In Vivo Assessment of Retinal Phenotypes in Axenfeld-Rieger Syndrome.

Purpose: Axenfeld-Rieger syndrome (ARS) is characterized by ocular anomalies including posterior embryotoxon, iridocorneal adhesions, corectopia/iris hypoplasia, and developmental glaucoma. Although anterior segment defects and glaucoma contribute to decreased visual acuity, the role of potential posterior segment abnormalities has not been explored. We used high-resolution retinal imaging to test the hypothesis that individuals with ARS have posterior segment pathology. Methods: Three individuals with FOXC1-ARS and 10 with PITX2-ARS completed slit-lamp and fundus photography, optical coherence tomography (OCT), OCT angiography, and adaptive optics scanning light ophthalmoscopy (AOSLO). Quantitative metrics were compared to previously published values for individuals with normal vision. Results: All individuals demonstrated typical anterior segment phenotypes. Average ganglion cell and inner plexiform layer thickness was lower in PITX2-ARS, consistent with the glaucoma history in this group. A novel phenotype of foveal hypoplasia was noted in 40% of individuals with PITX2-ARS (but none with FOXC1-ARS). Moreover, the depth and volume of the foveal pit were significantly lower in PITX2-ARS compared to normal controls, even excluding individuals with foveal hypoplasia. Analysis of known foveal hypoplasia genes failed to identify an alternative explanation. Foveal cone density was decreased in one individual with foveal hypoplasia and normal in six without foveal hypoplasia. Two individuals (one from each group) demonstrated non-foveal retinal irregularities with regions of photoreceptor anomalies on OCT and AOSLO. Conclusions: These findings implicate PITX2 in the development of the posterior segment, particularly the fovea, in humans. The identified posterior segment phenotypes may contribute to visual acuity deficits in individuals with PITX2-ARS.

Longitudinal Assessment of OCT-Based Measures of Foveal Cone Structure in Achromatopsia.

Purpose: Achromatopsia (ACHM) is an autosomal recessive retinal disease associated with reduced or absent cone function. There is debate regarding the extent to which cone structure shows progressive degeneration in patients with ACHM. Here, we used optical coherence tomography (OCT) images to evaluate outer nuclear layer (ONL) thickness and ellipsoid zone (EZ) integrity over time in individuals with ACHM. Methods: Sixty-three individuals with genetically confirmed ACHM with follow-up ranging from about 6 months to 10 years were imaged using either Bioptigen or Cirrus OCT. Foveal cone structure was evaluated by assessing EZ integrity and ONL thickness. Results: A total of 470 OCT images were graded, 243 OD and 227 OS. The baseline distribution of EZ grades was highly symmetrical between eyes (P = 0.99) and there was no significant interocular difference in baseline ONL thickness (P = 0.12). The EZ grade remained unchanged over the follow-up period for 60 of 63 individuals. Foveal ONL thickness showed a clinically significant change in only 1 of the 61 individuals analyzed, although detailed adaptive optics imaging revealed no changes in cone density in this individual. Conclusions: ACHM appears to be a generally stable condition, at least over the follow-up period assessed here. As cones are the cellular targets for emerging gene therapies, stable EZ and ONL thickness demonstrate therapeutic potential for ACHM, although other aspects of the visual system need to be considered when determining the best timing for therapeutic intervention.

Applications of Adaptive Optics Imaging for Studying Conditions Affecting the Fovea.

The fovea is a highly specialized region of the central retina, defined by an absence of inner retinal layers and the accompanying vasculature, an increased density of cone photoreceptors, a near absence of rod photoreceptors, and unique private-line photoreceptor to midget ganglion cell circuitry. These anatomical specializations support high-acuity vision in humans. While direct study of foveal shape and size is routinely performed using optical coherence tomography, examination of the other anatomical specializations of the fovea has only recently become possible using an array of adaptive optics (AO)-based imaging tools. These devices correct for the eye's monochromatic aberrations and permit cellular-resolution imaging of the living retina. In this article, we review the application of AO-based imaging techniques to conditions affecting the fovea, with an emphasis on how imaging has advanced our understanding of pathophysiology.

