Faculty Bibliography

PURPOSE/OBJECTIVE:To examine the effects of glucagon-like peptide-1 receptor (GLP-1) agonists compared to SGLT-2 inhibitors on diabetic retinopathy. DESIGN/METHODS:Retrospective clinical cohort study using TriNetX, a federated electronic health records network comprising multiple healthcare organizations. METHODS:Patients with an International Classification of Diseases, Tenth Revision (ICD-10) code of nonproliferative diabetic retinopathy (PDR) and monotherapy treatment, excluding insulin, with GLP-1 agonists or SGLT-2 inhibitors. Patients with a history of PDR prior to initiation of treatment were excluded. The rate of progression to PDR and rate of development of diabetic macular edema (DME) were compared between patients on GLP-1 agonists compared to those on SGLT-2 inhibitors. The groups were propensity score matched for age, gender, ethnicity, race, type of diabetes, and severity of PDR. Main outcomes included rate and relative risk (RR) of progression to PDR and risk of DME in the GLP-1 agonist group versus the SGLT-2 inhibitor group. RESULTS:A total of 6481 patients were identified in the GLP-1 cohort and the SGLT-2 inhibitor cohort after propensity score matching. At 1 and 3 years after initiation of therapy, a higher rate of progression of PDR was noted (RR: 1.26, CI 1.04-1.51, P = .017 at 1 year, RR: 1.284, CI 1.1-1.499, P = .002 at 3 years) in the GLP-1 agonist cohort compared to the SGLT-2 inhibitor cohort. There was a higher rate of DME noted at 3 months (RR: 1.192, CI 1.059-1.276, P = .002), 6 months (RR: 1.22, CI 1.13-1.32, P < .001), 1 year (RR: 1.24, CI 1.15-1.33, P < .001), and at 3 years (RR: 1.29, CI 1.21-1.38, P < .001) in the GLP-1 agonist cohort compared to the SGLT-2 inhibitor cohort. CONCLUSIONS:A higher rate of progression of PDR and risk of new-onset DME was observed in patients on monotherapy with GLP-1 agonists compared to those on SGLT-2 inhibitors. It is important for clinicians to be aware of these potential effects and to consider the current retinopathy status when initiating treatment with newer hypoglycemic agents to ensure these patients are appropriately monitored for developing potential vision-threatening complications.

PURPOSE/UNASSIGNED:Prior evidence suggests racial disparities in the utilization of visual field testing (VFT) for the diagnosis and monitoring of glaucoma. In this study, we considered the effect of baseline glaucoma severity and socioeconomic disadvantage along with other potential confounders such as test reliability, ancillary tests, and glaucoma surgeries on racial disparity in the frequency of VFT. METHODS/UNASSIGNED:The records of all subjects with a diagnosis of glaucoma who received VFT at an academic, tertiary care facility from January 2018 to December 2021 were accessed. Analysis was performed to compare VFT frequency, the total number of office visits (DoS), and the ratio of VFT frequency to DoS (VFT/DoS) across self-reported races while controlling for sex, age, socioeconomic disadvantage (Area Deprivation Index), VF reliability indicators and baseline mean deviation, optical coherence tomography frequency, and glaucoma surgeries. RESULTS/UNASSIGNED:Among the 2654 subjects (1515 White, 782 Black, and 357 Asian) included in this study, Black subjects had the worst socioeconomic status and disease severity at baseline. They also experienced a 3% lower VFT/DoS ratio compared to White subjects (P = 0.031). Asian subjects had a 5% lower VFT/DoS ratio compared to White subjects (P = 0.015). DISCUSSION/UNASSIGNED:We identified racial disparity in performing VFT in subjects with glaucoma even when multiple confounders were considered. Further investigation is necessary to identify other race-associated factors to work toward reducing racial disparities in VFT. TRANSLATIONAL RELEVANCE/UNASSIGNED:Black and Asian subjects with glaucoma receive fewer VFT per visit compared to White subjects even when considering socioeconomic disadvantage and disease severity.

