Utility of artificial intelligence in the diagnosis and management of keratoconus: a systematic review.

Introduction: The application of artificial intelligence (AI) systems in ophthalmology is rapidly expanding. Early detection and management of keratoconus is important for preventing disease progression and the need for corneal transplant. We review studies regarding the utility of AI in the diagnosis and management of keratoconus and other corneal ectasias. Methods: We conducted a systematic search for relevant original, English-language research studies in the PubMed, Web of Science, Embase, and Cochrane databases from inception to October 31, 2023, using a combination of the following keywords: artificial intelligence, deep learning, machine learning, keratoconus, and corneal ectasia. Case reports, literature reviews, conference proceedings, and editorials were excluded. We extracted the following data from each eligible study: type of AI, input used for training, output, ground truth or reference, dataset size, availability of algorithm/model, availability of dataset, and major study findings. Results: Ninety-three original research studies were included in this review, with the date of publication ranging from 1994 to 2023. The majority of studies were regarding the use of AI in detecting keratoconus or subclinical keratoconus (n=61). Among studies regarding keratoconus diagnosis, the most common inputs were corneal topography, Scheimpflug-based corneal tomography, and anterior segment-optical coherence tomography. This review also summarized 16 original research studies regarding AI-based assessment of severity and clinical features, 7 studies regarding the prediction of disease progression, and 6 studies regarding the characterization of treatment response. There were only three studies regarding the use of AI in identifying susceptibility genes involved in the etiology and pathogenesis of keratoconus. Discussion: Algorithms trained on Scheimpflug-based tomography seem promising tools for the early diagnosis of keratoconus that can be particularly applied in low-resource communities. Future studies could investigate the application of AI models trained on multimodal patient information for staging keratoconus severity and tracking disease progression.

Vernal keratoconjunctivitis in adults: a narrative review of prevalence, pathogenesis, and management.

Vernal keratoconjunctivitis (VKC) is a chronic, progressive, allergic ocular surface disorder that can lead to sight-threatening complications. VKC occurs primarily in children and generally resolves about the time of puberty; however, case series and retrospective analyses indicate that approximately 10% of patients with VKC are adults, and that a subset of adult cases develop after puberty. Consequently, two age-related variants of VKC have recently been described: early-onset VKC-which manifests during childhood and persists into adult life-and late-onset disease, which emerges de novo after puberty. Although the signs and symptoms of adult and childhood VKC are similar, adult VKC is a long-lasting disease characterized by severe inflammation and increased risk of conjunctival fibrosis, which may place adult patients at higher risk for sight-threatening complications and adverse impacts on daily life. This review discusses the epidemiology, signs, symptoms, immunopathogenesis of adult VKC variants, and highlights current gaps in research and management of patients with this condition.

Foveal photoreceptor atrophy, persistent fetal vasculature, congenital cataracts, and microphthalmia in a pediatric patient with BCOR-associated oculo-facio-cardio-dental (OFCD) syndrome.

Purpose: To report a case of oculo-facio-cardio-dental (OFCD) syndrome secondary to a novel BCOR variant in a pediatric patient with congenital cataracts, microphthalmia, persistent fetal vasculature (PFV), focal chorioretinal hyperpigmentation, peripheral retinal avascularity, and foveal photoreceptor atrophy. Observations: A 3-month-old female patient was referred for bilateral congenital cataracts with microphthalmia. Her past medical history was significant for syndactyly of the toes, left bifid rib, atrial septal defect, patent ductus arteriosus, mitral regurgitation, pulmonary hypertension, anemia of prematurity, vesicoureteral reflux, and duodenal atresia. Examination under anesthesia revealed persistent fetal vasculature (PFV) with peripheral avascularity, foveal photoreceptor atrophy, and focal chorioretinal hyperpigmentation. A bilateral lensectomy with anterior vitrectomy and posterior capsulotomy were performed. Genetic testing identified a novel heterozygous pathogenic variant in the BCOR gene (c.1612C > T (p.Gln538Ter)), confirming a diagnosis of OFCD syndrome. Conclusions and importance: This case describes novel posterior segment findings in a patient with OFCD. A detailed examination of both anterior and posterior segments in combination with multimodal imaging should be performed in patients suspected of having OFCD, as this may be critical in determining visual potential and appropriate surgical management.

