Accumulation of hydrogen in titanium under irradiation with neutrons

The course of the nuclear reaction in titanium under neutron irradiation with formation of hydrogen was experimentally confirmed. Additional hydrogen and gamma quanta with an energy of 889 and 1120 keV are observed. The gamma-field effect should be taken into account when creating neutron protection based on titanium borides. The irradiation of titanium leads to a change in the thermoelectric power to 20%

Specific Alleles of CLN7/MFSD8, a Protein That Localizes to Photoreceptor Synaptic Terminals, Cause a Spectrum of Nonsyndromic Retinal Dystrophy

Purpose: Recessive mutations in CLN7/MFSD8 usually cause variant late-infantile onset neuronal ceroid lipofuscinosis (vLINCL), a poorly understood neurodegenerative condition, though mutations may also cause nonsyndromic maculopathy. A series of 12 patients with nonsyndromic retinopathy due to novel CLN7/MFSD8 mutation combinations were investigated in this study. Methods: Affected patients and their family members were recruited in ophthalmic clinics at each center where they were examined by retinal imaging and detailed electrophysiology. Whole exome or genome next generation sequencing was performed on genomic DNA from at least one affected family member. Immunofluorescence confocal microscopy of murine retina cross-sections were used to localize the protein. Results: Compound heterozygous alleles were identified in six cases, one of which was always p.Glu336Gln. Such combinations resulted in isolated macular disease. Six further cases were homozygous for the variant p.Met454Thr, identified as a founder mutation of South Asian origin. Those patients had widespread generalized retinal disease, characterized by electroretinography as a rod-cone dystrophy with severe macular involvement. In addition, the photopic single flash electroretinograms demonstrated a reduced b- to a-wave amplitude ratio, suggesting dysfunction occurring after phototransduction. Immunohistology identified MFSD8 in the outer plexiform layer of the retina, a site rich in photoreceptor synapses. Conclusions: This study highlights a hierarchy of MFSD8 variant severity, predicting three consequences of mutation: (1) nonsyndromic localized maculopathy, (2) nonsyndromic widespread retinopathy, or (3) syndromic neurological disease. The data also shed light on the underlying pathogenesis by implicating the photoreceptor synaptic terminals as the major site of retinal disease

Association of Steroid 5α-Reductase Type 3 Congenital Disorder of Glycosylation With Early-Onset Retinal Dystrophy

Importance: Steroid 5α-reductase type 3 congenital disorder of glycosylation (SRD5A3-CDG) is a rare disorder of N-linked glycosylation. Its retinal phenotype is not well described but could be important for disease recognition because it appears to be a consistent primary presenting feature. Objective: To investigate a series of patients with the same mutation in the SRD5A3 gene and thereby characterize its retinal manifestations and other associated features. Design, Setting and Participants: Seven affected individuals from 4 unrelated families with early-onset retinal dystrophy as a primary manifestation underwent comprehensive ophthalmic assessment, including retinal imaging and electrodiagnostic testing. Developmental and systemic findings were also recorded. Molecular genetic approaches, including targeted next-generation sequencing, autozygosity mapping, and apex microarray, were tried to reach a diagnosis; all participants were mutation negative. Whole-exome sequencing or whole-genome sequencing was used to identify the causative variant. Biochemical profiling was conducted to confirm a CDG type I defect. Patient phenotype data were collected over the course of ophthalmic follow-up, spanning a period of 20 years, beginning March 20, 1997, through September 15, 2016. Main Outcomes and Measures: Detailed clinical phenotypes as well as genetic and biochemical results. Results: The cohort consisted of 7 participants (5 females and 2 males) whose mean (SD) age at the most recent examination was 17.1 (3.9) years and who were all of South Asian ethnicity. Whole-exome sequencing and whole-genome sequencing identified the same homozygous SRD5A3 c.57G>A, p.(Trp19Ter) variant as the underlying cause of early-onset retinal dystrophy in each family. Detailed ocular phenotyping identified early-onset (aged ≤3 years) visual loss (mean [SD] best-corrected visual acuity, +0.95 [0.34] logMAR [20/180 Snellen]), childhood-onset nyctalopia, myopia (mean [SD] refractive error, -6.71 [-4.22]), and nystagmus. Six of the 7 patients had learning difficulties and psychomotor delay. Fundus autofluorescence imaging and optical coherence tomographic scans were abnormal in all patients, and electrodiagnostic testing revealed rod and cone dysfunction in the 5 patients tested. Conclusions and Relevance: Mutations in the SRD5A3 gene may cause early-onset retinal dystrophy, a previously underdescribed feature of the SRD5A3-CDG disorder that is progressive and may lead to serious visual impairment. SRD5A3 and other glycosylation disorder genes should be considered as a cause of retinal dystrophy even when systemic features are mild. Further delineation of SRD5A3-associated eye phenotypes can help inform genetic counseling for prognostic estimation of visual loss and disease progression

