Retinoic acid related orphan receptor α is a genetic modifier that rescues retinal degeneration in a mouse model of Stargardt disease and Dry AMD.

Degeneration of the macula is associated with several overlapping diseases including age-related macular degeneration (AMD) and Stargardt Disease (STGD). Mutations in ATP Binding Cassette Subfamily A Member 4 (ABCA4) are associated with late-onset dry AMD and early-onset STGD. Additionally, both forms of macular degeneration exhibit deposition of subretinal material and photoreceptor degeneration. Retinoic acid related orphan receptor α (RORA) regulates the AMD inflammation pathway that includes ABCA4, CD59, C3 and C5. In this translational study, we examined the efficacy of RORA at attenuating retinal degeneration and improving the inflammatory response in Abca4 knockout (Abca4-/-) mice. AAV5-hRORA-treated mice showed reduced deposits, restored CD59 expression and attenuated amyloid precursor protein (APP) expression compared with untreated eyes. This molecular rescue correlated with statistically significant improvement in photoreceptor function. This is the first study evaluating the impact of RORA modifier gene therapy on rescuing retinal degeneration. Our studies demonstrate efficacy of RORA in improving STGD and dry AMD-like disease.

Temporal evolution of chest radiographic appearances in COVID-19 with clinicoradiological associations: a multicentre United Kingdom resident-led study.

AIM: To describe the (a) frequency of improving, static, and worsening chest radiograph (CXR) appearances; (b) differences in demographic, initial rudimentary haematological and CXR variables and these patterns; and (c) frequency of different trajectories of serial CXR evolution, in COVID-19 patients presenting consecutively. MATERIALS AND METHODS: This multicentre retrospective study included all COVID-19 patients admitted from 1-30 April 2020, meeting the inclusion criteria across 24 (blinded) hospitals. Follow-up CXRs on admission, the subsequent (where available), and at 4-8 weeks were scored for the presence of parenchymal opacities across six zones. Three cohorts were defined: improved, static, and/or worsened. The chi-squared and Kruskal-Wallis tests were used to compare demographic, laboratory, and CXR variables. Trajectories of CXR evolution were assessed when all three CXRs were available (226 patients). RESULTS: Of 452 included patients (median age 66 years, interquartile range 54.3-79, 262 men), 211 (46.7%) improved, 140 (31%) were static, and 101 (22.3%) worsened. Improving patients were more likely younger, with a classic COVID-19 radiograph and higher initial CXR zonal severity scores (both p<0.001), while worsening patients had lower initial lymphocyte counts (p=0.008). The most frequent trajectory was worsened then improved (n=63, 27.9%) followed by static then improved (n=46, 20.4%) and static (n=42, 18.6%). CONCLUSION: Most patients with COVID-19 during the first wave of the pandemic demonstrated radiographic improvement; these patients were more likely younger with classic COVID-19 appearances and initially more extensive abnormality. Conversely, radiographic deterioration was associated with lower lymphocyte counts. The three most common trajectories were worsening then improvement, static then improvement, and static throughout.

COVID-19 Stroke Apical Lung Examination Study 2: a national prospective CTA biomarker study of the lung apices, in patients presenting with suspected acute stroke (COVID SALES 2).

BACKGROUND: Apical ground-glass opacification (GGO) identified on CT angiography (CTA) performed for suspected acute stroke was developed in 2020 as a coronavirus-disease-2019 (COVID-19) diagnostic and prognostic biomarker in a retrospective study during the first wave of COVID-19. OBJECTIVE: To prospectively validate whether GGO on CTA performed for suspected acute stroke is a reliable COVID-19 diagnostic and prognostic biomarker and whether it is reliable for COVID-19 vaccinated patients. METHODS: In this prospective, pragmatic, national, multi-center validation study performed at 13 sites, we captured study data consecutively in patients undergoing CTA for suspected acute stroke from January-March 2021. Demographic and clinical features associated with stroke and COVID-19 were incorporated. The primary outcome was the likelihood of reverse-transcriptase-polymerase-chain-reaction swab-test-confirmed COVID-19 using the GGO biomarker. Secondary outcomes investigated were functional status at discharge and survival analyses at 30 and 90 days. Univariate and multivariable statistical analyses were employed. RESULTS: CTAs from 1,111 patients were analyzed, with apical GGO identified in 8.5 % during a period of high COVID-19 prevalence. GGO showed good inter-rater reliability (Fleiss κ = 0.77); and high COVID-19 specificity (93.7 %, 91.8-95.2) and negative predictive value (NPV; 97.8 %, 96.5-98.6). In subgroup analysis of vaccinated patients, GGO remained a good diagnostic biomarker (specificity 93.1 %, 89.8-95.5; NPV 99.7 %, 98.3-100.0). Patients with COVID-19 were more likely to have higher stroke score (NIHSS (mean +/- SD) 6.9 +/- 6.9, COVID-19 negative, 9.7 +/- 9.0, COVID-19 positive; p = 0.01), carotid occlusions (6.2 % negative, 14.9 % positive; p = 0.02), and larger infarcts on presentation CT (ASPECTS 9.4 +/- 1.5, COVID-19 negative, 8.6 +/- 2.4, COVID-19 positive; p = 0.00). After multivariable logistic regression, GGO (odds ratio 15.7, 6.2-40.1), myalgia (8.9, 2.1-38.2) and higher core body temperature (1.9, 1.1-3.2) were independent COVID-19 predictors. GGO was associated with worse functional outcome on discharge and worse survival after univariate analysis. However, after adjustment for factors including stroke severity, GGO was not independently predictive of functional outcome or mortality. CONCLUSION: Apical GGO on CTA performed for patients with suspected acute stroke is a reliable diagnostic biomarker for COVID-19, which in combination with clinical features may be useful in COVID-19 triage.