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Maher MD, Douglas VP, Douglas KA, Collens SI, Gilbert AL, Torun N, Klein JP, Sobrin L, Buchbinder BR, Gupta R, Mukerji SS, Chwalisz BK. Clinical and neuroradiologic characteristics in varicella zoster virus reactivation with central nervous system involvement. J Neurol Sci 2022;437:120262.Abstract
OBJECTIVE: To investigate the clinical and magnetic resonance imaging (MRI) characteristics of patients with varicella zoster virus (VZV) reactivation involving the cranial nerves and central nervous system (CNS). METHODS: This is a retrospective, multi-center case-series of 37 patients with VZV infection affecting the cranial nerves and CNS. RESULTS: The median age was 71 years [IQR 51.5-76]; 21 (57%) were men. Cerebrospinal fluid (CSF) was available in 24/37 (65%); median CSF white blood cell count was 11 [IQR 2-23] cells/μL and protein was 45.5 [IQR 34.5-75.5] mg/dL. VZV polymerase chain reaction (PCR) assays were positive in 6/21 (29%) CSF and 8/9 (89%) ocular samples. Clinical involvement included the optic nerve in 12 (32%), other cranial nerves in 20 (54%), brain parenchyma in 12 (32%) and spinal cord or nerve roots in 4 (11%). Twenty-seven/28 immunocompetent patients' MRIs were available for review (96%). Of the 27, 18 had T1 postcontrast fat saturated sequences without motion artifact to evaluate for cranial nerve enhancement and optic perineuritis (OPN). Eight/18 (44%) demonstrated OPN. All 8 experienced vision loss: 3 optic neuritis, 1 acute retinal necrosis, and 3 CNS vasculitis with 1 central and 1 branch retinal artery occlusion and 1 uveitis. Diplopic patients had cranial nerve and cavernous sinus enhancement. All immunosuppressed patients were imaged. Seven/9 (88%) had extensive neuraxis involvement, including encephalitis, vasculitis and transverse myelitis; one case had OPN. CONCLUSION: OPN is a frequent manifestation in VZV-associated vision loss among immunocompetent patients. Immunosuppressed patients had greater neuraxis involvement. Optimizing MRI protocols may improve early diagnosis in VZV reactivation.
Okumura Y, Inomata T, Midorikawa-Inomata A, Sung J, Fujio K, Akasaki Y, Nakamura M, Iwagami M, Fujimoto K, Eguchi A, Miura M, Nagino K, Hirosawa K, Huang T, Kuwahara M, Dana R, Murakami A. DryEyeRhythm: A reliable and valid smartphone application for the diagnosis assistance of dry eye. Ocul Surf 2022;Abstract
PURPOSE: Undiagnosed or inadequately treated dry eye disease (DED) decreases the quality of life. We aimed to investigate the reliability, validity, and feasibility of the DryEyeRhythm smartphone application (app) for the diagnosis assistance of DED. METHODS: This prospective, cross-sectional, observational, single-center study recruited 82 participants (42 with DED) aged ≥20 years (July 2020-May 2021). Patients with a history of eyelid disorder, ptosis, mental disease, Parkinson's disease, or any other disease affecting blinking were excluded. Participants underwent DED examinations, including the Japanese version of the Ocular Surface Disease Index (J-OSDI) and maximum blink interval (MBI). We analyzed their app-based J-OSDI and MBI results. Internal consistency reliability and concurrent validity were evaluated using Cronbach's alpha coefficients and Pearson's test, respectively. The discriminant validity of the app-based DED diagnosis was assessed by comparing the results of the clinical-based J-OSDI and MBI. The app feasibility and screening performance were evaluated using the precision rate and receiver operating characteristic curve analysis. RESULTS: The app-based J-OSDI showed good internal consistency (Cronbach's α = 0.874). The app-based J-OSDI and MBI were positively correlated with their clinical-based counterparts (r = 0.891 and r = 0.329, respectively). Discriminant validity of the app-based J-OSDI and MBI yielded significantly higher total scores for the DED cohort (8.6 ± 9.3 vs. 28.4 ± 14.9, P < 0.001; 19.0 ± 11.1 vs. 13.2 ± 9.3, P < 0.001). The app's positive and negative predictive values were 91.3% and 69.1%, respectively. The area under the curve (95% confidence interval) was 0.910 (0.846-0.973) with concurrent use of the app-based J-OSDI and MBI. CONCLUSIONS: DryEyeRhythm app is a novel, non-invasive, reliable, and valid instrument for assessing DED.
