In Vivo Assessment of Retinal Phenotypes in Axenfeld-Rieger Syndrome.

Purpose: Axenfeld-Rieger syndrome (ARS) is characterized by ocular anomalies including posterior embryotoxon, iridocorneal adhesions, corectopia/iris hypoplasia, and developmental glaucoma. Although anterior segment defects and glaucoma contribute to decreased visual acuity, the role of potential posterior segment abnormalities has not been explored. We used high-resolution retinal imaging to test the hypothesis that individuals with ARS have posterior segment pathology. Methods: Three individuals with FOXC1-ARS and 10 with PITX2-ARS completed slit-lamp and fundus photography, optical coherence tomography (OCT), OCT angiography, and adaptive optics scanning light ophthalmoscopy (AOSLO). Quantitative metrics were compared to previously published values for individuals with normal vision. Results: All individuals demonstrated typical anterior segment phenotypes. Average ganglion cell and inner plexiform layer thickness was lower in PITX2-ARS, consistent with the glaucoma history in this group. A novel phenotype of foveal hypoplasia was noted in 40% of individuals with PITX2-ARS (but none with FOXC1-ARS). Moreover, the depth and volume of the foveal pit were significantly lower in PITX2-ARS compared to normal controls, even excluding individuals with foveal hypoplasia. Analysis of known foveal hypoplasia genes failed to identify an alternative explanation. Foveal cone density was decreased in one individual with foveal hypoplasia and normal in six without foveal hypoplasia. Two individuals (one from each group) demonstrated non-foveal retinal irregularities with regions of photoreceptor anomalies on OCT and AOSLO. Conclusions: These findings implicate PITX2 in the development of the posterior segment, particularly the fovea, in humans. The identified posterior segment phenotypes may contribute to visual acuity deficits in individuals with PITX2-ARS.

Mortality trends, disparities, and social vulnerability in cardiac arrest mortality in the young: A cross-sectional analysis.

BACKGROUND: Cardiac arrest (CA) is a leading cause of death in the United States (US). Social determinants of health may impact CA outcomes. We aimed to assess mortality trends, disparities, and the influence of the social vulnerability index (SVI) on CA outcomes in the young. METHODS: We conducted a cross-sectional analysis of age-adjusted mortality rates (AAMRs) related to CA in the United States from the Years 1999 to 2020 in individuals aged 35 years and younger. Data were obtained from death certificates and analyzed using log-linear regression models. We examined disparities in mortality rates based on demographic variables. We also explored the impact of the SVI on CA mortality. RESULTS: A total of 4792 CA deaths in the young were identified. Overall AAMR decreased from 0.20 in 1999 to 0.14 in 2020 with an average annual percentage change of -1.3% (p = .001). Black (AAMR: 0.30) and male populations (AAMR: 0.14) had higher AAMR compared with White (AAMR: 0.11) and female (AAMR: 0.11) populations, respectively. Nonmetropolitan (AAMR: 0.29) and Southern (AAMR: 0.26) regions were also impacted by higher AAMR compared with metropolitan (AAMR: 0.11) and other US census regions, respectively. A higher SVI was associated with greater mortality risks related to CA (risk ratio: 1.82 [95% CI, 1.77-1.87]). CONCLUSIONS: Our analysis of CA in the young revealed disparities based on demographics, with a decline in AAMR from 1999 to 2020. There is a correlation between a higher SVI and increased CA mortality risk, highlighting the importance of targeted interventions to address these disparities effectively.

TCM herbal prescription recommendation model based on multi-graph convolutional network.

