Phenotype and genotype of concurrent keratoconus and Fuchs endothelial corneal dystrophy.

PURPOSE: To characterise the phenotype and genotype of concurrent keratoconus and Fuchs endothelial corneal dystrophy (KC + FECD). METHODS: We recruited 20 patients with concurrent KC + FECD for a retrospective observational case series from the United Kingdom and the Czech Republic. We compared eight parameters of corneal shape (Pentacam, Oculus) with two groups of age-matched controls who had either isolated keratoconus (KC) or isolated FECD. We genotyped probands for an intronic triplet TCF4 repeat expansion (CTG18.1) and the ZEB1 variant c.1920G >T p.(Gln640His). RESULTS: The median age at diagnosis of patients with KC + FECD was 54 (interquartile range 46 to 66) years, with no evidence of KC progression (median follow-up 84 months, range 12 to 120 months). The mean (standard deviation (SD)) of the minimum corneal thickness, 493 (62.7) µm, was greater than eyes with KC, 458 (51.1) µm, but less than eyes with FECD, 590 (55.6) µm. Seven other parameters of corneal shape were more like KC than FECD. Seven (35%) probands with KC + FECD had a TCF4 repeat expansion of ≥50 compared to five controls with isolated FECD. The average of the largest TCF4 expansion in cases with KC + FECD (46 repeats, SD 36 repeats) was similar to the age-matched controls with isolated FECD (36 repeats, SD 28 repeats; p = 0.299). No patient with KC + FECD harboured the ZEB1 variant. CONCLUSIONS: The KC + FECD phenotype is consistent with KC but with superimposed stromal swelling from endothelial disease. The proportion of cases with a TCF4 expansion is similar in concurrent KC + FECD and age-matched controls with isolated FECD.

Comparison of 3-year outcomes of photodynamic therapy combined with intravitreal ranibizumab or aflibercept for polypoidal choroidal vasculopathy in a European cohort.

PURPOSE: Combined use of photodynamic therapy (PDT) with intravitreal anti-vascular endothelial growth factors (anti-VEGF) agents, such as ranibizumab (IVR) or aflibercept (IVA), has been shown to be effective for treating polypoidal choroidal vasculopathy (PCV). However, it is currently not well established which anti-VEGF agent provides superior outcomes for performing combination therapy. The present study compares the visual outcomes and re-treatment burden of combination therapy of PDT with either IVR or IVA in a European cohort of patients with PCV. METHODS: A retrospective analysis was done on PCV patients who had received combination therapy of PDT with either IVR or IVA. The demographic characteristics, visual outcome, and anti-VEGF re-treatment exposures were analysed and compared. RESULTS: A total of forty-four eyes (n = 11 male, 25%) were included in the analysis: 7 patients received IVR, 19 started with IVR but switched to IVA (IVS), and 18 received IVA, in combination with PDT. The BCVA improved in all three groups at 6-, 12-, 18-, 24-, 30-, and 36-month follow-ups after PDT, although the improvement was not statistically significant in the IVR group. The number of intravitreal anti-VEGF injections required/year after PDT was significantly fewer than before PDT. Significantly less eyes in the IVS group attained a good visual acuity of more than 70 ETDRS letters at the final visit. CONCLUSION: Both IVR and IVA combined with PDT were effective treatments for the European cohort of patients with PCV. In eyes refractory to IVR, performing PDT promptly may be more beneficial than switching to IVA.

LncRNA SNHG10 suppresses the development of doxorubicin resistance by downregulating miR-302b in triple-negative breast cancer.

Unlike other types of breast cancer, triple negative breast cancer (TNBC) does not respond to therapies targeting human epidermal growth factor receptor-2 (HER2) or hormone therapy, and the prognosis of patients with TNBC is usually poor. The role of long non-coding RNA (lncRNA) small nucleolar RNA host gene 10 (SNHG10) has been investigated in many types of cancer, but its role in TNBC is unknown. This study aimed to explore the role of SNHG10 in TNBC in the context of doxorubicin treatment, a common therapy for TNBC. Analysis of the TCGA dataset revealed the downregulation of SNHG10 in TNBC. The downregulation of SNHG10 of TNBC in TNBC was further confirmed by detecting its expression in 60 patients with TNBC by qPCR. The expression of SNHG10 was further downregulated after doxorubicin treatment. In TNBC, microRNA-302b (miR-302b) was downregulated and was positively correlated with SNHG10. In TNBC cells, overexpression of SNHG10 resulted in upregulation of miR-302b, and methylation-specific PCR analysis showed that SNHG10 negatively regulates the methylation of miR-302b. In addition, doxorubicin treatment resulted in the downregulation of SNHG10 in TNBC cells, and overexpression of SNHG10 and miR-302b promoted apoptosis of doxorubicin-treated TNBC cells. Furthermore, overexpression of both SNHG10 and miR-302b had a stronger effect on apoptosis than that of overexpression of SNHG10 alone. Our study showed that SNHG10 could inhibit the development of resistance to doxorubicin by upregulating miR-302b in TNBC through methylation. Our findings suggested that SNHG10 might serve as a molecular target for intervening in TBNC metastasis.

