Viral-specific T cells for Cytomegalovirus retinitis following hematopoietic stem cell transplantation: A success story.

Cytomegalovirus retinitis (CMVR) following hematopoietic stem cell transplantation (HCT) for a primary immunodeficiency is a rare but highly morbid condition with potential irreversible consequences despite optimal antiviral pharmacotherapy. Viral-specific T cells (VSTs) pose a promising and safe approach eradicating intractable viral disease. We describe the case of a 21-month-old male with Wiskott-Aldrich syndrome (WAS) and CMVR post HCT with sustained long-term virologic and clinical response after CMV-specific T-cell therapy. This case highlights the need to consider VST as an adjunct upfront strategy in refractory CMVR and for routine ophthalmologic screening and surveillance in high-risk patients post HCT.

REPRODUCTIVE OPHTHALMOLOGY: The Intersection of Inherited Eye Diseases and Reproductive Technologies.

PURPOSE: To propose a working framework for patients with inherited eye diseases presenting to ophthalmologists who are interested in assisted reproductive technology and preimplantation genetic testing. METHODS: Retrospective chart review and case series of three families with inherited eye diseases who successfully underwent preimplantation genetic testing, in vitro fertilization, and birth of unaffected children. RESULTS: Preimplantation genetic testing was performed for three families with different inherited eye diseases, which included autosomal dominant retinitis pigmentosa, autosomal recessive achromatopsia, and X-linked Goltz syndrome. Preimplantation genetic testing led to the identification of unaffected embryos, which were then selected for in vitro fertilization and resulted in the birth of unaffected children. CONCLUSION: A close collaboration between patients, families, ophthalmologists, reproductive genetic counselors, and reproductive endocrinology and infertility specialists is the ideal model for taking care of patients interested in preimplantation genetic testing for preventing the transmission of inherited eye diseases.

The retina revolution: signaling pathway therapies, genetic therapies, mitochondrial therapies, artificial intelligence.

PURPOSE OF REVIEW: The aim of this article is to review and discuss the history, current state, and future implications of promising biomedical offerings in the field of retina. RECENT FINDINGS: The technologies discussed are some of the more recent promising biomedical developments within the field of retina. There is a US Food and Drug Administration-approved gene therapy product and artificial intelligence device for retina, with many other offerings in the pipeline. SUMMARY: Signaling pathway therapies, genetic therapies, mitochondrial therapies, and artificial intelligence have shaped retina care as we know it and are poised to further impact the future of retina care. Retina specialists have the privilege and responsibility of shaping this future for the visual health of current and future generations.

ETIOLOGY AND CLINICAL CHARACTERISTICS OF MACULAR EDEMA IN PATIENTS WITH FAMILIAL EXUDATIVE VITREORETINOPATHY.

PURPOSE: To describe the etiology and clinical characteristics of macular edema (ME) in patients with familial exudative vitreoretinopathy. METHODS: Observational, retrospective case series of 30 patients (34 eyes) with ME and familial exudative vitreoretinopathy who underwent spectral-domain optical coherence tomography imaging between 2009 and 2016. Baseline and follow-up optical coherence tomographies were correlated with color fundus photography and fluorescein angiography. RESULTS: The average age was 20.6 years (6.6-68.7). Eighteen eyes exhibited cystoid ME (52.9%), 14 noncystoid ME (41.2%), and 2 eyes (5.9%) with both. Macular edema was foveal in 52.9% (n = 18). Eighteen of 24 eyes (64.3%) with an available fluorescein angiography showed leakage from ME. The most common structural feature was posterior hyaloidal organization/contraction (n = 15). Sixteen eyes were treated with topical or intravitreal steroids (n = 6), intravitreal anti-vascular endothelial growth factor (n = 3), or pars plana vitrectomy with membrane stripping (n = 7). There was no difference between mean preoperative and postoperative LogMAR visual acuity (0.63 [20/85] vs. 0.87 [20/148], P = 0.35) after vitrectomy despite a statistical improvement in the mean central foveal thickness (596 mm vs. 303 mm, P = 0.04). CONCLUSION: Macular edema in familial exudative vitreoretinopathy occurs most commonly because of traction. Vitrectomy is effective for relieving tractional forces with anatomical improvement.

STEM CELL THERAPIES, GENE-BASED THERAPIES, OPTOGENETICS, AND RETINAL PROSTHETICS: Current State and Implications for the Future.