Treat-and-Extend Versus Pro re nata Regimens of Ranibizumab and Aflibercept in Neovascular Age-Related Macular Degeneration: A Comparative Study from Routine Clinical Practice

INTRODUCTION: Anti-vascular endothelial growth factor (VEGF) is generally given using pro re nata or "treat-and-extend" (T&E) regimens for neovascular age-related macular degeneration (nAMD). Randomized clinical trials have reported that T&E is superior to Pro re nata (PRN), but results from clinical trials may not always be replicated in clinical practice. Real-world data comparing T&E and PRN regimens for nAMD are limited. The objective of this work was to report 24-month outcomes of PRN versus T&E regimens for ranibizumab and aflibercept to treat nAMD in routine clinical practice. METHODS: We conducted a retrospective analysis of data from a prospectively designed observational outcomes registry, the Fight Retinal Blindness! Project (FRB). Treatment-naïve eyes starting nAMD treatment with at least three injections using a T&E or PRN regimen were tracked by using the FRB. The primary outcome was the mean change in visual acuity (VA) measured by the number of letters read on a logarithm of the minimum angle of resolution chart at 2 years versus baseline. The secondary outcome was the number of injections at 2 years. RESULTS: From January 1, 2015 to January 31, 2019, 3313 eyes from 2948 patients with nAMD were included: 1243 eyes from 1065 patients were classified as PRN and 2070 eyes from 1935 patients started a T&E regimen. At 24 months, patients on the T&E regimen experienced significantly greater mean (95% confidence interval) improvement in VA than those on PRN (+ 4.2 [3.1, 5.2] vs. + 1.3 [0.1, 2.6] letters; p < 0.001), with more injections (14.9 standard deviation(SD) 4.3) vs. 9.8(SD 4.3); p < 0.001). CONCLUSIONS: Eyes treated with a T&E regimen had better VA outcomes from VEGF inhibitors than eyes treated PRN. This large real-world data assessment supports previous data from randomized clinical trials that the T&E regimen delivers better outcomes than PRN

Standardization of OCT Angiography Nomenclature in Retinal Vascular Diseases

Objective: To develop a consensus nomenclature for OCT angiography (OCTA) findings in retinal vascular diseases (RVDs). Design: Expert consensus using standardized online surveys with modified Likert scale. Participants: Retinal vascular disease imaging experts, OCT biomedical engineers, and the members of the International Retinal Imaging Society (IntRIS) Methods: A PubMed literature review identified quantitative and qualitative terms forming the basis for a consensus-building process using a modified Delphi method. Agreement levels were categorized as “Accepted” (median ≥6), “Considerable Consensus” (median, 6–7; interquartile range [IQR] ≤3), “Strong Consensus” (median ≥8; IQR ≤2), and “Refined Strong Consensus” (median ≥8, IQR ≤2, with ≥70% of responses in the 8–10 range). A multidisciplinary expert panel refined the terminology through 3 survey rounds, leading to a final survey conducted by IntRIS members. Main Outcome Measures: Consensus on OCTA nomenclature in RVD. Results: The literature review identified 58 relevant papers, yielding 51 quantitative and 108 qualitative terms. A series of 3 surveys was used to refine the nomenclature framework for describing OCTA findings. The selected framework includes a generic term (“OCTA signal”), adjective terms (“presence/absence,” “decreased/increased,” “normal/abnormal”), and descriptive/etiologic terms (“of unknown cause,” “due to blockage,” “due to non-perfusion”). In the final survey among 44 IntRIS members, the framework achieved strong consensus for overall acceptance (median, 8.0; IQR, 7.0–9.0). The term “OCTA signal” met refined strong consensus criteria (median, 8.0; IQR, 8.0–9.0, with ≥70% of responses in the 8–10 range). Adjective terms, including “absence/presence” and “increased/decreased,” were also rated with strong consensus (median, 8.0; IQR, 7.0–9.0). Similarly, descriptive/etiologic terms achieved strong consensus (median, 8.0; IQR, 7.0–9.0). Adoption of the framework for clinical practice and scientific reporting was rated with strong consensus (clinical: median, 8.0; IQR, 7.0–9.0; scientific: median, 9.0; IQR, 8.5–10.0). Conclusions: This study establishes a strong consensus framework for reporting OCTA findings in RVD for clinical and scientific contexts. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article

