Bressler NM, Beaulieu WT, Bressler SB, Glassman AR, Melia MB, Jampol LM, Jhaveri CD, Salehi-Had H, Velez G, Sun JK, Sun JK. ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR THERAPY AND RISK OF TRACTION RETINAL DETACHMENT IN EYES WITH PROLIFERATIVE DIABETIC RETINOPATHY: Pooled Analysis of Five DRCR Retina Network Randomized Clinical Trials. Retina 2020;40(6):1021-1028.Abstract
PURPOSE: To investigate whether anti-vascular endothelial growth factor (anti-VEGF) for diabetic macular edema or proliferative diabetic retinopathy (PDR) increases the risk of traction retinal detachment (TRD) among eyes with PDR. METHODS: Pooled analysis of PDR eyes from Protocols I, J, N, S, or T with Early Treatment Diabetic Retinopathy Study level ≥61 (prompt vitrectomy was not planned) randomly assigned to the control group (laser photocoagulation, sham, or intravitreal saline; 396 eyes) or anti-VEGF (487 eyes). The primary outcome was investigator-identified TRD within 1 year of randomization. RESULTS: The 1-year cumulative probability of TRD was 6.8% (95% confidence interval: 4.6%-9.9%, 25 events) in control-group eyes and 4.8% (95% confidence interval: 3.2%-7.3%, 22 events) in anti-VEGF group eyes (hazard ratio = 0.95 [95% confidence interval: 0.54-1.66, P = 0.86]). The cumulative probability of vitrectomy for TRD was 4.4% (16 events) in control-group eyes and 2.2% (9 events) in anti-VEGF group eyes (P = 0.19). Percentage with TRD and vitrectomy for TRD were similar within strata of diabetic retinopathy severity. CONCLUSION: These findings do not support the hypothesis that anti-VEGF therapy for diabetic macular edema or PDR increases the risk of TRD among eyes with PDR similar to those enrolled in five DRCR Retina Network protocols for which prompt vitrectomy was not planned.
Bronstein R, Capowski EE, Mehrotra S, Jansen AD, Navarro-Gomez D, Maher M, Place E, Sangermano R, Bujakowska KM, Gamm DM, Pierce EA. A combined RNA-seq and whole genome sequencing approach for identification of non-coding pathogenic variants in single families. Hum Mol Genet 2020;29(6):967-979.Abstract
Inherited retinal degenerations (IRDs) are at the focus of current genetic therapeutic advancements. For a genetic treatment such as gene therapy to be successful, an accurate genetic diagnostic is required. Genetic diagnostics relies on the assessment of the probability that a given DNA variant is pathogenic. Non-coding variants present a unique challenge for such assessments as compared to coding variants. For one, non-coding variants are present at much higher number in the genome than coding variants. In addition, our understanding of the rules that govern the non-coding regions of the genome is less complete than our understanding of the coding regions. Methods that allow for both the identification of candidate non-coding pathogenic variants and their functional validation may help overcome these caveats allowing for a greater number of patients to benefit from advancements in genetic therapeutics. We present here an unbiased approach combining whole genome sequencing (WGS) with patient-induced pluripotent stem cell (iPSC)-derived retinal organoids (ROs) transcriptome analysis. With this approach, we identified and functionally validated a novel pathogenic non-coding variant in a small family with a previously unresolved genetic diagnosis.
