Reliability of COVID-19 data: An evaluation and reflection.

IMPORTANCE: The rapid proliferation of COVID-19 has left governments scrambling, and several data aggregators are now assisting in the reporting of county cases and deaths. The different variables affecting reporting (e.g., time delays in reporting) necessitates a well-documented reliability study examining the data methods and discussion of possible causes of differences between aggregators. OBJECTIVE: To statistically evaluate the reliability of COVID-19 data across aggregators using case fatality rate (CFR) estimates and reliability statistics. DESIGN, SETTING, AND PARTICIPANTS: Cases and deaths were collected daily by volunteers via state and local health departments, as primary sources and newspaper reports, as secondary sources. In an effort to begin comparison for reliability statistical analysis, BroadStreet collected data from other COVID-19 aggregator sources, including USAFacts, Johns Hopkins University, New York Times, The COVID Tracking Project. MAIN OUTCOMES AND MEASURES: COVID-19 cases and death counts at the county and state levels. RESULTS: Lower levels of inter-rater agreement were observed across aggregators associated with the number of deaths, which manifested itself in state level Bayesian estimates of COVID-19 fatality rates. CONCLUSIONS AND RELEVANCE: A national, publicly available data set is needed for current and future disease outbreaks and improved reliability in reporting.

TOPICAL CARBONIC ANHYDRASE INHIBITORS IN THE LONG-TERM TREATMENT OF JUVENILE X-LINKED RETINOSCHISIS.

PURPOSE: To describe the response to long-term topical dorzolamide treatment in patients with juvenile X-linked retinoschisis and cystic-like foveal lesions. METHODS: This was a retrospective interventional case series that included 18 eyes of 10 patients with genetically confirmed juvenile X-linked retinoschisis examined at the Cleveland Clinic Cole Eye Institute, a tertiary referral center, between 2005 and 2021. Patients were treated with topical 2% dorzolamide two to three times daily in both eyes. Two eyes were excluded because of retinal detachment. Primary outcome measures were logarithm of minimum angle of resolution visual acuity and optical coherence tomography based central subfield thickness. RESULTS: The mean follow-up was 8.38 years (SD, 3.41 years). The mean baseline and final central subfield thickness was 429.88 µ m (SD, 143.36 µ m) and 372.28 µ m, respectively (SD, 147.13 µ m, P = 0.10). The mean baseline and final logarithm of minimum angle of resolution visual acuity was 0.45 (SD, 0.17) and 0.34, respectively (SD, 0.22, P < 0.01). None of the patients experienced any side effects from topical dorzolamide. CONCLUSION: The study data support previous reports of improved visual acuity in X-linked retinoschisis patients on topical dorzolamide treatment. This is the longest follow-up for a series of juvenile X-linked retinoschisis patients treated with a topical carbonic anhydrase inhibitor to date. A large, prospective, randomized clinical trial is needed to provide stronger evidence regarding the efficacy of topical carbonic anhydrase inhibitors in juvenile X-linked retinoschisis.

Evidence that the Ser192Tyr/Arg402Gln in cis Tyrosinase gene haplotype is a disease-causing allele in oculocutaneous albinism type 1B (OCA1B).

Oculocutaneous albinism type 1 (OCA1) is caused by pathogenic variants in the TYR (tyrosinase) gene which encodes the critical and rate-limiting enzyme in melanin synthesis. It is the most common OCA subtype found in Caucasians, accounting for ~50% of cases worldwide. The apparent 'missing heritability' in OCA is well described, with ~25-30% of clinically diagnosed individuals lacking two clearly pathogenic variants. Here we undertook empowered genetic studies in an extensive multigenerational Amish family, alongside a review of previously published literature, a retrospective analysis of in-house datasets, and tyrosinase activity studies. Together this provides irrefutable evidence of the pathogenicity of two common TYR variants, p.(Ser192Tyr) and p.(Arg402Gln) when inherited in cis alongside a pathogenic TYR variant in trans. We also show that homozygosity for the p.(Ser192Tyr)/p.(Arg402Gln) TYR haplotype results in a very mild, but fully penetrant, albinism phenotype. Together these data underscore the importance of including the TYR p.(Ser192Tyr)/p.(Arg402Gln) in cis haplotype as a pathogenic allele causative of OCA, which would likely increase molecular diagnoses in this missing heritability albinism cohort by 25-50%.

Impact of Amblyopia on the Central Nervous System.