ETHNOPHARMACOLOGICAL RELEVANCE: The recommendation of herbal prescriptions is a focus of research in traditional Chinese medicine (TCM). Artificial intelligence (AI) algorithms can generate prescriptions by analysing symptom data. Current models mainly focus on the binary relationships between a group of symptoms and a group of TCM herbs. A smaller number of existing models focus on the ternary relationships between TCM symptoms, syndrome-types and herbs. However, the process of TCM diagnosis (symptom analysis) and treatment (prescription) is, in essence, a "multi-ary" (n-ary) relationship. Present models fall short of considering the n-ary relationships between symptoms, state-elements, syndrome-types and herbs. Therefore, there is room for improvement in TCM herbal prescription recommendation models. PURPOSE: To portray the n-ary relationship, this study proposes a prescription recommendation model based on a multigraph convolutional network (MGCN). It introduces two essential components of the TCM diagnosis process: state-elements and syndrome-types. METHODS: The MGCN consists of two modules: a TCM feature-aggregation module and a herbal medicine prediction module. The TCM feature-aggregation module simulates the n-ary relationships between symptoms and prescriptions by constructing a symptom-'state element'-symptom graph (Se) and a symptom-'syndrome-type'-symptom graph (Ts). The herbal medicine prediction module inputs state-elements, syndrome-types and symptom data and uses a multilayer perceptron (MLP) to predict a corresponding herbal prescription. To verify the effectiveness of the proposed model, numerous quantitative and qualitative experiments were conducted on the Treatise on Febrile Diseases dataset. RESULTS: In the experiments, the MGCN outperformed three other algorithms used for comparison. In addition, the experimental data shows that, of these three algorithms, the SVM performed best. The MGCN was 4.51%, 6.45% and 5.31% higher in Precision@5, Recall@5 and F1-score@5, respectively, than the SVM. We set the K-value to 5 and conducted two qualitative experiments. In the first case, all five herbs in the label were correctly predicted by the MGCN. In the second case, four of the five herbs were correctly predicted. CONCLUSIONS: Compared with existing AI algorithms, the MGCN significantly improved the accuracy of TCM herbal prescription recommendations. In addition, the MGCN provides a more accurate TCM prescription herbal recommendation scheme, giving it great practical application value.

Socio-economic differences in accessing NHS spectacles amongst children with differing refractive errors living in Scotland.

BACKGROUND/OBJECTIVES: Adults living in more deprived areas are less likely to attend an eye examination, resulting in greater visual impairment from undiagnosed eye disease and a widening of health inequalities. It is unknown if the introduction of free NHS eye examinations and help with spectacle costs has benefited children in Scotland. This study aimed to explore factors associated with accessing NHS spectacles including level of deprivation, refractive error, urbanity and age. SUBJECTS/METHODS: NHS-financed General Ophthalmic Services (GOS) 3 supplement the cost of spectacles for children under 16 years. Administrative data on the spectacle refraction dispensed were obtained from Information Services Division (ISD) for mainland Scotland, 2018, and categorised by: Emmetropes/low hyperopes (reference group), myopes and moderate/high hyperopes. Data were linked to the Scottish Index of Multiple Deprivation (SIMD) quintile. RESULTS: Data included 108, 043 GOS 3 claims. Greater deprivation was associated with greater GOS 3 claims p = 0.041. This was most evident in emmetropic/low hyperopic children and in moderate/high hyperopic children. GOS 3 claims in the myopes group increased with age across all SIMD and decreased with age in the moderate/high hyperope group (all p < 0.001). GOS 3 claims were not associated with urbanity for all Health Boards (p = 0.13). CONCLUSIONS: Children in areas of greater deprivation and in more rural areas are not disadvantaged in accessing NHS spectacles. This did not vary by refractive error group. This suggests that health policy in Scotland is accessible to those from all deprivation levels and refractive errors.

The incidence and awareness of Rhegmatogenous retinal detachment in Pakistani population.

Retinal detachment (RD) describes the separation of neurosensory retina from the underlying pigment epithelium. There are various methods of treating RD but in many cases, an unusual delay between occurrence of retinal detachment and surgery has been observed. This study was conducted to find the extent of factors involved in delay in surgery. This cross sectional study was carried out at LRBT Eye Hospital, Lahore for 6 months. The non-probability, consecutive sampling technique was used. The demographic information was recorded. The patients were asked for causes of delay in retinal detachment surgery and all factors were measured. Data was analyzed by SPSS version 21. The mean age of patients was 52±9.86 years; the male to female ratio was 1.5:1. About 9.3% patients said that they do not know where to go, 30% patients thought that it was not a severe condition,36.4% patients thought that it would self-heal,17.1% patients didn't go to the doctor due to financial constraints whereas 7.1% patients did not have VR ophthalmologist near their residence. Statistically significant difference was found between the factors and education level of the patients i.e. p-value<0.05. Our study results concluded that people needed to be educated regarding the importance of retinal detachment and surgical procedures and complications associated with it.

Development and Psychometric Assessment of Novel Item Banks for Hereditary Retinal Diseases.