Bujakowska KM, Comander J. Moving Towards PDE6A Gene Supplementation Therapy. JAMA Ophthalmol 2020;
Busch C, Okada M, Zur D, Fraser-Bell S, Rodríguez-Valdés PJ, Cebeci Z, Lupidi M, Fung AT, Gabrielle P-H, Giancipoli E, Chaikitmongkol V, Laíns I, Santos AR, Kunavisarut P, Sala-Puigdollers A, Chhablani J, Ozimek M, Hilely A, Degenhardt V, Loewenstein A, Iglicki M, Rehak M, Rehak M. Baseline predictors for visual acuity loss during observation in diabetic macular oedema with good baseline visual acuity. Acta Ophthalmol 2020;98(7):e801-e806.Abstract
PURPOSE: To investigate clinical baseline characteristics and optical coherence tomography biomarkers predicting visual loss during observation in eyes with diabetic macular oedema (DMO) and good baseline visual acuity (VA). METHODS: A sub-analysis of a 12-month, retrospective study, including patients with baseline VA ≤0.1 logMAR (≥20/25 Snellen) and centre-involving DMO. The primary outcome measure was the correlation between baseline characteristics and VA loss ≥10 letters during follow-up. RESULTS: A total of 249 eyes were included in the initial study, of which 147 eyes were observed and 80 eyes received anti-vascular endothelial growth factor (VEGF) treatment at baseline. Visual acuity (VA) loss ≥10 letters occurred in 21.8% (observed cohort) and in 24.3% (treated cohort), respectively. Within observed eyes, presence of hyperreflective foci [HRF; odds ratio (OR): 3.18, p = 0.046], and disorganization of inner retina layers (DRIL; OR: 2.71, p = 0.026) were associated with a higher risk of VA loss ≥10 letters. In observed eyes with a combined presence of HRF, DRIL and ellipsoid zone (EZ) disruption, the risk of VA loss was further increased (OR: 3.86, p = 0.034). In eyes with combined presence of DRIL, HRF and EZ disruption, risk of VA loss was 46.7% (7/15 eyes) in the observed cohort, and 26.3% (5/19 eyes) in the treated cohort (p = 0.26). CONCLUSION: Patients with DMO and good baseline VA, managed by observation, are of increased risk for VA loss if DRIL, HRF and EZ disruption are present at baseline. Earlier treatment with anti-VEGF in these patients may potentially decrease the risk of VA loss at 12 months.
Cakir B, Hellström W, Tomita Y, Fu Z, Liegl R, Winberg A, Hansen-Pupp I, Ley D, Hellström A, Löfqvist C, Smith LEH. IGF1, serum glucose, and retinopathy of prematurity in extremely preterm infants. JCI Insight 2020;5(19)Abstract
BACKGROUNDHyperglycemia, insulin insensitivity, and low IGF1 levels in extremely preterm infants are associated with an increased risk of retinopathy of prematurity (ROP), but the interactions are incompletely understood.METHODSIn 117 extremely preterm infants, serum glucose levels and parenteral glucose intake were recoded daily in the first postnatal week. Serum IGF1 levels were measured weekly. Mice with oxygen-induced retinopathy alone versus oxygen-induced retinopathy plus streptozotocin-induced hyperglycemia/hypoinsulinemia were assessed for glucose, insulin, IGF1, IGFBP1, and IGFBP3 in blood and liver. Recombinant human IGF1 was injected to assess the effect on glucose and retinopathy.RESULTSThe highest mean plasma glucose tertile of infants positively correlated with parenteral glucose intake [r(39) = 0.67, P < 0.0001]. IGF1 plasma levels were lower in the high tertile compared with those in low and intermediate tertiles at day 28 (P = 0.038 and P = 0.03). In high versus lower glucose tertiles, ROP was more prevalent (34 of 39 versus 19 of 39) and more severe (ROP stage 3 or higher; 71% versus 32%). In oxygen-induced retinopathy, hyperglycemia/hypoinsulinemia decreased liver IGF1 expression (P < 0.0001); rh-IGF1 treatment improved normal vascular regrowth (P = 0.027) and reduced neovascularization (P < 0.0001).CONCLUSIONIn extremely preterm infants, high early postnatal plasma glucose levels and signs of insulin insensitivity were associated with lower IGF1 levels and increased ROP severity. In a hyperglycemia retinopathy mouse model, decreased insulin signaling suppressed liver IGF1 production, lowered serum IGF1 levels, and increased neovascularization. IGF1 supplementation improved retinal revascularization and decreased pathological neovascularization. The data support IGF1 as a potential treatment for prevention of ROP.TRIAL REGISTRATIONClinicalTrials.gov NCT02760472 (Donna Mega).FUNDINGThis study has been supported by the Swedish Medical Research Council (14940, 4732, 20144-01-3, and 21144-01-3), a Swedish government grant (ALFGB2770), Lund medical faculty grants (ALFL, 11615 and 11601), the Skåne Council Foundation for Research and Development, the Linnéa and Josef Carlsson Foundation, the Knut and Alice Wallenberg Foundation, the NIH/National Eye Institute (EY022275, EY017017, EY017017-13S1, and P01 HD18655), European Commission FP7 project 305485 PREVENT-ROP, Deutsche Forschungsgemeinschaft (CA-1940/1-1), and Stiftelsen De Blindas Vänner.
