The nanophthalmos protein TMEM98 inhibits MYRF self-cleavage and is required for eye size specification.

The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouse Tmem98 result in perinatal lethality, we produced mice deficient for Tmem98 in the retinal pigment epithelium (RPE), where Tmem98 is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas, compressed choroid and thin sclera. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations of MYRF are also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei. Our findings highlight the importance of the interplay between TMEM98 and MYRF in determining the size of the eye.

Effectiveness of the VA-Geriatric Resources for Assessment and Care of Elders (VA-GRACE) program: An observational cohort study.

BACKGROUND: As the Department of Veterans Affairs (VA) healthcare system seeks to expand access to comprehensive geriatric assessments, evidence-based models of care are needed to support community-dwelling older persons. We evaluated the VA Geriatric Resources for Assessment and Care of Elders (VA-GRACE) program's effect on mortality and readmissions, as well as patient, caregiver, and staff satisfaction. METHODS: This retrospective cohort included patients admitted to the Richard L. Roudebush VA hospital (2010-2019) who received VA-GRACE services post-discharge and usual care controls who were potentially eligible for VA-GRACE but did not receive services. The VA-GRACE program provided home-based comprehensive, multi-disciplinary geriatrics assessment, and ongoing care. Primary outcomes included 90-day and 1-year all-cause readmissions and mortality, and patient, caregiver, and staff satisfaction. We used propensity score modeling with overlapping weighting to adjust for differences in characteristics between groups. RESULTS: VA-GRACE patients (N = 683) were older than controls (N = 4313) (mean age 78.3 ± 8.2 standard deviation vs. 72.2 ± 6.9 years; p < 0.001) and had greater comorbidity (median Charlson Comorbidity Index 3 vs. 0; p < 0.001). VA-GRACE patients had higher 90-day readmissions (adjusted odds ratio [aOR] 1.55 [95%CI 1.01-2.38]) and higher 1-year readmissions (aOR 1.74 [95%CI 1.22-2.48]). However, VA-GRACE patients had lower 90-day mortality (aOR 0.31 [95%CI 0.11-0.92]), but no statistically significant difference in 1-year mortality was observed (aOR 0.88 [95%CI 0.55-1.41]). Patients and caregivers reported that VA-GRACE home visits reduced travel burden and the program linked Veterans and caregivers to needed resources. Primary care providers reported that the VA-GRACE team helped to reduce their workload, improved medication management for their patients, and provided a view into patients' daily living situation. CONCLUSIONS: The VA-GRACE program provides comprehensive geriatric assessments and care to high-risk, community-dwelling older persons with high rates of satisfaction from patients, caregivers, and providers. Widespread deployment of programs like VA-GRACE will be required to support Veterans aging in place.