Amblyopia is a common perceptual disorder resulting from abnormal visual input during development. The clinical presentation and visual deficits associated with amblyopia are well characterized. Less is known however, about amblyopia's impact on the central nervous system (CNS). While early insights into the neuropathophysiology of amblyopia have been based on findings from animal models and postmortem human studies, recent advances in noninvasive magnetic resonance imaging (MRI) techniques have enabled the study of amblyopia's effects in vivo. We review recent retinal and neuroimaging research documenting amblyopia's structural and functional impact on the CNS. Clinical imaging provides some evidence for retinal and optic nerve abnormalities in amblyopic eyes, although the overall picture remains inconclusive. Neuroimaging studies report clearer changes in both structure and function of the visual pathways. In the optic nerves, optic tracts, and optic radiations of individuals with amblyopia, white-matter integrity is decreased. In the lateral geniculate nuclei, gray matter volume is decreased and neural activity is reduced. Reduced responses are also seen in the amblyopic primary visual cortex and extrastriate areas. Overall, amblyopia impacts structure and function at multiple sites along the visual processing hierarchy. Moreover, there is some evidence that amblyopia's impact on the CNS depends on its etiology, with different patterns of results for strabismic and anisometropic amblyopia. To clarify the impact of amblyopia on the CNS, simultaneous collection of retinal, neural, and perceptual measures should be employed. Such an approach will help (1) distinguish cause and effect of amblyopic impairments, (2) separate the impact of amblyopia from other superimposed conditions, and (3) identify the importance of amblyopic etiology to specific neural and perceptual deficits.

Ocular evaluation and genetic test for an early Alström Syndrome diagnosis.

PURPOSE: We present 3 cases of Alström syndrome (ALMS) that highlight the importance of the ophthalmic exam, as well as the diagnostic challenges and management considerations of this ultra-rare disease. OBSERVATIONS: The first case is of a 2-year-old boy with history of spasmus nutans who presented with head bobbing and nystagmus. The second patient is a 5-year-old boy with history of infantile dilated cardiomyopathy status post heart transplant, Burkitt lymphoma status post chemotherapy, obesity, global developmental delay, and high hyperopia previously thought to have cortical visual impairment secondary to heart surgery/possible ischemic event. This patient presented with nystagmus, photophobia, and reduced vision. The third case involves a 8-year-old boy with history of obesity, bilateral optic nerve atrophy, hyperopic astigmatism, exotropia, and nystagmus. Upon presentation to the consulting pediatric ophthalmologist, none of the patients had yet been diagnosed with ALMS. All 3 cases were subsequently found to have an electroretinogram (ERG) that exhibited severe global depression and to carry ALMS1 pathogenic variants. CONCLUSIONS AND IMPORTANCE: ALMS is an autosomal recessive disease caused by ALMS1 variations, characterized by cone-rod dystrophy, obesity, progressive sensorineural hearing loss, cardiomyopathy, insulin resistance, and multiorgan dysfunction. Retinal dystrophy diagnosis is critical given clinical criteria and detection rates of genetic testing. Early diagnosis is extremely important because progression to flat ERG leads to the inability to differentiate between rod-cone or cone-rod involvement, either of which have their own differential diagnoses. In our series, the ophthalmic exam and abnormal ERG prompted further genetic testing and the subsequent diagnosis of ALMS. Multidisciplinary care ensures the best possible outcome with the ophthalmologist playing a key role.

Survey of practice patterns for the management of ophthalmic genetic disorders among AAPOS members: report by the AAPOS Genetic Eye Disease Task Force.

To better understand AAPOS member pediatric ophthalmologists' knowledge and needs regarding genetic eye disorders, the AAPOS Genetic Eye Disease Task Force developed a 16-question survey that was circulated to national and international AAPOS members. Responses to questions on practice patterns, baseline knowledge, and educational interests regarding patients with suspected ophthalmic genetic disorders were collected. A majority of respondents (93%) evaluate patients with suspected genetic disorders. Knowledge gaps were present in heritability of certain conditions, genetic testing strategies, and referral to clinical trials. Most respondents expressed interest in further education in these areas. A model for care is proposed as a first step in the education process.

Retinothalamic White Matter Abnormalities in Amblyopia.

Purpose: Amblyopia is associated with a broad array of perceptual and neural abnormalities in the visual system, particularly in untreated or unsuccessfully treated populations. Traditionally, it has been believed that the neural abnormalities are confined to the visual cortex and subcortex (e.g., lateral geniculate nucleus). Here, we investigate the presence of neuroanatomical abnormalities earlier in the visual stream, in the optic nerves and tracts, of participants with two predominant forms of amblyopia. Methods: We used diffusion magnetic resonance imaging and probabilistic tractography to compare the microstructural properties of five white matter visual pathways between 15 participants with amblyopia (eight anisometropic, five strabismic, and two exhibiting both etiologies), and 13 age-matched controls. Results: Participants with amblyopia exhibited significantly smaller mean fractional anisotropy in the optic nerve and optic tract (0.26 and 0.31 vs. 0.31 and 0.36 in controls, respectively). We also found greater mean diffusivity in the optic radiation compared to controls (0.72 µm2/s vs. 0.68 µm2/s, respectively). Comparing etiologies, the abnormalities in the precortical pathways tended to be more severe in participants with anisometropic compared to strabismic amblyopia, and anisometropic participants' optic nerves, optic tracts, and optic radiations significantly differed from control participants' (all, P < 0.05). Conclusions: The results indicate that amblyopia may be associated with microstructural abnormalities in neural networks as early as the retina, and these abnormalities may differ between amblyopic etiologies.