Chan CSY, Lonfat N, Zhao R, Davis AE, Li L, Wu M-R, Lin C-H, Ji Z, Cepko CL, Wang S. Cell type- and stage-specific expression of Otx2 is regulated by multiple transcription factors and -regulatory modules in the retina. Development 2020;147(14)Abstract
Transcription factors (TFs) are often used repeatedly during development and homeostasis to control distinct processes in the same and/or different cellular contexts. Considering the limited number of TFs in the genome and the tremendous number of events that need to be regulated, re-use of TFs is necessary. We analyzed how the expression of the homeobox TF, orthodenticle homeobox 2 (Otx2), is regulated in a cell type- and stage-specific manner during development in the mouse retina. We identified seven -regulatory modules (CRMs), among which the O5, O7 and O9 CRMs mark three distinct cellular contexts of Otx2 expression. We discovered that Otx2, Crx and Sox2, which are well-known TFs regulating retinal development, bind to and activate the O5, O7 or O9 CRMs, respectively. The chromatin status of these three CRMs was found to be distinct in different retinal cell types and at different stages. We conclude that retinal cells use a cohort of TFs with different expression patterns and multiple CRMs with different chromatin configurations to regulate the expression of Otx2 precisely.
Chang MY, Binenbaum G, Heidary G, Morrison DG, Galvin JA, Trivedi RH, Pineles SL. Imaging Methods for Differentiating Pediatric Papilledema from Pseudopapilledema: A Report by the American Academy of Ophthalmology. Ophthalmology 2020;127(10):1416-1423.Abstract
PURPOSE: To review the published literature on the accuracy of ophthalmic imaging methods to differentiate between papilledema and pseudopapilledema in children. METHODS: Literature searches were conducted in January 2020 in the PubMed database for English-language studies with no date restrictions and in the Cochrane Library database without any restrictions. The combined searches yielded 354 abstracts, of which 17 were reviewed in full text. Six of these were considered appropriate for inclusion in this assessment and were assigned a level of evidence rating by the panel methodologist. All 6 included studies were rated as level III evidence. RESULTS: Fluorescein angiography, a combination of 2 OCT protocols, and multicolor confocal scanning laser ophthalmoscopy (Spectralis SD-OCT; Heidelberg Engineering, Heidelberg, Germany) demonstrated the highest positive percent agreement (92%-100%; 95% confidence interval [CI], 69%-100%) and negative percent agreement (92%-100%; 95% CI, 70%-100%) with a clinical diagnosis of papilledema in children. However, results must be interpreted with caution owing to methodologic limitations, including a small sample size leading to wide CIs and an overall lack of data (there was only 1 study each for the above methods and protocols). Ultrasonographic measures showed either a high positive percent agreement (up to 95%) with low negative percent agreement (as low as 58%) or vice versa. Autofluorescence and fundus photography showed a lower positive (40%-60%) and negative (57%) percent agreement. CONCLUSIONS: Although several imaging methods demonstrated high positive and negative percent agreement with clinical diagnosis, no ophthalmic imaging method conclusively differentiated papilledema from pseudopapilledema in children because of the lack of high-quality evidence. Clinicians must continue to conduct thorough history-taking and examination and make judicious use of ancillary testing to determine which children warrant further workup for papilledema.