Creation of a neovascular age-related macular degeneration national database using a web-based platform: Fight Retinal Blindness Spain. Report 1: Visual outcomes

Background: To study the visual outcomes of neovascular AMD (nAMD) treated with anti-vascular endothelial growth factor (VEGF) drugs at national level. Methods: Multicenter national database of nAMD eyes treated with anti-VEGF intravitreal injections (ranibizumab, aflibercept, bevacizumab) in fixed bimonthly (FB) or treat-and-extend (TAE) regimens. Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution (logMAR) ETDRS letters at baseline and subsequent visits, number of injections and visits data were collected using a validated web-based tool (Fight Retinal Blindness!). Results: 1273 eyes (1014 patients) were included, 971 treatment naïve (TN) and 302 previously treated (PT). Baseline VA (mean ± SD) was 57.5 (±19.5) and 62.2 (±17) (p > 0.001), and 24 months final VA was 60.4 (±21.2) and 58.8 (±21.1) (p = 0.326), respectively. Mean VA change at 12/24 months was +4.2/+2.9 letters in TN eyes and +0.1/-3.4 letters in PT eyes (p < 0.001/p < 0.001). The percentage of ≥15 letters gainers/losers at 24 months was 24.8%/14.5% in TN, and 10.3%/15.7% in PT eyes. The median number of injections/visits at 12 months was 7/9 in TN and 6/8 in PT (p = 0.002/p < 0.001) and at 24 months was 11/16 in TN and 11/14 in PT (p = 0.329/p < 0.001). Study drugs included ranibizumab (39.5%), aflibercept (41.2%) and bevacizumab (19.3%). Conclusion: Independent, large-scale national audits are feasible if committed health care professionals are provided with efficient information technology systems to do them. The results described here represent an adequate measurement of the quality of care delivered nationwide and benchmark the clinical management of nAMD at a country level compared to other real-world international cohorts. Keywords: aflibercept; age-related macular degeneration; audit; benchmark standard; bevacizumab; national database; national dataset; neovascular AMD; ranibizumab

Distinct Clinical Effects of Two RP1L1 Hotspots in East Asian Patients With Occult Macular Dystrophy (Miyake Disease): EAOMD Report 4

PURPOSE: To characterize the clinical effects of two RP1L1 hotspots in patients with East Asian occult macular dystrophy (OMD). METHODS: Fifty-one patients diagnosed with OMD harboring monoallelic pathogenic RP1L1 variants (Miyake disease) from Japan, South Korea, and China were enrolled. Patients were classified into two genotype groups: group A, p.R45W, and group B, missense variants located between amino acids (aa) 1196 and 1201. The clinical parameters of the two genotypes were compared, and deep learning based on spectral-domain optical coherence tomographic (SD-OCT) images was used to distinguish the morphologic differences. RESULTS: Groups A and B included 29 and 22 patients, respectively. The median age of onset in groups A and B was 14.0 and 40.0 years, respectively. The median logMAR visual acuity of groups A and B was 0.70 and 0.51, respectively, and the survival curve analysis revealed a 15-year difference in vision loss (logMAR 0.22). A statistically significant difference was observed in the visual field classification, but no significant difference was found in the multifocal electroretinographic classification. High accuracy (75.4%) was achieved in classifying genotype groups based on SD-OCT images using machine learning. CONCLUSIONS: Distinct clinical severities and morphologic phenotypes supported by artificial intelligence-based classification were derived from the two investigated RP1L1 hotspots: a more severe phenotype (p.R45W) and a milder phenotype (1196-1201 aa). This newly identified genotype-phenotype association will be valuable for medical care and the design of therapeutic trials

Outcomes and predictive factors after cataract surgery in patients with neovascular age-related macular degeneration. The Fight Retinal Blindness! Project

