NR4A1 deletion promotes pro-angiogenic polarization of macrophages derived from classical monocytes in a mouse model of neovascular age-related macular degeneration.

BACKGROUND: Neovascular age-related macular degeneration causes vision loss from destructive angiogenesis, termed choroidal neovascularization (CNV). Cx3cr1-/- mice display alterations in non-classical monocytes and microglia with increased CNV size, suggesting that non-classical monocytes may inhibit CNV formation. NR4A1 is a transcription factor that is necessary for maturation of non-classical monocytes from classical monocytes. While Nr4a1-/- mice are deficient in non-classical monocytes, results are confounded by macrophage hyper-activation. Nr4a1se2/se2 mice lack a transcriptional activator, resulting in non-classical monocyte loss without macrophage hyper-activation. MAIN BODY: We subjected Nr4a1-/- and Nr4a1se2/se2 mice to the laser-induced CNV model and performed multi-parameter flow cytometry. We found that both models lack non-classical monocytes, but only Nr4a1-/- mice displayed increased CNV area. Additionally, CD11c+ macrophages were increased in Nr4a1-/- mice. Single-cell transcriptomic analysis uncovered that CD11c+ macrophages were enriched from Nr4a1-/- mice and expressed a pro-angiogenic transcriptomic profile that was disparate from prior reports of macrophage hyper-activation. CONCLUSIONS: These results suggest that non-classical monocytes are dispensable during CNV, and NR4A1 deficiency results in increased recruitment of pro-angiogenic macrophages.

Prevalence of Retinal Venous Malformations in Patients With Cerebral Cavernous or Arteriovenous Malformations.

BACKGROUND: Cerebral vascular malformations (CVMs) may result in hemorrhage, seizure, neurologic dysfunction, and death. CVMs include capillary telangiectasias, venous malformations, cavernous malformations, and arteriovenous malformations. Cavernous and arteriovenous malformations carry the highest risk of complications. Retinal venous malformations (RVMs) have been proposed as an associated finding. Our objective was to determine the prevalence of RVMs in patients with high-risk CVMs. METHODS: We retrospectively reviewed patients diagnosed with cerebral cavernous or arteriovenous malformations (high-risk CVMs) who were evaluated by the ophthalmology service at Northwestern University between 2017 and 2020. Patients were stratified into 3 cohorts based on level of certainty: dilated funduscopic examination (DFE), DFE with any form of ocular imaging, and DFE with complete imaging of the macula. We recorded ophthalmic examination abnormalities, ocular imaging findings, and major CVM complications. RESULTS: We evaluated 156 patients with high-risk CVMs who had undergone DFE. Ocular imaging of any type was performed in 56 patients, of whom 46 had complete imaging of the macula. Zero RVMs were identified in any cohort (95% confidence interval: 0%-1.9% for the entire cohort, 0%-5.4% for any ocular imaging cohort, and 0%-6.5% for the complete macular imaging cohort). Cerebral hemorrhage or seizure occurred in 15%-33% of patients. Associated visual field defects or cranial nerve palsies were found in 14%-20% of patients. CONCLUSIONS: Zero RVMs were identified in patients with high-risk CVMs. However, neuro-ophthalmic findings were common. Therefore, we recommend neuroimaging for patients with RVMs and neuro-ophthalmic signs or symptoms. In asymptomatic patients with RVMs, a potential algorithm for neuroimaging is proposed.

A Rapid MRI Protocol for the Evaluation of Acute Pediatric Musculoskeletal Infections: Eliminating Contrast and Decreasing Anesthesia, Scan Time, and Hospital Length of Stay and Charges.

