (Travoprost 0.004%; Alcon-Couvreur, Puurs, Antwerp, Belgium). Repeat ALPI was performed if the IOP reduction was less than 20% from baseline along with inadequate angle widening at the month 1 or month 3 visit. Intraocular pressure was controlled with systematic addition of medications when required. MAIN OUTCOME MEASURES: The primary outcome measure was success rates after ALPI at 1 year. Complete success was defined as an IOP of 21 mmHg or less without medication, and qualified success was defined as an IOP of 21 mmHg or less with medication. Failure was defined as an IOP more than 21 mmHg despite additional medications or requiring glaucoma surgery. RESULTS: Forty subjects (51 eyes) were randomized to ALPI and 40 subjects (55 eyes) were randomized to medical therapy. Complete success (IOP ≤21 mmHg without medication) was achieved in 35.0% eyes of the ALPI group compared with 85.0% of eyes in the prostaglandin analog (PGA) group (P < 0.001), and qualified success (IOP ≤21 mmHg with medication) was achieved in 35.0% and 7.5%, respectively (P = 0.003). The IOP decreased by 4.9 mmHg (95% confidence interval [CI], 3.5-6.3 mmHg) in the ALPI group (P < 0.001) and by 6.1 mmHg (95% CI, 5.1-7.1 mmHg) in the medication group (P < 0.001). A failure rate of 30.0% was noted in the ALPI group compared with 7.5% in the medication group (P = 0.01). No treatment-related complications were recorded in either group. CONCLUSIONS: After 1 year, ALPI was associated with higher failure rates and lower IOP reduction compared with PGA therapy in eyes with persistent appositional angle closure and raised IOP after LI.

Distinct iris gene expression profiles of primary angle closure glaucoma and primary open angle glaucoma and their interaction with ocular biometric parameters.

BACKGROUND: This study aimed to evaluate differences in iris gene expression profiles between primary angle closure glaucoma (PACG) and primary open angle glaucoma (POAG) and their interaction with biometric characteristics. DESIGN: Prospective study. PARTICIPANTS: Thirty-five subjects with PACG and thirty-three subjects with POAG who required trabeculectomy were enrolled at the Singapore National Eye Centre, Singapore. METHODS: Iris specimens, obtained by iridectomy, were analysed by real-time polymerase chain reaction for expression of type I collagen, vascular endothelial growth factor (VEGF)-A, -B and -C, as well as VEGF receptors (VEGFRs) 1 and 2. Anterior segment optical coherence tomography (ASOCT) imaging for biometric parameters, including anterior chamber depth (ACD), anterior chamber volume (ACV) and lens vault (LV), was also performed pre-operatively. MAIN OUTCOME MEASURES: Relative mRNA levels between PACG and POAG irises, biometric measurements, discriminant analyses using genes and biometric parameters. RESULTS: COL1A1, VEGFB, VEGFC and VEGFR2 mRNA expression was higher in PACG compared to POAG irises. LV, ACD and ACV were significantly different between the two subgroups. Discriminant analyses based on gene expression, biometric parameters or a combination of both gene expression and biometrics (LV and ACV), correctly classified 94.1%, 85.3% and 94.1% of the original PACG and POAG cases, respectively. The discriminant function combining genes and biometrics demonstrated the highest accuracy in cross-validated classification of the two glaucoma subtypes. CONCLUSIONS: Distinct iris gene expression supports the pathophysiological differences that exist between PACG and POAG. Biometric parameters can combine with iris gene expression to more accurately define PACG from POAG.

Layer-by-layer nanoparticles as an efficient siRNA delivery vehicle for SPARC silencing.

Efficient and safe delivery systems for siRNA therapeutics remain a challenge. Elevated secreted protein, acidic, and rich in cysteine (SPARC) protein expression is associated with tissue scarring and fibrosis. Here we investigate the feasibility of encapsulating SPARC-siRNA in the bilayers of layer-by-layer (LbL) nanoparticles (NPs) with poly(L-arginine) (ARG) and dextran (DXS) as polyelectrolytes. Cellular binding and uptake of LbL NPs as well as siRNA delivery were studied in FibroGRO cells. siGLO-siRNA and SPARC-siRNA were efficiently coated onto hydroxyapatite nanoparticles. The multilayered NPs were characterized with regard to particle size, zeta potential and surface morphology using dynamic light scattering and transmission electron microscopy. The SPARC-gene silencing and mRNA levels were analyzed using ChemiDOC western blot technique and RT-PCR. The multilayer SPARC-siRNA incorporated nanoparticles are about 200 nm in diameter and are efficiently internalized into FibroGRO cells. Their intracellular fate was also followed by tagging with suitable reporter siRNA as well as with lysotracker dye; confocal microscopy clearly indicates endosomal escape of the particles. Significant (60%) SPARC-gene knock down was achieved by using 0.4 pmole siRNA/µg of LbL NPs in FibroGRO cells and the relative expression of SPARC mRNA reduced significantly (60%) against untreated cells. The cytotoxicity as evaluated by xCelligence real-time cell proliferation and MTT cell assay, indicated that the SPARC-siRNA-loaded LbL NPs are non-toxic. In conclusion, the LbL NP system described provides a promising, safe and efficient delivery platform as a non-viral vector for siRNA delivery that uses biopolymers to enhance the gene knock down efficiency for the development of siRNA therapeutics.

