Spaceflight-induced contractile and mitochondrial dysfunction in an automated heart-on-a-chip platform.

With current plans for manned missions to Mars and beyond, the need to better understand, prevent, and counteract the harmful effects of long-duration spaceflight on the body is becoming increasingly important. In this study, an automated heart-on-a-chip platform was flown to the International Space Station on a 1-mo mission during which contractile cardiac function was monitored in real-time. Upon return to Earth, engineered human heart tissues (EHTs) were further analyzed with ultrastructural imaging and RNA sequencing to investigate the impact of prolonged microgravity on cardiomyocyte function and health. Spaceflight EHTs exhibited significantly reduced twitch forces, increased incidences of arrhythmias, and increased signs of sarcomere disruption and mitochondrial damage. Transcriptomic analyses showed an up-regulation of genes and pathways associated with metabolic disorders, heart failure, oxidative stress, and inflammation, while genes related to contractility and calcium signaling showed significant down-regulation. Finally, in silico modeling revealed a potential link between oxidative stress and mitochondrial dysfunction that corresponded with RNA sequencing results. This represents an in vitro model to faithfully reproduce the adverse effects of spaceflight on three-dimensional (3D)-engineered heart tissue.

Detailed Phenotype Supports Pathogenicity of Hypomorphic Variant in ABCC6-Associated Pattern Dystrophy.

Introduction: We report a case of pseudoxanthoma elasticum (PXE) with an atypical phenotype likely related to a hypomorphic variant in ABCC6. Case Presentation: A 66-year-old Caucasian female with a history of a maculopathy interpreted as either age-related macular degeneration or a pattern dystrophy underwent a detailed ophthalmic evaluation. Visual acuities were 20/25, OD, and 20/20, OS. Spectral domain optical coherence and fluorescein angiography demonstrated outer retinal disruptions and breaks in retinal pigment epithelium (RPE)/Bruch's membrane bilaterally, consistent with angioid streaks. A large area of hypo- and hyperautofluorescence extending from the central retina into the peripapillary retina was documented with short-wavelength excitation autofluorescence. The area of hypoautofluorescence, which was much larger on near-infrared excitation, spared the temporal retina. Two-color dark-adapted perimetries documented severe rod sensitivity losses and less severe cone sensitivity abnormalities co-localizing with the RPE abnormalities. No obvious skin findings were observed, and initial dermatologic biopsy was negative. Gene screening identified a pathogenic ABCC6 gene variant c.1552C>T and a previously reported variant of uncertain significance c.1171A>G. A second dermatologic biopsy demonstrated positive findings consistent with PXE. Conclusion: Although this patient had minimal skin findings, this patient had characteristic structural and functional abnormalities of a pattern dystrophy with angioid streaks and histologic evidence of PXE, suggesting compound heterozygous variants involving the hypomorphic ABCC6 c.1171A>G variant. These findings support the pathogenic role of both variants.

Posterior Retinal Breaks Secondary to Closed-Globe Blunt Ocular Trauma.

Purpose: To describe 2 cases of posterior pole retinal tears resulting from closed-globe trauma. Methods: Two cases of retinal breaks in the posterior pole after blunt ocular trauma were evaluated, and the relevant literature was reviewed. Results: Two eyes of 2 patients with posterior pole retinal tears secondary to closed-globe trauma were included. One patient had a pars plana vitrectomy with laser retinopexy and gas tamponade; the final Snellen visual acuity (VA) was 20/200. The second patient was treated with indirect laser retinopexy; the final Snellen VA was counting fingers. Conclusions: The rapid deformation of the globe in response to blunt ocular trauma may create significant tangential stress on the retina, leading to stretch breaks in the posterior pole. Clinicians should follow patients with a closed-globe injury to watch for retinal breaks in the posterior pole, in particular when a hemorrhage or other pathology obscures the view.

Bullous Variant of Central Serous Chorioretinopathy in Goodpasture's Disease - A Case Report and Review of Literature.

