RESUMEN
BACKGROUND: Glaucoma is a leading cause of visual disability and blindness. Release of iris pigment within the eye, pigment dispersion syndrome (PDS), can lead to one type of glaucoma known as pigmentary glaucoma. PDS has a genetic component, however, the genes involved with this condition are largely unknown. We sought to discover genes that cause PDS by testing cohorts of patients and controls for mutations using a tiered analysis of exome data. RESULTS: Our primary analysis evaluated melanosome-related genes that cause dispersion of iris pigment in mice (TYRP1, GPNMB, LYST, DCT, and MITF). We identified rare mutations, but they were not statistically enriched in PDS patients. Our secondary analyses examined PMEL (previously linked with PDS), MRAP, and 19 other genes. Four MRAP mutations were identified in PDS cases but not in controls (p = 0.016). Immunohistochemical analysis of human donor eyes revealed abundant MRAP protein in the iris, the source of pigment in PDS. However, analysis of MRAP in additional cohorts (415 cases and 1645 controls) did not support an association with PDS. We also did not confirm a link between PMEL and PDS in our cohorts due to lack of reported mutations and similar frequency of the variants in PDS patients as in control subjects. CONCLUSIONS: We did not detect a statistical enrichment of mutations in melanosome-related genes in human PDS patients and we found conflicting data about the likely pathogenicity of MRAP mutations. PDS may have a complex genetic basis that is not easily unraveled with exome analyses.
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Exoma , Glaucoma de Ángulo Abierto , Animales , Glaucoma de Ángulo Abierto/genética , Humanos , Iris , Glicoproteínas de Membrana , Ratones , Pigmentación , Secuenciación del ExomaRESUMEN
Glaucoma is the leading cause of irreversible blindness worldwide. Although most glaucoma patients are elderly, congenital glaucoma and glaucomas of childhood are also important causes of visual disability. Primary congenital glaucoma (PCG) is isolated, non-syndromic glaucoma that occurs in the first three years of life and is a major cause of childhood blindness. Other early-onset glaucomas may arise secondary to developmental abnormalities, such as glaucomas that occur with aniridia or as part of Axenfeld-Rieger syndrome. Congenital and childhood glaucomas have strong genetic bases and disease-causing mutations have been discovered in several genes. Mutations in three genes (CYP1B1, LTBP2, TEK) have been reported in PCG patients. Axenfeld-Rieger syndrome is caused by mutations in PITX2 or FOXC1 and aniridia is caused by PAX6 mutations. This review discusses the roles of these genes in primary congenital glaucoma and glaucomas of childhood.
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Glaucoma/congénito , Glaucoma/genética , Aniridia/genética , Segmento Anterior del Ojo/anomalías , Segmento Anterior del Ojo/metabolismo , Citocromo P-450 CYP1B1/genética , Citocromo P-450 CYP1B1/metabolismo , Anomalías del Ojo/genética , Anomalías del Ojo/metabolismo , Enfermedades Hereditarias del Ojo , Proteínas del Ojo/genética , Factores de Transcripción Forkhead/genética , Factores de Transcripción Forkhead/metabolismo , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Humanos , Proteínas de Unión a TGF-beta Latente/genética , Proteínas de Unión a TGF-beta Latente/metabolismo , Mutación , Factor de Transcripción PAX6/genética , Factor de Transcripción PAX6/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína del Homeodomínio PITX2Asunto(s)
Fístula Arteriovenosa , Malformaciones Vasculares del Sistema Nervioso Central , Embolización Terapéutica , Trombosis de los Senos Intracraneales , Trombosis de la Vena , Humanos , Malformaciones Vasculares del Sistema Nervioso Central/complicaciones , Malformaciones Vasculares del Sistema Nervioso Central/diagnóstico , Angiografía Cerebral , Fístula Arteriovenosa/terapia , Trombosis de los Senos Intracraneales/complicaciones , Trombosis de los Senos Intracraneales/diagnósticoRESUMEN
PURPOSE: Lacrimo-auriculo-dento-digital (LADD) syndrome is an autosomal dominant disorder displaying variable expression of multiple congenital anomalies including hypoplasia or aplasia of the lacrimal and salivary systems causing abnormal tearing and dry mouth. Mutations in the FGF10, FGFR2, and FGFR3 genes were found to cause some cases of LADD syndrome in prior genetic studies. The goal of this study is to identify the genetic basis of a case of LADD syndrome with glaucoma and thin central corneal thickness (CCT). METHODS: Whole exome sequencing was performed, and previously described disease-causing genes (FGF10, FGFR2, and FGFR3) were first evaluated for mutations. Fifty-eight additional prioritized candidate genes were identified