Chang W-C, Abe R, Anderson P, Anderson W, Ardern-Jones MR, Beachkofsky TM, Bellón T, Biala AK, Bouchard C, Cavalleri GL, Chapman N, Chodosh J, Choi HK, Cibotti RR, Divito SJ, Dewar K, Dehaeck U, Etminan M, Forbes D, Fuchs E, Goldman JL, Holmes JH, Hope EA, Hung S-I, Hsieh C-L, Iovieno A, Jagdeo J, Kim MK, Koelle DM, Lacouture ME, Le Pallec S, Lehloenya RJ, Lim R, Lowe A, McCawley J, McCawley J, Micheletti RG, Mockenhaupt M, Niemeyer K, Norcross MA, Oboh D, Olteanu C, Pasieka HB, Peter J, Pirmohamed M, Rieder M, Saeed HN, Shear NH, Shieh C, Straus S, Sukasem C, Sung C, Trubiano JA, Tsou S-Y, Ueta M, Volpi S, Wan C, Wang H, Wang Z-Q, Weintraub J, Whale C, Wheatley LM, Whyte-Croasdaile S, Williams KB, Wright G, Yeung SN, Zhou L, Chung W-H, Phillips EJ, Carleton BC. SJS/TEN 2019: From science to translation. J Dermatol Sci 2020;Abstract
Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are potentially life-threatening, immune-mediated adverse reactions characterized by widespread erythema, epidermal necrosis, and detachment of skin and mucosa. Efforts to grow and develop functional international collaborations and a multidisciplinary interactive network focusing on SJS/TEN as an uncommon but high burden disease will be necessary to improve efforts in prevention, early diagnosis and improved acute and long-term management. SJS/TEN 2019: From Science to Translation was a 1.5-day scientific program held April 26-27, 2019, in Vancouver, Canada. The meeting successfully engaged clinicians, researchers, and patients and conducted many productive discussions on research and patient care needs.
Charles NC, Jakobiec FA, Sherwood P, Belinsky I. Multicameral Steatocystoma Simplex of the Caruncle. Ophthalmic Plast Reconstr Surg 2020;Abstract
A yellow cyst of the caruncle in a 68-year-old man displayed the characteristic sebaceous glands and sebocytes of steatocystoma within the cyst wall, with a unique configuration of multiple branching compartments. The cyst lining was of trichilemmal character, lacking a keratohyalin granular layer, and replicated the immunohistochemical characteristics of a previously reported caruncular steatocystoma with the exception of a positive trichilemmal marker, calretinin, in the present case. Four previous cases of caruncular steatocystoma have been described, only one of which incorporated immunohistochemical analysis. Steatocystoma develops from a sebaceous gland duct, which displayed in this case multiple chambers subdividing what is usually a single round lumen.
Charles NC, Jakobiec FA, Chong JK, Godfrey KJ, Patel P, Ma L. Congenital respiratory-type ciliated cyst of the lacrimal sac. Can J Ophthalmol 2020;55(1):e30-e33.
Chauhan MZ, Arcuri J, Park KK, Zafar MK, Fatmi R, Hackam AS, Yin Y, Benowitz L, Goldberg JL, Samarah M, Bhattacharya SK. Multi-Omic Analyses of Growth Cones at Different Developmental Stages Provides Insight into Pathways in Adult Neuroregeneration. iScience 2020;23(2):100836.Abstract
Growth cones (GCs) are structures associated with growing neurons. GC membrane expansion, which necessitates protein-lipid interactions, is critical to axonal elongation in development and in adult neuritogenesis. We present a multi-omic analysis that integrates proteomics and lipidomics data for the identification of GC pathways, cell phenotypes, and lipid-protein interactions, with an analytic platform to facilitate the visualization of these data. We combine lipidomic data from GC and adult axonal regeneration following optic nerve crush. Our results reveal significant molecular variability in GCs across developmental ages that aligns with the upregulation and downregulation of lipid metabolic processes and correlates with distinct changes in the lipid composition of GC plasmalemma. We find that these processes also define the transition into a growth-permissive state in the adult central nervous system. The insight derived from these analyses will aid in promoting adult regeneration and functional innervation in devastating neurodegenerative diseases.
