Faculty Bibliography

Measuring whole-brain distributed functional activity is an important unmet need in neuroscience, requiring high temporal resolution and cellular specificity across large volumes. Functional optoacoustic neuro-tomography (FONT) with genetically encoded calcium ion indicators is a promising approach towards this goal. However, it has not yet been applied in the near-infrared (NIR) range that provides deep penetration and low vascular background optimal for in vivo neuroimaging. Here, we study the noninvasive multimodal fluorescence and optoacoustic imaging performance of state-of-the-art NIR calcium ion indicator NIR-GECO2G in the mouse brain. We observe robust in vivo signals with widefield fluorescence, and for the first time, with FONT. We also show that in both modalities, the NIR-GECO2G signal improves more than twofold in the biliverdin-enriched Blvra

PURPOSE OF REVIEW/OBJECTIVE:Cardiovascular disease (CVD) is a leading cause of preventable morbidity and mortality globally, and retinal imaging modalities (old and new) are being explored as noninvasive tools to predict latent atherosclerosis and cardiovascular disease. This review focuses on the emerging promise of fundoscopy, optical coherence tomography (OCT), and optical coherence tomography angiography (OCTA) in CVD prognostication. RECENT FINDINGS/RESULTS:High-quality studies have established the utility of vessel-based parameters and discrete conditions diagnosable via fundoscopy in subclinical atherosclerosis detection or CVD prediction. Recent research shows OCT measurements of different retinal layers and specific imaging findings (such as retinal ischemic perivascular lesions) are widely accessible and objective biomarkers for incipient CVD and ensuing risk. Myriad OCTA metrics appear to reliably inform on current CVD burden and cardiovascular risk. Fundoscopy, OCT, and OCTA all have a growing body of literature supporting their utility as adjuncts in CVD prediction and risk stratification.

BACKGROUND:Acanthamoeba keratitis (AK) is the most challenging corneal infection to treat, with conventional therapies often proving ineffective. While photoactivated chromophore for keratitis-corneal cross-linking (PACK-CXL) with riboflavin/UV-A has shown success in treating bacterial and fungal keratitis, and PACK-CXL with rose bengal/green light has demonstrated promise in fungal keratitis, neither approach has been shown to effectively eradicate AK. This case study explores a novel combined same-session treatment approach using both riboflavin/UV-A and rose bengal/green light in a single procedure. CASE PRESENTATION/METHODS:) in a single setting. The procedure was repeated twice due to persistent signs of inflammation and infection. After three combined same-session PACK-CXL treatments, the patient's cornea converted to a quiescent scar, and symptoms of ocular pain, photophobia, epiphora, and blepharospasm resolved. Confocal microscopy revealed no detectable Acanthamoeba cysts. The patient currently awaits penetrating keratoplasty. CONCLUSIONS:The same-session combination of riboflavin/UV-A and rose bengal/green light PACK-CXL effectively treated a patient with confirmed AK that was resistant to conventional medical therapy, suggesting that using two chromophores in a single procedure may represent a future treatment alternative for AK.

