PURPOSE. To develop pharmacokinetics models to describe the disposition of small lipophilic molecules in the cornea and retina after periocular (subconjunctival or posterior subconjunctival) administration. METHODS. Compartmental pharmacokinetics analysis was performed on the corneal and retinal data obtained after periocular administration of 3 mg of celecoxib (a selective COX-2 inhibitor) to Brown Norway (BN) rats. Berkeley Madonna, a differential and difference equation-based modeling software, was used for the pharmacokinetics modeling. The data were fit to different compartment models with first-order input and disposition, and the best fit was selected on the basis of coefficient of regression and Akaike information criteria (AIC). The models were validated by using the celecoxib data from a prior study in Sprague-Dawley (SD) rats. The corneal model was also fit to the corneal data for prednisolone at a dose of 2.61 mg in albino rabbits, and the model was validated at two other doses of prednisolone (0.261 and 26.1 mg) in these rabbits. Model simulations were performed with the finalized model to understand the effect of formulation on corneal and retinal pharmacokinetics after periocular administration. RESULTS. Celecoxib kinetics in the BN rat cornea can be described by a two-compartment (periocular space and cornea, with a dissolution step for periocular formulation) model, with parallel elimination from the cornea and the periocular space. The inclusion of a distribution compartment or a dissolution step for celecoxib suspension did not lead to an overall improvement in the corneal data fit compared with the two-compartment model. The more important parameter for enhanced fit and explaining the apparent lack of an increase phase in the corneal levels is the inclusion of the initial leak-back of the dose from the periocular space into the precorneal area. The predicted celecoxib concentrations from this model also showed very good correlation (r = 0.99) with the observed values in the SD rat corneas. Similar pharmacokinetics models explain drug delivery to the cornea in rat and rabbit animal models. Retinal pharmacokinetics after periocular drug administration can be explained with a four-compartment (periocular space, choroid-containing transfer compartment, retina, and distribution compartment) model with elimination from the periocular space, retina, and choroid compartment. Inclusion of a dissolution-release step before the drug is available for absorption or elimination better explains retinal tmax. Good fits were obtained in both the BN (r = 0.99) and SD (r = 0.99) rats for retinal celecoxib using the same model; however, the parameter estimates differed. CONCLUSIONS. Corneal and retinal pharmacokinetics of small lipophilic molecules after periocular administration can be described by compartment models. The modeling analysis shows that (1) leak-back from the site of administration most likely contributes to the apparent lack of an increase phase in corneal concentrations; (2) elimination via the conjunctival or periocular blood and lymphatic systems contributes significantly to drug clearance after periocular injection; (3) corneal pharmacokinetics of small lipophilic molecules can be explained by using similar models in rats and rabbits; and (4) although there are differences in some retinal pharmacokinetics parameters between the pigmented and nonpigmented rats, the physiological basis of these differences has yet to be ascertained.
Purpose: To evaluate capillaries perfusion and retinal nerve fiber layer (RNFL) thickness diurnal changes of macular/optic disc regions among participants with or without obstructive sleep apnea-hypopnea (OSA) using spectral-domain optical coherence tomography angiography (OCTA). Methods: In this study, we enrolled a cohort of 35 participants including 14 patients with mild-to-moderate OSA, 12 patients with severe OSA, and 9 healthy individuals. All participants had Berlin questionnaire filled. At 20:00 and 6:30, right before and after the polysomnography examination, a comprehensive ocular examination was conducted. The systemic and ocular clinical characteristics were collected, and OCTA scans were performed repeatedly. Blood flow and RNFL thickness parameters were then exported using built-in software and analyzed accordingly. Results: After sleep, the overall vessel density (VD) variables, especially macular and choriocapillaris VDs, were relatively comparative and stable. One exception was the RPC vessel density at the inside-disc region with a decreasing trend in the mild-to-moderate group (p=0.023). RNFL changes before and after sleep in the nasal-inferior and peripapillary region were statistically significant (p=0.003; p=0.043) among three groups. And multiple testing correction verified the significant difference in diurnal changes between the mild-to-moderate group and the control group in pairwise comparisons (p=0.006; p=0.02). Conclusions: The changes of imperceptible blood flow and RNFL thickness overnight around optic disc areas could be observed in OSA patients. Despite physiological fluctuations, aberrant diurnal changes might be useful for identifying a decrease in micro-environmental stability associated with the development of various ocular diseases such as glaucoma. Other VD variables, especially macular and choriocapillaris VDs, are relatively stable in eyes of patients having OSA with different severity.