From Admission to Discharge - A Total Friction Burn Review from a Single Institution.

While most friction burns are adequately managed in an outpatient setting, many may require hospital admission, operative excision, and extended care. To this day, there is a wide variance in friction burn management. Our goal is to review the etiology, management, and outcomes of such burns warranting hospitalization. We conducted a retrospective review of all friction burns admitted to a single, American Burn Association verified burn center from January 1, 2016 to December 31, 2020. 28 (34%) patients required surgery for their friction burns and 15 (18%) ultimately required a split-thickness skin graft. The mean number of operations was 2.4 (95% CI 1.6-3.1). Overall, the operative group was younger (29.9 vs 38.3 years, p=0.026), more likely to have a concomitant traumatic brain injury (25% vs 7%, p=0.027) and had a longer hospital length of stay (17.5 vs 3.9 days, p<0.001). Both groups had a similar overall TBSA (8.5% vs 10.0%, p=0.35), but the operative group had larger surface area comprised of 3rd degree burns (3.05% vs 0.2%, p<0.001). Overall, friction burns resulting in hospital admission are associated with high-energy traumatic mechanisms and concomitant injuries. Patients who need operative intervention of their burns typically require multiple procedures often culminating in a split-thickness skin graft. While non-operative management of friction burns with topical agents has been found to be successful, patients with higher injury severity scores should be monitored very closely as they may require surgical excision.

Quantitative Foveal Structural Metrics as Predictors of Visual Acuity in Human Albinism.

Purpose: To assess the degree to which quantitative foveal structural measurements account for variation in best-corrected visual acuity (BCVA) in human albinism. Methods: BCVA was measured and spectral domain optical coherence tomography (SD-OCT) images were acquired for 74 individuals with albinism. Categorical foveal hypoplasia grades were assessed using the Leicester Grading System for Foveal Hypoplasia. Foveal anatomical specialization (foveal versus parafoveal value) was quantified for inner retinal layer (IRL) thickness, outer segment (OS) length, and outer nuclear layer (ONL) thickness. These metrics, participant sex, and age were used to build a multiple linear regression of BCVA. This combined linear model's predictive properties were compared to those of categorical foveal hypoplasia grading. Results: The cohort included three participants with type 1a foveal hypoplasia, 23 participants with type 1b, 33 with type 2, ten with type 3, and five with type 4. BCVA ranged from 0.08 to 1.00 logMAR (mean ± SD: 0.53 ± 0.21). IRL ratio, OS ratio, and ONL ratio were measured in all participants and decreased with increasing severity of foveal hypoplasia. The best-fit combined linear model included all three quantitative metrics and participant age expressed as a binary variable (divided into 0-18 years and 19 years or older; adjusted R2 = 0.500). This model predicted BCVA more accurately than a categorical foveal hypoplasia model (adjusted R2 = 0.352). Conclusions: A quantitative model of foveal specialization accounts for more variance in BCVA in albinism than categorical foveal hypoplasia grading. Other factors, such as optical aberrations and eye movements, may account for the remaining unexplained variance.

Human iPSC-derived photoreceptor transplantation in the cone dominant 13-lined ground squirrel.

Several retinal degenerations affect the human central retina, which is primarily comprised of cones and is essential for high acuity and color vision. Transplanting cone photoreceptors is a promising strategy to replace degenerated cones in this region. Although this approach has been investigated in a handful of animal models, commonly used rodent models lack a cone-rich region and larger models can be expensive and inaccessible, impeding the translation of therapies. Here, we transplanted dissociated GFP-expressing photoreceptors from retinal organoids differentiated from human induced pluripotent stem cells into the subretinal space of damaged and undamaged cone-dominant 13-lined ground squirrel eyes. Transplanted cell survival was documented via noninvasive high-resolution imaging and immunohistochemistry to confirm the presence of human donor photoreceptors for up to 4 months posttransplantation. These results demonstrate the utility of a cone-dominant rodent model for advancing the clinical translation of cell replacement therapies.

Retinal and Choroidal Thickness in an Indigenous Population from Ghana: Comparison with Individuals with European or African Ancestry.