Leveraging baseline covariates to analyze small cluster-randomized trials with a rare binary outcome.

Cluster-randomized trials (CRTs) involve randomizing entire groups of participants-called clusters-to treatment arms but are often comprised of a limited or fixed number of available clusters. While covariate adjustment can account for chance imbalances between treatment arms and increase statistical efficiency in individually randomized trials, analytical methods for individual-level covariate adjustment in small CRTs have received little attention to date. In this paper, we systematically investigate, through extensive simulations, the operating characteristics of propensity score weighting and multivariable regression as two individual-level covariate adjustment strategies for estimating the participant-average causal effect in small CRTs with a rare binary outcome and identify scenarios where each adjustment strategy has a relative efficiency advantage over the other to make practical recommendations. We also examine the finite-sample performance of the bias-corrected sandwich variance estimators associated with propensity score weighting and multivariable regression for quantifying the uncertainty in estimating the participant-average treatment effect. To illustrate the methods for individual-level covariate adjustment, we reanalyze a recent CRT testing a sedation protocol in 31 pediatric intensive care units.

Association of multi-criteria derived air toxics hazard score with lung cancer incidence in a major metropolitan area.

Background: Lung cancer remains a major health problem world-wide. Environmental exposure to lung cancer carcinogens can affect lung cancer incidence. We investigated the association between lung cancer incidence and an air toxics hazard score of environmental carcinogen exposures derived previously under the exposome concept. Methods: Lung cancer cases diagnosed in Philadelphia and the surrounding counties between 2008 and 2017 were identified from the Pennsylvania Cancer Registry. Age-adjusted incidence rates at the ZIP code level were calculated based on the residential address at diagnosis. The air toxics hazard score, an aggregate measure for lung cancer carcinogen exposures, was derived using the criteria of toxicity, persistence, and occurrence. Areas with high incidence or hazard score were identified. Spatial autoregressive models were fitted to evaluate the association, with and without adjusting for confounders. Stratified analysis by smoking prevalence was performed to examine potential interactions. Results: We observed significantly higher age-adjusted incidence rates in ZIP codes that had higher air toxics hazard score values after controlling for demographic variables, smoking prevalence, and proximity to major highways. Analyzes stratified by smoking prevalence suggested that exposure to environmental lung carcinogens had a larger effect on cancer incidence in locations with higher smoking prevalence. Conclusion: The positive association between the multi-criteria derived air toxics hazard score and lung cancer incidence provides the initial evidence to validate the hazard score as an aggregate measure of carcinogenic exposures in the environment. The hazard score can be used to supplement the existing risk factors in identifying high risk individuals. Communities with higher incidence/hazard score may benefit from greater awareness of lung cancer risk factors and targeted screening programs.

Role of the ocular surface microbiome in allergic eye diseases.

PURPOSE OF REVIEW: The purpose of this review is to provide an update on emerging literature on the role of the ocular surface microbiome (OSM) in allergic eye diseases. RECENT FINDINGS: Findings in the literature suggest that the ocular surface microbiome plays a role in the pathophysiology and course of allergic disease of the ocular surface. SUMMARY: Knowledge regarding the role of the ocular surface microbiome in allergic disease is important to guide development of targets for future therapeutic interventions.

Approvals and Timing of New Formulations of Novel Drugs Approved by the US Food and Drug Administration Between 1995 and 2010 and Followed Through 2021.