by searching gene annotations for features of LADD syndrome. The potential pathogenicity of the identified mutations was assessed by determining their frequency in large public exome databases; through sequence analysis using the Blosum62 matrix, PolyPhen2, and SIFT algorithms; and through homology analyses. A structural analysis of the effects of the top candidate mutation in tumor protein 63 (TP63) was also conducted by superimposing the mutation over the solved crystal structure. RESULTS: No mutations were detected in FGF10, FGFR2, or FGFR3. The LADD syndrome patient's exome data was searched for mutations in the 58 candidate genes and only one mutation was detected, an Arg343Trp mutation in the tumor protein 63 (TP63) gene. This TP63 mutation is absent from the gnomAD sequence database. Analysis of the Arg343Trp mutation with Blosum62, PolyPhen2, and SIFT all suggest it is pathogenic. This arginine residue is highly conserved in orthologous genes. Finally, crystal structure analysis showed that the Arg343Trp mutation causes a significant alteration in the structure of TP63's DNA binding domain. CONCLUSIONS: We report a patient with no mutations in known LADD syndrome genes (FGF10, FGFR2, and FGFR3). Our analysis provides strong evidence that the Arg343Trp mutation in TP63 caused LADD syndrome in our patient and that TP63 is a fourth gene contributing to this condition. TP63 encodes a transcription factor involved in the development and differentiation of tissues affected by LADD syndrome. These data suggest that TP63 is a novel LADD syndrome gene and may also influence corneal thickness and risk for open-angle glaucoma.
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Anomalías Múltiples/genética , Predisposición Genética a la Enfermedad , Glaucoma/complicaciones , Glaucoma/genética , Pérdida Auditiva/complicaciones , Pérdida Auditiva/genética , Enfermedades del Aparato Lagrimal/complicaciones , Enfermedades del Aparato Lagrimal/genética , Sindactilia/complicaciones , Sindactilia/genética , Anomalías Dentarias/complicaciones , Anomalías Dentarias/genética , Factores de Transcripción/genética , Proteínas Supresoras de Tumor/genética , Secuencia de Aminoácidos , Secuencia Conservada , Humanos , Modelos Moleculares , Factores de Transcripción/química , Proteínas Supresoras de Tumor/químicaRESUMEN
OBJECTIVES: To examine the relationship between psychological well-being and depression in older adults and the relative contribution these psychological factors have on risk of functional disability, frailty, and mortality. METHODS: This is a secondary analysis of 1668 community-dwelling older adults without dementia who participated in the second wave of the Canadian Study of Health and Aging. Baseline assessments of psychological well-being (Ryff scale) and depression (Geriatric Depression Scale; GDS) were collected. At 5-year follow-up, mortality data were collected; frailty and disability in activities of daily living were evaluated using the frailty index (FI) and the Lawton-Brody scale, respectively. RESULTS: Area under the receiver-operating characteristic curve indicated that GDS and Ryff scores were able to independently discriminate whether individuals were considered frail (C = 0.66; C = 0.59, respectively), had limitations in basic (C = 0.64; C = 0.57, respectively) or instrumental (C = 0.70; C = 0.57, respectively) activities of daily living, or had died (C = 0.63; C = 0.57) at follow-up (all P < 0.01). Regression models in which the Ryff and GDS were included in the same model demonstrated that the GDS significantly predicted frailty, disability, and mortality, whereas the Ryff effect was not significant. Mediation analysis determined that the effect of psychological well-being on adverse outcomes was fully mediated by depression. CONCLUSIONS: Our results suggest that although both depression and psychological well-being appear to modulate risk for adverse physical health outcomes, depression mediates this relationship. Detecting and treating depressive symptoms should be of high priority in older patients to mitigate risk of future physical health adversities including mortality. Copyright © 2016 John Wiley & Sons, Ltd.
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Trastorno Depresivo/psicología , Anciano Frágil/psicología , Felicidad , Envejecimiento Saludable/psicología , Actividades Cotidianas/psicología , Anciano , Anciano de 80 o más Años , Canadá , Comorbilidad , Femenino , Evaluación Geriátrica/métodos , Estado de Salud , Humanos , Masculino , Mortalidad , Escalas de Valoración Psiquiátrica , Curva ROC , Análisis de RegresiónRESUMEN
This article discusses the experience of progressing from a young ophthalmic resident to a full-time professional and, ultimately, to service on the American Board of Ophthalmology.