PRCIS/CONCLUSIONS:Residence in a middle-class neighborhood correlated with lower follow-up compared to residence in more affluent neighborhoods. The most common explanations for not following up were the process of making an appointment and lack of symptoms. PURPOSE/OBJECTIVE:To explore which individual and neighborhood-level factors influence follow-up as recommended after positive ophthalmic and primary care screening in a vulnerable population using novel methodologies. PARTICIPANTS/METHODS:and Methods: From 2017 to 2018, 957 participants were screened for ophthalmic disease and cardiovascular risk factors as part of the Real-Time Mobile Teleophthalmology study. Individuals who screened positive for either ophthalmic or cardiovascular risk factors were contacted to determine whether or not they followed up with a healthcare provider. Data from the Social Vulnerability Index, a novel virtual auditing system, and personal demographics were collected for each participant. A multivariate logistic regression was performed to determine which factors significantly differed between participants who followed up and those who did not. RESULTS:As a whole, the study population was more socioeconomically vulnerable than the national average (mean summary Social Vulnerability Index score=0.81). Participants whose neighborhoods fell in the middle of the national per capita income distribution had lower likelihood of follow-up compared to those who resided in the most affluent neighborhoods (relative risk ratio=0.21, P-value<0.01). Participants cited the complicated process of making an eye care appointment and lack of symptoms as the most common reasons for not following up as instructed within four months. CONCLUSIONS:Residence in a middle-class neighborhood, difficulty accessing eye care appointments, and low health literacy may influence follow up among vulnerable populations.

PURPOSE/OBJECTIVE:To describe the clinical characteristics, multimodal imaging features, and anatomic basis of a distinctive pattern of deep retinal hemorrhages located in the central fovea, a presentation referred to as "central bouquet hemorrhage" (CBH). METHODS:Retrospective, observational, multicenter case series of eyes with CBH. Multimodal imaging features were reviewed and analyzed. RESULTS:Ten eyes from 10 patients (4 women and 6 men), with a mean age of 55.6±21.7 years (range 25-84 years) were included. Underlying etiologies were neovascular age-related macular degeneration (40%), lacquer cracks in pathological myopia (30%), macular telangiectasia type 2 (10%), proliferative diabetic retinopathy (10%), and ocular trauma associated with angioid streaks (10%). On ophthalmoscopy, all eyes with CBH displayed a deep retinal hemorrhage with round margins in the central fovea and associated with petaloid hemorrhages radiating in the surrounding Henle fiber layer (HFL). Cross-sectional optical coherence tomography (OCT) showed a well-delineated round hyperreflective lesion involving the central foveal HFL/outer nuclear layer (ONL) in all cases. Accompanying hyperreflective hemorrhages tracking along the obliquely oriented HFL were present in all eyes. Resolution occurred in all patients, either spontaneously (30%) or after treatment with intravitreal anti-vascular endothelial growth factor injections (70%), and was associated with partial visual acuity improvement (from 20/113 to 20/36). CONCLUSION/CONCLUSIONS:"Central bouquet hemorrhage" is a novel descriptive term describing a characteristic round pattern of intraretinal blood in the fovea associated with HFL hemorrhage and encountered in a spectrum of macular disease.

A feature issue is being presented by a team of guest editors containing papers based on contributed submissions including studies presented at Optics and the Brain, held April 24-27, 2023 as part of Optica Biophotonics Congress: Optics in the Life Sciences, in Vancouver, Canada.

Blood flow index (BFI) is an optically accessible parameter, with unit distance-squared-over-time, that is widely used as a proxy for tissue perfusion. BFI is defined as the dynamic scattering probability (i.e. the ratio of dynamic to overall reduced scattering coefficients) times an effective Brownian diffusion coefficient that describes red blood cell (RBC) motion. Here, using a wavelength division multiplexed, time-of-flight- (TOF) - resolved iNIRS system, we obtain TOF-resolved field autocorrelations at 773 nm and 855 nm via the same source and collector. We measure the human forearm, comprising biological tissues with mixed static and dynamic scattering, as well as a purely dynamic scattering phantom. Our primary finding is that forearm BFI increases from 773 nm to 855 nm, though the magnitude of this increase varies across subjects (23% ± 19% for N = 3). However, BFI is wavelength-independent in the purely dynamic scattering phantom. From these data, we infer that the wavelength-dependence of BFI arises from the wavelength-dependence of the dynamic scattering probability. This inference is further supported by RBC scattering literature. Our secondary finding is that the higher-order cumulant terms of the mean squared displacement (MSD) of RBCs are significant, but decrease with wavelength. Thus, laser speckle and related modalities should exercise caution when interpreting field autocorrelations.