Importance: New formulations of prescription drugs can improve convenience and tolerability for patients, but they also constitute manufacturer strategies to extend brand-name drug market exclusivity periods. Objective: To examine whether new formulations of brand-name novel drugs were associated with novel drugs' sales and/or therapeutic value, as well as characterize first new formulations' approval timing relative to the novel drug's generic approval. Design Setting and Participants: This cross-sectional study used the Drugs@FDA database to identify all novel tablet and capsule drugs approved by the US Food and Drug Administration (FDA) between 1995 and 2010 and followed through December 31, 2021. Exposures: Novel drugs' blockbuster status, defined as annual sales of $1 billion or greater, and therapeutic value, measured by (1) accelerated approval status, (2) World Health Organization Model Lists of Essential Medicines inclusion, (3) innovativeness, and (4) clinical usefulness. Main Outcomes and Measures: Approval of a new formulation and timing relative to a novel drug's first generic's approval. Results: Among the 206 novel drugs in tablet or capsule form approved by the FDA from 1995 to 2010, 81 (39.3%) were followed by an FDA-approved new formulation, and 167 (81.1%) had a generic version as of December 31, 2021. In multivariable analyses, new formulations were statistically significantly more likely among blockbuster drugs vs not (58.2% vs 27.6%; adjusted odds ratio [AOR], 4.72; 95% CI, 2.26-9.87; P < .001) and those granted accelerated approval vs not (50.0% vs 37.6%; AOR, 5.48; 95% CI, 1.52-19.67; P = .009), and less likely among orphan products vs not (11.8% vs 44.8%; AOR, 0.13; 95% CI, 0.03-0.52; P = .004). Essential medicine listing vs no listing (47.8% vs 36.9%; AOR, 1.32; 95% CI, 0.52-3.34; P = .56), first-in-class or advance-in-class status vs addition-to-class status (37.8% vs 40.5%; AOR, 0.71; 95% CI, 0.32-1.58; P = .40), and categorization as clinically useful vs not useful (40.9% vs 44.8%; AOR, 0.81; 95% CI, 0.34-1.92; P = .64) were not associated with increased likelihood of a new formulation. First new formulations were statistically significantly less likely to be approved after the novel drug's first generic approval (84.6% vs 15.4%; P < .001). Conclusions and Relevance: In this cross-sectional study of novel drugs in tablet or capsule form approved by the FDA between 1995 and 2010, manufacturers pursued new formulations of best-selling brand-name drugs and those granted accelerated approval but did so less frequently once generic competitors entered the market. Other measures of therapeutic value were not associated with new formulations.

Longitudinal association of atopic dermatitis progression and keratin 6A.

Atopic dermatitis is a common skin disease characterized by loss of skin integrity. Risk and severity have been associated with genetic variation especially with respect to the filaggrin gene, suggesting the importance of skin barrier function in atopic dermatitis pathogenesis. The keratin protein plays a role in epithelial health but its relationship with disease severity would benefit from further exploration. In this study, we evaluate the association between common keratin 6 variants and severity of atopic dermatitis over time using a Bayesian generalized linear mixed model to account for repeated measures. We identify groups of variants within which individual variants have similar effects on skin repair. Further assessment of the biological mechanisms by which these contribute to repair of epidermis may inform treatment of atopic dermatitis.

Novel heterozygous variants in PXDN cause different anterior segment dysgenesis phenotypes in monozygotic twins.

BACKGROUND: Since bi-allelic variants in the PXDN gene were first discovered in 2011 to be associated with anterior segment dysgenesis, a spectrum of ophthalmologic and systemic clinical manifestations has been described. This manuscript reports two distinct clinical phenotypes in monozygotic twin sisters, including the previously unreported ocular manifestation of bilateral primary aphakia, associated with novel compound heterozygous variants in the PXDN gene. MATERIALS AND METHODS: We used genome sequencing to study a non-consanguineous family with monozygotic twin sister probands: one presenting with bilateral microphthalmia, primary aphakia, total corneal opacification, congenital glaucoma, and complex systemic comorbidities; the other with anterior persistent fetal vasculature in the right eye, and Peters anomaly type 2 with cataract and iris coloboma in the left eye but no systemic issues. These findings were compared to published reports of PXDN-related ocular diseases upon comprehensive review of prior literature. RESULTS: In both affected sisters, genome sequencing identified two novel heterozygous variants in trans in the PXDN gene: c.1569_1570insT, predicting p.(Thr524TyrfsTer53), and c.3206 C > A, predicting p.(Ala1069Asp), respectively. No other potentially diagnostic variants were identified in any other genes. CONCLUSIONS: This report on two novel compound heterozygous variants in the PXDN gene associated with previously unreported clinical manifestations further expands the genotypic and phenotypic spectrum associated with this gene. Our finding of distinctive clinical phenotypes associated with identical compound heterozygous PXDN variants in monozygotic twins emphasizes the significant clinical variability that can occur, suggesting a potential role for stochastic developmental and/or epigenetic factors in the ultimate pathophysiologic pathway.