Chen D, Wang J, Sullivan DA, Kam WR, Liu Y. Effects of Terpinen-4-ol on Meibomian Gland Epithelial Cells In Vitro. Cornea 2020;39(12):1541-1546.Abstract
PURPOSE: Infestation with demodex mites has been linked to the development of chalazion, meibomian gland dysfunction, and blepharitis. An effective treatment is the eyelid application of terpinen-4-ol (T4O), a tea tree oil component. However, T4O is also known to be toxic to nonocular epithelial cells. We hypothesize that T4O toxicity also extends to human meibomian gland epithelial cells (HMGECs). METHODS: Immortalized (I) HMGECs were cultured with varying concentrations (1.0%-0.001%) of T4O under proliferating or differentiating conditions up to 5 days. Experimental procedures included analyses of cell appearance, survival, P-Akt signaling, lysosome accumulation, and neutral lipid content. RESULTS: Our findings show that T4O causes a dose- and time-dependent decrease in the cell survival of IHMGECs. After 15 minutes of exposure to 1% T4O, IHMGECs exhibited rounding, atrophy, and poor adherence. Within 90 minutes of such treatment, almost all cells died. Reducing the T4O concentration to 0.1% also led to a marked decrease in P-Akt signaling and cell survival of IHMGECs. Decreasing the T4O amount to 0.01% caused a slight, but significant, reduction in the IHMGEC number after 5 days of culture and did not influence the ability of these cells to differentiate. CONCLUSIONS: T4O, even at levels 10-fold to 100-fold lower than demodicidal concentrations, is toxic to HMGECs in vitro.
Chen XH, Amorim JA, Moustafa GA, Lee J-J, Yu Z, Ishihara K, Iesato Y, Barbisan P, Ueta T, Togka KA, Lu L, Sinclair DA, Vavvas DG. Neuroprotective effects and mechanisms of action of nicotinamide mononucleotide (NMN) in a photoreceptor degenerative model of retinal detachment. Aging (Albany NY) 2020;12Abstract
Currently, no pharmacotherapy has been proven effective in treating photoreceptor degeneration in patients. Discovering readily available and safe neuroprotectants is therefore highly sought after. Here, we investigated nicotinamide mononucleotide (NMN), a precursor of nicotinamide adenine dinucleotide (NAD), in a retinal detachment (RD) induced photoreceptor degeneration. NMN administration after RD resulted in a significant reduction of TUNEL photoreceptors, CD11b macrophages, and GFAP labeled glial activation; a normalization of protein carbonyl content (PCC), and a preservation of the outer nuclear layer (ONL) thickness. NMN administration significantly increased NAD levels, SIRT1 protein expression, and heme oxygenase-1 (HO-1) expression. Delayed NMN administration still exerted protective effects after RD. Mechanistic studies using 661W cells revealed a SIRT1/HO-1 signaling as a downstream effector of NMN-mediated protection under oxidative stress and LPS stimulation. In conclusion, NMN administration exerts neuroprotective effects on photoreceptors after RD and oxidative injury, suggesting a therapeutic avenue to treating photoreceptor degeneration.
