Anti-angiogenic biomolecules in neovascular age-related macular degeneration; therapeutics and drug delivery systems.

Blindness in the elderly is often caused by age-related macular degeneration (AMD). The advanced type of AMD known as neovascular AMD (nAMD) has been linked to being the predominant cause of visual impairment in these people. Multiple neovascular structures including choroidal neovascular (CNV) membranes, fluid exudation, hemorrhages, and subretinal fibrosis, are diagnostic of nAMD. These pathological alterations ultimately lead to anatomical and visual loss. It is known that vascular endothelial growth factor (VEGF), a type of proangiogenic factor, mediates the pathological process underlying nAMD. Therefore, various therapies have evolved to directly target the disease. In this review article, an attempt has been made to discuss general explanations about this disease, all common treatment methods based on anti-VEGF drugs, and the use of drug delivery systems in the treatment of AMD. Initially, the pathophysiology, angiogenesis, and different types of AMD were described. Then we described current treatments and future treatment prospects for AMD and outlined the advantages and disadvantages of each. In this context, we first examined the types of therapeutic biomolecules and anti-VEGF drugs that are used in the treatment of AMD. These biomolecules include aptamers, monoclonal antibodies, small interfering RNAs, microRNAs, peptides, fusion proteins, nanobodies, and other therapeutic biomolecules. Finally, we described drug delivery systems based on liposomes, nanomicelles, nanoemulsions, nanoparticles, cyclodextrin, dendrimers, and composite vehicles that are used in AMD therapy.

Donor Risk Factors and Environmental Conditions Associated With Poor-Quality Corneas: An Analysis of the Central Eye Bank of Iran (2018-2021).

PURPOSE: The purpose of this study was to investigate the donor risk factors and environmental conditions associated with poor-quality corneas using the database of the Central Eye Bank of Iran over 4 years. METHODS: This cohort study was conducted on the recorded data of all donated corneas at the Central Eye Bank of Iran database from March 2018 to March 2022. Donors' characteristics and tissue variables were extracted from the database. The final corneal quality was determined based on slitlamp biomicroscopic observations and the results of specular microscopy. Environmental variables were also obtained from reliable resources. Risk factors for poor-quality corneas were calculated using logistic mixed-effect regression analysis. All analyses were performed with STATA 17.0. The significance level of 0.05 was considered for all the analyses. RESULTS: The data of 20,625 eyes of 10,601 donors were evaluated. We found that donor age had an inverse correlation with endothelial cell density (r = -0.28, P < 0.001). The trend of donated corneal poor quality decreased between 2018 and 2021. Several factors, including intoxication (odds ratio [OR] = 1.29), obesity (OR = 1.34), diabetes mellitus (OR = 1.63), hypertension (OR = 1.52), and pseudophakic eyes (OR = 1.56), were associated with the poor quality of donated corneal tissues. The outdoor temperature over 26°C was associated with higher odds of poor corneal quality (OR = 1.31), whereas high relative humidity decreased the odds of poor corneal quality (OR = 0.82). CONCLUSIONS: This study revealed that the cause of donor death, obesity, donor comorbidities, pseudophakia, and environmental factors could affect the corneal quality and make the donated corneas less suitable for transplantation.

A registration trend in eyelid skin cancers and associated risk factors in Iran, 2005-2016.

BACKGROUND: Eyelid skin cancers are the most prevalent ophthalmic malignancies. This study aimed to evaluate the association of the Human Development Index (HDI) and lifestyle risk factors with eyelid skin cancers in Iran. METHODS: This ecological study analyzed the data collected from the Iranian National Population-based Cancer Registry (2005-2016). The data on provincial-level eyelid skin cancer risk factors were obtained from national sources. The association between provincial HDI and lifestyle risk factors with the prevalence of eyelid skin cancers was assessed. RESULTS: The mean 12-year age-standardized incidence rate (ASIR) of eyelid skin cancers was 16.22 per 100,000 (9,104 cases). The overall ASIR showed an upward trend with an estimated annual average increase of 0.006 per year. There were positive correlations between the prevalence of overall eyelid skin cancers and provincial HDI, smoking, and obesity (r = 0.32, 0.42, and 0.37, respectively). In multivariate analysis, obesity/overweight remained a positive predictor for high prevalence of total eyelid skin cancers (OR = 1.97, 95%CI = 1.08-3.58, P = 0.026), carcinoma (2.10, 1.15-3.83, P = 0.015), and basal cell carcinoma (1.48, 0.99-2.20, P = 0.054). CONCLUSIONS: An increasing trend in ASIR of eyelid skin cancers was observed in more than a decade in Iran which was positively associated with provincial HDI and prevalence of obesity. The findings of the study highlight the importance of promotional programs for preventing obesity/overweight and appropriate allocation of screening facilities based on the HDI level.

