Faculty Bibliography

Optineurin (OPTN) is a gene associated with familial normal tension glaucoma (NTG). While NTG involves intraocular pressure (IOP)-independent neurodegeneration of the visual pathway that progresses with age, how OPTN dysfunction leads to NTG remains unclear. Here, we generated an OPTN knockout mouse (Optn^-/

Sino-orbital cutaneous fistulas (SOCFs) are a rare and challenging complication from conditions including granulomatosis with polyangiitis. SOCFs are difficult to manage due to poor vascular supply, compromised tissue, and systemic immunocompromise, which lead to a high rate of recurrence. Given the overall rarity of SOCFs, optimal surgical repair remains controversial, with options ranging from conservative management, onlay grafts, and vascularized flaps. This case report describes a novel one-step approach to SOCF closure using a composite chondral mucosal nasoseptal flap in a patient with a large left medial canthal SOCF that had recurred despite 2 prior attempts at closure including a vascularized paramedian forehead flap. Nasoseptal flaps may provide vascularized mucosal tissue to allow for greater success in closure over traditional, external flaps, and skin grafts.

OBJECTIVE: Recent studies have reported associations between severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection during pregnancy and adverse perinatal outcomes but the extent to which these associations vary by race/ethnicity remains uncertain. Therefore, we examined how the association between prenatal SARS-CoV-2 infection and adverse perinatal outcomes may be modified by race/ethnicity. STUDY DESIGN/METHODS: A retrospective cohort study was performed using data on 67,986 pregnant women extracted from the Kaiser Permanente Southern California electronic health records between April 6, 2020, and December 31, 2021. Upon admission to labor and delivery, all women were routinely tested for coronavirus disease 2019 (COVID-19) using real-time reverse-transcriptase polymerase chain reaction test. Adjusted odds ratios (aORs) were used to estimate associations. RESULTS: During the study period, COVID-19 was diagnosed in 4,960 (7%) of singleton pregnancies, with the highest rates observed among Hispanics (9.4%) and non-Hispanic Blacks (6.2%). Compared with non-Hispanic Whites, Hispanics (aOR: 1.12, 95% CI: 1.03, 1.21) with SARS-CoV-2 infection had the highest odds of a pregnancy associated with nonreassuring fetal heart rate tracing. Neonates of all races/ethnicities, except for non-Hispanic Blacks, showed significantly increased odds of SARS-CoV-2 infection, with the highest risk observed among Asians/Pacific Islanders (aOR: 10.88, 95% CI: 1.33, 89.04). Non-Hispanic White mothers who tested positive were admitted to intensive care unit (ICU) at a higher rate at delivery and within 7 days of delivery (aOR: 34.77, 95% CI: 11.3, 107.04; aOR: 26.48, 95% CI: 9.55, 73.46, respectively). Hispanics were also at a significantly higher odds of admission to ICU (aOR: 4.62, 95% CI: 2.69, 7.94; aOR: 4.42, 95% CI: 2.58, 7.56, respectively). Non-Hispanic Black, Hispanic, and Asian/Pacific Islander mothers who tested positive for SARS-CoV-2 prenatally, were at increased risk for preeclampsia/eclampsia, and preterm birth as compared to non-Hispanic White mothers. CONCLUSION/CONCLUSIONS: The findings highlight racial/ethnic disparities in the association between SARS-CoV-2 infection and adverse perinatal outcomes. The risk of neonatal SARS-CoV-2 infection was highest for Asian/Pacific Islanders. We also observed a remarkably high risk of ICU admission for non-Hispanic White mothers infected with SARS-CoV-2. KEY POINTS/CONCLUSIONS:· Race/ethnicity influences perinatal outcomes in pregnancies impacted by SARS-CoV-2.. · The risk of neonatal SARS-CoV-2 infection was highest for Asian/Pacific Islanders.. · White mothers had a notably high risk of ICU admission at delivery following SARS-CoV-2 infection..

Keratoconus is a progressive eye disorder primarily affecting individuals in adolescence and early adulthood. The ectatic changes in the cornea cause thinning and cone-like steepening leading to irregular astigmatism and reduced vision. Keratoconus is a complex disorder with a multifaceted aetiology and pathogenesis, including genetic, environmental, biomechanical and cellular factors. Environmental factors, such as eye rubbing, UV light exposure and contact lens wearing, are associated with disease progression. On the cellular level, a complex interplay of hormonal changes, alterations in enzymatic activity that modify extracellular membrane stiffness, and changes in biochemical and biomechanical signalling pathways disrupt collagen cross-linking within the stroma, contributing to structural integrity loss and distortion of normal corneal anatomy. Clinically, keratoconus is diagnosed through clinical examination and corneal imaging. Advanced imaging platforms have improved the detection of keratoconus, facilitating early diagnosis and monitoring of disease progression. Treatment strategies for keratoconus are tailored to disease severity and progression. In early stages, vision correction with glasses or soft contact lenses may suffice. As the condition advances, rigid gas-permeable contact lenses or scleral lenses are prescribed. Corneal cross-linking has emerged as a pivotal treatment aimed at halting the progression of corneal ectasia. In patients with keratoconus with scarring or contact lens intolerance, surgical interventions are performed.