PURPOSE: To review and discuss current innovations and future implications of promising biotechnology and biomedical offerings in the field of retina. We focus on therapies that have already emerged as clinical offerings or are poised to do so. METHODS: Literature review and commentary focusing on stem cell therapies, gene-based therapies, optogenetic therapies, and retinal prosthetic devices. RESULTS: The technologies discussed herein are some of the more recent promising biotechnology and biomedical developments within the field of retina. Retinal prosthetic devices and gene-based therapies both have an FDA-approved product for ophthalmology, and many other offerings (including optogenetics) are in the pipeline. Stem cell therapies offer personalized medicine through novel regenerative mechanisms but entail complex ethical and reimbursement challenges. CONCLUSION: Stem cell therapies, gene-based therapies, optogenetics, and retinal prosthetic devices represent a new era of biotechnological and biomedical progress. These bring new ethical, regulatory, care delivery, and reimbursement challenges. By addressing these issues proactively, we may accelerate delivery of care to patients in a safe, efficient, and value-based manner.

NONDAMAGING RETINAL LASER THERAPY FOR TREATMENT OF CENTRAL SEROUS CHORIORETINOPATHY: What is the Evidence?

PURPOSE: To summarize the literature addressing subthreshold or nondamaging retinal laser therapy (NRT) for central serous chorioretinopathy (CSCR) and to discuss results and trends that provoke further investigation. METHODS: Analysis of current literature evaluating NRT with micropulse or continuous wave lasers for CSCR. RESULTS: Sixteen studies including 398 patients consisted of retrospective case series, prospective nonrandomized interventional case series, and prospective randomized clinical trials. All studies but one evaluated chronic CSCR, and laser parameters varied greatly between studies. Mean central macular thickness decreased, on average, by ∼80 µm by 3 months. Mean best-corrected visual acuity increased, on average, by about 9 letters by 3 months, and no study reported a decrease in acuity below presentation. No retinal complications were observed with the various forms of NRT used, but six patients in two studies with micropulse laser experienced pigmentary changes in the retinal pigment epithelium attributed to excessive laser settings. CONCLUSION: Based on the current evidence, NRT demonstrates efficacy and safety in 12-month follow-up in patients with chronic and possibly acute CSCR. The NRT would benefit from better standardization of the laser settings and understanding of mechanisms of action, as well as further prospective randomized clinical trials.

A simplified, validated protocol for measuring fibular reduction on ankle CT.

BACKGROUND: Inadequate ankle syndesmotic reduction is a common and important cause of poor outcome after surgery. It is not clear what magnitude or planes of displacement impact most. Many computerised tomography (CT) measurement techniques rely on landmarks that are difficult to reproduce, and none measure all types of mal-positioning in a single protocol. The purpose of this study was to design and validate a protocol for measuring the distal tibio-fibular relationship. METHODS: We devised a method for measuring fibular diastasis, antero-posterior translation (APT) and fibular length on CT images. CTs of sixteen un-injured ankles were examined using our protocol and that of an established alternative method for comparison. The measurements were recorded by two independent observers and repeated for inter- and intra-observer agreement scores. RESULTS: Our method showed inter- and intra-observer agreement of r=0.994 and r=0.999, demonstrating strong agreement. This compared to r=0.218 and r=0.820 respectively for the comparative protocol. CONCLUSION: This ankle CT measurement protocol is accurate, reproducible and simple to use. Its aim is to be a useful tool for clinicians to quantify post-operative mal-positioning of the distal fibula in comparison to the un-injured ankle. We believe that routine, bilateral, post-operative CT imaging will lead to improvements in the understanding and outcomes of the treatment of complex ankle fractures. To our knowledge no other validated measurement of fibular length on CT images exists in the literature.

Visual acuity measured with a smartphone app is more accurate than Snellen testing by emergency department providers.

PURPOSE: To assess the accuracy of best-corrected visual acuity (BCVA) measured by non-ophthalmic emergency department (ED) staff with a standard Snellen chart versus an automated application (app) on a handheld smartphone (Paxos Checkup, San Francisco, CA, USA). METHODS: The study included 128 subjects who presented to the Stanford Hospital ED for whom the ED requested an ophthalmology consultation. We conducted the study in two phases. During phase 1 of the study, ED staff tested patient BCVA using a standard Snellen test at 20 feet. During phase 2 of the study, ED staff tested patient near BCVA using the app. During both phases, ophthalmologists measured BCVA with a Rosenbaum near chart, which was treated as the gold standard. ED BCVA measurements were benchmarked prospectively against ophthalmologists' measurements and converted to logMAR. RESULTS: ED logMAR BCVA was 0.21 ± 0.35 (approximately 2 Snellen lines difference ± 3 Snellen lines) higher than that of ophthalmologists when ED staff used a Snellen chart (p = .0.00003). ED BCVA was 0.06 ± 0.40 (less than 1 Snellen line ± 4 Snellen lines) higher when ED staff used the app (p = 0.246). Inter-observer difference was therefore smaller by more than 1 line (0.15 logMAR) with the app (p = 0.046). CONCLUSIONS: BCVA measured by non-ophthalmic ED staff with an app was more accurate than with a Snellen chart. Automated apps may provide a means to standardize and improve the efficiency of ED ophthalmologic care.