Chen X, Lei F, Zhou C, Chodosh J, Wang L, Huang Y, Dohlman CH, Paschalis EI. Glaucoma after Ocular Surgery or Trauma: The Role of Infiltrating Monocytes and Their Response to Cytokine Inhibitors. Am J Pathol 2020;190(10):2056-2066.Abstract
Glaucoma is a frequent and devastating long-term complication following ocular trauma, including corneal surgery, open globe injury, chemical burn, and infection. Postevent inflammation and neuroglial remodeling play a key role in subsequent ganglion cell apoptosis and glaucoma. To this end, this study was designed to investigate the amplifying role of monocyte infiltration into the retina. By using three different ocular injury mouse models (corneal suture, penetrating keratoplasty, and globe injury) and monocyte fate mapping techniques, we show that ocular trauma or surgery can cause robust infiltration of bone marrow-derived monocytes into the retina and subsequent neuroinflammation by up-regulation of Tnf, Il1b, and Il6 mRNA within 24 hours. This is accompanied by ganglion cell apoptosis and neurodegeneration. Prompt inhibition of tumor necrosis factor-α or IL-1β markedly suppresses monocyte infiltration and ganglion cell loss. Thus, acute ocular injury (surgical or trauma) can lead to rapid neuroretinal inflammation and subsequent ganglion cell loss, the hallmark of glaucoma. Infiltrating monocytes play a central role in this process, likely amplifying the inflammatory cascade, aiding in the activation of retinal microglia. Prompt administration of cytokine inhibitors after ocular injury prevents this infiltration and ameliorates the damage to the retina-suggesting that it may be used prophylactically for neuroprotection against post-traumatic glaucoma.
Chen JJ, Flanagan EP, Bhatti TM, Jitprapaikulsan J, Dubey D, Lopez Chiriboga ASS, Fryer JP, Weinshenker BG, McKeon A, Tillema J-M, Lennon VA, Lucchinetti CF, Kunchok A, McClelland CM, Lee MS, Bennett JL, Pelak VS, Van Stavern G, Adesina O-OO, Eggenberger ER, Acierno MD, Wingerchuk DM, Lam BL, Moss H, Beres S, Gilbert AL, Shah V, Armstrong G, Heidary G, Cestari DM, Stiebel-Kalish H, Pittock SJ. Steroid-sparing maintenance immunotherapy for MOG-IgG associated disorder. Neurology 2020;95(2):e111-e120.Abstract
OBJECTIVE: Myelin oligodendrocyte glycoprotein-immunoglobulin G (MOG-IgG) associated disorder (MOGAD) often manifests with recurrent CNS demyelinating attacks. The optimal treatment for reducing relapses is unknown. To help determine the efficacy of long-term immunotherapy in preventing relapse in patients with MOGAD, we conducted a multicenter retrospective study to determine the rate of relapses on various treatments. METHODS: We determined the frequency of relapses in patients receiving various forms of long-term immunotherapy for MOGAD. Inclusion criteria were history of ≥1 CNS demyelinating attacks, MOG-IgG seropositivity, and immunotherapy for ≥6 months. Patients were reviewed for CNS demyelinating attacks before and during long-term immunotherapy. RESULTS: Seventy patients were included. The median age at initial CNS demyelinating attack was 29 years (range 3-61 years; 33% <18 years), and 59% were female. The median annualized relapse rate (ARR) before treatment was 1.6. On maintenance immunotherapy, the proportion of patients with relapse was as follows: mycophenolate mofetil 74% (14 of 19; ARR 0.67), rituximab 61% (22 of 36; ARR 0.59), azathioprine 59% (13 of 22; ARR 0.2), and IV immunoglobulin (IVIG) 20% (2 of 10; ARR 0). The overall median ARR on these 4 treatments was 0.3. All 9 patients treated with multiple sclerosis (MS) disease-modifying agents had a breakthrough relapse on treatment (ARR 1.5). CONCLUSION: This large retrospective multicenter study of patients with MOGAD suggests that maintenance immunotherapy reduces recurrent CNS demyelinating attacks, with the lowest ARR being associated with maintenance IVIG therapy. Traditional MS disease-modifying agents appear to be ineffective. Prospective randomized controlled studies are required to validate these conclusions.