Purpose: To evaluate the thickness of the macular retina and central choroid in an indigenous population from Ghana, Africa and to compare them with those measured among individuals with European or African ancestry. Design: Cross-sectional study, systematic review, and meta-analyses. Participants: Forty-two healthy Ghanaians, 37 healthy individuals with European ancestry, and an additional 1427 healthy subjects with African ancestry from previously published studies. Methods: Macular retinal thickness in the fovea, parafovea, and perifovea and central choroidal thickness were extracted from OCT volume scans. Associations with ethnicity, age, and sex were assessed using mixed-effect regression models. Monte Carlo simulations were performed to determine the sensitivity of significant associations to additional potential confounders. Pooled estimates of retinal thickness among other groups with African ancestry were generated through systematic review and meta-analyses. Main Outcome Measures: Macular retinal thickness and central choroidal thickness and their association with ethnicity, age, and sex. Results: When adjusted for age and sex, the macular retina and central choroid of Ghanaians are significantly thinner as compared with subjects with European ancestry (P < 0.001). A reduction in retinal and choroidal thickness is observed with age, although this effect is independent of ethnicity. Meta-analyses indicate that retinal thickness among Ghanaians differs markedly from that of African Americans and other previously reported indigenous African populations. Conclusions: The thickness of the retina among Ghanaians differs not only from those measured among individuals with European ancestry, but also from those obtained from African Americans. Normative retinal and choroidal parameters determined among individuals with African or European ancestry may not be sufficient to describe indigenous African populations. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Peak Cone Density Predicted from Outer Segment Length Measured on Optical Coherence Tomography.

PURPOSE: To compare peak cone density predicted from outer segment length measured on optical coherence tomography with direct measures of peak cone density from adaptive optics scanning light ophthalmoscopy. METHODS: Data from 42 healthy participants with direct peak cone density measures and optical coherence tomography line scans available were used in this study. Longitudinal reflectivity profiles were analyzed using two methods of identifying the boundaries of the ellipsoid and interdigitation zones to estimate maximum outer segment length: peak-to-peak and the slope method. These maximum outer segment length values were then used to predict peak cone density using a previously described geometrical model. A comparison between predicted and direct peak cone density measures was then performed. RESULTS: The mean bias between observers for estimating maximum outer segment length across methods was less than 2 µm. Cone density predicted from the peak-to-peak method against direct cone density measures showed a mean bias of 6,812 cones/mm2 with 50% of participants displaying a 10% difference or less between predicted and direct cone density values. Cone density derived from the slope method showed a mean bias of -17,929 cones/mm2 relative to direct cone density measures, with only 41% of participants demonstrating less than a 10% difference between direct and predicted cone density values. CONCLUSION: Predicted foveal cone density derived from peak-to-peak outer segment length measurements using commercial optical coherence tomography show modest agreement with direct measures of peak cone density from adaptive optics scanning light ophthalmoscopy. The methods used here are imperfect predictors of cone density, however, further exploration of this relationship could reveal a clinically relevant marker of cone structure.

The Pearls and Pitfalls of a Migrating Bullet Embolus.

Venous bullet embolism is an exceedingly rare trauma diagnosis that presents diagnostic and therapeutic challenges. We present the case of a 32-year-old man who sustained multiple gunshot wounds with a venous bullet embolism to the right pulmonary artery. Imaging at first demonstrated a bullet lodged within the right lower lobe. The patient underwent multiple bronchoscopies and ultimately was found to have a bullet embolus in the right pulmonary artery. Repeat endovascular attempts failed at removal, and during a right thoracotomy, the bullet migrated to the left pulmonary artery. Coil embolization of the left lower lobe pulmonary artery was performed, and the patient was found to be asymptomatic at the 1-year follow-up. To our knowledge, this is the first case to demonstrate coil embolization of the pulmonary artery as a method of endovascular treatment for a venous bullet embolus. We present this case report to emphasize the difficulty in diagnosis, localization, and management of a migratory bullet within the pulmonary circulation.