SIGNIFICANCE/UNASSIGNED:Pulsed infrared neural stimulation (INS, 1875 nm) is an emerging neurostimulation technology that delivers focal pulsed heat to activate functionally specific mesoscale networks and holds promise for clinical application. However, little is known about its effect on excitatory and inhibitory cell types in cerebral cortex. AIM/UNASSIGNED:Estimates of summed population neuronal response time courses provide a potential basis for neural and hemodynamic signals described in other studies. APPROACH/UNASSIGNED:Using two-photon calcium imaging in mouse somatosensory cortex, we have examined the effect of INS pulse train application on hSyn neurons and mDlx neurons tagged with GCaMP6s. RESULTS/UNASSIGNED:We find that, in anesthetized mice, each INS pulse train reliably induces robust response in hSyn neurons exhibiting positive going responses. Surprisingly, mDlx neurons exhibit negative going responses. Quantification using the index of correlation illustrates responses are reproducible, intensity-dependent, and focal. Also, a contralateral activation is observed when INS applied. CONCLUSIONS/UNASSIGNED:In sum, the population of neurons stimulated by INS includes both hSyn and mDlx neurons; within a range of stimulation intensities, this leads to overall excitation in the stimulated population, leading to the previously observed activations at distant post-synaptic sites.

OBJECTIVES/OBJECTIVE:To evaluate patterns and determinants of longitudinal growth among children requiring complex biventricular repair for congenital heart disease, as well as to assess for associations of growth with early feeding modality, comorbidities, postoperative complications, and socioeconomic characteristics. STUDY DESIGN/METHODS:A single-institution retrospective cohort study was performed in children born February 1999 to March 2009 with complex congenital heart disease who underwent biventricular repair before age 4 years, defined by Risk Adjustment in Congenital Heart Surgery-1 category 3-5. Clinical characteristics, height, weight, and body mass index (BMI) from ages 2-12 years were collected by chart review. Neighborhood-level socioeconomic data were identified using a geographic information system approach. The adjusted association of covariates with growth outcomes was estimated using multivariable linear regression models using generalized estimating equations. RESULTS:Compared with population growth curves, the cohort (n = 150) trended toward early decrease in age-adjusted weight and height. Early tube feeding was significantly associated with decreased BMI before adolescence (-0.539; 95% CI -1.02, -0.054; P = .029). In addition, other clinical and perioperative characteristics had significant associations with growth, including low birth weight, preoperative tube feeds, need for multiple bypass runs, and diagnosis of feeding disorder. CONCLUSIONS:Early childhood growth in children with complex biventricular repair may be impaired. Early tube feeding was associated with decreased BMI over the course of early childhood, which may indicate a need for continued close nutrition follow-up and support even beyond the duration of tube feeds.

Striatal dopamine axons co-release dopamine and gamma-aminobutyric acid (GABA), using GABA provided by uptake via GABA transporter-1 (GAT1). Functions of GABA co-release are poorly understood. We asked whether co-released GABA autoinhibits dopamine release via axonal GABA type A receptors (GABA_ARs), complementing established inhibition by dopamine acting at axonal D2 autoreceptors. We show that dopamine axons express α3-GABA_AR subunits in mouse striatum. Enhanced dopamine release evoked by single-pulse optical stimulation in striatal slices with GABA_AR antagonism confirms that an endogenous GABA tone limits dopamine release. Strikingly, an additional inhibitory component is seen when multiple pulses are used to mimic phasic axonal activity, revealing the role of GABA_AR-mediated autoinhibition of dopamine release. This autoregulation is lost in conditional GAT1-knockout mice lacking GABA co-release. Given the faster kinetics of ionotropic GABA_ARs than G-protein-coupled D2 autoreceptors, our data reveal a mechanism whereby co-released GABA acts as a first responder to dampen phasic-to-tonic dopamine signaling.

The availability of big data can transform the studies in biomedical research to generate greater scientific insights if expert labeling is available to facilitate supervised learning. However, data annotation can be labor-intensive and cost-prohibitive if pixel-level precision is required. Weakly supervised semantic segmentation (WSSS) with image-level labeling has emerged as a promising solution in medical imaging. However, most existing WSSS methods in the medical domain are designed for single-class segmentation per image, overlooking the complexities arising from the co-existence of multiple classes in a single image. Additionally, the multi-class WSSS methods from the natural image domain cannot produce comparable accuracy for medical images, given the challenge of substantial variation in lesion scales and occurrences. To address this issue, we propose a novel anomaly-guided mechanism (AGM) for multi-class segmentation in a single image on retinal optical coherence tomography (OCT) using only image-level labels. AGM leverages the anomaly detection and self-attention approach to integrate weak abnormal signals with global contextual information into the training process. Furthermore, we include an iterative refinement stage to guide the model to focus more on the potential lesions while suppressing less relevant regions. We validate the performance of our model with two public datasets and one challenging private dataset. Experimental results show that our approach achieves a new state-of-the-art performance in WSSS for lesion segmentation on OCT images.