BACKGROUND: Acute musculoskeletal infection affects >1 in 6,000 children in the United States annually. Magnetic resonance imaging (MRI) is the gold standard for the diagnosis of musculoskeletal infection, but it traditionally requires contrast and anesthesia for children, delaying management. A rapid MRI protocol involves MRI without anesthesia and with limited non-contrast sequences optimized for fluid detection and diffusion-weighted images to identify abscesses. We hypothesized that a rapid MRI protocol would improve imaging and treatment efficiency for pediatric patients undergoing musculoskeletal infection evaluation without substantially affecting accuracy. METHODS: This was a single-center, retrospective study of patients undergoing evaluation for musculoskeletal infection before (60 patients in the traditional cohort [TC]) and after (68 patients in the rapid cohort [RC]) implementation of the rapid MRI protocol. Sociodemographic and clinical variables were extracted from electronic health records, and statistical comparisons were performed. RESULTS: The anesthesia rates were 53% for the TC and 4% for the RC, and the contrast administration rates were 88% for the TC and 0% for the RC. The median time to MRI after ordering was 6.5 hours (95% confidence interval [CI], 5.0 to 8.6 hours) for the TC and 2.2 hours (95% CI, 1.4 to 3.6 hours) for the RC (p < 0.01). The median duration of MRI was 63.2 minutes (95% CI, 56.8 to 69.6 minutes) for the TC and 24.0 minutes (95% CI, 21.1 to 29.5 minutes) for the RC (p < 0.01). The median hospital length of stay was 5.3 days (95% CI, 3.7 to 6.9 days) for the TC and 3.7 days (95% CI, 1.9 to 4.1 days) for the RC (p < 0.01). The median hospital charges were $47,309 (95% CI, $39,137 to $58,769) for the TC and $32,824 (95% CI, $22,865 to $45,339) for the RC (p < 0.01). Only 2 positive cases of musculoskeletal infection in the RC were missed on the initial imaging, but these instances were not attributable to the rapid protocol itself. Although 10 of 68 rapid MRI scans resulted in nondiagnostic outcomes due to patient motion, only 6 of 68 required repeat MRI with anesthesia. CONCLUSIONS: In patients evaluated for musculoskeletal infection, the rapid MRI protocol eliminated contrast and minimized anesthesia while improving MRI access and decreased scan and interpretation times, hospital length of stay, and hospital charges. The rapid MRI protocol had high sensitivity for diagnosing musculoskeletal infection and a low rate of imaging failure. LEVEL OF EVIDENCE: Diagnostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Assessment of the Web Site Availability and Content of Pediatric Ophthalmology Fellowship Programs: A Cross-Sectional Nationwide Study.

Background Fellowship program Web sites are a crucial source of information for prospective pediatric ophthalmology applicants, especially in light of the restrictions on in-person interactions due to the coronavirus disease 2019 pandemic. Objective This study examined all pediatric ophthalmology fellowship Web sites for availability and presented recruitment and training content. Methods A full list of all pediatric ophthalmology and strabismus (POAS) fellowship programs were compiled from the Association of University Professors of Ophthalmology (AUPO) directory and the San Francisco Match (SFMatch) application listing. Each fellowship was queried by Google Internet search to identify the program's corresponding Web site. The content of Web sites was evaluated using 20 predetermined recruitment and training criteria. All data were collected in February 2022. Kruskal-Wallis and Mann-Whitney U tests were constructed to examine differences by geographic location, program size, number of teaching faculty, and affiliation with a top ophthalmology residency program. Results There were 45 pediatric ophthalmology fellowships identified from the AUPO and SFMatch. All pediatric ophthalmology fellowships had an available program Web site. However, there was significant variability in content, and the average Web site had approximately half of the evaluated criteria. POAS Web sites reported a greater number of recruitment criteria than program training criteria. There were no differences by program size, number of faculty, affiliation with a top residency program, or geographic location in the number of observed criteria. Conclusions This study provides data to drive efforts to improve pediatric ophthalmology fellowship Web sites. Pediatric ophthalmology fellowship Web sites are missing important information, and there are opportunities to improve program Web sites, regardless of program size, number of faculty, affiliation with a top residency, and geographic location. Informative, accurate Web sites may attract qualified candidates, and as a result, elevate the likelihood that interviewed candidates are well-suited to the program. As such, improvements to fellowship Web sites can streamline the application process and increase a program's success rate in the match.

Diagnostic Yield of Genetic Testing for Ocular and Oculocutaneous Albinism in a Diverse United States Pediatric Population.