Chen EM, Armstrong GW, Cox JT, Wu DM, Hoover DR, Del Priore LV, Parikh R. Association of the Affordable Care Act Medicaid Expansion with Dilated Eye Examinations among the United States Population with Diabetes. Ophthalmology 2020;127(7):920-928.Abstract
PURPOSE: To evaluate the association between Medicaid expansion and diabetic dilated eye examinations. DESIGN: A retrospective difference in differences (DiD) analysis using individual-level survey response data from January 1, 2009, to December 31, 2017. PARTICIPANTS: A total of 52 392 survey responses from 50 states and the District of Columbia between 2009 and 2017. Responders were adults aged 18 to 64 years reporting a previous diagnosis of diabetes and a household income below 138% of the US federal poverty line (FPL). METHODS: The Centers for Disease Control and Prevention's Behavioral Risk Factor Surveillance System data were used to identify survey responders who were asked about the presence of dilated eye examinations from years before and after Medicaid expansion implementation. MAIN OUTCOME MEASURES: The DiD in proportion of dilated eye examinations among diabetic persons aged 18 to 64 years with household incomes below 138% of the FPL between states that did and did not implement Medicaid expansion. RESULTS: Implementation of Medicaid expansion policies was associated with a 1.3% (95% confidence interval [CI], -3.8 to 6.4; P = 0.61), 6.3% (95% CI, 1.3-11.3; P = 0.016), 4.1% (95% CI, -0.8 to 9.0; P = 0.11), and 2.3% (95% CI, -1.6 to 6.2; P = 0.23) increase in the proportion of diabetic persons aged 18 to 64 years with incomes below 138% of the FPL receiving a dilated eye examination within the past year due to Medicaid expansion 1, 2, 3, and 4 cumulative years after expansion, respectively. CONCLUSIONS: Medicaid expansion policies were significantly associated with an increase in dilated eye examination rates within the first 2 years after implementation. However, this increase did not persist beyond this period, with nonsignificant increases 3 and 4 cumulative years after implementation. Healthcare policymakers should be aware that additional measures beyond expanding insurance coverage may be necessary to increase and sustain the rate of dilated eye examinations among diabetic populations.
Chen TC, Jurkunas U, Chodosh J. A Patient With Glaucoma With Corneal Edema. JAMA Ophthalmol 2020;
Chen D, Liu Y, Shu G, Chen C, Sullivan DA, Kam WR, Hann S, Fowler M, Warman ML. Ocular Manifestations of Chordin-like 1 Knockout Mice. Cornea 2020;39(9):1145-1150.Abstract
PURPOSE: In humans, loss-of-function mutations in the gene encoding Chordin-like 1 (CHRDL1) cause X-linked megalocornea (MGC1), characterized by bilateral corneal enlargement, decreased corneal thickness, and increased anterior chamber depth (ACD). We sought to determine whether Chrdl1 knockout (KO) mice would recapitulate the ocular findings found in patients with MGC1. METHODS: We generated mice with a Chrdl1 KO allele and confirmed that male Chrdl1 hemizygous KO mice do not express Chrdl1 mRNA. We examined the eyes of male mice that were hemizygous for either the wild-type (WT) or KO allele and measured corneal diameter, corneal area, corneal thickness, endothelial cell density, ACD, tear volume, and intraocular pressure. We also harvested retinas and counted retinal ganglion cell numbers. Eye segregation pattern in the dorsal lateral geniculate nucleus were also compared between male Chrdl1 KO and WT mice. RESULTS: Male Chrdl1 KO mice do not have larger cornea diameters than WT mice. KO mice have significantly thicker central corneas (116.5 ± 3.9 vs. 100.9 ± 4.2 μm, P = 0.013) and smaller ACD (325.7 ± 5.7 vs. 405.6 ± 6.3 μm, P < 0.001) than WT mice, which is the converse of what occurs in patients who lack CHRDL1. Retinal-thalamic projections and other ocular measurements did not significantly differ between KO and WT mice. CONCLUSIONS: Male Chrdl1 KO mice do not have the same anterior chamber abnormalities seen in humans with CHRDL1 mutations. Therefore, Chrdl1 KO mice do not recapitulate the human MGC1 phenotype. Nevertheless, Chrdl1 plays a role during mouse ocular development because corneas in KO mice differ from those in WT mice.
