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Non-immune hydrops fetalis (NIHF) is a rare entity characterized by excessive accumulation of fluid within the fetal extravascular compartments and body cavities. Here we present two intrauterine fetal demises with NIHF presenting with oligohydramnios, cystic hygroma, pleural effusion, and generalized hydrops with predominance of subcutaneous edema. The fetuses also presented with ascites, severe and precocious IUGR and skeletal anomalies. Whole exome sequencing was applied in order to screen for a possible genetic cause. The results identified biallelic variants in MYBBP1A in both fetuses. A previous report described another case with a similar phenotype having compound heterozygous variants in the same gene. The protein encoded by MYBBP1A is involved in several cellular processes including the synthesis of ribosomal DNA, the response to nucleolar stress, and tumor suppression. Our functional protein analysis through immunohistochemistry indicates that MYBBP1A is a gene expressed during fetal stages. Altogether, we concluded that MYBBP1A is associated with the development of hydrops fetalis. More cases and further studies are necessary to understand the role of this gene and the mechanism associated with NIHF.
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PURPOSE: To evaluate and compare subbasal corneal nerve parameters of the inferior whorl in patients with dry eye disease (DED), neuropathic corneal pain (NCP), and controls using a novel deep-learning-based algorithm to analyze in-vivo confocal microscopy (IVCM) images. METHODS: Subbasal nerve plexus (SNP) images of the inferior whorl of patients with DED (n = 49, 77 eyes), NCP (n = 14, 24 eyes), and controls (n = 41, 59 eyes) were taken with IVCM and further analyzed using an open-source artificial intelligence (AI)-based algorithm previously developed by our group. This algorithm automatically segments nerves, immune cells, and neuromas in the SNP. The following parameters were compared between groups: nerve area density, average nerve thickness, average nerve segment tortuosity, junction point density, neuroma density, and immune cell density. RESULTS: 160 eyes of 104 patients (63 % females), aged 56.8 ± 15.4 years, were included. The mean nerve area density was significantly lower in the DED (P = 0.012) and NCP (P < 0.001) groups compared to the control group. The junction point density was lower in the NCP group compared with control (P = 0.001) and DED (P = 0.004) groups. The immune cell density was higher in the DED group compared with controls (P < 0.001). CONCLUSIONS: Deep-learning-based analysis of IVCM images of the corneal SNP inferior whorl distinguished a decreased mean nerve area density in patients with DED and NCP compared with controls and an increased immune cell density in patients with oGVHD- and SS-associated DED. These findings suggest that the inferior whorl could be used as landmark to distinguish between patients with DED and NCP.
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INTRODUCTION: This study aimed to analyze corneal sensitivity with a new noncontact and handheld esthesiometer (Brill Engines, Spain) in patients with dry eye disease (DED) and patients on hypotensive drops, and to compare it with healthy subjects. METHODS: A total of 31 patients (57 eyes) with DED, 23 patients (46 eyes) with glaucoma, and 21 healthy patients (33 eyes) were recruited. In all patients, corneal sensitivity was measured. Subsequently, a keratography test (Keratograph 5M, Oculus) was carried out to measure tear meniscus height (TMH), non-invasive breakup time (NIBUT), bulbar redness (Jenvis scale), and corneal staining (CS, Oxford scale). Both corneal sensitivity and ocular surface parameters were compared between DED, glaucoma, and healthy subjects. Linear mixed models were constructed to utilize data from both eyes of patients. An alpha level of 0.05 was considered statistically significant. RESULTS: The mean age was 56.1 ± 16.1 years in the DED group, 69.5 ± 11.7 years in the glaucoma group, and 37.190 ± 11.677 years in the control group. After adjustment for age and sex, corneal sensitivity was significantly reduced in DED and glaucoma vs control group (P = 0.02 and P = 0.009, respectively). NIBUT was lower in DED and glaucoma groups (P < 0.001 and P = 0.001, respectively). Redness and CS values were higher in the DED group (P = 0.04 and P = 0.001, respectively). TMH was lower in the glaucoma group (P = 0.03). CONCLUSIONS: Corneal sensitivity measured with a novel noncontact esthesiometer was reduced in DED and glaucoma groups compared to controls. In clinical practice, this esthesiometer could be an easy-to-use device to screen for patients with subclinical neurotrophic keratopathy.