PURPOSE/UNASSIGNED:Abetalipoproteinemia (ABL, MIM 200,100) is a rare autosomal recessive disorder caused by nonfunctional microsomal triglyceride transfer protein leading to absence of apolipoprotein B-containing lipoproteins in plasma and a retinitis pigmentosa-like fundus. The MTTP gene is expressed in retinal pigment epithelium (RPE) and ganglion cells of the human retina. Understanding ABL pathophysiology would benefit from new cellular-level clinical imaging of affected retinas. METHODS/UNASSIGNED:We report multimodal retinal imaging in two patients with ABL. Case 1 (67-year-old woman) exhibited a bilateral decline of vision due to choroidal neovascularization (CNV) associated with angioid streaks and calcified Bruch membrane. Optical coherence tomography were consistent with basal laminar deposits and subretinal drusenoid deposits (SDD). RESULTS/UNASSIGNED:Case 2 (46-year-old woman) exhibited unusual hyperpigmentation at the right fovea with count-fingers vision and a relatively unremarkable left fundus with 20/30 vision. The left eye exhibited the presence of nodular drusen and SDD and the absence of macular xanthophyll pigments. CONCLUSION/UNASSIGNED:We propose that mutated MTTP within the retina may contribute to ABL retinopathy in addition to systemic deficiencies of fat-soluble vitamins. This concept is supported by a new mouse model with RPE-specific MTTP deficiency and a retinal degeneration phenotype. The observed range of human pathology, including angioid streaks, underscores the need for continued monitoring in adulthood, especially for CNV, a treatable condition.

PURPOSE/OBJECTIVE:Evaluate effectiveness and safety of a crosslinked hyaluronate (HA) canalicular filler (Lacrifill Canalicular Gel) compared to a commercially available hydrogel canalicular plug (Form Fit). SETTING/METHODS:5 sites in United States. DESIGN/METHODS:Prospective, multicenter, controlled, double-masked, randomized 2:1 (filler:plug). METHODS:Adults (≥22 years) with Schirmer test (with anesthesia) ≤10 mm/5 minutes, presence of corneal staining, ocular surface disease index (OSDI) of ≥23 with ≤3 responses of "not applicable," patent lacrimal drainage system, and bilateral best-corrected distance visual acuity of 20/40 or better. Filler or plugs were instilled bilaterally in the inferior canaliculi. Primary effectiveness endpoint was non-inferiority of the mean within subject change from baseline to Month 3 in Schirmer score for patients receiving filler compared to plugs. The key secondary effectiveness endpoint was non-inferiority of the proportion of patients with filler achieving improvement from baseline to Month 3 in OSDI by a minimal clinically important difference (MCID). Additional endpoints included the mean change from baseline to 3 and 6 months in tear meniscus height, OSDI, corneal staining, tear break-up time, and safety. RESULTS:157 patients were randomized; 99 patients with crosslinked HA filler and 52 patients with hydrogel plugs completed the study. Filler was non-inferior to plugs in the mean Schirmer score change from baseline and in the proportion of patients achieving a clinically important improvement in OSDI. CONCLUSIONS:Crosslinked HA filler is a safe, well-tolerated, and effective method to treat dry eye. Clinically and statistically significant improvements in signs and symptoms of dry eye were sustained through 6 months.

NOise Reduction with DIstribution Corrected (NORDIC) principal component analysis (PCA) has been shown to selectively suppress thermal noise and improve the temporal signal-to-noise ratio (tSNR) in human functional magnetic resonance imaging (fMRI). However, the feasibility to improve data quality for rodent fMRI using NORDIC PCA remains uncertain. NORDIC PCA may also be particularly beneficial for improving topological brain mapping, as conventional mapping requires precise spatiotemporal signals from large datasets (ideally ~1 hour acquisition) for individual representations. In this study, we evaluated the effects of NORDIC PCA compared with "Standard" processing in various rodent fMRI contexts that range from task-evoked optogenetic fMRI to resting-state fMRI. We also evaluated the effects of NORDIC PCA on human resting-state and retinotopic mapping fMRI via population receptive field (pRF) modeling. In rodent optogenetic fMRI, apart from doubling the tSNR, NORDIC PCA resulted in a larger number of activated voxels and a significant decrease in the variance of evoked brain responses without altering brain morphology. In rodent resting-state fMRI, we found that NORDIC PCA induced a nearly threefold increase in tSNR and preserved task-free relative cerebrovascular reactivity (rCVR) across cortical depth. NORDIC PCA further improved the detection of TGN020-induced aquaporin-4 inhibition on rCVR compared with Standard processing without NORDIC PCA. NORDIC PCA also increased the tSNR for both human resting-state and pRF fMRI, and for the latter also increased activation cluster sizes while retaining retinotopic organization. This suggests that NORDIC PCA preserves the spatiotemporal precision of fMRI signals needed for pRF analysis, and effectively captures small activity changes with high sensitivity. Taken together, these results broadly demonstrate the value of NORDIC PCA for the enhanced detection of neural dynamics across various rodent and human fMRI contexts. This can in turn play an important role in improving fMRI image quality and sensitivity for translational and preclinical neuroimaging research.