Huang JJ, Geduldig JE, Jacobs EB, Tai TYT, Ahmad S, Chadha N, Buxton DF, Vinod K, Wirostko BM, Kang JH, Wiggs JL, Ritch R, Pasquale LR. Head and neck region dermatological UV-related cancers are associated with exfoliation syndrome in a clinic-based population. Ophthalmol Glaucoma 2022;Abstract
OBJECTIVE: We assessed the relation between UV-associated dermatological carcinomas (basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)) and exfoliation syndrome with or without glaucoma (XFS/XFG). DESIGN: Case-control study. Subjects, participants, and controls:321 participants with XFS/XFG, primary open angle glaucoma (POAG), and control subjects (XFS/XFG = 98, POAG = 117, control = 106, ages 50-90) were recruited between 2019-2021. METHODS: Subjects were recruited for a cross-sectional survey assessing medical history, maximum known intraocular pressure, cup-to-disc ratio, Humphrey Visual Field 24-2 (HVF), propensity to tan or burn in early life, history of BCC and/or SCC and XFS/XFG diagnosis. We generated multivariable models adjusting for age, sex, medical history, eye color, hair color, and likeliness of tanning vs burning at a young age. MAIN OUTCOME MEASURES: History of diagnosed XFS/XFG. RESULTS: Any history of BCC/SCC in the head and neck region was associated with a 2-fold higher risk for having XFS/XFG versus having POAG or being a control subject (odds ratio (OR) = 2.01, 95% confidence interval (CI) = 1.04 - 3.89) in multivariable-adjusted analysis. Additionally, we observed a dose-response association where the chance of having XFS/XFG was higher by 67% per head and neck BCC/SCC occurrence (OR = 1.67, 95% CI = 1.09 - 2.56). When we excluded POAG participants, head and neck BCC/SCC was associated with 2.8-fold higher risk of XFS/XFG (OR = 2.80, 95% CI = 1.12 - 7.02) and each additional occurrence of head and neck BCC/SCC had a 2-fold higher risk for XFS/XFG (OR = 1.97, 95% CI = 1.09 - 3.58). The association between head and neck region BCC/SCC and POAG compared to control subjects was null (OR = 1.42, 95% CI = 0.58 - 3.48). When BCC/SCC located anywhere on the body was considered, there was a non-significant higher risk of XFS/XFG compared to having POAG or being a control subject (OR = 1.65, 95% CI = 0.88 - 3.09). CONCLUSIONS: Head and neck region BCC/SCCs are associated with a higher risk for having XFS/XFG. These findings support prior evidence that head and neck UV exposure may be a risk factor for XFS.
Li S, Tang L, Zhou J, Anchouche S, Li D, Yang Y, Liu Z, Wu J, Hu J, Zhou Y, Yin J, Liu Z, Li W. Sleep deprivation induces corneal epithelial progenitor cell over-expansion through disruption of redox homeostasis in the tear film. Stem Cell Reports 2022;Abstract
Sleep deficiency, a common public health problem, causes ocular discomfort and affects ocular surface health. However, the underlying mechanism remains unclear. Herein, we identified that short-term sleep deprivation (SD) resulted in hyperproliferation of corneal epithelial progenitor cells (CEPCs) in mice. The expression levels of p63 and Keratin 14, the biomarkers of CEPCs, were upregulated in the corneal epithelium after short-term SD. In addition, SD led to elevated levels of reactive oxygen species (ROS), and subsequent decrease in antioxidant capacity, in the tear film. Exogenous hydrogen peroxide (H2O2) could directly stimulate the proliferation of CEPCs in vivo and in vitro. Topical treatment of antioxidant L-glutathione preserved the over-proliferation of CEPCs and attenuated corneal epithelial defects in SD mice. Moreover, the activation of the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway is essential to ROS-stimulated cell proliferation in CEPCs. However, long-term SD ultimately led to early manifestation of limbal stem cell deficiency.
Lin LY, Reshef ER, Lansberg MP, Barshak MB, Chwalisz BK, Holbrook EH, Wolkow N. Posterior Ischemic Optic Neuropathy in the Setting of Cocaine-Induced Orbital and Sinonasal Inflammation. Ophthalmic Plast Reconstr Surg 2022;Abstract
Intranasal cocaine abuse can lead to significant sinus and orbital complications, including optic neuropathy. A 46-year-old man with a history of recurrent cocaine-induced sino-orbital inflammation and infection with bony destruction presented with acute, painless, vision loss. Examination revealed no light perception vision. MRI of the orbits demonstrated new restricted diffusion of the right optic nerve on diffusion-weighted imaging and apparent diffusion coefficient sequences, consistent with posterior ischemic optic neuropathy. This is the first among cases of cocaine-induced optic neuropathy in the literature to illustrate ischemic changes on MRI in the optic nerve, highlighting the utility of diffusion-weighted imaging/apparent diffusion coefficient sequences when optic neuropathy is suspected and further suggesting an underlying ischemic etiology in similar cases.