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BACKGROUND: To analyze the clinical course and outcomes of autoimmune vs. non-autoimmune surgically induced scleral necrosis (SISN). METHODS: Multicentric, retrospective, comparative cohort study. Eighty-two eyes of 70 patients with SISN were classified according to pathogenic mechanism into autoimmune vs. non-autoimmune. Main outcome measures included necrosis onset, type of surgery, associated systemic disease, visual acuity, and treatment were analysed in patients followed for ≥ 6 months. RESULTS: Forty-six (65.7%) patients were women, and the median age was 66 (range: 24-90) years. Most patients (82.9%) had unilateral disease. The median time between surgery and SISN onset was 58 (1-480) months. Thirty-one (37.8%) eyes were classified as autoimmune, and 51 (62.2%) as non-autoimmune SISN. Autoimmune SISN was associated with a shorter time between the surgical procedure and SISN onset than non-autoimmune cases (median of 26 vs. 60 months, p = 0.024). Also, autoimmune SISN was associated with cataract extraction (93.5% vs. 25.5%, p < 0.001), severe scleral inflammation (58.1% vs. 17.6%, p < 0.001), and higher incidence of ocular complications (67.7% vs. 33.3%, p = 0.002) than non-autoimmune cases. Remission was achieved with medical management alone in 44 (86.3%) eyes from the non-autoimmune and in 27 (87.1%) from the autoimmune group (p = 0.916). Surgical management was required in 11 (13.4%) eyes, including two requiring enucleations due to scleral perforation and phthisis bulbi. CONCLUSIONS: Eyes with autoimmune SISN had a higher rate of cataract surgery, severe scleral inflammation, and ocular complications. Early SISN diagnosis and appropriate management, based on clinical features and pathogenic mechanisms, are critical to avoid sight-threatening complications.
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Several gaps and barriers remain for transplanting stem cells into the eye to treat ocular disease, especially diseases of the retina. While the eye has historically been considered immune privileged, recent thinking has identified the immune system as both a barrier and an opportunity for eye stem cell transplantation. Recent approaches leveraging scaffolds or cloaking have been considered in other tissues beyond immune suppression. This perspective paper outlines approaches for transplantation and proposes opportunities to overcome barriers of the immune system in stem cell transplantation in the eye.
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Retina , Trasplante de Células Madre , Humanos , Retina/inmunología , Retina/citología , Trasplante de Células Madre/métodos , Animales , Inmunología del Trasplante , Enfermedades de la Retina/terapia , Enfermedades de la Retina/inmunologíaRESUMEN
Purpose: To assess the effectiveness of topical and subconjunctival bevacizumab in suppressing vascularization in graft and host bed after high-risk corneal transplantation. Design: Secondary analysis of prospective, randomized, double-blind, placebo-controlled multicentric clinical trial. Participants: The study includes patients aged > 18 years who underwent high-risk penetrating keratoplasty, which was defined as corneal vascularization in ≥ 1 quadrants of the corneal graft and host bed, excluding the limbus. Methods: Patients were randomized to treatment and control groups. The patients in the treatment group received subconjunctival injection of bevacizumab (2.5 mg/0.1 ml) on the day of the procedure, followed by topical bevacizumab (10 mg/ml) 4 times per day for 4 weeks. The patients in control group received injection of vehicle (0.9% sodium chloride) on the day of procedure, followed by