Clinical Outcomes of Secondary Scleral-Sutured Foldable Hydrophilic Acrylic Intraocular Lens Placement by Trainees: A Single-Site Analysis.

PURPOSE: To evaluate the outcomes of a 4-point scleral-fixated foldable Akreos AO60 intraocular lens (IOL) insertion using Gore-Tex suture performed by trainees under supervision of a single attending surgeon. METHODS: Retrospective chart review for 53 eyes of 50 patients whose surgery was performed by trainees under supervision of a single surgeon between 2015 and 2018 at a tertiary care hospital (Johns Hopkins Wilmer Eye Institute, Baltimore, MD). Indications for surgery, preoperative risk factors, and intraoperative techniques were analyzed. Outcome measures included final best-corrected visual acuity (BCVA), change in BCVA, difference between expected and final spherical equivalent (SE), and postoperative complications. RESULTS: Mean patient age was 62.8 years (range 26.9 to 88.4). The most common indication for surgery was IOL dislocation (59.6%) due to trauma in 21 cases (40.4%) and pseudoexfoliation in 6 (11.5%). Combined pars plana vitrectomy was performed simultaneously in 46 cases (88.5%). Mean BCVA improved from 20/100 to 20/40 (p < 0.001). The difference between expected and final SE was within 1.0 D in 28 cases (53.8%). Postoperative hypotony occurred in 12 eyes (21.2%) on day 1; all were resolved at last follow-up. Postoperative cystoid macular edema (CME) occurred in 20 cases (38.5%); 11 (21.2%) persisted through last follow-up. CONCLUSION: Scleral-fixation of Akreos AO60 IOL in absence of capsular support can be performed by trainees under supervision and results in effective visual rehabilitation. Postoperative CME occurred at a higher rate than previously reported in the literature. Future studies should assess the rates of postoperative complications amongst different techniques of secondary IOL fixation performed by trainees to determine which is the safest.

Practice Patterns in the Surgical Management of Pediatric Traumatic Cataracts.

PURPOSE: To facilitate the development of standardized guidelines for the surgical management of patients with pediatric traumatic cataracts by assessing current ophthalmologists' practice patterns. METHODS: This was a cross-sectional, observational, and retrospective study. A 24-question electronic survey of current practices pertaining to the surgical management of pediatric traumatic cataracts was sent to pediatric ophthalmologists worldwide. Preferences for pre-operative evaluation, surgical timing and techniques, and postoperative management were analyzed. RESULTS: Of the 56 respondents, 62.5% practiced in academic settings. Of the 49 respondents (87.5%) who performed pediatric ruptured globe repair, 41.7% would perform simultaneous cataract extraction if anterior capsular violation existed, whereas 4.1% would do so without capsular violation (P < .001). Most respondents (50.9%) would remove visually significant cataracts within 4 weeks in patients within the amblyogenic age range (P = .02), whereas 63.6% would wait longer outside the amblyogenic range. Preferences for intraocular lens selection, primary posterior capsulotomy, and timing of amblyopia therapy differed. CONCLUSIONS: Individual management practices regarding pediatric traumatic cataracts vary depending on associated globe injuries and patient age. Trends exist in surgical planning, intraoperative techniques, and visual rehabilitation methods, but no single approach has achieved complete unanimity. Therefore, further investigation into optimal timing and the extent of surgical intervention, refractive correction, and postoperative care is necessary prior to developing evidence-based guidelines for enhancing visual outcomes in this population. [J Pediatr Ophthalmol Strabismus. 2020;57(3):190-198.].

Effects of collagen crosslinking on porcine and human tarsal plate.