Interpretable deep learning for diagnosis of fungal and acanthamoeba keratitis using in vivo confocal microscopy images.

Infectious keratitis refers to a group of corneal disorders in which corneal tissues suffer inflammation and damage caused by pathogenic infections. Among these disorders, fungal keratitis (FK) and acanthamoeba keratitis (AK) are particularly severe and can cause permanent blindness if not diagnosed early and accurately. In Vivo Confocal Microscopy (IVCM) allows for imaging of different corneal layers and provides an important tool for an early and accurate diagnosis. In this paper, we introduce the IVCM-Keratitis dataset, which comprises of a total of 4001 sample images of AK and FK, as well as non-specific keratitis (NSK) and healthy corneas classes. We use this dataset to develop multiple deep-learning models based on Convolutional Neural Networks (CNNs) to provide automated assistance in enhancing the diagnostic accuracy of confocal microscopy in infectious keratitis. Densenet161 had the best performance among these models, with an accuracy, precision, recall, and F1 score of 93.55%, 92.52%, 94.77%, and 96.93%, respectively. Our study highlights the potential of deep learning models to provide automated diagnostic assistance for infectious keratitis via confocal microscopy images, particularly in the early detection of AK and FK. The proposed model can provide valuable support to both experienced and inexperienced eye-care practitioners in confocal microscopy image analysis, by suggesting the most likely diagnosis. We further demonstrate that these models can highlight the areas of infection in the IVCM images and explain the reasons behind their diagnosis by utilizing saliency maps, a technique used in eXplainable Artificial Intelligence (XAI) to interpret these models.

Diagnostic accuracy of confocal scan in detecting acanthamoeba keratitis and fungal keratitis: a systematic review and meta-analysis.

PURPOSE: Acanthamoeba keratitis (AK) and fungal keratitis (FK) are two microbial keratitis that cause serious damage and, without early accurate diagnosis and treatment, may lead to blindness. In vivo corneal confocal scan, as an emerging ocular diagnostic method in comparison with microbiological smears and cultures as the gold standard, may assist in accelerating appropriate diagnosis. OBJECTIVE: To determine the diagnostic accuracy of confocal scan for the diagnosis of AK and FK. METHODS: Data were collected via a comprehensive literature search of PubMed, Web of Science, Cochrane Library, Embase and Scopus using keywords related to diagnostic accuracy of confocal scan in AK and FK up to October 2022. Pooled data underwent meta-analysis in terms of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall diagnostic odds ratio (DOR) of confocal scan for the diagnosis of AK and FK. RESULTS: The final 14 relevant studies were identified, including 1950 eyes. Meta-analysis in AK group revealed 94% sensitivity, 87% specificity, 89% PPV, 92% NPV, and DOR of 143.32, and in FK group disclosed 88% sensitivity, 85% specificity, 85% PPV, 88% NPV, and DOR of 75.98. CONCLUSION: The accuracy of confocal scan for the diagnosis of AK was significantly more than that for detecting FK; despite the limitations such as limited numbers of available retrospective studies for the detection of FK, confocal scan had an acceptable performance in detecting FK eyes. The overall performance of NCS was similar with that of HRT-RCM for the detection of both types of keratitis.

A joinpoint and age-period-cohort analysis of ocular cancer secular trends in Iran from 2004 to 2016.