Current Perspectives on Corneal Transplantation (Part 2).

Disease of the cornea is the third leading cause of blindness worldwide. Corneal graft surgery is one of the most successful forms of solid organ transplantations in humans, with ever increasing developments in surgical technique. To date, approximately 4504 corneal transplants are performed in the UK each year. While full thickness transplantation was the most commonly performed keratoplasty over the last few decades, selective lamellar transplantation of the diseased layers of the cornea has been universally adopted. This comprehensive review aims to provide an updated synthesis on different types of corneal transplantations, their treatment outcomes, and the associated complications of each procedure both in adult and pediatric populations. In addition, we also present an up-to-date summary of the emerging therapeutic approaches that have the potential to reduce the demand for donor-dependent keratoplasty.

Current Perspectives on Corneal Transplantation.

Disease of the cornea is the third leading cause of blindness worldwide. Corneal graft surgery is one of the most successful forms of solid organ transplantations in humans, with ever-increasing developments in surgical technique. To date, approximately 4504 corneal transplants are performed in the United Kingdom each year. While full thickness transplantation was the most commonly performed keratoplasty over the last few decades, selective lamellar transplantation of the diseased layers of the cornea has been universally adopted. This comprehensive review aims to provide an updated synthesis on different types of corneal transplantations, their treatment outcomes, and the associated complications of each procedure in both adult and paediatric population. In addition, we also present an up-to-date summary of the emerging therapeutic approaches that have the potential to reduce the demand for donor-dependent keratoplasty.

Impact of COVID-19-associated anxiety on the adherence to intravitreal injection in patients with macular diseases a year after the initial outbreak.

BACKGROUND: As the primary burden of treating COVID-19 patients began to ease in the United Kingdom, ophthalmology clinic volume within the National Health Service has since recovered. Alarmingly, the rate of non-attendance remains higher than the pre-pandemic level. PURPOSE: The purpose was to assess how the perceived risk of contracting coronavirus disease 2019 (COVID-19) influences the willingness of individuals with sight-threatening macular conditions to attend intravitreal anti-vascular endothelial growth factor (anti-VEGF) injection appointments during the second wave of the pandemic. METHODS: This prospective cross-sectional survey was conducted at the Macular Treatment Centre, Manchester Royal Eye Hospital. Patients who missed their appointment in January 2021 were invited to complete an anonymous survey over the telephone. The survey consisted of two parts: (1) a 23-item questionnaire aiming to assess fear of contracting COVID-19 in different hospital-related settings; and (2) the validated COVID-19 Anxiety Syndrome Scale (C-19ASS) to evaluate COVID-19-related anxiety. RESULTS: A total of 104 patients agreed to participate in the survey. Only a small proportion of patients believed COVID-19 vaccination (23 out of 88, 26.1%) had influenced their willingness to attend injection appointments. Majority of patients felt concerned about contracting COVID-19 during hospital appointments (n = 63, 60.6%). Only a minority of patients (n = 36, 34.6%) agreed with the hospital guidance on minimising clinical examinations during clinic visit. The C-19ASS was significantly higher in female patients, those older than 70 years and those with mobility issues. Higher C-19ASS, older age and living alone were predictors of clinic nonattendance. CONCLUSION: COVID-19 anxiety and fear of viral exposure could adversely affect patient adherence to clinic appointments during the pandemic. Particular attention should be provided to older patients, those who live alone and patients with impaired mobility. This is particularly relevant as hospital eye services across the world are in the process of restarting.

Real-world outcomes of combined therapy of photodynamic therapy with anti-vascular endothelial growth factor for polypoidal choroidal vasculopathy.