Assessing the Sensitivity of OCT-A Retinal Vasculature Metrics.

Purpose: The purpose of this study was to examine the sensitivity of quantitative metrics of the retinal vasculature derived from optical coherence tomography angiography (OCT-A) images. Methods: Full retinal vascular slab OCT-A images were obtained from 94 healthy participants. Capillary loss, at 1% increments up to 50%, was simulated by randomly removing capillary segments (1000 iterations of randomized loss for each participant at each percent loss). Thirteen quantitative metrics were calculated for each image: foveal avascular zone (FAZ) area, vessel density, vessel complexity index (VCI), vessel perimeter index (VPI), fractal dimension (FD), and parafoveal intercapillary area (PICA) measurements with and without the FAZ (mean PICA, summed PICA, PICA regularity, and PICA standard deviation [PICA SD]). The sensitivity of each metric was calculated as the percent loss at which 80% of the iterations for a participant fell outside of two standard deviations from the sample's normative mean. Results: The most used OCT-A metrics, FAZ area and vessel density, were not significantly different from normative values until 27.69% and 16.00% capillary loss, respectively. Across the remaining metrics, metric sensitivity ranged from 6.37% (PICA SD without FAZ) to 39.78% (Summed PICA without FAZ). Conclusions: The sensitivity of vasculature metrics for detecting random capillary loss varies substantially. Further efforts simulating different patterns of capillary loss are needed for comparison. Additionally, mapping the repeatability of metrics over time in a normal population is needed to further define metric sensitivity. Translational Relevance: Quantitative metrics vary in their ability to detect vascular abnormalities in OCT-A images. Metric choice in screening studies will need to balance expected capillary abnormalities and the quality of the OCT-A images being used.

The Shape of the Foveal Avascular Zone: When a Circle Isn't Round.

Translational Relevance: Quantitative assessment of OCT-A images includes evaluating circularity and roundness of the FAZ. Inconsistent or inaccurate mathematical definitions of these metrics impacts their utility as biomarkers and impairs the ability to combine and compare results across studies.

Detection of a pair density wave state in UTe2.

Spin-triplet topological superconductors should exhibit many unprecedented electronic properties, including fractionalized electronic states relevant to quantum information processing. Although UTe2 may embody such bulk topological superconductivity1-11, its superconductive order parameter Δ(k) remains unknown12. Many diverse forms for Δ(k) are physically possible12 in such heavy fermion materials13. Moreover, intertwined14,15 density waves of spin (SDW), charge (CDW) and pair (PDW) may interpose, with the latter exhibiting spatially modulating14,15 superconductive order parameter Δ(r), electron-pair density16-19 and pairing energy gap17,20-23. Hence, the newly discovered CDW state24 in UTe2 motivates the prospect that a PDW state may exist in this material24,25. To search for it, we visualize the pairing energy gap with µeV-scale energy resolution using superconductive scanning tunnelling microscopy (STM) tips26-31. We detect three PDWs, each with peak-to-peak gap modulations of around 10 µeV and at incommensurate wavevectors Pi=1,2,3 that are indistinguishable from the wavevectors Qi=1,2,3 of the prevenient24 CDW. Concurrent visualization of the UTe2 superconductive PDWs and the non-superconductive CDWs shows that every Pi:Qi pair exhibits a relative spatial phase δϕ ≈ π. From these observations, and given UTe2 as a spin-triplet superconductor12, this PDW state should be a spin-triplet PDW24,25. Although such states do exist32 in superfluid 3He, for superconductors, they are unprecedented.

Change in Cone Structure Over 24 Months in USH2A-Related Retinal Degeneration.