topical vehicle (carboxymethylcellulose sodium 1%) 4 times a day for 4 weeks. Main Outcome Measures: Vessel and invasion area of vessels in the corneal graft and host beds. Results: This study included 56 eyes of 56 patients who underwent high-risk corneal transplantation, with equal numbers in the bevacizumab and vehicle (control) treatment groups. The mean age of patients who received bevacizumab was 61.2 ± 15.9 years, and the mean age of those treated with vehicle was 60.0 ± 16.1 years. The vessel area at baseline was comparable in the bevacizumab (16.72% ± 3.19%) and control groups (15.48% ± 3.12%; P = 0.72). Similarly, the invasion areas were also similar in the treatment (35.60% ± 2.47%) and control (34.23% ± 2.64%; P = 0.9) groups at baseline. The reduction in vessel area was significantly higher in the bevacizumab-treated group (83.7%) over a period of 52 weeks compared with the control group (61.5%; P < 0.0001). In the bevacizumab-treated group, invasion area was reduced by 75.8% as compared with 46.5% in the control group. The vessel area was similar at 52 weeks postprocedure in cases of first (3.54% ± 1.21%) and repeat (3.80% ± 0.40%) corneal transplantation in patients who received bevacizumab treatment. In the vehicle-treated patients, the vessel area was significantly higher in repeat (9.76% ± 0.32%) compared with first (8.06% ± 1.02%; P < 0.0001) penetrating keratoplasty. In the bevacizumab treatment group, invasion areas at week 52 were comparable in first (11.70% ± 3.38%) and repeat (11.64% ± 1.74%) procedures, whereas invasion area was significantly higher in repeat (27.87% ± 2.57%) as compared with first (24.11% ± 2.17%) penetrating keratoplasty in vehicle-treated patients. Conclusions: In patients undergoing vascularized high-risk corneal transplantation, bevacizumab is efficacious in reducing vascularization of corneal graft and host bed, thereby reducing the risk of corneal graft rejection in vascularized host beds. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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ABSTRACT: The ocular surface inflammatory disorders (OSIDs) comprise a group of conditions characterized by persistent inflammation of the ocular surface and adnexal tissues. Systemic autoimmune diseases and hypersensitivity reactions cause them, and, if left untreated, can result in severe inflammatory dry eye, corneal damage, and vision loss. Ocular graft-versus-host disease (oGVHD) forms part of the ocular surface inflammatory disease umbrella. It is a condition occurring after allogeneic hematopoietic stem cell or bone marrow transplantation, usually in chronic graft-versus-host disease. oGVHD can virtually affect any ocular adnexal tissue, especially the meibomian glands, and cause persistent inflammation, tissue fibrosis, and subsequent chronic, severe dry eye disease. Among the OSIDs, oGVHD has the particularity that it has a "time zero," meaning we know when the disease started. As such, preclinical models have leveraged this to investigate the molecular mechanisms involved in the damage oGVHD causes to the ocular surface. In oGVHD, establishing a "time zero" allows for predicting the clinical course and establishing adequate treatment. This is also possible because the inflammatory infiltration occurs in ocular surface tissues, which are readily accessible. Using oGVHD, we might be able to understand the immune response mechanisms in other OSIDs better (i.e., Sjögren syndrome, Stevens-Johnson syndrome, among others). This review presents an up-to-date overview of the pathogenesis, clinical presentation, and treatment of oGVHD. In addition, we will discuss the value of the "time zero" concept in the study of oGVHD.