Investigating secular trends of ocular cancer registration in Iran. After acquiring Iranian national population-based cancer registry data, trends of age-standardised incidence rates (ASIR) of ocular cancers and annual percent changes (APC) between 2004 and 2016 were analysed in age groups, gender, topography and morphology types with joinpoint regression analysis. Age, period, and cohort effects on incidence rates were estimated by age-period-cohort model. Geographic distribution of ASIR was assessed using GIS. Overall ASIR of ocular cancers was 16.04/100,000 (95% CI 15.77-16.32). Joinpoint regression analysis showed a significant increase of ASIR between 2004 and 2009 for males (APC = 5.5, 95% CI 0.9-10.2), ages over 50 years (APC = 5.2, 1.2-9.4), skin/canthus/adnexal cancers (APC = 4.2, 0.8-7.7), and carcinomas/adenocarcinomas (APC = 4.3, 0.6-8.1); however, between 2009 and 2016 a declining trend was observed in all investigated variables. ASIR of retinoblastoma was significantly increased (averaged APC = 20.7, 9-33.7) between 2004 and 2016. age-period-cohort analyses showed that incidence rates of ocular cancers significantly increased with aging, time periods, and birth cohort effects (p < 0.001). ASIR varied from 6.7/100,000 to 21.7/100,000 in Iran. Excepting retinoblastoma, all ocular cancer incidence trends were downward over a 13-year period; however, it was increasing between 2004 and 2009 cancer. ASIR was significant aging in Iran.

RONA Technique: A Novel ILM Peeling Method for Treatment of Large Full-Thickness Macular Holes.

PURPOSE: To present a new technique, RONA, for internal limiting membrane peeling and show its comparable success rate in closure of large full-thickness macular holes (FTMHs). METHODS: This prospective interventional case series was implemented from January 2018 to November 2019. Consecutive cases with large FTMH with an aperture size of more than 500 µ m were included. The RONA technique was used to make consecutive flaps; the central border of which remained adherent to the FTMH edge. The emphasis is that the central border of all flaps should remain adherent to the FTMH edge, letting the flaps remain there spontaneously. RESULTS: Seventeen eyes of 17 patients (4 males and 13 females; age 62.3 ± 7.8 years) were included. The mean size of opening and base of FTMH were 651.1 ± 141.1 µ m (range: 501-950) and 964.6 ± 383.8 µ m (range: 527-2098), respectively. One week after the surgery, complete closure of all FTMHs occurred with no hole reopening until the end of 12 months. The mean best-corrected visual acuity at baseline and 12 months after surgery were 1.57 ± 0.30 and 0.75 ± 0.028 logarithm of the minimum angle of resolution, respectively, with statistically significant improvement ( P < 0.001). CONCLUSION: The first advantage of this efficacious technique is that there is no need to manipulate FTMH edge or underneath tissues. Another and of course, the most important advantage is that there is no need to care about flap unfolding during the exchange stage.

Risk of Induction of Corneal Neovascularization with Topical Erythropoietin: An Animal Safety Study.

Purpose: To evaluate the pro-angiogenic effect of topical erythropoietin on cornea in chemical burn-injured rabbit eyes. Methods: The corneal alkali-burn injury was induced in 10 eyes of 10 rabbits using filter paper saturated with 1.0 mol sodium hydroxide. The eyes were categorized into the treatment group (n = 5) that received topical erythropoietin (3000 IU/mL) every 8 hr for one month versus the control group (n = 5) that received normal saline every 8 hr for one month. All eyes were treated with topical ciprofloxacin every 8 hr until corneal re-epithelialization was complete. Corneal epithelial defects, stromal opacity, and neovascularization were evaluated after the injury. At the conclusion of the study, the rabbits were euthanized and their corneas were submitted to histopathological examination. Results: Baseline characteristics including the rabbits' weight and the severity of corneal injury were comparable in two groups. Time to complete corneal re-epithelialization was 37 days in the treatment group and 45 days in the control group (P = 0.83). There was no significant difference between the groups in the rate of epithelial healing or corneal opacification. Clinical and microscopic corneal neovascularization was observed in one eye (20%) in the treatment group and two eyes (40%) in the control group (P = 0.49). Conclusion: Recombinant human erythropoietin administered topically did not induce vessel formation in rabbit corneas after chemical burn.

Eye Bank Records on Pediatric Keratoplasty.