PURPOSE: To describe a case of bullous variant of central serous chorioretinopathy (CSR) in Goodpasture's disease (GD) compared to an identical twin without GD, and summarize the literature on ocular manifestations of GD. METHODS: Interventional/observational case report and literature review. RESULTS: A 46-year-old white female with a history of GD presented with decreased vision. She demonstrated bilateral multifocal pigment epithelial detachments and a large inferior exudative retinal detachment in the left eye consistent with bilateral CSR with bullous variant CSR (bvCSR) in the left eye. Despite treatment, her disease remained refractory, with final VA of 20/200 in the left eye. The patient's identical twin sister did not have GD and demonstrated milder CSR on presentation with a more typical, self-limited disease course. Her final VA was 20/20 bilaterally. CONCLUSION: GD is associated with severe manifestations of CSR (exudative RD). Additional studies focusing on the association between GD and CSR severity may be of interest.

Congenital Retinal Macrovessel and Cavernous Hemangioma in Cowden Syndrome - A Case Report and Review of Literature.

PURPOSE: To describe a case of unilateral congenital retinal macrovessel with a retinal cavernous hemangioma in a patient with Cowden syndrome (CS). In addition, we summarize previously reported cases of ocular findings in CS in the literature. METHODS: Observational case report and literature review. RESULTS: A 45-year-old white female with Cowden syndrome presented for routine ocular examination. She had a history of thyroid carcinoma, fallopian para-tubal cyst, chromophobe type renal cell carcinoma, multiple benign skin lesions, and macrocephaly. At presentation, she was asymptomatic with good vision. On dilated fundus examination, the right eye revealed a congenital retinal macrovessel and retinal cavernous hemangioma. Previously performed genetic testing revealed a pathogenic c.46dupT mutation in the PTEN gene which was consistent with CS. CONCLUSION: Our patient had a history of multiple malignancies and hamartomas consistent with her genetic diagnosis of CS. We incidentally discovered a congenital retinal macrovessel with a retinal cavernous hemangioma. Patients with CS should be referred for interdisciplinary evaluation including routine ocular examinations.

Erythropoiesis-Stimulating Agents and the Risk of Vision-Threatening Diabetic Retinopathy.

PURPOSE: Animal studies have suggested that Erythropoiesis-Stimulating Agents (ESAs) may increase vascular endothelial growth factor (VEGF)-related retinopathies, but this effect is unclear in humans. This study evaluates the risk of vision-threatening diabetic retinopathy (VTDR), defined as either diabetic macular edema (DME) or proliferative diabetic retinopathy (PDR), in patients exposed to an ESA. METHODS: Two analyses were performed. First, a retrospective matched-cohort study was designed using a de-identified commercial and Medicare Advantage medical claims database. The ESA cohort of non-proliferative diabetic retinopathy patients who were new users of an ESA from 2000 to 2022 was matched to controls up to a 3:1 ratio. Exclusion criteria included less than 2 years in the plan, history of VTDR or history of other retinopathy. Multivariable Cox proportional hazards regression with inverse proportional treatment weighting (IPTW) was used to assess the hazard of developing VTDR, DME, and PDR. The second analysis was a self-controlled case series (SCCS) evaluating the incidence rate ratios (IRR) of VTDR during 30-day periods before and after initiating an ESA. RESULTS: After inclusion of 1502 ESA-exposed patients compared with 2656 controls, IPTW-adjusted hazard ratios found the ESA cohort had an increased hazard of progressing to VTDR (HR = 3.0 95%CI:2.3-3.8;p < .001) and DME (HR = 3.4,95%CI:2.6-4.4,p < .001), but not PDR (HR = 1.0,95%CI:0.5-2.3,p = .95). Similar results were found within the SCCS which demonstrated higher IRRs for VTDR (IRRs = 1.09-1.18;p < .001) and DME (IRRs = 1.16-1.18;p < .001), but not increased IRRs in PDR (IRR = 0.92-0.97,p = .02-0.39). CONCLUSION: ESAs are associated with higher risks for VTDR and DME, but not PDR. Those studying ESAs as adjunctive therapy for DR should be cautious of possible unintended effects.