SIGNIFICANCE: This study develops psychometrically valid item banks across 10 areas of quality of life (QoL) specific to people with hereditary retinal diseases, which will enable clinicians and researchers to explore the impact of hereditary retinal diseases across all aspects of QoL. PURPOSE: The purpose of this study was to assess the psychometric properties of hereditary retinal disease QoL item banks using Rasch analysis and demonstrate the effectiveness of a computerized adaptive testing (CAT) system in obtaining precise measurement of QoL using only a few items. METHODS: The hereditary retinal disease item banks were answered by 233 participants (median age, 58 years; range, 18 to 94 years; female participants, 59%). The hereditary retinal disease item banks cover 10 QoL domains: activity limitation, mobility, emotional, social, convenience, economic, health concerns, visual symptoms, ocular comfort symptoms, and general symptoms. Rasch analysis assessed the psychometric properties of the 10 item banks and provided item calibrations for the development of CAT. Computerized adaptive testing simulations were performed to calculate the average number of items required to gain precise measurement of each QoL domain. RESULTS: The convenience, economic, visual symptoms, and the social domains formed unidimensional scales. However, the activity limitation and health concerns domains demonstrated multidimensionality and required major modifications to resolve this, which resulted in four new QoL domains, namely, reading, driving, lighting, and concerns about the disease progression. In total, 10 item banks underwent CAT simulation testing, which indicated that 8 to 12 items were required to gain precise measurement of each QoL domain. CONCLUSIONS: We have developed 10 psychometrically valid item banks to measure the QoL domains relevant to people with hereditary retinal diseases. On average, only 5 and 10 items were required to gain measurement at moderate and high precision, respectively.

Guidance of Medical Care for Familial Exudative Vitreoretinopathy：Research on Rare and Intractable Diseases, Health and Labour Sciences Research Grants.

Familial exudative vitreoretinopathy is a hereditary insufficiency of retinal vascularture, which manifests a variety of vitreoretinal abnormalities, including nonvascularlized retina, abnormality of retinal vessel growing, dragged retina, retinal folds and total retinal detachment. While causative genes have been identified, cases are often sporadic. Periodic examination is necessary to find recurrence of the disease and late complications, including rhegmatogenous retinal detachment, cataract and glaucoma.

Current landscape of direct-to-consumer genetic testing and its role in ophthalmology: a review.

The sequencing of the human genome has seen the emergence of the direct-to-consumer (DTC) genetic-testing market, which allows individuals to obtain information about their genetic profile and its many health and lifestyle implications. Genetics play an important role in the development of many eye diseases, however, little information is available describing the influence of the DTC industry in ophthalmology. In this review, we examined DTC companies providing genetic test products for eye disease. Of all eye conditions, the majority of DTC companies provided susceptibility testing or risk assessment for age-related macular degeneration (AMD). For the 15 companies noted to offer products, we found considerable variation in the cost, scope and clarity of informational content of DTC genetic testing for ophthalmic conditions. The clinical utility of these tests remains in question, and the American Academy of Ophthalmology recommendations against routine testing for many conditions probably still apply.

Should patients with ocular genetic disorders have genetic testing?

PURPOSE OF REVIEW: To discuss the risks, benefits and value of genetic testing for ocular genetic disease. RECENT FINDINGS: Testing for ocular genetics diseases is becoming more available and successful gene therapy is being reported. Clinicians must prepare for this trend by considering diagnostic genetic testing for their patients. SUMMARY: As advances continually occur in genetic testing for ocular genetic disorders, clinicians must develop an understanding of the potential risks and benefits for their patients.

The cost of genetic testing for ocular disease: who pays?

PURPOSE OF REVIEW: To facilitate ophthalmologists' understanding on the cost of genetic testing in ocular disease, the complexities of insurance coverage and its impact on the availability of testing. RECENT FINDINGS: Many insurance carriers address coverage for genetic testing in written clinical policies. They provide criteria for medically necessary testing. These policies mostly cover testing for individuals who are symptomatic and in whom testing will have a direct impact on medical treatment. In cases in which no treatments are currently available, other than research trials, patients may have difficulty in getting insurance coverage for genetic testing. SUMMARY: Genetic testing for inherited eye diseases can be costly but has many benefits to patient care, including confirmation of a diagnosis, insight into prognostic information, and identification of associated health risks, inheritance patterns, and possible current and future treatments. As gene therapy advances progress, the availability for treatment in ocular diseases, coverage for genetic testing by third-party payers could increase on the basis of current clinical policies.