BACKGROUND: Floppy eyelid syndrome is a disorder in which the tarsal plate is easily distensible and is currently treated with conservative or surgical measures. Human tarsal plate contains type I collagen, which is crosslinked in corneal tissue as a treatment for keratoconus. We hypothesized that collagen crosslinking would similarly stiffen tarsal plate tissue and investigated this in porcine and human tarsal plate specimens. METHODS: Riboflavin-sensitized porcine and human tarsus samples were irradiated with ultraviolet-A light. Porcine experiments were analyzed with gross photographs, anterior segment optical computed tomography (AS-OCT) imaging, and tensile testing. A prospective study of human tarsus was performed on samples from patients undergoing wedge resection for floppy eyelid syndrome and was analyzed with AS-OCT and tensile testing. RESULTS: 73 porcine adnexa and 9 patients (16 eyelids) who underwent wedge excision were included in the study. Grossly, greater stiffness was observed in crosslinked porcine tissue. AS-OCT imaging in porcine tissue showed a distinct hyperreflective band in crosslinked specimens whose area and intensity increased with longer treatment time (P = 0.003); this band was also visible in crosslinked human specimens. Tensile testing was performed, but results were not statistically significant. CONCLUSIONS: AS-OCT imaging, which has not been previously described for tarsal plate, showed a characteristic change in crosslinked porcine and human specimens. Tissue stiffness was increased grossly, but changes in tensile properties were not statistically significant. Further study is warranted to determine relevance as a potential treatment for floppy eyelid syndrome.

Combined Protocols for Corneal Collagen Cross-Linking with Photorefractive Surgery for Refractive Management of Keratoconus: Update on Techniques and Review of Literature.

With the development and gradual dissemination of corneal collagen cross-linking (CXL) in the twenty-first century as an early treatment for keratoconus, the management paradigm has shifted to include a greater focus on complete refractive correction for these patients. Though supplemental hard contact lens therapy remains a mainstay of visual rehabilitation in keratoconus, there has been increasing appeal in a completely surgical approach by combining CXL with adjuvant refractive procedures to both halt the ectatic process and enhance functional visual outcomes. Collectively termed "CXL plus" procedures, several combined protocols have been studied to various degrees in conjunction with CXL, involving photorefractive keratectomy (PRK), transepithelial phototherapeutic keratectomy (PTK), conductive keratoplasty (CK), intrastromal corneal ring segments (ICRS) implantation, phakic intraocular lens (PIOL) implantation, or multiple of these techniques together. The scope of this review aims to encompass a summary of current CXL protocols and present the current status of studies involving adjunctive keratorefractive procedures combined with CXL. By discussing the results to date of these CXL plus protocols, we can assess what further areas of investigation are necessary within this field as the next step to optimizing treatment modalities and outcomes for our keratoconus patients, regardless of disease severity.

Recent Surgical Trends in Pediatric Corneal Transplantation: A 13-Year Review.

PURPOSE: Corneal transplantation is the standard of care for pediatric corneal opacities, but little consensus exists on optimal surgical management. Our goal was to evaluate cross-sectional data of donor and recipient characteristics collected from eye banks providing tissue for pediatric corneal transplant cases to assess surgical trends in pediatric keratoplasty over the past 13 years. METHODS: We performed a retrospective review of recipient data, collected from 4 major eye banks, for pediatric patients (<18 years) who underwent corneal transplantation between January 2005 and December 2017. We analyzed trends in surgical indications, types of keratoplasty, and donor/recipient characteristics. RESULTS: Our database included 2620 total pediatric cases. Penetrating keratoplasty (PKP) remains the most common surgery performed (79.8%), but more partial-thickness transplant cases [eg, endothelial keratoplasty (EK)] have been performed since 2008. The most commonly reported transplant indication was ectasias/thinnings (34.1%) overall and congenital opacities (17.0%) in children less than 5 years. Average donor age was significantly lower for the youngest recipient age group of less than 5 years (P < 0.001); endothelial cell count was also higher, and death-to-surgery time was lower for PKP and EK cases versus other keratoplasties. CONCLUSIONS: Indications for transplant vary across age groups but are consistent with previous reports. Popularity of partial-thickness transplants has increased since 2008. Surgeons prefer younger donor tissue for younger patients and have higher thresholds for endothelial cell count for PKP and EK cases. Centralized tracking of pediatric keratoplasty cases is necessary for further investigation of long-term outcomes.