Teclistamab-Associated Sclerouveitis with Hypopyon.

PURPOSE: To report a case of presumed teclistamab-associated sclerouveitis with hypopyon. METHODS: Case report. RESULTS: A 62-year-old female with relapsed refractory multiple myeloma presented with right eye pain and decreased vision one week after starting teclistamab, and was found to have sclerouveitis with hypopyon. She received intravitreal vancomycin and ceftazidime due to concern for infectious endophthalmitis, but cultures were negative. Systemic workup for infectious and inflammatory etiologies was unremarkable. Her signs and symptoms improved with topical steroids and a one-week pause in teclistamab. This case constituted a Naranjo Adverse Drug Reaction Probability Scale score of 5, representing a "probable" association. CONCLUSION: Teclistamab, a novel bispecific antibody recently approved for the treatment of relapsed or refractory multiple myeloma, may be associated with sclerouveitis with hypopyon.

Bilateral retinal hemorrhages after sequential endovascular treatment of bilateral unruptured cerebral aneurysms.

PURPOSE: To report a case of bilateral retinal hemorrhages in a patient undergoing two separate endovascular interventions for bilateral cerebral aneurysms. METHODS: A comprehensive ophthalmic examination was performed after the patient underwent each of two separate endovascular interventions for bilateral cerebral aneurysms. Multimodal imaging including widefield pseudocolor fundus photography, optical coherence tomography, and widefield fluorescein angiography (FA) was obtained. A systemic workup including genetic testing and hypercoagulability studies was performed. RESULTS: Dilated fundus examination revealed new visually significant ipsilateral retinal hemorrhages after each endovascular procedure. FA showed evidence of a peripheral retinal microangiopathy present in both eyes before the patient underwent her second endovascular procedure. Systemic workup revealed persistently elevated serum anticardiolipin IgM antibody levels at >99th percentile. CONCLUSION: Retinal complications after endovascular intracranial interventions are uncommon. This patient who developed bilateral retinal complications was found to have persistently elevated anticardiolipin antibody levels, a risk factor for thrombosis. Patients who develop retinal complications after endovascular intracranial intervention may benefit from systemic workup for hypercoagulable conditions.

COMBINED RHEGMATOGENOUS RETINAL AND CHOROIDAL DETACHMENT: A Systematic Review.

PURPOSE: To review the literature on eyes with concurrent rhegmatogenous retinal and choroidal detachment (RRD-CD). METHODS: Several databases were searched for "rhegmatogenous retinal detachment" and "choroidal detachment" through October 2022. All English language primary literature was reviewed. RESULTS: Studies demonstrated that eyes with RRD-CD were very uncommon and had diminished baseline visual acuity (VA) and intraocular pressure (IOP) compared with eyes with RRD only. Although no randomized trials have been performed, pars plana vitrectomy with or without scleral buckle (SB) have reported higher surgical success rates than SB alone. Reattachment rates were affected by age, IOP, adjuvant steroids, and grade of proliferative vitreoretinopathy. CONCLUSION: Low IOP and poor initial VA are salient features of eyes with RRD-CD. Steroids can be useful adjuvants administered safely using several routes including periocular and intravitreal injection. PPV ± SB may result in best surgical outcomes.

Association of Treatment Type and Loss to Follow-up With Tractional Retinal Detachment in Proliferative Diabetic Retinopathy.