Assessment of night vision problems in patients with congenital stationary night blindness.

Congenital Stationary Night Blindness (CSNB) is a retinal disorder caused by a signal transmission defect between photoreceptors and bipolar cells. CSNB can be subdivided in CSNB2 (rod signal transmission reduced) and CSNB1 (rod signal transmission absent). The present study is the first in which night vision problems are assessed in CSNB patients in a systematic way, with the purpose of improving rehabilitation for these patients. We assessed the night vision problems of 13 CSNB2 patients and 9 CSNB1 patients by means of a questionnaire on low luminance situations. We furthermore investigated their dark adapted visual functions by the Goldmann Weekers dark adaptation curve, a dark adapted static visual field, and a two-dimensional version of the "Light Lab". In the latter test, a digital image of a living room with objects was projected on a screen. While increasing the luminance of the image, we asked the patients to report on detection and recognition of objects. The questionnaire showed that the CSNB2 patients hardly experienced any night vision problems, while all CSNB1 patients experienced some problems although they generally did not describe them as severe. The three scotopic tests showed minimally to moderately decreased dark adapted visual functions in the CSNB2 patients, with differences between patients. In contrast, the dark adapted visual functions of the CSNB1 patients were more severely affected, but showed almost no differences between patients. The results from the "2D Light Lab" showed that all CSNB1 patients were blind at low intensities (equal to starlight), but quickly regained vision at higher intensities (full moonlight). Just above their dark adapted thresholds both CSNB1 and CSNB2 patients had normal visual fields. From the results we conclude that night vision problems in CSNB, in contrast to what the name suggests, are not conspicuous and generally not disabling.

Relative frequencies of inherited retinal dystrophies and optic neuropathies in Southern France: assessment of 21-year data management.

PURPOSE: Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France. METHODS: Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing. RESULTS: There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes (ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis. CONCLUSIONS: Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined.

Incidence and patterns of detection and management of childhood-onset hereditary retinal disorders in the UK.

BACKGROUND: A prospective, national population-based cross-sectional study to enable understanding of the burden and management in the UK of hereditary retinal disorders presenting in childhood. METHODS: Children aged <16 years with a new diagnosis of an inherited retinal disorder made between September 2006 and February 2008 in the UK were identified through two national active surveillance schemes. Clinical and socio-demographic information was collected on each child at diagnosis and 9 months later using standardised questionnaires. RESULTS: 241 patients were reported with 24 distinct diagnoses. 14% had additional systemic disorders and 13% had dual sensory impairment. Annual incidence was 1.4/100,000 children (aged 0-15 years) and the cumulative incidence by age 16 years was 22.3/100,000 children. The most common mode of inheritance was autosomal recessive. A significantly higher rate was seen in males than females (relative rate (RR) 1.53), in children of Asian compared with White ethnicity (RR 7.12) and in those in the worst quintile of socio-economic deprivation compared with those in the best (RR 1.43). Parents most commonly detected a problem with their child's vision. Up to seven different health professionals were involved in a child's early management, and variations were noted in the proportion of eligible children having assessments for low vision aids, statement of educational needs and certification as sight-impaired. CONCLUSIONS: These findings illustrate the highly heterogeneous nature of childhood retinal dystrophies and provide previously unavailable data on disease incidence, distributions and management, which are important for service provision and for planning future treatment programmes, particularly as novel therapies become available.

Longitudinal assessment of retinal structure and function reveals a rod-cone degeneration in a guinea pig model initially presented as night blind.

We have previously reported a naturally occurring retinopathy in a population of guinea pigs, where the affected animals presented a defect of the rod-mediated vision. The purpose of this study was to investigate if the mutants were affected with a stationary or degenerative retinopathy and to identify the cellular origin of this unique disorder. Electroretinogram (ERG) [postnatal day 1 (P1) to P450], light (LM) and electron microscopy (EM) [P5, P150, P450], and immunohistochemistry [P30, P150, P450] were evaluated from normal and mutant animals. Irrespective of age, the scotopic ERGs of mutants could only be evoked by bright flashes, and the resulting ERGs were of photopic waveform. Interestingly, the amplitude of the cone and the rod/cone a-waves was always of smaller amplitude in mutants, but this difference tended to decrease with age. In contrast, the b-waves were of larger amplitude than normal in photopic ERGs obtained prior to age 25 (days) and prior to age 10 for rod/cone ERGs. LM revealed, in mutants, an absence of the outer segment layer (OSL) with a reduction in the outer nuclear layer (ONL) thickness. EM disclosed the presence of cone outer segment (OS) while no rod OS could be evidenced. Immunohistochemistry revealed the presence of rhodopsin, both cone opsins as well as normal synaptophysin immunoreactivity. Finally, neither the retinal structure nor the function in the mutants achieved normal development. Results suggest that mutant animals are suffering from a degenerative retinal disorder that affects the structure and function of rods and cones.