Purpose: To report eye bank records for pediatric keratoplasty in Iran between 2006 and 2019. Methods: In a retrospective study, all electronic records of the Central Eye Bank of Iran for pediatric keratoplasty between April 2006 and March 2019 were analyzed in terms of indications for keratoplasty, surgical techniques, their corresponding trends, and post-transplantation graft clarity. Results: Our database included 2178 eyes from 2050 pediatric cases. The leading indications for keratoplasty included acquired nontraumatic diseases (75.8%), congenital abnormalities (12.7%), corneal regraft (8.3%), and acquired traumatic diseases (3.2%). Keratoconus was the most common acquired nontraumatic cause (58%) and more common in the age group > 12 years than those ≤ 12 years (P < 0.001). Congenital corneal abnormalities and regrafts were more common in the age group ≤ 12 years (both P < 0.001). The most common surgical technique was penetrating keratoplasty (PKP, 90.9%) followed by deep anterior lamellar keratoplasty (DALK, 7.3%), Descemet stripping automated endothelial keratoplasty (DSAEK, 1.1%), anterior lamellar keratoplasty (0.5%), and keratolimbal allograft transplantation (0.2%). DSAEK was more common in the age group ≤ 12 years (P = 0.002), which, unlike PKP and DALK, showed a significant ascending trend over the 14-year period (P = 0.018). Post-transplantation graft clarity was 96.8%. Conclusion: Keratoconus was the leading indication for pediatric keratoplasty in Iran. Although PKP was the predominant keratoplasty procedure for the treatment of pediatric corneal disorders, it showed a significant descending trend over the 14 years.

Comparison of penetrating keratoplasty and deep anterior lamellar keratoplasty in keratoconus eyes with vernal keratoconjunctivitis.

PURPOSE: The purpose of the study is to compare outcomes after penetrating keratoplasty (PK) against deep anterior lamellar keratoplasty (DALK) for keratoconus in patients with vernal keratoconjunctivitis (VKC). METHODS: Keratoconic patients with VKC who received PK (n = 55, group 1) or DALK (n = 62, group 2) were retrospectively enrolled. The Student's t test, Mann-Whitney test, Fisher's exact test, chi-square test, and Kaplan-Meier survival curve were used to compare outcomes between the groups. RESULTS: The follow-up period was 59.4 ± 44.1 and 62.4 ± 38.9 months in groups 1 and 2, respectively (p = 0.70). Postoperative best spectacle-corrected visual acuity was 0.24 ± 0.18 and 0.29 ± 0.19 logMAR, respectively (p = 0.13). Graft rejection occurred in 34.6% and 25.8% of eyes in groups 1 and 2, respectively (p = 0.30). Groups 1 and 2 were comparable in the rates of cataract (3.6% and 12.9%, respectively, p = 0.07) and high intraocular pressure (3.6% and 8.1%, respectively, p = 0.31). Compared with the eyes with inactive VKC, PK eyes that experienced postoperative disease reactivation had a higher rate of suture abscesses (10.9% versus 50.0%, respectively, p = 0.01) and suture-tract vascularization (6.5% versus 33.3%, respectively, p = 0.03). Similarly, disease reactivation significantly increased suture abscesses from 27.3% to 51.7% (p = 0.03) and suture-tract vascularization from 18.2% to 49.6% (p = 0.005) in the DALK group. The graft survival rates were 95.3% in group 1 and 87.9% in group 2 at the 4-year follow-up, with mean durations of 14.4 and 11.1 months, respectively (p = 0.20). CONCLUSION: The results indicate no difference in outcomes between PK and DALK for keratoconus in patients with VKC. Postoperative VKC reactivation increased the rate of suture-related problems after both techniques of keratoplasty.

Penetrating Keratoplasty Versus Deep Anterior Lamellar Keratoplasty in Children and Adolescents With Keratoconus.

PURPOSE: To compare the outcomes of penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) for pediatric keratoconus. DESIGN: Retrospective comparative interventional case series. METHODS: This study included consecutive pediatric keratoconus cases (≤18 years of age) who received PK (n=45) or DALK (n=54) in 2 different time periods. Postoperative best spectacle-corrected visual acuity (BSCVA), refraction, and complications were compared between the study groups. RESULTS: The mean follow-up was 83.3±46.1 and 63.3±45.6 months in the PK and DALK groups, respectively (P = .10). Postoperatively, BSCVA was 0.20±0.19 logMAR in the PK group and 0.26±0.19 logMAR in the DALK group (P = .11), with a BSCVA of ≥20/40 in 91.1% and 83.3% of eyes, respectively (P = .25). Two groups were comparable regarding postoperative refractive outcomes. Graft epitheliopathy and suture-associated complications were more commonly encountered after DALK, which was attributable to the effect of low-quality grafts on the clinical outcomes of DALK. Ten PK eyes (22.2%) and 9 DALK eyes (16.7%) experienced at least 1 episode of graft rejection within 5 years of corneal transplantation (P = .49). Rejection was reversible in 93.1% and 100% of episodes in the PK and DALK groups, respectively (P = .63). At the postoperative year 5, 95.6% of grafts in the PK group and 98.2% in the DALK group remained clear (P = .45). CONCLUSION: No significant difference was observed in the outcomes between PK and DALK in pediatric keratoconus. Low-quality donor tissues in DALK increased the incidence of graft epithelial problems and suture-related complications as compared to PK.