Purpose: We report endothelial cell (EC) characteristics and central corneal thickness (CCT) from Infant Aphakia treatment Study (IATS) patients at the 5-year exam.
Design: Randomized, controlled trial of the treatment of unilateral cataract with aphakic contact lens (CL) versus primary intraocular lens implant (IOL).
Subjects: 114 infants with unilateral cataract.
Methods: EC density, coefficient of variation (CV), and percent hexagonal cells were measured by non-contact specular microscopy. Central corneal thickness (CCT) was measured using contact pachymetry. Fellow eyes served as controls.
Main outcome measures: Mean differences between treated and fellow eyes of CL and IOL groups were compared with a paired t test. A one-way analysis of variance model and the Tukey-Kramer multiple comparison procedure were used to assess the effect of a diagnosis of glaucoma or glaucoma suspect.
Results: 105 (52 CL, 53 IOL) had either specular microscopy or corneal thickness data recorded. Mean EC densities were higher in the aphakic eyes compared to fellow eyes (3921 and 3495 cells/mm2, p < 0.0001). Mean CV was higher in aphakic eyes (27 vs 24, p=0.0002), and mean percent hexagonal cells was lower (72% vs 76%, p=0.002). Mean CCT of aphakic eyes was higher than controls (637 vs 563 μm, p < 0.0001). There was no difference in EC densisty in eyes treated with IOL compared to fellow eyes (3445 and 3487 cells/mm2, p=0.68). Means for CV (25 vs 24, p=0.07) and percent hexagonal cells (74 vs 76%, p=0.27) were also not significantly different. Mean CCT was higher in eyes with IOL (605 vs 571 μm, p < 0.0001) compared to fellow eyes. Compared to treated eyes without glaucoma or glaucoma suspect, treated eyes with glaucoma had lower EC density (3289 vs 3783 cells/mm2, p = 0.03) and treated eyes with glaucoma suspect had greater mean corneal thickness (660 vs 612 μm, p = 0.0036).
Conclusion: Cataract extraction during infancy with IOL implantation was not associated with a reduced EC count in treated compared to fellow eyes, although CCT was increased. Extended wear aphakic CL may cause corneal polymegathism with increased EC density and CCT. Glaucoma diagnosis was associated with reduced EC counts and increased CCT.
AIM: To investigate the influence of unilateral congenital ptosis on the development of the eye and vision in children. METHODS: In this prospective observational study, 41 patients with unilateral congenital ptosis were enrolled (age range 3-15y). The blepharoptosis was divided into 3 subgroups according to the margin reflex distance-1 (MRD-1), including mild group (MRD-1≥2 mm), moderate group (0≤MRD-1<2 mm), and severe group (MRD-1<0 mm). The fellow eyes served as controls. All subjects underwent ocular examinations, including axial length, keratometry, and refractive error. RESULTS: The incidence of astigmatism (ptotic eyes: 58.5% vs fellow eyes: 24.4%, P=0.002) and magnitude of cylindrical power (ptotic eyes: -0.86±0.79 D vs fellow eyes: -0.43±0.63 D, P=0.003) differed significantly between the ptotic eyes and the fellow eyes. The spherical equivalent refraction (P=0.006), spherical power (P=0.01), cylindrical power (P=0.011), axial length-corneal radius (AL/CR) ratio (P=0.009), frequency of hyperopia (P=0.002) and astigmatism (P=0.004) were significantly different among the ptotic eye subgroups and the fellow eye group. In addition, in patients with congenital ptosis, the incidence of amblyopia is 43.9% and the incidence of anisometropia is 24.4%. More importantly, the ratio of AL/CR showed significantly positive correlation with the severity of ptosis (P=0.002). CONCLUSION: Congenital ptosis may lead to a delayed eyeball development in the aspect of AL/CR. The risk of amblyopia is also increased due to visual deprivation and aggravated anisometropia, particularly in severe ptosis case.