Enhancing the structure-function relationship in glaucoma using anatomical compensation of retinal nerve fibre layer.

BACKGROUND/AIMS: To investigate whether compensating retinal nerve fibre layer (RNFL) thickness measurements for demographic and anatomical ocular factors can strengthen the structure-function relationship in patients with glaucoma. METHODS: 600 eyes from 412 patients with glaucoma (mean deviation of the visual field (MD VF) -6.53±5.55 dB) were included in this cross-sectional study. Participants underwent standard automated perimetry and spectral-domain optical coherence tomography imaging (Cirrus; Carl Zeiss Meditec). Compensated RNFL thickness was computed considering age, refractive error, optic disc parameters and retinal vessel density. The relationship between MD VF and RNFL thickness measurements, with or without demographic and anatomical compensation, was evaluated sectorally and focally. RESULTS: The superior arcuate sector exhibited the highest correlation between measured RNFL and MD VF, with a correlation of 0.49 (95% CI 0.37 to 0.59). Applying the compensated RNFL data increased the correlation substantially to 0.62 (95% CI 0.52 to 0.70; p<0.001). Only 61% of the VF locations showed a significant relationship (Spearman's correlation of at least 0.30) between structural and functional aspects using measured RNFL data, and this increased to 78% with compensated RNFL measurements. In the 10°-20° VF region, the slope below the breakpoint for compensated RNFL thickness demonstrated a more robust correlation (slope=1.66±0.18 µm/dB; p<0.001) than measured RNFL (slope=0.27±0.67 µm/dB; p=0.688). CONCLUSION: Compensated RNFL data improve the correlation between RNFL measurements and VF parameters. This indicates that creating structure-to-function maps that consider anatomical variances may aid in identifying localised structural and functional loss in glaucoma.

The Singapore 5-fluorouracil trial: intraocular pressure outcomes at 8 years.

OBJECTIVE: To report the 8-year outcomes of Asian subjects who underwent trabeculectomy augmented by intraoperative 5-fluorouracil (5-FU) or placebo. DESIGN: Retrospective review of a randomized controlled trial. PARTICIPANTS: Subjects with primary open-angle or angle-closure glaucoma. METHODS: Study subjects were prospectively followed up for 3 years. After the last subject recruited had completed 8 years of follow-up, the charts of all subjects were reviewed to capture data from the year 3 visit onward. Kaplan-Meier survival function with Cox regression was performed to identify risk factors associated with trabeculectomy failure at 8 years. MAIN OUTCOME MEASURES: The primary outcome was trabeculectomy failure defined as intraocular pressure (IOP) >21 or <6 mmHg on 2 consecutive occasions after the first 6 weeks after surgery, repeat glaucoma surgery, or loss of light perception. Further end points were defined at IOP levels >17 and >14 mmHg. Secondary outcomes included IOP at 8 years and number of glaucoma medications. Complete success was defined using IOP end points ≤ 21, ≤ 17, or ≤ 14 mmHg at 8 years without medications. RESULTS: Of the 243 enrolled subjects, 170 (70.0%) completed 8 years follow-up, 86 in the 5-FU and 84 in the placebo group. There was no significant difference in failure rates at 8 years for the failure definitions of IOP >21 mmHg (11.6% of the 5-FU group vs. 16.7% of the placebo group; P = 1.00), IOP >17 mmHg (23.3% of the 5-FU group vs. 31% of the placebo group; P = 0.78), and IOP >14 mmHg (46.5% of the 5-FU group vs. 58.3% of the placebo group; P = 0.37). Mean IOP at 8 years was 13.7 mmHg in the 5-FU versus 14.4 mmHg in the placebo group (P = 0.24). Mean number of medications was 0.65 drops in the 5-FU versus 0.93 drops in the placebo group (P = 0.06). Complete success with IOP ≤ 21 mmHg at 8 years was achieved in 48 subjects (55.8%) in the 5-FU and 33 subjects (39.3%) in the placebo group (P = 0.09). Absence of bleb microcysts at 1 year, preoperative IOP, and number of bleb needlings performed within the first year were significantly associated with failure. CONCLUSIONS: There was no significant difference in IOP between the 5-FU and the placebo group at 8 years. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Intraocular lens as a drug delivery reservoir.