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Síndromes de Ojo Seco , Enfermedad Injerto contra Huésped , Humanos , Síndromes de Ojo Seco/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
PURPOSE: Analyze the influence of risk factors at presentation in the long-term immunosuppressive therapy (IMT) outcomes of ocular mucous membrane pemphigoid (OMMP). DESIGN: Retrospective multicenter study. PARTICIPANTS: Patients with OMMP seen at the Duke Eye Center, Tecnologico de Monterrey, and Hospital Clinic of Barcelona from 1990 to 2022. METHODS: Data at presentation on demographics, direct immunofluorescence, ocular findings, sites of extraocular manifestations (EOMs), and previous treatments in patients with a clinical or laboratory diagnosis of OMMP, were analyzed with multivariable analysis and Kaplan-Meier plots to identify factors associated with adverse outcomes. MAIN OUTCOME MEASURES: (1) Inflammatory control (no conjunctival inflammation in both eyes at 3 months on IMT); (2) relapse (new-onset inflammation after absolute control in either eye); (3) progression (≥ 1 cicatrizing stage progression in either eye); and (4) vision loss (≥ 2 Snellen lines). RESULTS: A total of 117 patients (234 eyes), 61% (71/117) of whom were women, with a mean age of 66.6 (SD: 12.4) years (range: 37-97 years) and median follow-up of 34 months (interquartile range: 16-66 months; range: 3-265 months), were enrolled. Inflammatory control was achieved in 57% of patients (67/117), with high-risk EOM (HR-EOM), including esophageal, nasopharyngeal, and/or genital involvement (adjusted odds ratio [aOR]: 12.51; 95% confidence interval [CI]: 2.61-59.99; P = 0.002) and corneal scarring (aOR: 3.06; 95% CI, 1.15-8.14; P = 0.025), as significant risk factors for persistent inflammation. Disease relapse, progression, and vision loss occurred in 20% of patients (23/117), 12% of patients (14/117), and 27% of patients (32/117), respectively. Baseline corneal scarring was a risk factor for relapse (adjusted hazard ratio: 4.14; 95% CI: 1.61-10.62; P = 0.003), progression (aOR: 11.46; 95% CI: 1.78-73.75; P = 0.010), and vision loss (aOR: 3.51; 95% CI: 1.35-9.10; P = 0.010). HR-EOM was associated with stage progression (aOR, 34.57; 95% CI, 6.57-181.89; P<0.001) and vision loss (aOR, 8.42; 95% CI, 2.50-28.42; P = 0.001). No significant differences were found between IMT regimes and relapse (P = 0.169). CONCLUSIONS: Ocular mucous membrane pemphigoid presenting with HR-EOMs and corneal scarring has an increased risk of stage progression and vision loss. Corneal scarring and severe inflammation at baseline were associated with an increased risk of relapse. A disease progression staging system incorporating both the HR-EOMs and corneal involvement is required to predict the visual outcome of OMMP better. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Inmunosupresores , Penfigoide Benigno de la Membrana Mucosa , Humanos , Penfigoide Benigno de la Membrana Mucosa/tratamiento farmacológico , Penfigoide Benigno de la Membrana Mucosa/diagnóstico , Penfigoide Benigno de la Membrana Mucosa/fisiopatología , Femenino , Masculino , Anciano , Estudios Retrospectivos , Factores de Riesgo , Persona de Mediana Edad , Anciano de 80 o más Años , Adulto , Inmunosupresores/uso terapéutico , Resultado del Tratamiento , Agudeza Visual/fisiología , Progresión de la Enfermedad , Estudios de Seguimiento , Recurrencia , Glucocorticoides/uso terapéuticoRESUMEN
PURPOSE: The purpose of this study was to evaluate the pharmacogenomics of response to topical ocular tumor necrosis factor α (TNFα) inhibitor licaminlimab in patients with DED. METHODS: Three single-nucleotide polymorphisms (SNPs) associated with Sjögren syndrome, 3 in the TNFα gene and 1 in the TNF receptor 1 (TNFR1) gene, were assessed for association with response to licaminlimab in participants from a randomized, vehicle-controlled, Phase 2 study in which adults with DED and severe ocular discomfort persisting despite treatment with artificial tears received licaminlimab or vehicle for 6 weeks. Response was assessed for change from baseline in Global Ocular Discomfort score at Day 29 of treatment. The pharmacogenomic analysis was a prospectively specified exploratory objective of the study. mRNA expression for TNFα, interleukin (IL) 1ß, and IL8 in conjunctival epithelium cells was determined. The relationship between SNPs and response to licaminlimab was assessed using a mixed model repeated measures analysis. RESULTS: SNP rs1800693 in the TNFR1 gene showed a significant effect on response to licaminlimab (P < 0.0001, initial association test); no effect was seen for any of the other SNPs tested. The CC genotype of rs1800693 was associated with much greater response to licaminlimab than the CT or TT genotypes: LS mean changes from baseline to Day 29 in Global Ocular Discomfort score were -29.5, -0.09, and -3.90, in patients with the CC, CT, and TT genotypes, respectively (P < 0.0001). No significant effect was observed in vehicle-treated patients. Improvements from baseline were seen in 3/4 licaminlimab-treated participants with the CC genotype. Conjunctival epithelium cell levels of mRNA for TNFα, IL1ß, and IL8 decreased from baseline in participants with the CC genotype, but not with the CT or TT genotypes. Between-genotype differences in mRNA levels were not observed in participants receiving vehicle. CONCLUSIONS: The CC genotype of rs1800693, relatively common in patients with DED, was strongly associated with response to licaminlimab and decreased inflammatory cytokine gene expression in ocular surface cells during treatment. This study is one of the first to our knowledge to investigate pharmacogenomics in the treatment of DED.