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Movilidad Laboral , Internado y Residencia , Oftalmología , Competencia Clínica , Estados UnidosRESUMEN
PURPOSE: A vector force model for the determination of upper eyelid position in the setting of a trabeculectomy bleb is presented. The model is used to explain the clinical courses of 5 patients with bleb-induced upper eyelid malposition and the efficacy of modalities previously described for the treatment of bleb-induced upper eyelid retraction. The novel use of botulinum toxin in the treatment of bleb-induced eyelid retraction and unique surgical considerations in patients with trabeculectomy blebs undergoing upper eyelid surgery are discussed. METHODS: A vector force analysis was conducted and a force diagram constructed. The clinical and surgical courses of 5 patients with trabeculectomy blebs and upper eyelid malposition were reviewed. The vector force model was applied to these cases and the previously described treatment modalities for bleb-induced upper eyelid retraction. RESULTS: Vector force analysis demonstrates that in the case of trabeculectomy bleb-induced upper eyelid retraction, the net force vector, which represents the sum of all the individual forces acting on the eyelid, has a positive vertical component resulting in superior displacement of the eyelid. In contrast, bleb-induced ptosis results when the net force vector has a negative vertical component. In 3 patients, alterations in the bleb resulted in resolution of upper eyelid malposition. Botulinum toxin was used to achieve a normal upper eyelid position in 1 patient with lateral canthal tendon disinsertion and unilateral eyelid retraction and 1 patient with bilateral eyelid retraction. One patient developed unilateral ptosis in concert with the emergence of a large Tenon cyst that resolved with the treatment of the cyst via eyelid massage. One patient with unilateral ptosis and an ipsilateral bleb underwent external levator advancement but was unable to achieve the desired upper eyelid height as retraction over the bleb occurred with any attempt to elevate the eyelid above a marginal reflex distance of 1.5 mm. The efficacy of previously reported modalities for the treatment of trabeculectomy bleb-induced upper eyelid retraction can be explained by either a reduction in the positive vertical component of the net force vector or augmentation of the negative vertical component. CONCLUSIONS: A vector force model systematically accounts for the multiple determinants of upper eyelid position in the setting of a trabeculectomy bleb. This model provides a framework for the evaluation of bleb-induced upper eyelid malposition and offers a logical, mathematical explanation for the occurrence of bleb-induced upper eyelid retraction and the usefulness of previously reported treatment modalities for this clinical entity.
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Enfermedades de los Párpados/etiología , Párpados/fisiopatología , Modelos Biológicos , Músculos Oculomotores/fisiología , Trabeculectomía/efectos adversos , Anciano , Fenómenos Biomecánicos , Enfermedades de los Párpados/fisiopatología , Enfermedades de los Párpados/terapia , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Patients with a congenital optic nerve disease, cavitary optic disc anomaly (CODA), are born with profound excavation of the optic nerve resembling glaucoma. We previously mapped the gene that causes autosomal-dominant CODA in a large pedigree to a chromosome 12q locus. Using comparative genomic hybridization and quantitative PCR analysis of this pedigree, we report identifying a 6-Kbp heterozygous triplication upstream of the matrix metalloproteinase 19 (MMP19) gene, present in all 17 affected family members and no normal members. Moreover, the triplication was not detected in 78 control subjects or in the Database of Genomic Variants. We further detected the same 6-Kbp triplication in one of 24 unrelated CODA patients and in none of 172 glaucoma patients. Analysis with a Luciferase assay showed that the 6-Kbp sequence has transcription enhancer activity. A 773-bp fragment of the 6-Kbp DNA segment increased downstream gene expression eightfold, suggesting that triplication of this sequence may lead to dysregulation of the downstream gene, MMP19, in CODA patients. Lastly, immunohistochemical analysis of human donor eyes revealed strong expression of MMP19 in optic nerve head. These data strongly suggest that triplication of an enhancer may lead to overexpression of MMP19 in the optic nerve that causes CODA.