The management of posterior ankle impingement syndrome in sport: a review.

A literature review has been undertaken to assess the efficacy of management of Posterior Ankle Impingement Syndrome with an emphasis on sport. The evidence is confined to Level IV and V studies. There is a lack of prospective studies on the natural history of this condition and the outcomes of conservative treatment. Dance dominates the literature accounting for 62% of reported sports. Forty-seven papers have reported on the surgical outcomes of 905 procedures involving both open and artho-endoscopic techniques. 81% of patients required excision of osseous pathology and 42% soft-tissue problems resolving. There is a lack of standardisation of outcome reporting particularly in the open surgery group. However, the complication rates are relatively low: 3.9% for open medial, 12.7% for open lateral and 4.8% for arthro-endocopic surgery. Return to sport appears quicker for all activities in the arthro-endoscopic group but comparison of long term outcomes is more difficult with no evidence supporting superior long term results of one technique over another. Soccer players appear to return more quickly to activity than dancers.

Colorado drugged driving prevalence and impaired driving conviction rates: Effects of impaired driving definitions and a 5-nanogram limit for delta-9 tetrahydrocannabinol.

Objectives: How prevalent is drugged driving among Colorado drivers convicted of Driving Under the Influence (DUI)? What are the conviction rates of Colorado drivers charged with DUI, including impairment by marijuana's delta-9 tetrahydrocannabinol (THC)? Is Colorado's THC permissible inference law effective? To answer these questions, this report analyzes data published primarily in appendices of Colorado drugged driving reports.Methods: In 2017 Colorado began requiring annual analyses of Driving Under the Influence (DUI) offenses, including causes and judicial consequences of DUI offenses. These analyses are performed by the Division of Criminal Justice's Office of Research and Statistics (ORS) within the Department of Public Safety. Each analysis requires ORS to link toxicology and court data bases. Data linking enables reporting of charges and convictions by categories including alcohol only, THC only, and polydrug use (two or more drugs simultaneously). Reports have been published annually for 5 years, the latest published in 2023 which covers case filings for 2020.Results: A rough estimate of one-half of the state's DUI filings were attributed to drug use and half were attributed to alcohol only. The largest component of drugged driving was polydrug impairment, rather than impairment by a single drug like THC. Conviction rates in 2020 were 91% for alcohol only, 90% for polydrug cases, and 72% for THC only. Blood drug levels and law structure (per se, permissible inference, DUI definition) affected conviction rates significantly by defendant subsets. THC conviction rates in 2020 ranged from 11% to 100%, depending on blood drug levels and the legal charges.Conclusions: Efforts to educate the public about the dangers of drugged driving should emphasize polydrug impairment, not simply THC impairment. States should analyze data on causes and consequences of DUI arrests to understand what their drugged driving problems are and what they are not. Non-zero drug per se levels and defining DUI as "incapable of safe driving" can severely reduce the effectiveness of DUI laws.

The Incidence and Timing of Treatment-Requiring Retinopathy of Prematurity in Nanopremature and Micropremature Infants in the United States: A National Multicenter Retrospective Cohort Study.

PARTICIPANTS: This article includes 7293 infants (14 586 eyes) screened for ROP across 5 centers in the United States (Austin Retina Associates, Austin, TX; Bascom Palmer Eye Institute, Miami, FL; Beaumont Eye Institute, Royal Oak, MI; Massachusetts Eye and Ear, Boston, MA; and Stanford Byers Eye Institute, Stanford, CA). PURPOSE: To analyze the incidence and timing of treatment requiring retinopathy of prematurity (ROP) in extremely small premature infants. We hypothesize that the smaller the infant by gestational age and birthweight, the higher their likelihood of requiring treatment for ROP. DESIGN: Premature infants screened for Retinopathy of Prematurity from 2002-2022 were divided into cohorts based on the following criteria based on gestational age (GA) and birth weight (BW). "Micropremature infants" are infants born between 24-26 weeks GA and between 600-799 g BW. "Nanopremature infants" are born ≤ 24 weeks GA and ≤ 600 g BW. METHODS: Retrospective chart review. MAIN OUTCOME MEASURES: The incidence and timing of treatment-requiring ROP. RESULTS: We found that infants defined as nanopremature had a ∼63% chance of requiring treatment at an average postmenstrual age (PMA) of 36.6 weeks, whereas those defined as micropremature had a 30% chance of requiring treatment at an average PMA of 36.3 weeks. This significantly contrasts with the risk of all screened babies for ROP where the risk of requiring treatment was 8.5%. CONCLUSION: Micropremature and nanopremature infants are significantly more likely to require treatment for ROP. With demographic data matched to all 5 major US regions spanning the last decade, these results have the potential to inform neonatologists, pediatricians, and ophthalmologists of an important shift in the landscape of prematurity in the United States. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Time to Treatment of Pediatric Retinal Detachments: A US Claims-based Analysis.