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Meibomian gland dysfunction (MGD) is a leading cause of dry eye disease and one of the most common ophthalmic conditions encountered in eye clinics worldwide. These holocrine glands are situated in the eyelid, where they produce specialized lipids, or meibum, needed to lubricate the eye surface and slow tear film evaporation - functions which are critical to preserving high-resolution vision. MGD results in tear instability, rapid tear evaporation, changes in local microflora, and dry eye disease, amongst other pathological entities. While studies identifying the mechanisms of MGD have generally focused on gland obstruction, we now know that age is a major risk factor for MGD that is associated with abnormal cell differentiation and renewal. It is also now appreciated that immune-inflammatory disorders, such as certain autoimmune diseases and atopy, may trigger MGD, as demonstrated through a T cell-driven neutrophil response. Here, we independently discuss the underlying roles of gland and immune related factors in MGD, as well as the integration of these two distinct mechanisms into a unified perspective that may aid future studies. From this unique standpoint, we propose a revised model in which glandular dysfunction and immunopathogenic pathways are not primary versus secondary contributors in MGD, but are fluid, interactive, and dynamic, which we likened to the Yin and Yang of MGD.
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Disfunción de la Glándula de Meibomio , Glándulas Tarsales , Lágrimas , Humanos , Síndromes de Ojo Seco/inmunología , Síndromes de Ojo Seco/fisiopatología , Disfunción de la Glándula de Meibomio/inmunología , Glándulas Tarsales/inmunología , Glándulas Tarsales/patología , Glándulas Tarsales/metabolismo , Lágrimas/metabolismoRESUMEN
PURPOSE: The aim of this study was to validate the C-DU(KE) calculator as a predictor of treatment outcomes on a data set derived from patients with culture-positive ulcers. METHODS: C-DU(KE) criteria were compiled from a data set consisting of 1063 cases of infectious keratitis from the Steroids for Corneal Ulcer Trial (SCUT) and Mycotic Ulcer Treatment Trial (MUTT) studies. These criteria include corticosteroid use after symptoms, visual acuity, ulcer area, fungal etiology, and elapsed time to organism-sensitive therapy. Univariate analysis was performed followed by multivariable logistic regressions on culture-exclusive and culture-inclusive models to assess for associations between the variables and outcome. The predictive probability of treatment failure, defined as the need for surgical intervention, was calculated for each study participant. Discrimination was assessed using the area under the curve for each model. RESULTS: Overall, 17.9% of SCUT/MUTT participants required surgical intervention. Univariate analysis showed that decreased visual acuity, larger ulcer area, and fungal etiology had a significant association with failed medical management. The other 2 criteria did not. In the culture-exclusive model, 2 of 3 criteria, decreased vision [odds ratio (OR) = 3.13, P < 0.001] and increased ulcer area (OR = 1.03, P < 0.001), affected outcomes. In the culture-inclusive model, 3 of 5 criteria, decreased vision (OR = 4.9, P < 0.001), ulcer area (OR = 1.02, P < 0.001), and fungal etiology (OR = 9.8, P < 0.001), affected results. The area under the curves were 0.784 for the culture-exclusive model and 0.846 for the culture-inclusive model which were comparable to the original study. CONCLUSIONS: The C-DU(KE) calculator is generalizable to a study population from large international studies primarily taking place in India. These results support its use as a risk stratification tool assisting ophthalmologists in patient management.