Avaliação genética e oftalmológica de pacientes com síndrome de Stickler tipo II / Genetic and ophthalmological assessment of patients with type II Stickler syndrome

OBJETIVOS: Diagnosticar, avaliar e descrever os achados clínico-genéticos e oftalmológicos de pacientes com síndrome de Stickler tipo II de uma mesma família. MÉTODOS: Todos os pacientes com alterações oftalmológicas foram submetidos à radiografia de mãos e punhos para idade óssea e posteriormente analisados pelo exame clínico-genético. O diagnóstico de síndrome de Stickler foi dado mediante análise clínica e correlação com o perfil metacarpofalangeano visualizado na radiografia. RESULTADOS: Síndrome de Stickler tipo II foi comprovada em 11 pacientes. Os achados oculares mais importantes foram: alta miopia (80 por cento), subluxação do cristalino (70 por cento), exotropia (50 por cento) e anomalias vítreo-retinianas (80 por cento) incluindo vazio vítreo (50 por cento). O exame clínico-genético revelou que 30 por cento dos pacientes apresentavam micrognatia, 50 por cento hipoacusia, 40 por cento depressão nasal e 60 por cento palato alto. Hipermotilidade articular e dedos longos foram demonstrados em 7 casos (70 por cento) e artropatia esteve presente em 3 pacientes (30 por cento dos casos). CONCLUSÕES: O diagnóstico da síndrome de Stickler é difícil devido à variabilidade fenotípica e a existência de outras síndromes genéticas com características semelhantes. As radiografias de mão e punho são de particular importância no diagnóstico desta síndrome.

PURPOSE: To diagnose, evaluate and describe the clinical, genetic and ophthalmic characteristics of a family with type II Stickler syndrome. METHODS: X-rays for bone age, clinical and genetic evaluation were performed in all patients with ocular alterations. The Stickler syndrome diagnosis was established after correlating these examinations. RESULTS: Type II Stickler syndrome was found in 11 patients. The most important ocular findings were: high myopia (80 percent), lens subluxation (70 percent), exotropia (50 percent) and vitreoretinal abnormalities (80 percent) including vitreous cavity (50 percent). The clinical genetic examination disclosed that 30 percent of the patients had micrognathia, 50 percent hearing loss, 40 percent nasal depression and 60 percent high palate. Seven cases had articular hypermotility and long fingers and arthropathy was present in 3 cases. CONCLUSION: Diagnosis of the Stickler syndrome is difficult due to its phenotypic variability and the existence of other genetic syndromes with similar characteristics. Hand and wrist radiographs are of particular importance in the diagnosis of this syndrome.

High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1.

Stickler syndrome is a genetically heterogeneous disorder that affects the ocular, skeletal, and auditory systems. To date three genes, COL2A1, COL11A1, and COL11A2, encoding the heterotypic type II/XI collagen fibrils present in vitreous and cartilage have been shown to have mutations that result in Stickler syndrome. As systemic features in this disorder are variable we have used an ophthalmic examination to differentiate those patients with a membranous vitreous phenotype associated with mutations in COL2A1, from other patients who may have mutations in other genes. Gene amplification and exon sequencing was used to screen 50 families or sporadic cases with this membranous phenotype, for mutations in COL2A1. Mutations were detected in 47 (94%) cases consisting of 166 affected and 78 unaffected individuals. We also demonstrate that the predominantly ocular form of type 1 Stickler syndrome is not confined to mutations in the alternatively spliced exon 2. Using splicing reporter constructs we demonstrate that a mutant GC donor splice site in intron 51 can be spliced normally; this contributed to the predominantly ocular phenotype in the family in which it occurred.