Impression cytology for detection of clinically suspected ocular surface disorders: A cross-sectional study.

PURPOSE: Investigating impression cytology (IC) results of various types of clinically suspected ocular surface lesions over a 14-year period in a referral center in Iran. METHODS: IC findings obtained from patients with different types of ocular surface disorders between 2005 and 2018 were reviewed. Agreement between clinical suspicions and IC results was evaluated by calculating Cohen's Kappa coefficient (CKC). RESULTS: Clinical suspicions in 688 surveyed eyes were ocular surface squamous neoplasia (OSSN, 42.0%), limbal stem cell deficiency (LSCD, 36.3%), dry eye-related disorders (DERD, 11.5%), Acanthamoeba keratitis (AK, 7.2%), benign pigmented lesions (BPL, 1.9%), immune-related conjunctivitis (IRC, 0.7%), and malignant pigmented lesions (MPL, 0.4%). General agreement between clinical suspicions and IC results was 0.68 for all groups. This agreement was almost perfect in AK (CKC = 0.966) and BPLs (CKC = 0.843), and was substantial in MPLs (CKC = 0.749), OSSNs (CKC = 0.684), and LSCD (CKC = 0.612). CKC in IRC (0.567) and DERDs (0.443) was moderate. Histopathologic results were available in 22 eyes and were well-correlated with corresponding IC results (CKC = 0.86). Multiple post-treatment follow-up sessions of IC were performed in 51 eyes (11.4%) that had diagnosis of LSCD (31), OSSN (17), and MPL (3) at the first IC session. CONCLUSION: Our survey not only demonstrated an overall substantial agreement between IC results and primary clinical suspicions, but also showed an almost perfect correlation between IC results and existent histopathologic data. Therefore, IC as a non-invasive diagnostic modality can be of great importance in proper diagnosis of various ocular surface diseases especially when distinguishing malignant from benign lesions is required.

Outcomes of big-bubble deep anterior lamellar keratoplasty for pediatric keratoconus.

PURPOSE: To evaluate the outcomes and complications of deep anterior lamellar keratoplasty (DALK) performed for pediatric keratoconus. METHODS: This retrospective study enrolled 44 consecutive eyes of 39 keratoconus-affected children (≤ 18 years of age). All patients underwent big-bubble DALK from March 2004 to June 2016. The outcome measures included postoperative best spectacle-corrected visual acuity (BSCVA), manifest refraction, keratometry readings, and complications. RESULTS: The mean participant age was 16.8 ± 1.4 years, and the mean follow-up period was 68.5 ± 39.9 months. Successful big bubble was achieved in 33 eyes (75.0%), while the surgical technique was predescemetic DALK in 11 (25.0%). The mean BSCVA changed from 1.34 ± 0.49 LogMAR preoperatively to 0.24 ± 0.10 LogMAR postoperatively (P < 0.001). The mean keratometry decreased from 59.54 ± 5.17 D preoperatively to 46.23 ± 2.17 D postoperatively (P < 0.001). The complications encountered during the study period were intraoperative Descemet's membrane perforation (n = 5, 11.4%), the Urrets Zavalia syndrome (n = 1, 2.3%), graft epithelial problems (n = 3, 6.8%), subepithelial graft rejection (n = 5, 11.4%), high intraocular pressure (n = 8, 18.2%), and traumatic wound dehiscence (n = 2, 4.6%). Suture-related complications included premature loosening (n = 13, 29.6%), broken sutures (n = 12, 27.3%), suture-tract vascularization (n = 6, 13.6%), suture-associated abscesses (n = 5, 11.4%), and suture cheese wiring (n = 2, 4.6%). A clear graft was found in 40 eyes (90.9%) at the last follow-up examination. CONCLUSION: This study showed promising results with big-bubble DALK in keratoconus-affected children. A frequent and close follow-up with dedicated parental involvement is essential for the early recognition and management of postoperative complications.