Lundgren P, Morsing E, Hård A-L, Rakow A, Hellström-Westas L, Jacobson L, Johnson M, Holmström G, Nilsson S, Smith LE, Sävman K, Hellström A. National cohort of infants born before 24 gestational weeks showed increased survival rates but no improvement in neonatal morbidity. Acta Paediatr 2022;Abstract
AIM: To describe survival and neonatal morbidities in infants born before 24 weeks of gestation during a 12-year period. METHODS: Data were retrieved from national registries and validated in medical files of infants born before 24 weeks of gestation 2007-2018 in Sweden. Temporal changes were evaluated. RESULTS: In 2007-2018, 282 live births were recorded at 22 weeks and 460 at 23 weeks of gestation. Survival to discharge from hospital of infants born alive at 22 and 23 weeks increased from 20% to 38% (p = 0.006) and from 45% to 67% (p < 0.001) respectively. Caesarean section increased from 12% to 22% (p = 0.038) for infants born at 22 weeks. Neonatal morbidity rates in infants alive at 40 weeks of postmenstrual age (n = 399) were unchanged except for an increase in necrotising enterocolitis from 0 to 33% (p = 0.017) in infants born at 22 weeks of gestation. Bronchopulmonary dysplasia was more common in boys than girls, 90% versus 82% (p = 0.044). The number of infants surviving to 40 weeks doubled over time. CONCLUSION: Increased survival of infants born before 24 weeks of gestation resulted in increasing numbers of very immature infants with severe neonatal morbidities likely to have a negative impact on long-term outcome.
Maciorowski D, Diop C, Bhatt U, Estelien R, Li D, Chauhan R, Vandenberghe LH, Zabaleta N. Immunogenicity of an AAV-Based COVID-19 Vaccine in Murine Models of Obesity and Aging. Viruses 2022;14(4)Abstract
The SARS-CoV-2 pandemic has had a disastrous impact on global health. Although some vaccine candidates have been effective in combating SARS-CoV-2, logistical, economical, and sociological aspects still limit vaccine access globally. Recently, we reported on two room-temperature stable AAV-based COVID-19 vaccines that induced potent and protective immunogenicity following a single injection in murine and primate models. Obesity and old age are associated with increased mortality in COVID-19, as well as reduced immunogenicity and efficacy of vaccines. Here, we investigated the effectiveness of the AAVCOVID vaccine candidates in murine models of obesity and aging. Results demonstrate that obesity did not significantly alter the immunogenicity of either vaccine candidate. In aged mice, vaccine immunogenicity was impaired. These results suggest that AAV-based vaccines may have limitations in older populations and may be equally applicable in obese and non-obese populations.
Tam EK, Elhusseiny AM, Shah AS, Mantagos IS, VanderVeen DK. Etiology and outcomes of childhood glaucoma at a tertiary referral center. J AAPOS 2022;Abstract
PURPOSE: To describe the etiology, clinical features, and outcomes for a large contemporary cohort of children presenting with glaucoma at a tertiary referral center. METHODS: The medical records of patients presenting to Boston Children's Hospital from January 2014 to July 2019 with a diagnosis of childhood glaucoma were retrospectively reviewed. Data regarding etiology, treatment, and visual and anatomic outcomes were collected; visual acuity outcomes were analyzed by laterality and diagnosis categories, using the Childhood Glaucoma Research Network (CGRN) classifications. RESULTS: A total of 373 eyes of 246 patients (51% males) diagnosed with glaucoma before 18 years of age were identified. Mean follow-up was 7.04 ± 5.61 years; 137 cases were bilateral. The mean age at diagnosis was 4.55 ± 5.20 years. The most common diagnoses were glaucoma following cataract surgery (GFCS, 36.5%) and primary congenital glaucoma (PCG, 29.0%). Overall, 164 eyes (44.0%) underwent at least one glaucoma surgery. Intraocular pressure (IOP) was ≤21 mm Hg with or without glaucoma medications in 300 eyes (80.4%) at the last follow-up visit. Poor final best-corrected visual acuity (≤20/200) was found in 110 eyes; patients with poor final visual acuity tended to have poor visual acuity at presentation. The most common reason for poor vision was amblyopia. Uncontrolled IOP was an uncommon cause for vision loss. CONCLUSIONS: Childhood glaucoma can be challenging to manage, but poor vision usually results from amblyopia or presence of other ocular abnormalities or syndromes rather than glaucomatous optic neuropathy.
