Doheny Eye Institute (Doheny Eye or DEI) established in 1947, is a nonprofit ophthalmic research institute. The doctors and scientists of Doheny Eye Institute undertake basic and clinical research, a role known as a physician-scientist.
To characterise morphological changes in neovascular age-related macular degeneration (nAMD) during anti-angiogenic therapy and explore relationships with best-corrected visual acuity (BCVA) and development of macular atrophy (MA). Post-hoc analysis of the phase III HARBOR trial. SD-OCT scans from 1097 treatment-naïve nAMD eyes were analysed. Volumes of intraretinal cystoid fluid (ICF), subretinal hyperreflective material (SHRM), subretinal fluid (SRF), pigment epithelial detachment (PED) and cyst-free retinal volume (CFRV) were measured by deep-learning model. Volumes were analysed by treatment regimen, macular neovascularisation (MNV) subtypes and topographic location. Associations of volumetric features with BCVA and MA development were quantified at month 12/24. Differences in feature volume changes by treatment regimens and MNV subtypes were observed. Each additional 100 nanolitre unit (AHNU) of residual ICF, SHRM and CFRV at month 1 in the fovea was associated with deficits of 10.3, 7.3 and 12.2 letters at month 12. Baseline AHNUs of ICF, CFRV and PED were associated with increased odds of MA development at month 12 by 10
Our understanding of the genetic landscape of inherited optic neuropathies has grown significantly over the past decades, and it is now known to involve many genes found in both the nuclear and mitochondrial genomes, exhibiting all possible inheritance patterns. Furthermore, pathogenic variants in nuclear genes of mitochondrial respiratory Complex I (CI) subunits have been identified in some cases of ION, in addition to the more common severe presentation of CI deficiencies, usually with early onset. We conducted NGS screening of CI genes to identify potential causative variants in patients with optic atrophy, also performing comprehensive clinical assessments, including neuroimaging studies (MRI) and neurological evaluations. Detailed molecular structure modeling was performed to better evaluate the damaging effects of both novel and previously reported variants in the relevant CI subunits. We identified and characterized candidate causative variants in 31 patients from 23 unrelated families, with biallelic or hemizygous variants in 11 different nuclear CI-related genes encoding polypeptides involved in the structure of CI, including 3 core subunits (NDUFS7, NDUFV1, NDUFV2), 4 accessory subunits (NDUFA1, NDUFA10, NDUFA12, NDUFB11), and 4 assembly factors (NDUFAF2, NDUFAF3, NDUFAF4, NDUFAF8). Notably, defects in core CI subunits in this cohort lead to isolated optic atrophy, while defects in accessory CI subunits and assembly factors resulted in a spectrum of phenotypes, from isolated to syndromic optic atrophy. For 12 cases, the subacute onset of vision loss enabled us to associate or confirm novel genes (NDUFS7, NDUFV1, NDUFAF2, NDUFAF4, NDUFAF8) with the autosomal recessive Leber Hereditary Optic Neuropathy (arLHON) phenotype. Moreover, in the NDUFS7 subunit a partial spatial segregation was noted for missense variants causing either Leigh syndrome or isolated optic atrophy, hinting at possible disease-specific molecular defects. Our case series broadens the genetic spectrum of inherited optic neuropathies, emphasizing the crucial role of nuclear CI genes in its pathogenesis. The arLHON phenotype emerges as linked to numerous nuclear CI genes for which an insidious onset of optic atrophy is also reported, and in some cases the same variant may underlie both phenotypes. Overall, we highlight the possibly so far underestimated prevalence of CI nuclear subunits in the molecular diagnosis of ION, prompting to include all CI-related genes in the standard diagnostic screening.