PURPOSE: To describe cone structure changes using adaptive optics scanning laser ophthalmoscopy (AOSLO) in the Rate of Progression of USH2A-related Retinal Degeneration (RUSH2A) study. DESIGN: Multicenter, longitudinal natural history study. METHODS: AOSLO images were acquired at 4 centers, twice at baseline and annually for 24 months in this natural history study. For each eye, at least 10 regions of interest (ROIs) with ≥50 contiguous cones were analyzed by masked, independent graders. Cone spacing Z-scores, standard deviations from the normal mean at the measured location, were compared between graders and tests at baseline. The association of cone spacing with clinical characteristics was assessed using linear mixed effects regression models weighted by image quality score. Annual rates of change were calculated based on differences between visits. RESULTS: Fourteen eyes of 14 participants were imaged, with 192 ROIs selected at baseline. There was variability among graders, which was greater in images with lower image quality score (P < .001). Cone spacing was significantly correlated with eccentricity, quality score, and disease duration (P < .02). On average, the cone spacing Z-score increased 0.14 annually (about 9%, P < .001). We observed no significant differences in rate of change between disease type (Usher syndrome or retinitis pigmentosa), imaging site, or grader. CONCLUSIONS: Using current methods, the analysis of quantitative measures of cone structure showed some challenges, yet showed promise that AOSLO images can be used to characterize progressive change over 24 months. Additional multicenter studies using AOSLO are needed to advance cone mosaic metrics as sensitive outcome measures for clinical trials. NOTE: Publication of this article is sponsored by the American Ophthalmological Society.

Extracting spacing-derived estimates of rod density in healthy retinae.

Quantification of the rod photoreceptor mosaic using adaptive optics scanning light ophthalmoscopy (AOSLO) remains challenging. Here we demonstrate a method for deriving estimates of rod density and rod:cone ratio based on measures of rod spacing, cone numerosity, and cone inner segment area. Twenty-two AOSLO images with complete rod visualization were used to validate this spacing-derived method for estimating density. The method was then used to estimate rod metrics in an additional 105 images without complete rod visualization. The spacing-derived rod mosaic metrics were comparable to published data from histology. This method could be leveraged to develop large normative databases of rod mosaic metrics, though limitations persist with intergrader variability in assessing cone area and numerosity.

Cone Structure and Function in RPGR- and USH2A-Associated Retinal Degeneration.

PURPOSE: To compare cone structure and function between RPGR- and USH2A-associated retinal degeneration. DESIGN: Retrospective, observational, cross-sectional study. METHODS: This multicenter study included 13 eyes (9 participants) with RPGR-related X-linked retinitis pigmentosa (RPGR), 15 eyes (10 participants) with USH2A-related Usher syndrome type 2 (USH2), 16 eyes (9 participants) with USH2A-related autosomal recessive retinitis pigmentosa (ARRP), and 7 normal eyes (6 participants). Structural measures included cone spacing and density from adaptive optics scanning laser ophthalmoscopy and photoreceptor inner segment (IS), outer segment (OS), and outer nuclear layer (ONL) thickness from optical coherence tomography (OCT) images. OCT angiography images were used to study choriocapillaris flow deficit percent (CCFD). Cone function was assessed by fundus-guided microperimetry. Measures were compared at designated regions using analysis of variance with pairwise comparisons among disease groups, adjusted for disease duration and eccentricity. RESULTS: OCT segmentation revealed shorter OS and IS, with reduced ONL thickness in RPGR compared to normal (OS: P < .001, IS: P = .001, ONL: P = .005), USH2 (OS: P = .01, IS: P = .03, ONL: P = .03), or ARRP (OS: P = .001, ONL: P = .03). Increased cone spacing was observed in both RPGR (P = .03) and USH2 compared with normal (P = .048). The mean CCFD in RPGR was greater than in USH2 (P = .02). Microperimetry demonstrated below-normal regional sensitivity in RPGR (P = .004), USH2 (P = .02), and ARRP (P = .009), without significant intergroup differences. CONCLUSIONS: Outer retinal structure and choriocapillaris perfusion were more abnormal in RPGR- than USH2A-related retinal degenerations, whereas there were no significant differences in below-normal regional sensitivity between each rod-cone degeneration associated with variants in these 2 genes expressed at the photoreceptor-connecting cilium.

Temperature Profiles of Sunlight-Exposed Surfaces in a Desert Climate: Determining the Risk for Pavement Burns.