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Úlcera de la Córnea , Infecciones Fúngicas del Ojo , Micosis , Humanos , Antifúngicos/uso terapéutico , Úlcera de la Córnea/diagnóstico , Úlcera de la Córnea/tratamiento farmacológico , Úlcera de la Córnea/microbiología , Infecciones Fúngicas del Ojo/diagnóstico , Infecciones Fúngicas del Ojo/tratamiento farmacológico , Infecciones Fúngicas del Ojo/microbiología , Micosis/microbiología , Esteroides , Úlcera/tratamiento farmacológico , Ensayos Clínicos como AsuntoRESUMEN
Purpose: We compare outcomes in eyes with dry eye disease (DED) treated with TearCare (TC) or topical cyclosporine 0.05% (RESTASIS; CsA). Setting: Nineteen ophthalmic and optometric practices in 11 US states. Design: Multicenter, randomized, assessor-masked, controlled IRB-approved trial. Eligible subjects: ≥22 years of age, dry eye symptoms within 3-6 months, Tear Break-up Time (TBUT) ≥1 to ≤7 s, Meibomian Gland Secretion Score (MGSS) ≤12, Ocular Surface Disease Index (OSDI) of 23-79. Randomized (1:1) to TC or CsA. TC subjects treated at baseline and month 5; CsA was twice daily for 6 months. Methods: Follow-up visits were scheduled for Day 1, Week 1, Months 1, 3, and 6 with primary inference at Month 6. Primary outcomes: TBUT and OSDI; secondary outcomes: MGSS, conjunctival and corneal staining, eye dryness score (EDS), symptoms assessment in dry eye (SANDE) score, and Schirmer tear score (STS). Safety assessments included adverse events, best corrected visual acuity, intraocular pressure, and slit-lamp findings. Results: Overall, 345 subjects, 172 TC and 173 CsA. TBUT improved at all time points in both groups (p<0.0001), with statistically greater improvement for TC versus CsA (p=0.0006). OSDI improved significantly at all time points in both groups (p<0.0001) with no significant differences between treatments. MGSS and other measures of meibomian gland function improved significantly more with TC eyes versus CsA; other secondary outcomes showed significant improvements in both groups with no difference between groups. Treatment-related adverse events were uncommon (10 total, 8 in the CsA group consistent with prior CsA studies); most (9/10) mild. Conclusion: TC provides statistically superior and sustained improvement in TBUT and multiple measures of meibomian gland secretion, and non-inferior improvement in OSDI, corneal and conjunctival staining, SANDE, EDS, and STS versus CsA. TC should be a preferred treatment for DED associated with MGD.
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Surgically induced scleral necrosis (SISN) is an uncommon complication of ocular procedures. Cosmetic eye-whitening surgery involves conjunctival and Tenon's capsule dissection, cautery, and mitomycin C application. We report the case of a 36-year-old white woman referred to our clinic for severe pain, scleral inflammation, and necrosis in both eyes 9 years after I-BRITE, an elective eye-whitening procedure. An extensive workup yielded negative results. The patient improved with aggressive lubrication and topical and high-dose systemic prednisone (60 mg), with recurrence upon steroid tapering. Concomitant weekly methotrexate was added, resulting in inflammatory control and allowing discontinuance of topical and oral steroids.