PURPOSE:To characterize the prevalence of some critical OCT biomarkers-including cuticular drusen and acquired vitelliform lesions (AVLs)-and to identify their relative risk for progression to late age-related macular degeneration (AMD) over 2 years in subjects with early or intermediate AMD in the Amish Eye Study. DESIGN:Prospective, observational, longitudinal, population-based cohort study. PARTICIPANTS:This study included 276 eyes from 171 subjects with early or intermediate AMD at baseline who completed the 2-year follow-up. METHODS:Baseline OCT scans were evaluated for the presence of cuticular drusen, AVLs, subretinal drusenoid deposits (SDDs), high drusen volume (defined as ≥0.2 mm3 within the central 5 mm), intraretinal hyperreflective foci (IHRF), hyporeflective drusen cores (hDCs), thick/thin double-layer sign (DLS), and incomplete retinal pigment epithelium and outer retinal atrophy (iRORA). Subfoveal choroidal thickness (SFCT) was also measured. MAIN OUTCOME MEASURES:Incidence of late AMD (geographic atrophy or macular neovascularization) at 2 years as determined by multimodal imaging (OCT, color fundus photography, and confocal fundus autofluorescence). RESULTS:By 2 years of follow-up, 26 eyes (10.7%) progressed to late AMD. The most prevalent baseline features in this cohort, in descending order, were cuticular drusen (52.3%), IHRF (17.3%), hDC (16.0%), thin DLS (11.9%), SDD (8.2%), iRORA (7.8%), AVL (7.0%), and high drusen volume (2.5%). The mean SFCT was 243.23 ± 75.45 μm. Univariate analysis demonstrated that the presence of thick DLS, iRORA, AVL, SDD, IHRF, hDC, and SFCT was associated with an increased risk of progression. In multivariate regression, only the presence of iRORA (odds ratio [OR], 29.60; 95% confidence interval [CI], 6.86-127.84; P < 0.001) and AVL (OR, 15.90; 95% CI, 3.24-78.00; P < 0.001) remained significant, whereas the presence of IHRF showed borderline significance (OR, 4.71; 95% CI, 1.00-22.16; P = 0.050). CONCLUSIONS:In this cohort, the presence of iRORA and AVL was independently associated with progression to late AMD over 2 years. Although cuticular drusen were highly prevalent, their presence, as assessed in this study, was not significantly associated with an increased risk of progression to late AMD. FINANCIAL DISCLOSURE(S):Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
Tacrolimus (TAC) is recognized as a promising therapy for Dry Eye Disease (DED). Recent experimental studies indicate that TAC formulations, such as nanoemulsions and liposomes, notably improve tear production, stabilize the tear film, and reduce corneal damage in animal models. TAC achieves these effects by inhibiting T-cell activation and suppressing the production of inflammatory cytokines, primarily through the NF-κB signaling pathway. Clinical trials report that topical TAC, especially at 0.03% concentration, significantly alleviates both symptoms and signs in patients with Sjögren's syndrome and ocular graft-versushost disease. Critical clinical improvements include higher Schirmer test values, prolonged tear film break-up time, and decreased ocular surface staining. Comparative analyses suggest that TAC is at least as effective as cyclosporine and offers a favorable safety profile. Combining TAC with agents such as sodium hyaluronate may further enhance therapeutic outcomes. Despite the need for further studies to optimize dose and longterm safety, current evidence supports the use of TAC as an effective solution for individuals with refractory or severe DED, providing a vital option where conventional treatments may fail.
To compare automated and manual quantification of retinal haemorrhages in eyes with diabetic retinopathy (DR) and to analyse the risk of progression to proliferative DR (PDR). Retinal haemorrhages on ultra-widefield (UWF) pseudocolor images in eyes with non-proliferative diabetic retinopathy (NPDR) were manually segmented. DR severity was assessed within the seven ETDRS fields at baseline and 1-year follow-up. Lesions were also automatically segmented using EyeRead UWF software (Eyenuk) and the frequency and area of retinal haemorrhages and the average distance of haemorrhages from the optic nerve centre were computed. Manual and automated results were compared and correlated with progression to PDR at one year. Sixty-three eyes with NPDR at baseline were included, of which 29 progressed to PDR over one year. The automated measurements of total haemorrhage frequency, area and the distance from the optic nerve were significantly lower compared to manual grading, but the parameters were significantly correlated (r = 0.5–0.96; all P < 0.001). The distance of the haemorrhages from the optic nerve was found to be a significant risk factor for progression to proliferative DR from both approaches. Automated detection of retinal haemorrhages may serve as a surrogate to the manual grading in predicting the progression to PDR. Although the automated approach detects a lower number of lesions compared to manual grading, the results are correlated and the automatically determined parameters are still predictive of progression.