Plentiful sunlight and high temperatures in desert climates cause burn injuries from contact with sun-exposed surfaces. The peak temperature, times, and surfaces of greatest risk are not well described. This work recorded temperature measurements of six materials in a desert climate. Surface temperatures of asphalt, brick, concrete, sand, porous rock, and galvanized metal were measured throughout the summer, along with ambient temperature, and sunlight intensity. Samples were placed in both shade and direct sunlight for evaluation of sunlight effect. Seventy-five thousand individual measurements were obtained from March to August 2020. Maximum recorded temperatures for sunlight-exposed porous rock were 170°F, asphalt 166°F, brick 152°F, concrete 144°F, metal 144°F, and sand 143°F, measured on August 6, 2020 at 2:10 pm, when ambient temperature was 120°F and solar irradiation 940 W/m2. Sunlight-exposed materials ranged 36 to 56°F higher than shaded materials measured at the same time. The highest daily temperatures were achieved between 2:00 and 4:00 pm due to maximum solar irradiance. Contour plots of surface temperature as a function of both solar irradiation and time of day were created for all materials tested. A computational fluid dynamics model was created to validate the data and serve as a predictive model based upon temperature and sunlight inputs. This information is useful to inform the public of the risks of contact burn due to sunlight-exposed surfaces in a desert climate.

Adaptive Optics Imaging of Inherited Retinal Disease.

The human retina is amenable to direct, noninvasive visualization using a wide array of imaging modalities. In the ∼140 years since the publication of the first image of the living human retina, there has been a continued evolution of retinal imaging technology. Advances in image acquisition and processing speed now allow real-time visualization of retinal structure, which has revolutionized the diagnosis and management of eye disease. Enormous advances have come in image resolution, with adaptive optics (AO)-based systems capable of imaging the retina with single-cell resolution. In addition, newer functional imaging techniques provide the ability to assess function with exquisite spatial and temporal resolution. These imaging advances have had an especially profound impact on the field of inherited retinal disease research. Here we will review some of the advances and applications of AO retinal imaging in patients with inherited retinal disease.

Foveal Cone Structure in Patients With Blue Cone Monochromacy.

Purpose: Blue cone monochromacy (BCM) is a rare inherited cone disorder in which both long- (L-) and middle- (M-) wavelength sensitive cone classes are either impaired or nonfunctional. Assessing genotype-phenotype relationships in BCM can improve our understanding of retinal development in the absence of functional L- and M-cones. Here we examined foveal cone structure in patients with genetically-confirmed BCM, using adaptive optics scanning light ophthalmoscopy (AOSLO). Methods: Twenty-three male patients (aged 6-75 years) with genetically-confirmed BCM were recruited for high-resolution imaging. Eight patients had a deletion of the locus control region (LCR), and 15 had a missense mutation-Cys203Arg-affecting the first two genes in the opsin gene array. Foveal cone structure was assessed using confocal and non-confocal split-detection AOSLO across a 300 × 300 µm area, centered on the location of peak cell density. Results: Only one of eight patients with LCR deletions and 10 of 15 patients with Cys203Arg mutations had analyzable images. Mean total cone density for Cys203Arg patients was 16,664 ± 11,513 cones/mm2 (n = 10), which is, on average, around 40% of normal. Waveguiding cone density was 2073 ± 963 cones/mm2 (n = 9), which was consistent with published histological estimates of S-cone density in the normal eye. The one patient with an LCR deletion had a total cone density of 10,246 cones/mm2 and waveguiding density of 1535 cones/mm2. Conclusions: Our results show that BCM patients with LCR deletions and Cys203Arg mutations have a population of non-waveguiding photoreceptors, although the spectral identity and level of function remain unknown.

A two-dimensional discrete delay-differential system model of viremia.

A deterministic model is proposed to describe the interaction between an immune system and an invading virus whose target cells circulate in the blood. The model is a system of two ordinary first order quadratic delay-differential equations with stipulated initial conditions, whose coefficients are eventually constant, so that the system becomes autonomous. The long-term behavior of the solution is investigated with some success. In particular, we find two simple functions of the parameters of the model, whose signs often, but not always, determine whether the virus persists above a nonzero threshold in the circulation or heads toward extinction.