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Mitomicina , Esclerótica , Femenino , Humanos , Adulto , Mitomicina/uso terapéutico , Esclerótica/cirugía , Conjuntiva/cirugía , Necrosis/etiología , Terapia de InmunosupresiónRESUMEN
Graft versus host disease (GVHD) remains a major and serious complication of allogeneic hematopoietic stem cell transplantation. Based on the time of onset, clinical phenotypes, progression kinetics, and pathophysiology, GVHD is stratified into acute, chronic, and overlapping types. The eyes are among the most commonly affected organs in GVHD. Mouse models have played an important role in understanding the several key elements of GVHD pathobiology. The current review discusses the immunology, pathology, and key phenotypic features of mouse models of systemic GVHD. Furthermore, a critical appraisal of mouse models of ocular GVHD (oGVHD) is provided. The disease mechanisms underlying the ocular surface, meibomian gland, and lacrimal gland injury in these models are reviewed, and the relevance of oGVHD murine models to clinical oGVHD is also included.
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Síndromes de Ojo Seco , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Aparato Lagrimal , Animales , Ratones , Síndromes de Ojo Seco/etiología , Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/metabolismo , Aparato Lagrimal/metabolismoRESUMEN
PURPOSE: The aim of this study was to perform automated segmentation of corneal nerves and other structures in corneal confocal microscopy (CCM) images of the subbasal nerve plexus (SNP) in eyes with ocular surface diseases (OSDs). METHODS: A deep learning-based 2-stage algorithm was designed to perform segmentation of SNP features. In the first stage, to address applanation artifacts, a generative adversarial network-enabled deep network was constructed to identify 3 neighboring corneal layers on each CCM image: epithelium, SNP, and stroma. This network was trained/validated on 470 images of each layer from 73 individuals. The segmented SNP regions were further classified in the second stage by another deep network as follows: background, nerve, neuroma, and immune cells. Twenty-one-fold cross-validation was used to assess the performance of the overall algorithm on a separate data set of 207 manually segmented SNP images from 43 patients with OSD. RESULTS: For the background, nerve, neuroma, and immune cell classes, the Dice similarity coefficients of the proposed automatic method were 0.992, 0.814, 0.748, and 0.736, respectively. The performance metrics for automatic segmentations were statistically better or equal as compared to human segmentation. In addition, the resulting clinical metrics had good to excellent intraclass correlation coefficients between automatic and human segmentations. CONCLUSIONS: The proposed automatic method can reliably segment potential CCM biomarkers of OSD onset and progression with accuracy on par with human gradings in real clinical data, which frequently exhibited image acquisition artifacts. To facilitate future studies on OSD, we made our data set and algorithms freely available online as an open-source software package.
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Córnea , Neuroma , Humanos , Algoritmos , Benchmarking , Microscopía ConfocalRESUMEN
Ellis van Creveld syndrome and Weyers acrofacial dysostosis are two rare genetic diseases affecting skeletal development. They are both ciliopathies, as they are due to malfunction of primary cilia, microtubule-based plasma membrane protrusions that function as cellular antennae and are required for Hedgehog signaling, a key pathway during skeletal morphogenesis. These ciliopathies are caused by mutations affecting the EVC-EVC2 complex, a transmembrane protein heterodimer that regulates Hedgehog signaling from inside primary cilia. Despite the importance of this complex, the mechanisms underlying its stability, targeting and function are poorly understood. To address this, we characterized the endogenous EVC protein interactome in control and Evc-null cells. This proteomic screen confirmed EVC's main known interactors (EVC2, IQCE, EFCAB7), while revealing new ones, including USP7, a deubiquitinating enzyme involved in Hedgehog signaling. We therefore looked at EVC-EVC2 complex ubiquitination. Such ubiquitination exists but is independent of USP7 (and of USP48, also involved in Hh signaling). We did find, however, that monoubiquitination of EVC-EVC2 cytosolic tails greatly reduces their protein levels. On the other hand, modification of EVC-EVC2 cytosolic tails with the small ubiquitin-related modifier SUMO3 has a different effect, enhancing complex accumulation at the EvC zone, immediately distal to the ciliary transition zone, possibly via increased binding to the EFCAB7-IQCE complex. Lastly, we find that EvC zone targeting of EVC-EVC2 depends on two separate EFCAB7-binding motifs within EVC2's Weyers-deleted peptide. Only one of these motifs had been characterized previously, so we have mapped the second herein. Altogether, our data shed light on EVC-EVC2 complex regulatory mechanisms, with implications for ciliopathies.