Importance: The association of proliferative diabetic retinopathy (PDR) interventions of panretinal photocoagulation (PRP) and intravitreal injections (IVIs) with tractional retinal detachment (TRD) is unclear. Objectives: To determine whether different treatment types or a 6-month or longer period of loss to follow-up (LTFU) is associated with TRD. Design, Setting, and Participants: This nested case-control study included data from January 1, 2000, to June 30, 2021, of patients with PDR. Those who progressed to TRD were matched to non-TRD controls up to a 5:1 ratio. Exclusion criteria included 2 or fewer years in the plan, history of nondiabetic retinopathy, vitreous hemorrhage, previous RD, or any other surgically indicated diagnosis. Patient data were obtained from a deidentified commercial and Medicare Advantage medical claims database. Statistical analysis was performed from January to May 2022. Exposures: Primary exposures of interest were prior treatment (PRP, IVI, both) and any period of 6 months or longer in which the patient received no eye care. Main Outcomes and Measures: Odds ratios (ORs) of IVI only compared with PRP and 6-month or longer LTFU on development of TRD. Results: After application of inclusion and exclusion criteria, a total of 214 patients (mean [SD] age, 55.6 [12.4] years; 115 female [53.7%]) with PDR and TRD were matched to 978 controls (mean [SD] age, 65.6 [11.3] years; 507 female [51.8%]) with only PDR. Among patients with TRD, 69 (32.2%) were treated with laser only, 17 (7.9%) were treated with injection only, 39 (18.2%) were treated with both, and 89 (41.6%) had no prior treatment. Among patients in the PDR-only group, 207 (21.2%) received laser only, 83 (8.5%) received injection only, 57 (5.8%) received both, and 631 (64.5%) received no treatment. After adjusted analysis, no difference in odds of TRD for patients who received injection only compared with patients who received laser only was found (adjusted OR [aOR], 0.56; 95% CI, 0.27-1.14). Patients who received both treatments had higher odds of TRD compared with those who received laser only (aOR, 2.33; 95% CI, 1.21-4.48), and patients who had no treatment had lower odds of TRD (aOR, 0.46; 95% CI, 0.29-0.71; P < .001 for treatment category). Similarly, no difference was seen in the odds of TRD between those with LTFU for 6 months or longer and those without LTFU (aOR, 0.72; 95% CI, 0.49-1.07; P = .11). Conclusions and Relevance: Results of this case-control analysis suggest that there is no increased risk of TRD associated with IVI-only treatment or with 6-month or longer periods of LTFU, which supports the findings of other investigations. Nonetheless, LTFU rates continue to remain high in patients with PDR, which can contribute to substantial vision loss regardless of treatment regimen.

Efficacy of Maribavir in Valganciclovir-Resistant Cytomegalovirus Retinitis.

PURPOSE: To determine whether maribavir is effective at treating ganciclovir-resistant cytomegalovirus retinitis. METHODS: Retrospective case report of a lung transplant patient with bilateral cytomegalovirus retinitis documented with serum and aqueous humor studies and color fundus photographs. RESULTS: A 72-year-old lung transplant patient with active ganciclovir-resistant cytomegalovirus was treated with intravitreal foscarnet therapy in one eye. Retinitis developed in the contralateral eye and was managed with systemic maribavir alone. Active retinitis regressed in both the eye treated with intravitreal foscarnet and the un-injected eye. CONCLUSIONS: This patient's results suggest that systemic maribavir is an effective treatment for treatment-resistant cytomegalovirus retinitis.

Rhegmatogenous Retinal Detachment with concurrent Choroidal Detachment and Macular Hole Formation after Uncomplicated Cataract Extraction and Intraocular Lens Implantation - A Case Report and Review of Literature.

PURPOSE: To describe a case of concurrent rhegmatogenous retinal detachment, choroidal detachment, and macular hole (RRD-CD-MH) formation in a patient after uncomplicated cataract extraction and intraocular lens implantation (CEIOL). In addition, we summarize the previously reported cases of RRD-CD-MH in the literature. METHODS: Interventional case report and literature review. RESULTS: A 71-year-old white man without relevant past medical or ocular history underwent an uncomplicated CEIOL. He presented three weeks later with counting fingers vision and intraocular pressure (IOP) of 5 mmHg. On dilated fundus examination, multiple superior tears and total RRD with a serous CD was evident. Intraoperatively, a full-thickness MH was identified. The patient underwent routine RRD and MH repair, with instillation of 1000 centistoke silicone oil (SiO). The retina successfully re-attached, the CD resolved, and the IOP normalized; however, the MH did not initially close. The SiO was removed ∼4 months later and, while the MH remained open, the patient's vision improved to 20/80. Approximately three years after the surgical repair, the MH closed spontaneously, and the vision remained at 20/80. CONCLUSION: Our patient developed an RRD-CD-MH post-uncomplicated CEIOL. The MH displayed delayed closure. The vision improved after surgical repair, and remained stable in the long-term.