PURPOSE: To characterize delays in diagnosis and treatment of retinal detachments (RDs) in a pediatric population. DESIGN: Retrospective cohort study using insurance claims data. SUBJECTS: Pediatric patients with RD who underwent repair in the outpatient setting. METHODS: A retrospective analysis of commercially insured patients from a national cohort (IBM MarketScan Research Databases) aged ≤ 18 years with an incident diagnosis of RD between 2007 and 2016. Patients with preceding eye-related visits, time to diagnosis, and time to repair were calculated and compared between patients with pre-existing ocular diagnosis and those without. MAIN OUTCOME MEASURES: The time from diagnosis to specialist consultation, time from diagnosis to repair, time from specialist consultation to repair, number of preceding visits, and presence of previous eye-related diagnosis. RESULTS: Our sample consisted of 826 patients, the majority (77%) of whom were diagnosed with rhegmatogenous RD. Only 40% of patients had at least 1 preceding eye-related visit, and 33% had at least 2 visits before RD diagnosis, with a median time from the last eye-related visit of 32 days (4-197 days) and median time from the second to last visit of 118 days (24-437 days). The median time from RD diagnosis to repair was 2 days (0-9 days). The 323 (37.9%) patients with pre-existing ocular diagnoses more frequently had at least 1 (44% vs. 37%; P = 0.079) or 2 preceding eye-related visits (40% vs. 29%; P = 0.002) compared with those without and also had a shorter time to RD diagnosis (median, 14.5 days vs. 44.5 days; P = 0.011) and repair (1 day vs. 3 days; P = 0.003). CONCLUSIONS: Retinal detachment is an important cause of morbidity in children. This work highlighted how pediatric patients without previous ocular diagnoses and visits with eye care professional may have a delayed diagnosis and repair of their RD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Cellular and subcellular optogenetic approaches towards neuroprotection and vision restoration.

Optogenetics is defined as the combination of genetic and optical methods to induce or inhibit well-defined events in isolated cells, tissues, or animals. While optogenetics within ophthalmology has been primarily applied towards treating inherited retinal disease, there are a myriad of other applications that hold great promise for a variety of eye diseases including cellular regeneration, modulation of mitochondria and metabolism, regulation of intraocular pressure, and pain control. Supported by primary data from the authors' work with in vitro and in vivo applications, we introduce a novel approach to metabolic regulation, Opsins to Restore Cellular ATP (ORCA). We review the fundamental constructs for ophthalmic optogenetics, present current therapeutic approaches and clinical trials, and discuss the future of subcellular and signaling pathway applications for neuroprotection and vision restoration.

A Literary Pediatric Retina Fellowship With Michael T. Trese, MD.

Michael T. Trese, MD (1946-2022), a vitreoretinal surgeon, made significant contributions to the field of retina. Although most known for his work in pediatric retina surgery, he was a pioneer in areas such as medical retina, translational research, and telemedicine. This article reviews his major contributions to spread his knowledge more widely to vitreoretinal trainees and specialists. We discuss six areas where Trese made a lasting impact: lens-sparing vitrectomy, familial exudative vitreoretinopathy, congenital X-linked retinoschisis, autologous plasmin enzyme, regenerative medicine, and telemedicine. [Ophthalmic Surg Lasers Imaging Retina 2023;54:701-712.].

Genetic analysis and multimodal imaging identify novel mtDNA 12148T>C leading to multisystem dysfunction with tissue-specific heteroplasmy.

Patients with mitochondrial disorders present with clinically diverse symptoms, largely driven by heterogeneous mutations in mitochondrial-encoded and nuclear-encoded mitochondrial genes. These mutations ultimately lead to complex biochemical disorders with a myriad of clinical manifestations, often accumulating during childhood on into adulthood, contributing to life-altering and sometimes fatal events. It is therefore important to diagnose and characterize the associated disorders for each mitochondrial mutation as early as possible since medical management might be able to improve the quality and longevity of life in mitochondrial disease patients. Here we identify a novel mitochondrial variant in a mitochondrial transfer RNA for histidine (mt-tRNA-his) [m.12148T>C], that is associated with the development of ocular, aural, neurological, renal, and muscular dysfunctions. We provide a detailed account of a family harboring this mutation, as well as the molecular underpinnings contributing to cellular and mitochondrial dysfunction. In conclusion, this investigation provides clinical, biochemical, and morphological evidence of the pathogenicity of m.12148T>C. We highlight the importance of multiple tissue testing and in vitro disease modeling in diagnosing mitochondrial disease.