The diagnostic yield of genetic testing for ocular/oculocutaneous albinism (OA/OCA) in a diverse pediatric population in the United States (U.S.) is unclear. Phenotypes of 53 patients who presented between 2006-2022 with OA/OCA were retrospectively correlated with genetic testing results. Genetic diagnostic yield was defined as detection of pathogenic/likely pathogenic variant(s) matching the anticipated inheritance for that gene-disease relationship. Variant reclassifications of those with variants of uncertain significance (VUS) and without positive diagnostic yield were completed. Overall initial genetic diagnostic yield of OA/OCA was 66%. There was no significant difference (p = 0.59) between race and ethnicities (Black (78%), White (59%), Hispanic/Latino (64%)); however, the diagnostic yield of OA (33%) was significantly lower (p = 0.007) than OCA (76%). Causative variants in OCA2 (28%) and TYR (20%) were most common. Further, Hermansky-Pudlak syndrome variants were identified in 9% of patients. Re-classification of VUS in non-diagnostic cases resulted in genetic diagnoses for 29% of individuals and increased overall diagnostic yield to 70% of all subjects. There is a high diagnostic yield of genetic testing of patients overall with OA/OCA in a diverse U.S. based pediatric population. Presence or absence of cutaneous involvement of albinism significantly affects genetic diagnostic yield.

Analysis of socioeconomic and demographic factors on post-treatment outcomes for metastatic spinal tumors.

OBJECTIVE: Sociodemographic factors may play a role in incidence and treatment of metastatic spinal tumors, as there is a delay in diagnosis and increased incidence of relevant primaries. There has yet to be a detailed analysis of the impact of sociodemographic factors on surgical outcomes for spinal metastases. We sought to examine the influence of socioeconomic factors on outcomes for patients with metastatic spinal tumors. METHODS: Two hundred and sixty-three patients who underwent surgery for metastatic spinal tumors were identified. Sociodemographic characteristics were then collected and assigned to patients based on their ZIP code. The Chi-square test and the Mann-Whitney-U test were used for binary and continuous variables, respectively. Multivariate regression models were also used to control for age, smoking status, body mass index, and Charlson Comorbidity Index. RESULTS: Males had significantly lower rates of post-treatment complication compared to females (22.7 % vs 39.3 %, p = 0.0052), and those in high educational attainment ZIP codes had significantly shorter length of stay (LOS) compared to low educational attainment ZIP codes (9.3 days vs 12.2 days, p = 0.0058). Multivariate regression revealed that living in a high percentage white ZIP code and being male significantly decreased risk of post-treatment complication by 19 % (p = 0.042) and 14 % (p = 0.032), respectively. Living in a high educational attainment ZIP code decreased LOS by 3 days (p = 0.019). CONCLUSIONS: Males had significantly lower rates of post-treatment complication. Patients in high percentage white areas also had decreased rate of post-treatment complications. Patients living in areas with high educational attainment had shorter length of stay.

Neurologic, functional, and survival outcomes following surgical management of metastatic breast cancer to the spine.

OBJECTIVE: Metastatic spinal tumors commonly arise from primary breast cancer. We assessed outcomes and identified associated variables for patients who underwent surgical management for spinal metastases of breast cancer. METHODS: We retrospectively reviewed patients surgically treated for spinal metastases of breast cancer. Neurologic and functional outcomes were analyzed via Frankel scale and Karnofksy Performance Status (KPS) scores, respectively. Variables associated with Frankel and KPS scores after surgery were identified. Multivariable analysis was used to assess predictors for postoperative survival. RESULTS: Forty-nine patients were identified. There was no significant difference in Frankel scores postoperatively and at last follow-up. KPS scores (P = 0.002) significantly improved at last follow-up. Preoperative non-ambulation and postprocedural complications were associated with non-ambulation postoperatively. Postprocedural complications and disease-free interval (DFI) < 24 and < 60 months were associated with functional impairment at last follow-up. Current smoking status at the time of surgery (P = 0.021) and triple negative (negative immunohistochemistry for estrogen receptor, progesterone receptor, and HER2) breast cancer (P = 0.038) were significantly associated with shortened postoperative survival. CONCLUSION: When indicated, surgery for spinal metastases of breast cancer leads to preservation of neurologic status and long-term functional improvement. Preoperative ambulatory status and postprocedural complications were associated with ambulatory status after surgery, while postprocedural complications and shortened DFI were associated with functional status after surgery.Current smoking status at the time of surgery and triple negative breast cancer are negative predictors for postoperative survival after metastatic breast cancer to the spine.