Salamzade R, Manson AL, Walker BJ, Brennan-Krohn T, Worby CJ, Ma P, He LL, Shea TP, Qu J, Chapman SB, Howe W, Young SK, Wurster JI, Delaney ML, Kanjilal S, Onderdonk AB, Bittencourt CE, Gussin GM, Kim D, Peterson EM, Ferraro MJ, Hooper DC, Shenoy ES, Cuomo CA, Cosimi LA, Huang SS, Kirby JE, Pierce VM, Bhattacharyya RP, Earl AM. Inter-species geographic signatures for tracing horizontal gene transfer and long-term persistence of carbapenem resistance. Genome Med 2022;14(1):37.Abstract
BACKGROUND: Carbapenem-resistant Enterobacterales (CRE) are an urgent global health threat. Inferring the dynamics of local CRE dissemination is currently limited by our inability to confidently trace the spread of resistance determinants to unrelated bacterial hosts. Whole-genome sequence comparison is useful for identifying CRE clonal transmission and outbreaks, but high-frequency horizontal gene transfer (HGT) of carbapenem resistance genes and subsequent genome rearrangement complicate tracing the local persistence and mobilization of these genes across organisms. METHODS: To overcome this limitation, we developed a new approach to identify recent HGT of large, near-identical plasmid segments across species boundaries, which also allowed us to overcome technical challenges with genome assembly. We applied this to complete and near-complete genome assemblies to examine the local spread of CRE in a systematic, prospective collection of all CRE, as well as time- and species-matched carbapenem-susceptible Enterobacterales, isolated from patients from four US hospitals over nearly 5 years. RESULTS: Our CRE collection comprised a diverse range of species, lineages, and carbapenem resistance mechanisms, many of which were encoded on a variety of promiscuous plasmid types. We found and quantified rearrangement, persistence, and repeated transfer of plasmid segments, including those harboring carbapenemases, between organisms over multiple years. Some plasmid segments were found to be strongly associated with specific locales, thus representing geographic signatures that make it possible to trace recent and localized HGT events. Functional analysis of these signatures revealed genes commonly found in plasmids of nosocomial pathogens, such as functions required for plasmid retention and spread, as well survival against a variety of antibiotic and antiseptics common to the hospital environment. CONCLUSIONS: Collectively, the framework we developed provides a clearer, high-resolution picture of the epidemiology of antibiotic resistance importation, spread, and persistence in patients and healthcare networks.
Gotti G, Stevenson K, Kay-Green S, Blonquist TM, Mantagos JS, Silverman LB, Place AE. Ocular abnormalities at diagnosis and after the completion of treatment in children and adolescents with newly diagnosed acute lymphoblastic leukemia. Pediatr Blood Cancer 2022;69(4):e29542.Abstract
BACKGROUND: Ocular abnormalities (OA) in pediatric patients with acute lymphoblastic leukemia (ALL) are common findings both at diagnosis and later in follow-up. The frequency, predictors, and prognostic impact of OA in the context of recent ALL protocols are not well characterized. PROCEDURE: Single-center retrospective analysis of the medical records of 224 patients with ALL enrolled on Dana-Farber Cancer Institute (DFCI) ALL Consortium Protocol 05-001. RESULTS: Overall, 217 (98%) patients had at least one ophthalmic exam. Retinal hemorrhages were the most frequent abnormalities at diagnosis (11%) and cataracts at later time points (13%). OA at diagnosis were associated with age ≥10 years and with the severity of anemia and thrombocytopenia; they were also univariately associated with lower 5-year event-free survival (EFS) (high risk [HR] = 3.09 [95% CI: 1.38-6.94]; p = .006), but not in a disease-free survival (DFS) model adjusted for end-induction minimal residual disease (p = .82). The cumulative incidence of cataract was 13.1% ± 2.8% at 43 months from diagnosis; its development was associated with high presenting white blood cell count (≥50,000/μl) (p = .010), male sex (p = .036), higher risk group (p = .025), and cranial radiation (p = .004). Cataract was associated with decreased visual acuity. CONCLUSIONS: OA at diagnosis, present in 12% of patients, were associated with older age, anemia, and thrombocytopenia and did not carry a significant prognostic impact. Cataracts were detected in over 10% of patients and were associated with decreased visual acuity, thus supporting routine screening after completion of therapy, especially for those treated with high-risk protocols.