Purpose: To evaluate outcomes and predictive factors of visual acuity (VA) change after cataract surgery in patients being treated for neovascular age-related macular degeneration (nAMD). Design: Retrospective, matched case-control study. Methods: We studied eyes undergoing cataract surgery that had been tracked since they first started treatment for nAMD. These eyes were compared with a cohort of unoperated phakic eyes being treated for nAMD (three per case) matched for treatment duration before cataract surgery, baseline VA, age and length of follow-up. Results: We included 124 patients that had cataract surgery and 372 matched controls. The mean (95% CI) VA gained was 10.6 letters (7.8, 13.2; P < 0.001) 12 months following surgery; 26.0% had gained ≥ 3 lines and 1.6% had lost ≥ 3 lines of VA. Visual acuity (mean [SD]) 12 months after surgery was higher in eyes that had cataract extraction compared with controls (65.8 [17.1] vs. 61.3 [20.8] letters respectively, P = 0.018). The proportion of visits where the choroidal neovascular (CNV) lesion was graded active and the mean number of injections were similar before and after surgery (P = 0.506 and P = 0.316, respectively), while both decreased in the control group, suggesting that surgery modestly increased the level of activity of the CNV lesion. Mean [SD] VA prior to surgery was lower in eyes that gained ≥15 letters compared with eyes that gained 0-14 letters (40.2 [21.4] vs. 62.1 [15.1], P < 0.001). Patients undergoing cataract surgery within the first 6 months of anti-VEGF therapy were more likely to lose rather than gain vision (20.8% lost vision vs. 12.8% and 4.4% gaining ≥15 or 0-14 letters respectively, P = 0.023). Age, receiving an injection at least 2 weeks before surgery, and the CNV lesion type had no discernible association with VA outcomes. Conclusions: We found evidence of a modest effect of cataract surgery on CNV lesion activity in eyes being treated for nAMD. Despite this, visual outcomes were reassuringly good. Cataract surgery within 6 months of starting treatment for nAMD should be avoided if possible.The Fight Retinal Blindness Project was supported by a grant from the Royal Australian NZ College of Ophthalmologists Eye Foundation (2007-2009), a grant from the National Health and Medical Research Council, Australia (NHMRC 2010-2012) and a grant from the Macula Disease Foundation, Australia. Mark Gillies is a Sydney Medical Foundation Fellow and is supported by an NHMRC practitioner fellowship. Daniel Barthelmes was supported by the Walter and Gertud Siegenthaler Foundation Zurich, Switzerland and the Swiss National Foundation. Vincent Daien was supported by the research grant of the French Society of Ophthalmology and by Servier. Funding was also provided by Novartis and Bayer

Scleral Buckling for Primary Retinal Detachment: Outcomes of Scleral Tunnels versus Scleral Sutures

Purpose: There are primarily two techniques for affixing the scleral buckle (SB) to the sclera in the repair of rhegmatogenous retinal detachment (RRD): scleral tunnels or scleral sutures. Methods: This retrospective study examined all patients with primary RRD who were treated with primary SB or SB combined with vitrectomy from January 1, 2015 through December 31, 2015 across six sites. Two cohorts were examined: SB affixed using scleral sutures versus scleral tunnels. Pre- and postoperative variables were evaluated including visual acuity, anatomic success, and postoperative strabismus. Results: The mean preoperative logMAR VA for the belt loop cohort was 1.05 ± 1.06 (Snellen 20/224) and for the scleral suture cohort was 1.03 ± 1.04 (Snellen 20/214, p = 0.846). The respective mean postoperative logMAR VAs were 0.45 ± 0.55 (Snellen 20/56) and 0.46 ± 0.59 (Snellen 20/58, p = 0.574). The single surgery success rate for the tunnel cohort was 87.3% versus 88.6% for the suture cohort (p = 0.601). Three patients (1.0%) in the scleral tunnel cohort developed postoperative strabismus, but only one patient (0.1%) in the suture cohort (p = 0.04, multivariate p = 0.76). All cases of strabismus occurred in eyes that underwent SB combined with PPV (p = 0.02). There were no differences in vision, anatomic success, or strabismus between scleral tunnels versus scleral sutures in eyes that underwent primary SB. Conclusion: Scleral tunnels and scleral sutures had similar postoperative outcomes. Combined PPV/SB in eyes with scleral tunnels might be a risk for strabismus post retinal detachment surgery

Recessive Retinopathy Consequent on Mutant G-Protein β Subunit 3 (GNB3)

IMPORTANCE: Mutations in phototransduction and retinal signaling genes are implicated in many retinopathies. To our knowledge, GNB3 encoding the G-protein β subunit 3 (Gβ3) has not previously been implicated in human disease. OBSERVATIONS: In this brief report, whole-exome sequencing was conducted on a patient with distinct inherited retinal disease presenting in childhood, with a phenotype characterized by nystagmus, normal retinal examination, and mild disturbance of the central macula on detailed retinal imaging. This sequencing revealed a homozygous GNB3 nonsense mutation (c.124C>T; p.Arg42Ter). Whole-exome sequencing was conducted from April 2015 to July 2015. CONCLUSIONS AND RELEVANCE: Expressed in cone photoreceptors and ON-bipolar cells, Gβ3 is essential in phototransduction and ON-bipolar cell signaling. Knockout of Gnb3 in mice results in dysfunction of cone photoreceptors and ON-bipolar cells and a naturally occurring chicken mutation leads to retinal degeneration. Identification of further affected patients may allow description of the phenotypic and genotypic spectrum of disease associated with GNB3 retinopathy