PURPOSE OF REVIEW: To describe the development and use of intraocular lenses (IOLs) as drug delivery systems and to review the current literature on their application and efficacy. RECENT FINDINGS: Many drugs have been loaded onto IOLs by coating or by attachment in a separate reservoir. With incorporation of polymeric materials either as a coating or by attachment as a separate reservoir, it is possible to achieve a sustained and controlled release of drugs. Experimental evidence in animal models has shown that IOL drug delivery systems are effective in the prevention and treatment of inflammation, infection and posterior capsule opacification after cataract surgery. SUMMARY: The use of IOLs as drug delivery reservoirs appears to show great promise. Although excellent results with therapeutic potential have been reported in experimental animal studies, further studies are needed to reach clinical use.

Efficacy and safety of collagen matrix implants in phacotrabeculectomy and comparison with mitomycin C augmented phacotrabeculectomy at 1 year.

BACKGROUND: To assess the efficacy and safety of collagen matrix implant (Ologen) in phacotrabeculectomy. DESIGN: Prospective, non-randomized, comparative study. PARTICIPANTS: Sixty-six Asian patients. METHODS: Thirty three consecutive patients underwent phacotrabeculectomy with Ologen implant and intraocular lens implantation, and 33 subjects recruited as controls underwent surgery with mitomycin C augmentation. MAIN OUTCOME MEASURES: The primary outcome measure was postoperative intraocular pressure at month 12. Additional postoperative treatments, such as bleb needling, and adverse events were secondary outcomes. RESULTS: The overall percentage reduction in intraocular pressure was 13% (95% confidence interval 6.7-19.2) in the Ologen group and 26% (95% confidence interval 14.8-37.9) in the mitomycin C group (P = 0.05). At 1 year after surgery (after adjusting for baseline differences), intraocular pressure decreased by 4.2 mmHg (95% confidence interval 2.8-5.6 mmHg) and 5.6 mmHg (95% confidence interval 4.2-7.0 mmHg), respectively (P = 0.16). Needling with 5-fluorouracil was required more often in the Ologen group (39% vs. 6%; P = 0.003). There was similar frequency (<10%) of adverse events in both groups, and there were no complications directly related to the Ologen implant. The blebs in the mitomycin C group had greater central area (P = 0.005), maximal area (P = 0.01) and height (P = 0.005), and were less vascular (P = 0.023) than the Ologen blebs. CONCLUSIONS: At 1 year, the overall performance of Ologen in combined phacotrabeculectomy was suboptimal compared with combined surgery with mitomycin C. Eyes in the Ologen group required more frequent bleb needling procedures.

Three-year Outcomes of an Expanded Asynchronous Virtual Glaucoma Clinic in Singapore.

PURPOSE: Virtual glaucoma clinics can help increase health care capacity, easing the disease burden of glaucoma. This study assesses the safety, rate of glaucoma progression, time efficiency, and cost-savings of our expanded Glaucoma Observation Clinic (GLOC) at the Singapore National Eye Centre over 3 years. METHODS: All patients seen at GLOC between July 2018 and June 2021 were included. Visual acuity, intraocular pressure, and visual fields or optic nerve head imaging were recorded, followed by a virtual review of the data by an ophthalmologist. An objective review of the management of 100 patients was conducted by 2 senior consultants independently as a safety audit. Patient outcomes including the rate of instability (due to worsening of clinical parameters necessitating a conventional clinic visit), glaucoma progression, the consultation review time efficiency, and cost-savings of GLOC were measured. RESULTS: Of 3458 patients, 16% had glaucoma, and the others had risk factors for glaucoma. The safety audit demonstrated a 95% interobserver agreement. The rate of instability was 14.6%, of which true progression was observed in 3.12%. The time taken for a glaucoma specialist to review a GLOC patient was 5.75±0.75 minutes compared with 13.7±2.3 minutes in a conventional clinic. The per capita manpower cost per GLOC patient per visit was $36.77 compared with $65.62 in the conventional clinic. This translates to a cost-saving of $280.65 over the lifetime of a hypothetical patient. CONCLUSIONS: Our expanded virtual glaucoma clinic is a safe, time-efficient, and cost-effective model with low rates of glaucoma progression, which could allow for significant health care capacity expansion.

Handheld chromatic pupillometry can reliably detect functional glaucomatous damage in eyes with high myopia.