by
Yaohui Sun;
Brian Reid;
Yan Zhang;
Kan Zhu;
Fernando Ferreira;
Alejandro Estrada;
Yuxin Sun;
Bruce W Draper;
Haicen Yue;
Calina Copos;
Francis Lin;
Yelena Y Bernadskaya;
Min Zhao;
Alex Mogilner
Recent research has elucidated mechanochemical pathways of single cell polarization, but much less is known about collective motility initiation in adhesive cell groups. We used galvanotactic assays of zebrafish keratocyte cell groups, pharmacological perturbations, electric field switches, particle imaging velocimetry, and cell tracking to show that large cell groups initiate motility in minutes toward the cathode. Interestingly, while PI3K-inhibited single cells are biased toward the anode, inhibiting PI3K does not affect the cathode-directed cell group migration. We observed that control groups had the fastest cathode-migrating cell at the front, while the front cells in PI3K-inhibited groups were the slowest. Both control and PI3K-inhibited groups rapidly repolarized when the electric field direction was reversed, and the group migration continued after the electric field was switched off. Inhibiting myosin disrupted the cohesiveness of keratocyte groups and abolished the collective directionality and ability to switch direction when the electric field is reversed. Our data are consistent with a model according to which cells in the group sense the electric field individually and mechanical integration of the cells results in coherent group motility.
Purpose: This meta-analysis aims to investigate the worldwide prevalence of primary angle-closure glaucoma (PACG) and its risk factors in the last 20 years. Methods: We conducted a systematic review and meta-analysis of 37 population-based studies and 144,354 subjects. PubMed, Embase, and Web of Science databases were searched for cross-sectional or cohort studies published in the last 20 years (2000–2020) that reported the prevalence of PACG. The prevalence of PACG was analyzed according to various risk factors. A random-effects model was used for the meta-analysis. Results: The global pooled prevalence of PACG was 0.6% [95% confidence interval (CI) = 0.5–0.8%] for the last 20 years. The prevalence of PACG increases with age. Men are found less likely to have PACG than women (risk ratio = 0.71, 95% CI = 0.53–0.93, p < 0.01). Asia is found to have the highest prevalence of PACG (0.7%, 95% CI = 0.6–1.0%). The current estimated population with PACG is 17.14 million (95% CI = 14.28–22.85) for people older than 40 years old worldwide, with 12.30 million (95% CI = 10.54–17.57) in Asia. It is estimated that by 2050, the global population with PACG will be 26.26 million, with 18.47 million in Asia. Conclusion: PACG affects more than 17 million people worldwide, especially leading a huge burden to Asia. The prevalence of PACG varies widely across different ages, sex, and population geographic variation. Asian, female sex, and age are risk factors of PACG.
Objective: To evaluate the characteristics of strabismus in infants who underwent cataract surgery with and without intraocular lens (IOL) implantation.
Design: Secondary outcome analysis in a prospective, randomized clinical trial. Participants: The Infant Aphakia Treatment Study is a randomized, multicenter (n = 12), clinical trial comparing treatment of aphakia with a primary IOL or contact lens in 114 infants with a unilateral congenital cataract.
Intervention: Infants underwent cataract surgery with or without placement of an IOL.