Chen EM, Cox JT, Begaj T, Armstrong GW, Khurana RN, Parikh R. Private Equity in Ophthalmology and Optometry: Analysis of Acquisitions from 2012 through 2019 in the United States. Ophthalmology 2020;127(4):445-455.Abstract
PURPOSE: To identify temporal and geographic trends in private equity (PE)-backed acquisitions of ophthalmology and optometry practices in the United States. DESIGN: A cross-sectional study using private equity acquisition and investment data from January 1, 2012, through October 20, 2019. PARTICIPANTS: A total of 228 PE acquisitions of ophthalmology and optometry practices in the United States between 2012 and 2019. METHODS: Acquisition and financial investment data were compiled from 6 financial databases, 4 industry news outlets, and publicly available press releases from PE firms or platform companies. MAIN OUTCOME MEASURES: Yearly trends in ophthalmology and optometry acquisitions, including number of total acquisitions, clinical locations, and providers of acquired practices as well as subsequent sales, median holding period, geographic footprint, and financing status of each platform company. RESULTS: A total of 228 practices associated with 1466 clinical locations and 2146 ophthalmologists or optometrists were acquired by 29 PE-backed platform companies. Of these acquisitions, 127, 9, and 92 were comprehensive or multispecialty, retina, and optometry practices, respectively. Acquisitions increased rapidly between 2012 and 2019: 42 practices were acquired between 2012 and 2016 compared to 186 from 2017 through 2019. Financing rounds of platform companies paralleled temporal acquisition trends. Three platform companies, comprising 60% of platforms formed before 2016, were subsequently sold or recapitalized to new PE investors by the end of this study period with a median holding period of 3.5 years. In terms of geographic distribution, acquisitions occurred in 40 states with most PE firms developing multistate platform companies. New York and California were the 2 states with the greatest number of PE acquisitions with 22 and 19, respectively. CONCLUSIONS: Private equity-backed acquisitions of ophthalmology and optometry practices have increased rapidly since 2012, with some platform companies having already been sold or recapitalized to new investors. Additionally, private equity-backed platform companies have developed both regionally focused and multistate models of add-on acquisitions. Future research should assess the impact of PE investment on patient, provider, and practice metrics, including health outcomes, expenditures, procedural volume, and staff employment.
Chen CT, Schultz JA, Haven SE, Wilhite B, Liu C-H, Chen J, Hibbeln JR. Loss of RAR-related orphan receptor alpha (RORα) selectively lowers docosahexaenoic acid in developing cerebellum. Prostaglandins Leukot Essent Fatty Acids 2020;152:102036.Abstract
Deficiency in retinoid acid receptor-related orphan receptor alpha (RORα) of staggerer mice results in extensive granule and Purkinje cell loss in the cerebellum as well as in learned motor deficits, cognition impairments and perseverative tendencies that are commonly observed in autistic spectrum disorder (ASD). The effects of RORα on brain lipid metabolism associated with cerebellar atrophy remain unexplored. The aim of this study is to examine the effects of RORα deficiency on brain phospholipid fatty acid concentrations and compositions. Staggerer mice (Rora) and wildtype littermates (Rora) were fed n-3 polyunsaturated fatty acids (PUFA) containing diets ad libitum. At 2 months and 7 or more months old, brain total phospholipid fatty acids were quantified by gas chromatography-flame ionization detection. In the cerebellum, all fatty acid concentrations were reduced in 2 months old mice. Since total fatty acid concentrations were significantly different at 2-month-old, we examined changes in fatty acid composition. The composition of ARA was not significantly different between genotypes; though DHA composition remained significantly lowered. Despite cerebellar atrophy at >7-months-old, cerebellar fatty acid concentrations had recovered comparably to wildtype control. Therefore, RORα may be necessary for fatty acid accretions during neurodevelopment. Specifically, the effects of RORα on PUFA metabolisms are region-specific and age-dependent.