Ocular Toxoplasmosis after Exposure to Wild Game.

PURPOSE: To describe eight patients with toxoplasma retinochoroiditis following exposure to wild game. METHODS: Retrospective, multicenter case series. RESULTS: Eight men, aged 29 to 71 (mean, 56 years), developed toxoplasmic retinochoroiditis after hunting and/or consuming wild game in the United States, including seven deer and one bear. Five patients developed the disease after eating undercooked game meat, while three developed ocular findings after cleaning hunted animals. Seven patients were healthy prior to exposure. LogMAR visual acuity at presentation was 0.697 ± 0.745, improving to 0.256 ± 0.335 by last follow-up. Disease complications developed in five (62.5%) patients, of which recurrence of retinochoroiditis was the most common. CONCLUSIONS: Contact with wild game is a potential source of primary ocular toxoplasmosis in immunocompetent adults. Hunters and consumers of rare game are at risk of serious ocular disease and appropriate contact precautions and cooking may reduce this complication.

Fabrication of nanomolded Nafion thin films with tunable mechanical and electrical properties using thermal evaporation-induced capillary force lithography.

In this paper, we report a simple and facile method to fabricate nanomolded Nafion thin films with tunable mechanical, and electrical properties. To achieve this, we combine a novel thermal evaporation-induced capillary force lithography method with swelling process to obtain enhanced pattern fidelity in nanomolded Nafion films. We demonstrate that structural fidelity and mechanical properties of patterned Nafion thin films can be modulated by changing fabrication parameters such as swelling time, Nafion polymer concentration, and curing temperature. Interestingly, we also find that impedance properties of nanomolded Nafion thin films are associated with the Nafion polymer concentration and curing temperature. In particular, 20% Nafion thin films exhibit greater impedance stability and lower impedance values than 5% Nafion thin films at lower frequencies. Moreover, curing temperature-specific impedance changes are observed. These results suggest that capillary lithography can be used to fabricate Nafion nanostructures with high pattern fidelity capable of modifying mechanical and electrical properties of Nafion thin films.

Tunable electroconductive decellularized extracellular matrix hydrogels for engineering human cardiac microphysiological systems.

Cardiomyocytes differentiated from human induced pluripotent stem cells (hiPSCs) offer tremendous potential when used to engineer human tissues for drug screening and disease modeling; however, phenotypic immaturity reduces assay reliability when translating in vitro results to clinical studies. To address this, we have developed hybrid hydrogels comprised of decellularized porcine myocardial extracellular matrix (dECM) and reduced graphene oxide (rGO) to provide a more instructive microenvironment for proper cell and tissue development. A tissue-specific protein profile was preserved post-decellularization, and through the modulation of rGO content and degree of reduction, the mechanical and electrical properties of the hydrogels could be tuned. Engineered heart tissues (EHTs) generated using dECM-rGO hydrogel scaffolds and hiPSC-derived cardiomyocytes exhibited significantly increased twitch forces and had increased expression of genes that regulate contractile function. Improvements in various aspects of electrophysiological function, such as calcium-handling, action potential duration, and conduction velocity, were also induced by the hybrid biomaterial. dECM-rGO hydrogels could also be used as a bioink to print cardiac tissues in a high-throughput manner, and these tissues were utilized to assess the proarrhythmic potential of cisapride. Action potential prolongation and beat interval irregularities was observed in dECM-rGO tissues at clinical doses of cisapride, indicating that the enhanced electrophysiological function of these tissues corresponded well with a capability to produce physiologically relevant drug responses.