Main Outcome Measures: The proportion of patients in whom strabismus developed during the first 12 months of follow-up was calculated using the life-table method and was compared across treatment groups and age strata using a log-rank test.
Results: Strabismus developed within the first 12 months of follow-up in 38 pseudophakic infants (life-table estimate, 66.7%) and 42 infants (life-table estimate, 74.5%) treated with contact lenses (P = 0.59). The younger cohort (<49 days) at the time of surgery demonstrated less strabismus (29 of 50; life-table estimate, 58.0%) than the older cohort (≥49 days; 51 of 64; life-table estimate, 80.0%; P<0.01).
Conclusions: Intraocular lens placement does not prevent the early development of strabismus after congenital cataract surgery. However, strabismus was less likely to develop in infants whose cataract was removed at an earlier age. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.
This retrospective cohort study investigated whether unilateral vision impairment (UVI) or amblyopia are associated with driver licensing and crash risk among young adults. Electronic health records for New Jersey residents who were patients with the Children's Hospital of Philadelphia's healthcare network were linked to statewide driver licensing and crash data. We compared young adults with a diagnosis of UVI and/or amblyopia to peers without such a diagnosis. Young adults with UVI or amblyopia were less likely to acquire a driver's license than those without these conditions. However, among licensed drivers, the risk of a police-reported crash was similar in all three groups.
PURPOSE: To compare retinal toxicity as measured by electroretinogram, ocular, and patient survival in retinoblastoma treated with intravitreal melphalan at two concentrations (25 vs. 30 µg). METHODS: Single-center, retrospective analysis of retinoblastoma eyes receiving 25-µg or 30-µg intravitreal melphalan from September 2012 to January 2019. Ocular toxicity was measured by electroretinogram of evaluable injections in 449 injections in 136 eyes. A repeated-measures linear mixed model with a random intercept and slope was applied to account for repeated measures for each eye. RESULTS: Average decline in electroretinogram after each additional injection was -4.9 µV (95% confidence interval -6.3 to -3.4); electroretinogram declined by -4.6 µV (95% confidence interval -7.0 to -2.2) after 25-µg injections and -5.2 µV (95% confidence interval -6.6 to -3.8) after 30-µg injections (P = 0.66). Injection at a new clock site hour was associated with a -3.91-µV lower average (95% confidence interval -7.8 to -0.04). CONCLUSION: Electroretinogram-measured toxicity in retinoblastoma eyes treated with intravitreal injections was not found to be different across 25-µg and 30-µg injections. There were no cases of extraocular extension or metastatic deaths in our patient population.
Objective: To evaluate the accuracy of detecting clinically significant retinopathy of prematurity (ROP) using wide-angle digital retinal photography. Methods: Literature searches of PubMed and the Cochrane Library databases were conducted last on December 7, 2010, and yielded 414 unique citations. The authors assessed these 414 citations and marked 82 that potentially met the inclusion criteria. These 82 studies were reviewed in full text; 28 studies met inclusion criteria. The authors extracted from these studies information about study design, interventions, outcomes, and study quality. After data abstraction, 18 were excluded for study deficiencies or because they were superseded by a more recent publication. The methodologist reviewed the remaining 10 studies and assigned ratings of evidence quality; 7 studies were rated level I evidence and 3 studies were rated level III evidence. Results: There is level I evidence from < 5 studies demonstrating that digital retinal photography has high accuracy for detection of clinically significant ROP. Level III studies have reported high accuracy, without any detectable complications, from real-world operational programs intended to detect clinically significant ROP through remote site interpretation of wide-angle retinal photographs. Conclusions: Wide-angle digital retinal photography has the potential to complement standard ROP care. It may provide advantages through objective documentation of clinical examination findings, improved recognition of disease progression by comparing previous photographs, and the creation of image libraries for education and research. Financial Disclosure(s): Proprietary or commercial disclosure may be found after the references.