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Ocular surface disease (OSD), a disorder affecting the lacrimal and meibomian glands and the corneal and conjunctival epithelium, is a well-known complication of topical glaucoma therapy. OSD can present as a new or pre-existing condition that virtually any anti-glaucoma formulation can exacerbate. As such, both glaucoma and OSD frequently coexist. Typical OSD symptoms include ocular discomfort, redness, burning, and dryness, whereas signs include periorbital and eyelid skin pigmentation, conjunctival scarring, and superficial punctate keratitis. Pressure-lowering eyedrops can cause toxic, allergic, and inflammatory reactions on the ocular surface. The latter can result from either preservatives or direct toxicity from the active molecule. Although usually mild, OSD can cause significant symptoms that lead to poor quality of life, decreased compliance to therapy, glaucoma progression, and worse visual outcomes. Given the chronic nature of glaucoma, lack of curative therapy, and subsequent lifelong treatment, addressing OSD is necessary. This manuscript aims to provide an up-to-date overview of OSD's signs, symptoms, and pathogenic mechanisms from glaucoma therapy toxicity.
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Purpose: This epidemiologic study evaluates the variance in incidence of Herpes Zoster (HZ) and Herpes Zoster Ophthalmicus (HZO) within a single healthcare system with an aim to analyze their relationship to the COVID-19 pandemic. Methods: All patients attending the Duke University Health System (DUHS) from January 1, 2018, to December 31, 2021, were included. General and COVID-related trends of HZO and HZ were analyzed based on new ICD-9 or ICD-10 diagnosis codes, compared with the total number of patients seen at DUHS during this period, and the number of reported COVID-19 cases in North Carolina obtained using the CDC data tracker. Results: This study included 16,287 cases of HZ of whom 1,294 (7.94%) presented with HZO. The overall incidence of HZO showed an average yearly increase of 5.6%, however HZ incidence decreased by 5.3% per year. When comparing incidence rates of HZO in the 12-months before and after the COVID-19 pandemic onset in the United States (March 2020), the average incidence from March 2020 to February 2021 was 27.6 ± 11.6 compared to 18.0 ± 2.7 from March 2019 to February 2020 (p = 0.01). Moreover, 10/12 (83.3%) of the months had a higher incidence rate of HZO in the post-COVID onset year compared to their corresponding month in the pre-COVID year. Conclusion: The results show HZO incidence may be increasing, despite an overall lower HZ incidence. This could suggest a distinct mechanism for HZO appearance. The COVID pandemic, directly or indirectly, may have accelerated the already increasing HZO incidence.
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The word "elective" refers to medications and procedures undertaken by choice or with a lower grade of prioritization. Patients usually use elective medications or undergo elective procedures to treat pathologic conditions or for cosmetic enhancement, impacting their lifestyle positively and, thus, improving their quality of life. However, those interventions can affect the homeostasis of the tear film and ocular surface. Consequently, they generate signs and symptoms that could impair the patient's quality of life. This report describes the impact of elective topical and systemic medications and procedures on the ocular surface and the underlying mechanisms. Moreover, elective procedures performed for ocular diseases, cosmetic enhancement, and non-ophthalmic interventions, such as radiotherapy and bariatric surgery, are discussed. The report also evaluates significant anatomical and biological consequences of non-urgent interventions to the ocular surface, such as neuropathic and neurotrophic keratopathies. Besides that, it provides an overview of the prophylaxis and management of pathological conditions resulting from the studied interventions and suggests areas for future research. The report also contains a systematic review investigating the quality of life among people who have undergone small incision lenticule extraction (SMILE). Overall, SMILE refractive surgery seems to cause more vision disturbances than LASIK in the first month post-surgery, but less dry eye symptoms in long-term follow up.