PURPOSE/UNASSIGNED:The purpose of this study was to develop ground-truth histology about contributors to variable fundus autofluorescence (FAF) signal and thus inform patient selection for treating geographic atrophy (GA) in age-related macular degeneration (AMD). METHODS/UNASSIGNED:One woman with bilateral multifocal GA, foveal sparing, and thick choroids underwent 535 to 580 nm excitation FAF in 6 clinic visits (11 to 6 years before death). The left eye was preserved 5 hours after death. Eye-tracked ex vivo imaging aligned sub-micrometer epoxy resin sections (n = 140, 60 µm apart) with clinic data. Light microscopic morphology corresponding to FAF features assessed included drusen-driven atrophy, persistent hyperautofluorescence (hyperFAF) islands and peninsulas within atrophy, and hyperFAF and hypoautofluorescence (hypoFAF) inner junctional zone (IJZ) and outer junctional zone (OJZ) relative to descent of external limiting membrane (ELM). Atrophy growth rate was calculated. RESULTS/UNASSIGNED:HypoFAF atrophic spots appeared in association with drusen, and then expanded and coalesced. Over drusen (n = 45, all calcified), RPE was continuous and thin, photoreceptors were short or absent, and initially intact ELM descended where RPE was absent. In persistent hyperFAF within atrophy and in the OJZ, the RPE was continuous and dysmorphic, photoreceptors were present and short, and BLamD was thick. In the IJZ, mottled FAF corresponded to dissociated RPE atop persistent BLamD. Overall linear growth rate (0.198 mm/ year) typified multifocal GA. CONCLUSIONS/UNASSIGNED:FAF in GA is locally multifactorial, with photoreceptor shortening potentially promoting hyperFAF by increasing incoming excitation light available to RPE fluorophores. RPE dysmorphia may lead to either longer or shorter pathlength for excitation light. At both atrophy initiation and expansion Müller glia are major participants.

PURPOSE/UNASSIGNED:This study assessed objective performance, usability, and acceptance of artificial intelligence (AI) by people with vision impairment. The goal was to provide evidence-based data to enhance technology selection for people with vision loss (PVL) based on their loss and needs. METHODS/UNASSIGNED:Using a cross-sectional, counterbalanced, cross-over study involving 25 PVL, we compared performance using two smart glasses (OrCam and Envision Glasses) and two AI apps (Seeing AI and Google Lookout). We refer to these as assistive artificial intelligence implementations (AAIIs). Completion and timing were quantified for three task categories: text, text in columns, and searching and identifying. Usability was evaluated with the System Usability Scale (SUS). RESULTS/UNASSIGNED:The odds ratios (ORs) of being able to complete Text tasks were significantly higher when using AAIIs compared to the baseline. OR when performing "Searching and Identifying" tasks varied among AAIIs, with Seeing AI and Envision improving the performance of more tasks than Lookout or OrCam. Participants expressed high satisfaction with the AAIIs. CONCLUSIONS/UNASSIGNED:Despite the findings that performance on some tasks and when using some AAIIs did not result in a greater number of PVL being able to complete the tasks, there was overall high satisfaction, reflecting an acceptance of AI as an assistive technology and the promise of this developing technology. TRANSLATIONAL RELEVANCE/UNASSIGNED:This evidence-based performance data provide guidelines for clinicians when recommending an AAII to PVL.

PURPOSE/OBJECTIVE:To report the multimodal imaging features of hyperpigmented chorioretinal lesions originating from the retinal pigment epithelium (RPE) within punched-out lesions of punctate inner choroidopathy (PIC). METHODS:Retrospective case report. Multimodal imaging findings including fundus photography, optical coherence tomography (OCT), and OCT-angiography (OCTA) were analyzed. RESULTS:A 49-year-old female with myopic degeneration developed progressive lesions of PIC requiring immunosuppressive therapy with adalimumab. Within areas of punched-out chorioretinal atrophic lesions, the occurrence of hyperpigmented lesions were observed which enlarged and extended into the choroid over a multiyear follow-up. CONCLUSION/CONCLUSIONS:This case illustrates the development of pigmented choroidal lesions appearing to originate from the RPE through transdifferentiation following previous chorioretinal inflammatory lesions. The introduction of adalimumab treatment may have activated the cellular migration of the RPE. To the best of our knowledge, this is the first report of intrachoroidal RPE migration in PIC.