Hallal R, Armstrong GW, Pineda R. Long-Term Outcomes of Big Bubble Deep Anterior Lamellar Keratoplasty in Mucopolysaccharidoses: A Retrospective Case Series and Review of the Literature. Cornea 2022;Abstract
PURPOSE: The purpose of this study was to report the long-term surgical and visual outcomes of patients with mucopolysaccharidoses (MPS) after big bubble deep anterior lamellar keratoplasty (BB-DALK). METHODS: This was a retrospective case series of patients with MPS who underwent BB-DALK at a single academic institution. All patients had corneal clouding secondary to MPS limiting visual acuity for which keratoplasty was indicated. Each patient was evaluated and underwent surgery by a single surgeon. Reported data included age at keratoplasty, sex, MPS type, best spectacle-corrected visual acuity, change in pachymetry, ocular comorbidities, surgical complications, and MPS-related medication use. RESULTS: Outcomes of 12 eyes from 7 patients with MPS type I (Hurler, Scheie, and Hurler-Scheie) are reported using the newest nomenclature. The mean follow-up was 5.58 years (range: 1-10 years). All cases underwent BB-DALK with a type 1 big bubble during the surgery. Two cases (16.6%) required rebubbling because of partial Descemet membrane detachment. One case was complicated by a suture abscess and required a penetrating keratoplasty. No episodes of rejection occurred. Statistically significant improvement in the best spectacle-corrected visual acuity (from a mean 0.85-0.33 logarithm of the minimum angle of resolution, P = logarithm of the minimum angle of resolution 0.0054) and pachymetry (mean reduction of -145.4 μm, P = 0.0018) was observed. CONCLUSIONS: BB-DALK seems to be an acceptable long-term surgical option in patients with MPS. Our findings suggest that this technique is reproducible and can achieve clear corneal grafts with good visual results on a long-term follow-up.
Weakley DR, Nizam A, VanderVeen DK, Wilson EM, Kruger S, Lambert SR, Lambert SR. Myopic Shift at 10 Years Follow-up in the Infant Aphakia Treatment Study. Ophthalmology 2022;Abstract
We studied the myopic shift and anisometropia at 10.6 (+/-0.3) years of age in the Infant Aphakia Treatment Study. We found myopic shift continues in the operated eye from 5-10.5 years at a lower rate than that prior to age five years while anisometropia increases proportionally. The Infant Aphakia Treatment Study (IATS) is a randomized clinical trial initially designed to compare outcomes in infants under seven months of age who underwent primary implantation of an intraocular lens (IOL) versus being left aphakic and receiving a contact lens correction following cataract surgery in infancy.1 Patients were enrolled from 2004 through 2009 with the last 10-year follow-up exam completed in 2019. The study design was approved by the institutional review boards of the 12 participating sites and followed the tenets of the Declaration of Helsinki. The off-label use of the AcrySof SN60AT and MA60AC IOLs (Alcon Laboratories, Fort Worth Tx.) was covered under the United States Food and Drug Administration investigational device exemption. The trial is registered at www.ClinicalTrials.gov (identifier, NCT00212134).
Fan N-W, Wang S, Ortiz G, Chauhan SK, Chen Y, Dana R. Autoreactive memory Th17 cells are principally derived from T-bet+RORγt +Th17/1 effectors. J Autoimmun 2022;129:102816.Abstract
Effector Th17 cells, including IFN-γ-IL-17+ (eTh17) and IFN-γ+IL-17+ (eTh17/1) subsets, play critical pathogenic functions in the induction of autoimmunity. As acute inflammation subsides, a small proportion of the effectors survive and convert to memory Th17 cells (mTh17), which sustain chronic inflammation in autoimmune diseases. Herein, we investigated the differential contributions of eTh17 versus eTh17/1 to the memory pool using an experimental model of ocular autoimmune disease. Our results show that adoptive transfer of Tbx21-/- CD4+ T cells or conditional deletion of Tbx21 in Th17 cells leads to diminished eTh17/1 in acute phase and functionally compromised mTh17 in chronic phase. Further, adoptive transfer of disease-specific eTh17/1, but not eTh17, leads to generation of mTh17 and sustained ocular inflammation. Collectively, our data demonstrate that T-bet-dependent eTh17/1 cells generated during the acute inflammation are the principal effector precursors of pathogenic mTh17 cells that sustain the chronicity of autoimmune inflammation.

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