IMPORTANCE/UNASSIGNED:While combined treatment of anti-vascular endothelial growth factor (VEGF) injections plus panretinal photocoagulation (PRP) is a common approach for treating proliferative diabetic retinopathy (PDR) in the clinical practice setting, large randomized clinical trials typically use monotherapy. Subsequently, information is limited as to whether the order of treatment when combining PRP and anti-VEGF injections for PDR affects outcomes. OBJECTIVE/UNASSIGNED:To compare outcomes of patients with PDR treated with PRP and subsequent anti-VEGF injections with outcomes of matched patients treated with anti-VEGF injections and subsequent PRP. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This retrospective cohort study used data from January 2003 to January 2024 in the TriNetX aggregated electronic health records network, with data analysis performed in January 2024. Patients with PDR treated with PRP and anti-VEGF injections were eligible for inclusion. EXPOSURES/UNASSIGNED:Patients with new PDR diagnoses stratified by therapy with PRP and subsequent anti-VEGF injections or anti-VEGF injections and subsequent PRP. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was the need for pars plana vitrectomy (PPV), defined by Current Procedural Terminology codes 67040 or 67113. The secondary outcome included incidence of PPV, vitreous hemorrhage (VH), or tractional retinal detachment (TRD). Relative risk ratios, relative risk differences, and 95% CIs were all calculated for univariate comparison of the cohorts and the development of primary outcomes after matching. RESULTS/UNASSIGNED:Before propensity score matching (PSM), which controlled for baseline demographic characteristics and medical comorbidities, 2167 patients with PDR treated with PRP first and subsequent anti-VEGF injections and 1549 patients with PDR treated with anti-VEGF injections and subsequent PRP were included. Post-PSM, mean (SD) participant age was 63.0 (13.1) years in cohort 1 (PRP and subsequent anti-VEGF injection) and 63.0 (12.4) years in cohort 2 (anti-VEGF injection and subsequent PRP). Of 1377 total participants in each cohort, 641 patients (46.6%) and 663 patients (48.1%) in cohorts 1 and 2 were female, respectively. Treatment with PRP first and subsequent anti-VEGF injection was associated with higher rates of PPV at 5 years compared with patients treated with anti-VEGF injection and subsequent PRP (relative risk [RR], 1.88; 95% CI, 1.55-2.27; risk difference [RD], 8.93%; 95% CI, 6.31%-11.55%; P < .001), with similar associations at 6 months, 1 year, and 3 years. Treatment with PRP and subsequent anti-VEGF injection was associated with higher rates of VH at 5 years (RR, 1.40; 95% CI, 1.09-1.80; RD, 6.47%; 95% CI, 1.66%-11.29%; P < .001) and TRD at 5 years (RR, 1.85; 95% CI, 1.35-2.53; RD, 4.31%; 95% CI, 2.10%-6.52%; P < .001), with similar findings at 6 months, 1 year, and 3 years compared with patients treated with anti-VEGF injection and subsequent PRP. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this retrospective cohort study, findings suggest that patients with PDR treated with PRP first then subsequent anti-VEGF injection are more likely to undergo PPV for VH and TRD compared with matched patients treated with anti-VEGF agents first, then PRP. These findings support the need for further investigations to determine if the order of PRP and anti-VEGF injections should be considered when treating patients with PDR.

OBJECTIVES/UNASSIGNED:Accelerating demand for patient messaging has impacted the practice of many providers. Messages are not recommended for urgent medical issues, but some do require rapid attention. This presents an opportunity for artificial intelligence (AI) methods to prioritize review of messages. Our study aimed to highlight some patient portal messages for prioritized review using a custom AI system integrated into the electronic health record (EHR). MATERIALS AND METHODS/UNASSIGNED:We developed a Bidirectional Encoder Representations from Transformers (BERT)-based large language model using 40 132 patient-sent messages to identify patterns involving high acuity topics that warrant an immediate callback. The model was then implemented into 2 shared pools of patient messages managed by dozens of registered nurses. A primary outcome, such as the time before messages were read, was evaluated with a difference-in-difference methodology. RESULTS/UNASSIGNED: = 396 466), an improvement exceeding the trend was observed in the time high-scoring messages sit unread (21 minutes, 63 vs 42 for messages sent outside business hours). DISCUSSION/UNASSIGNED:Our work shows great promise in improving care when AI is aligned with human workflow. Future work involves audience expansion, aiding users with suggested actions, and drafting responses. CONCLUSION/UNASSIGNED:Many patients utilize patient portal messages, and while most messages are routine, a small fraction describe alarming symptoms. Our AI-based workflow shortens the turnaround time to get a trained clinician to review these messages to provide safer, higher-quality care.