PURPOSE/OBJECTIVE:To characterize private equity (PE) acquisition of ophthalmology and optometry practices and compare procedural utilization before and after acquisition. METHODS:Ophthalmologists and optometrists in practices acquired from 2012 to 2016 were identified and characterized using an internet archive with an additional search in 2017 to characterize doctor turnover. United States Census Bureau and Internal Revenue Service Data were used to determine population health insurance and adjusted gross income (AGI). Healthcare Common Procedure Coding System codes were drawn from the Medicare database. RESULTS:Six platform companies acquired 36 practices between 2012 and 2016, including 518 optometrists and 136 ophthalmologists with a net doctor decrease of 3% and 7%, respectively (years 2016 to 2017). PE firm-owned practices were primarily located in metropolitan core areas with above-average AGI and insurance coverage. Diagnostic procedures, total encounters, cataract surgery, and yttrium aluminum garnet (YAG) capsulotomy volume increased per physician 1-year post-acquisition. In adjusted difference-in-difference comparisons, cataract surgery (13.3% relative increase, P<0.001) and YAG capsulotomy (35.6% relative increase, P<0.001) remained significant. PE practices demonstrated an increase in cataract surgery procedures (28,813/platform pre-acquisition to 33,930/platform post-acquisition, P=0.015). CONCLUSION/CONCLUSIONS:PE acquisitions of ophthalmology and optometry practices were centered in metropolitan core areas with above-average AGI and insurance coverage. PE acquisition led to less optometrists and ophthalmologists employed at the practice. Overall, they exhibited doctor turnover with a net doctor decrease. When compared to non-PE doctors, PE-acquired doctors demonstrated an increase in cataract surgery and YAG capsulotomy volume. Overall, cataract surgery volume increased among PE practices after acquisition.

OBJECTIVES/OBJECTIVE:To systematically review the safety and efficacy of nonbiological (NBAL) or biological artificial liver support systems (BAL) and whole-organ extracorporeal liver perfusion (W-ECLP) systems, in adults with acute liver failure (ALF) and acute-on-chronic liver failure (ACLF). DATA SOURCES/METHODS:Eligible NBAL/BAL studies from PubMed/Embase searches were randomized controlled trials (RCTs) in adult patients with ALF/ACLF, greater than or equal to ten patients per group, reporting outcomes related to survival, adverse events, transplantation rate, and hepatic encephalopathy, and published in English from January 2000 to July 2023. Separately, we searched for studies evaluating W-ECLP in adult patients with ALF or ACLF published between January1990 and July 2023. STUDY SELECTION AND DATA EXTRACTION/METHODS:Two researchers independently screened citations for eligibility and, of eligible studies, retrieved data related to study characteristics, patients and interventions, outcomes definition, and intervention effects. The Cochrane Risk of Bias 2 tool and Joanna Briggs Institute checklists were used to assess individual study risk of bias. Meta-analysis of mortality at 28-30 days post-support system initiation and frequency of at least one serious adverse event (SAE) generated pooled risk ratios (RRs), based on random (mortality) or fixed (SAE) effects models. DATA SYNTHESIS/RESULTS:Of 17 trials evaluating NBAL/BAL systems, 11 reported 28-30 days mortality and five reported frequency of at least one SAE. Overall, NBAL/BAL was not statistically associated with mortality at 28-30 days (RR, 0.85; 95% CI, 0.67-1.07; p = 0.169) or frequency of at least one SAE (RR, 1.15; 95% CI, 0.99-1.33; p = 0.059), compared with standard medical treatment. Subgroup results on ALF patients suggest possible benefit for mortality (RR, 0.67; 95% CI, 0.44-1.03; p = 0.069). From six reports of W-ECLP (12 patients), more than half (58%) of severe patients were bridged to transplantation and survived without transmission of porcine retroviruses. CONCLUSIONS:Despite no significant pooled effects of NBAL/BAL devices, the available evidence calls for further research and development of extracorporeal liver support systems, with larger RCTs and optimization of patient selection, perfusion durability, and treatment protocols.