BACKGROUND/AIMS: To assess pupillary light responses (PLRs) in eyes with high myopia (HM) and evaluate the ability of handheld chromatic pupillometry (HCP) to identify glaucomatous functional loss in eyes with HM. METHODS: This prospective, cross-sectional study included 28 emmetropes (EM), 24 high myopes without glaucoma (HM) and 17 high myopes with confirmed glaucoma (HMG), recruited at the Singapore National Eye Center. Monocular PLRs were evaluated using a custom-built handheld pupillometer that recorded changes in horizontal pupil radius in response to 9 s of exponentially increasing blue (469.1 nm) and red (640.1 nm) lights. Fifteen pupillometric features were compared between groups. A logistic regression model (LRM) was used to distinguish HMG eyes from non-glaucomatous eyes (EM and HM). RESULTS: All pupillometric features were similar between EM and HM groups. Phasic constriction to blue (p<0.001) and red (p=0.006) lights, and maximum constriction to blue light (p<0.001) were reduced in HMG compared with EM and HM. Pupillometric features of melanopsin function (postillumination pupillary response, PIPR area under the curve (AUC) 0-12 s (p<0.001) and PIPR 6 s (p=0.01) to blue light) were reduced in HMG. Using only three pupillometric features, the LRM could classify glaucomatous from non-glaucomatous eyes with an AUC of 0.89 (95% CI 0.77 to 1.00), sensitivity 94.1% (95% CI 82.4% to 100.0%) and specificity 78.8% (95% CI 67.3% to 90.4%). CONCLUSION: PLRs to ramping-up light stimuli are unaltered in highly myopic eyes without other diagnosed ocular conditions. Conversely, HCP can distinguish glaucomatous functional loss in eyes with HM and can be a useful tool to detect/confirm the presence of glaucoma in patients with HM.

Oral Ibuprofen is Associated With Reduced Likelihood of Early Bleb Failure After Trabeculectomy in High-Risk Glaucoma Patients.

PRCIS: Individuals prescribed ibuprofen after trabeculectomy have better postoperative intraocular pressure (IOP) control and a higher chance of bleb survival despite being at a higher risk of scarring. PURPOSE: To investigate the effects of early adjunctive oral ibuprofen treatment on IOP and bleb failure in eyes at high risk of scarring. METHODS: In these retrospective analyses, 288 eyes of 273 patients (mean ± SD age: 68.56 ± 10.47 y; 32.60% females) with primary glaucoma who underwent trabeculectomy/phacotrabeculectomy at the Singapore National Eye Centre between April 2020 and April 2021 with a follow-up duration ≥1 year were included. Of these, 77 (26.7%) eyes deemed to be at high risk of scarring were administered oral ibuprofen ≥3 months postoperatively (mean ± SD ibuprofen administration duration: 4.08 ± 2.28 wk). Participant's IOPs at baseline and at postoperative weeks 1, 2-3; and months 1, 2, 3, 6, and 12 were recorded. Bleb failure was defined as 2 consecutive IOP readings of >21, >18, and >15 mm Hg, and/or requiring remedial postoperative laser or surgery. RESULTS: The ibuprofen group experienced significantly greater postoperative IOP reductions at week 1 [mean difference, 95%CI: -2.89 (-5.22, -0.56) mm Hg] and month 1 [-2.29 (-4.53, -0.05) mm Hg]; and substantially lower odds of bleb failure at the >18 mm Hg [odds ratio, 95% CI: 0.39 (0.20-0.79)] and >15 mm Hg [0.52 (0.29-0.94)] thresholds, compared with the non-ibuprofen group. No differences in adverse ocular hypotony events were observed. CONCLUSION: Early adjunctive oral ibuprofen administered to individuals at high risk of posttrabeculectomy scarring is associated with greater IOP reductions and reduced likelihood of bleb failure. Our results suggest that oral nonsteroidal anti-inflammatory drugs may be a safe way of improving trabeculectomy survival in high-risk eyes.

In vitro analyses of the anti-fibrotic effect of SPARC silencing in human Tenon's fibroblasts: comparisons with mitomycin C.

Failure of glaucoma filtration surgery (GFS) is commonly attributed to scarring at the surgical site. The human Tenon's fibroblasts (HTFs) are considered the major cell type contributing to the fibrotic response. We previously showed that SPARC (secreted protein, acidic, rich in cysteine) knockout mice had improved surgical success in a murine model of GFS. To understand the mechanisms of SPARC deficiency in delaying subconjunctival fibrosis, we used the gene silencing approach to reduce SPARC expression in HTFs and examined parameters important for wound repair and fibrosis. Mitomycin C-treated HTFs were used for comparison. We demonstrate that SPARC-silenced HTFs showed normal proliferation and negligible cellular necrosis but were impaired in motility and collagen gel contraction. The expression of pro-fibrotic genes including collagen I, MMP-2, MMP-9, MMP-14, IL-8, MCP-1 and TGF-ß(2) were also reduced. Importantly, TGF-ß(2) failed to induce significant collagen I and fibronectin expressions in the SPARC-silenced HTFs. Together, these data demonstrate that SPARC knockdown in HTFs modulates fibroblast functions important for wound fibrosis and is therefore a promising strategy in the development of anti-scarring therapeutics.