OBJECTIVES: To describe the real-world outcomes of photodynamic therapy (PDT) as a rescue therapy in eyes with polypoidal choroidal vasculopathy (PCV) refractory to anti-vascular endothelial growth factor (VEGF) monotherapy in a British cohort of patients. METHODS: This is a retrospective chart review of 53 eyes with PCV. Based on the timing of PDT, the eyes were stratified into two groups (9 in the Initial-PDT group, 44 in the Deferred group). The number of anti-VEGF injections/year and the best corrected visual acuity (BCVA) before and after PDT were analysed. Multivariate regression model was created to identify factors predictive of visual outcome and treatment burden after PDT. RESULTS: The Deferred group received a mean of 9.4 injections/year but significantly reduced to 7.2 after PDT (p < 0.001). The Initial-PDT group required significantly fewer injections after PDT compared to the Deferred group (p = 0.004). The Deferred group experienced improvement in BCVA from 58.7 letters at baseline to 63.8 at 18-months follow-up (p < 0.001), but no significant increase was observed in the Initial-PDT group (p = 0.310). Better baseline BCVA is associated with higher likelihood of achieving good BCVA ≥ 70 letters after PDT (Odd Ratio=1.12, 95% CI: 1.03-1.21, p = 0.006), while increased number of anti-VEGF injections/year before PDT reduces the likelihood of easing treatment burden to ≥12 weeks apart between each injection after PDT (Odd Ratio=0.724, 95% CI: 0.58-0.91, p = 0.006). CONCLUSIONS: PDT as a rescue therapy is beneficial in the long-term management of PCV, particularly in eyes that had experienced a significant period of prior exposure to anti-VEGF monotherapy.

Current and emerging treatments for albinism.

Albinism is a group of rare inherited disorders arising from impairment of melanin biosynthesis. The reduction of melanin synthesis leads to hypopigmentation of the skin and eyes. A wide range of ophthalmic manifestations arise from albinism, including reduction of visual acuity, nystagmus, strabismus, iris translucency, foveal hypoplasia, fundus hypopigmentation, and abnormal decussation of retinal ganglion cell axons at the optic chiasm. Currently, albinism is incurable, and treatment aims either surgically or pharmacologically to optimize vision and protect the skin; however, novel therapies that aim to directly address the molecular errors of albinism, such as l-dihydroxyphenylalanine and nitisinone, are being developed and have entered human trials though with limited success. Experimental gene-based strategies for editing the genetic errors in albinism have also met early success in animal models. The emergence of these new therapeutic modalities represents a new era in the management of albinism. We focus on the known genetic subtypes, clinical assessment, and existing and emerging therapeutic options for the nonsyndromic forms of albinism.

Differential Distribution of Laminin N-Terminus α31 Across the Ocular Surface: Implications for Corneal Wound Repair.

Purpose: Laminin N-terminus (LaNt) α31 is a relatively unstudied protein derived from the laminin α3 gene but structurally similar to netrins. LaNt α31 has, to date, been investigated only in two-dimensional (2D) keratinocyte culture where it influences cell migration and adhesion, processes integral to wound repair. Here we investigated LaNt α31 distribution in ocular surface epithelium, during limbal stem cell activation, and corneal wound healing. Methods: Human, mouse, and pig eyes, ex vivo limbal explant cultures, and alkali burn wounds were processed for immunohistochemistry with antibodies against LaNt α31 along with progenitor cell-associated proteins. LaNt α31 expression was induced via adenoviral transduction into primary epithelial cells isolated from limbal explants, and cell spreading and migration were analyzed using live imaging. Results: LaNt α31 localized to the basal layer of the conjunctival, limbal, and corneal epithelial cells. However, staining was nonuniform with apparent subpopulation enrichment, and some suprabasal reactivity was also noted. This LaNt α31 distribution largely matched that of keratin 15, epidermal growth factor receptor, and transformation-related protein 63α (p63α), and displayed similar increases in expression in activated limbal explants. During active alkali burn wound repair, LaNt α31 displayed increased expression in limbal regions and loss of basal restriction within the cornea. Distribution returned to predominately basal cell restricted once the wounded epithelium matured. Cultured corneal epithelial cells expressing LaNt α31 displayed increased 2D area and reduced migration, suggesting a functional link between this protein and key wound repair activities. Conclusions: These data place LaNt α31 in position to influence laminin-dependent processes including wound repair and stem cell activation.

Gene-based antiangiogenic applications for corneal neovascularization.

Corneal avascularity is maintained by angiogenic privilege, an active process involving the production of higher level of angiostatic factors to offset the effect of angiogenic factors. A wide range of pathological insults to the cornea can disrupt this intricate equilibrium and promote angiogenesis and corneal neovascularization with resultant visual impairment. Corneal neovascularization is also a major risk factor for graft failure after keratoplasty. Current treatment options for corneal neovascularization are restricted by limited efficacy, adverse effects, and a short duration of action. The unique anatomical position and relative immune privilege of cornea make it an ideal tissue for gene-based therapies. Gene transfer vectors have been used to deliver or target genes involved in the pathogenesis of corneal neovascularization in animal models. Several proangiogenic and antiangiogenic factors have been targeted and assessed in experimentally induced corneal neovascularization. Antisense oligonucleotides targeting corneal neovascularization have entered human clinical trials and have not required vector delivery systems. The emergence of these RNA-based strategies heralds a new era in the management of corneal neovascularization and ocular therapeutics.