Pediatric Corneal Transplants: Review of Current Practice Patterns.

PURPOSE: To facilitate development of standardized guidelines for management of pediatric patients undergoing keratoplasty, particularly the youngest cohort, through a comprehensive survey assessing recent trends in practice patterns of corneal specialists and pediatric ophthalmologists. METHODS: A cross-sectional, observational study of current practices pertaining to pediatric keratoplasty was performed by designing a 20-question survey focused on preoperative indications, surgical techniques, and postoperative management. This survey was sent electronically to corneal specialists and pediatric ophthalmologists. Results were compared with the findings of previous studies regarding pediatric keratoplasty. RESULTS: Of the 80 ophthalmologists who responded, 51.3% currently perform pediatric keratoplasty; only 20% have performed >50 cases. The majority (73.8%) completed solely corneal fellowships; all perform penetrating keratoplasty, 35.2% also perform endothelial keratoplasty, and 37% also perform lamellar keratoplasty. Peters anomaly was the most common indication for transplantation (34.3%). The majority believe that 1 to 3 months is the optimal age range to perform keratoplasty for both monocular and binocular congenital corneal opacities, although 13% stated that they would never perform keratoplasty in a patient with a monocular opacity. All surgeons report modifying their intraoperative techniques for pediatric patients, but specific practices and postoperative management protocols vary. There is a consensus regarding the importance of amblyopia therapy in these patients. CONCLUSIONS: Our results were consistent with the published literature regarding the indication and types of surgery performed. Variability among surgical techniques and postoperative management protocols highlights the necessity of creating standardized guidelines to optimize management of pediatric patients undergoing keratoplasty. Collaborative efforts between corneal and pediatric specialists are crucial for defining visual rehabilitation protocols to enhance visual outcomes.

MicroRNA-29b Overexpression Decreases Extracellular Matrix mRNA and Protein Production in Human Corneal Endothelial Cells.

PURPOSE: MicroRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level. We reported that levels of microRNA (miR)-29 family are decreased in corneas of patients with Fuchs endothelial corneal dystrophy (FECD). The miR-29 family regulates the production of extracellular matrix (ECM) proteins. Accumulation of ECM proteins in Descemet membrane is an important pathologic change in FECD. In this study, we transfected miR-29b into human corneal endothelial cells and tissues and evaluated ECM protein expression levels. METHODS: An immortalized Fuchs human corneal endothelial cell line (iFECD) was established by infection of corneal endothelial cells from patients with FECD with hTERT lentivirus. MiR-29b was transfected into iFECD, and the expression levels of ECMs collagen type 1 alpha 1 (COL1A1), collagen type 4 alpha 1 (COL4A1), and laminin gamma 1 (LAMC1) were evaluated with quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) and Western blot. Expression level of LAMC1 protein in miR-29b-transfected donor corneal endothelium was also evaluated by Western blot. RESULTS: Compared with control, miR-29b expression level after transfection of iFECD was increased to 335.6% (±91.0%), and ECM expression levels were significantly decreased. Compared with control, qRT-PCR demonstrated reduction of ECM to the following levels: COL1A1: 1.9% (±0.4%); COL4A1: 7.1% (±1.7%); and LAMC1: 21.5% (±2.7%). Western blot showed reduced protein expression: COL1A1: 4.8% (±3.2%); COL4A1: 42.5% (±25.0%); and LAMC1: 44.8% (±3.1%). In miR-29b-transfected corneal tissue, LAMC1 protein expression level was decreased to 14.4% (±20.5%). CONCLUSIONS: Overexpression of miR-29b decreased ECM protein production in human corneal endothelial cells. Thus, miR-29 replacement therapy might be a new treatment strategy for FECD aimed at reducing pathologic production of ECM proteins in Descemet membrane.