SIGNIFICANCE/CONCLUSIONS:Optimal meibography utilization and interpretation are hindered due to poor lid presentation, blurry images, or image artifacts and the challenges of applying clinical grading scales. These results, using the largest image dataset analyzed to date, demonstrate development of algorithms that provide standardized, real-time inference that addresses all of these limitations. PURPOSE/OBJECTIVE:This study aimed to develop and validate an algorithmic pipeline to automate and standardize meibomian gland absence assessment and interpretation. METHODS:A total of 143,476 images were collected from sites across North America. Ophthalmologist and optometrist experts established ground-truth image quality and quantification (i.e., degree of gland absence). Annotated images were allocated into training, validation, and test sets. Convolutional neural networks within Google Cloud VertexAI trained three locally deployable or edge-based predictive models: image quality detection, over-flip detection, and gland absence detection. The algorithms were combined into an algorithmic pipeline onboard a LipiScan Dynamic Meibomian Imager to provide real-time clinical inference for new images. Performance metrics were generated for each algorithm in the pipeline onboard the LipiScan from naive image test sets. RESULTS:Individual model performance metrics included the following: weighted average precision (image quality detection: 0.81, over-flip detection: 0.88, gland absence detection: 0.84), weighted average recall (image quality detection: 0.80, over-flip detection: 0.87, gland absence detection: 0.80), weighted average F1 score (image quality detection: 0.80, over-flip detection: 0.87, gland absence detection: 0.81), overall accuracy (image quality detection: 0.80, over-flip detection: 0.87, gland absence detection: 0.80), Cohen κ (image quality detection: 0.60, over-flip detection: 0.62, and gland absence detection: 0.71), Kendall τb (image quality detection: 0.61, p<0.001, over-flip detection: 0.63, p<0.001, and gland absence detection: 0.67, p<001), and Matthews coefficient (image quality detection: 0.61, over-flip detection: 0.63, and gland absence detection: 0.62). Area under the precision-recall curve (image quality detection: 0.87 over-flip detection: 0.92, gland absence detection: 0.89) and area under the receiver operating characteristic curve (image quality detection: 0.88, over-flip detection: 0.91 gland absence detection: 0.93) were calculated across a common set of thresholds, ranging from 0 to 1. CONCLUSIONS:Comparison of predictions from each model to expert panel ground-truth demonstrated strong association and moderate to substantial agreement. The findings and performance metrics show that the pipeline of algorithms provides standardized, real-time inference/prediction of meibomian gland absence.

PURPOSE/OBJECTIVE:We developed human cornea organoids (HCOs) from induced pluripotent stem cells (iPSCs) where single-cell RNA-sequence (scRNA-seq) analysis suggested similarity with developing rather than mature human corneas. We performed immunohistology to determine the presence of corneal glycosaminoglycans as an assessment of maturity. We undertook a detailed comparison of the HCO scRNA-seq data with a recent scRNA-seq study of human fetal corneas at different stages to gauge the HCO's maturity. METHODS:We generated HCOs from a second iPSC line, NCRM-1, to assess the reproducibility of HCO development. We stained sections from both HCO lines with Alcian blue and picrosirius red to determine deposition of sulfated glycosaminoglycans and fibrillar collagens. We immunolocalized glycosaminoglycan biosynthetic enzymes and proteoglycan core proteins. The scRNA-seq data from IMR90.4 HCOs were compared to that of fetal corneas using MetaNeighbor analysis to assess the similarity of HCOs to different stages of human corneal development. RESULTS:The MetaNeighbor analysis suggests closer alignment of the IMR90.4 HCOs with 17-18 post-conception week fetal human corneas. HCOs from both iPSC lines deposit sulfated glycosaminoglycans and fibrillar collagens. Immunohistology showed chondroitin/dermatan sulfate (CS/DS) and keratan sulfate in the presumptive stromal and some epithelial layers. The NCRM-1-derived HCOs show increased CS/DS staining compared to the IMR90.4 derived HCOs. CONCLUSIONS:Both HCO lines show similar developmental patterns and timeline. The NCRM-1 HCO line may have more glycosaminoglycan deposition. Overall, the glycosaminoglycan deposition pattern is consistent with an immature tissue. Optimizations based on our current findings may yield more mature stromal cells and cornea-typical proteoglycans.