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Enfermedades Hereditarias del Ojo/genética , Heterocigoto , Metaloproteinasas de la Matriz Secretadas/metabolismo , Disco Óptico/anomalías , Secuencias Reguladoras de Ácidos Nucleicos , Cromosomas Humanos Par 12 , Enfermedades Hereditarias del Ojo/metabolismo , Glaucoma/genética , Humanos , Disco Óptico/metabolismo , LinajeRESUMEN
PURPOSE: Autosomal dominant nanophthalmos is an inherited eye disorder characterized by a structurally normal but smaller eye. Patients with nanophthalmos have high hyperopia (far-sightedness), a greater incidence of angle-closure glaucoma, and increased risk of surgical complications. In this study, the clinical features and the genetic basis of nanophthalmos were investigated in two large autosomal dominant nanophthalmos pedigrees. METHODS: Fourteen members of a Caucasian pedigree from the United States and 15 members of a pedigree from the Mariana Islands enrolled in a genetic study of nanophthalmos and contributed DNA samples. Twenty of 29 family members underwent eye examinations that included measurement of axial eye length and/or refractive error. The genetic basis of nanophthalmos in the pedigrees was studied with linkage analysis, whole exome sequencing, and candidate gene (i.e., TMEM98) sequencing to identify the nanophthalmos-causing gene. RESULTS: Nine members of the pedigree from the United States and 11 members of the pedigree from the Mariana Islands were diagnosed with nanophthalmos that is transmitted as an autosomal dominant trait. The patients with nanophthalmos had abnormally short axial eye lengths, which ranged from 15.9 to 18.4 mm. Linkage analysis of the nanophthalmos pedigree from the United States identified nine large regions of the genome (greater than 10 Mbp) that were coinherited with disease in this family. Genes within these "linked regions" were examined for disease-causing mutations using exome sequencing, and a His196Pro mutation was detected in the TMEM98 gene, which was recently reported to be a nanophthalmos gene. Sanger sequencing subsequently showed that all other members of this pedigree with nanophthalmos also carry the His196Pro TMEM98 mutation. Testing the Mariana Islands pedigree for TMEM98 mutations identified a 34 bp heterozygous deletion that spans the 3' end of exon 4 in all affected family members. Neither TMEM98 mutation was detected in public exome sequence databases. CONCLUSIONS: A recent report identified a single TMEM98 missense mutation in a nanophthalmos pedigree. Our discovery of two additional TMEM98 mutations confirms the important role of the gene in the pathogenesis of autosomal dominant nanophthalmos.
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Glaucoma de Ángulo Cerrado/diagnóstico , Glaucoma de Ángulo Cerrado/genética , Hiperopía/diagnóstico , Hiperopía/genética , Proteínas de la Membrana/genética , Microftalmía/diagnóstico , Microftalmía/genética , Mutación , Linaje , Adulto , Anciano , Secuencia de Aminoácidos , Longitud Axial del Ojo , Exoma , Femenino , Expresión Génica , Ligamiento Genético , Glaucoma de Ángulo Cerrado/etnología , Glaucoma de Ángulo Cerrado/patología , Heterocigoto , Humanos , Hiperopía/etnología , Hiperopía/patología , Islas , Masculino , Microftalmía/etnología , Microftalmía/patología , Persona de Mediana Edad , Datos de Secuencia Molecular , Nativos de Hawái y Otras Islas del Pacífico , Errores de Refracción , Estados Unidos , Población BlancaRESUMEN
Glaucoma is a common cause of visual disability and affects â¼1.6% of individuals over 40 years of age ( 1). Non-synonymous coding sequence variations in the ankyrin repeat and SOCS box containing gene 10 (ASB10) were recently associated with 6.0% of cases of primary open angle glaucoma (POAG) in patients from Oregon and Germany. We tested a cohort of POAG patients (n= 158) and normal control subjects (n= 82), both from Iowa, for ASB10 mutations. Our study had 80% power to detect a 4.9% mutation frequency in POAG patients. A total of 11 non-synonymous coding sequence mutations were detected in the cohort, but no association with POAG was detected when analyzed individually or as a group (P > 0.05). Furthermore, a survey of the National Heart, Lung, and Blood Institute's (NHLBI's) Exome Sequencing Project revealed that non-synonymous ASB10 mutations are present in the general population at a far higher frequency than the prevalence of POAG. These data suggest that non-synonymous mutations in ASB10 do not cause Mendelian forms of POAG.
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Glaucoma de Ángulo Abierto/genética , Proteínas Supresoras de la Señalización de Citocinas/genética , Estudios de Cohortes , Alemania , Humanos , Presión Intraocular/genética , Iowa , Masculino , Persona de Mediana Edad , Mutación , OregonRESUMEN
BACKGROUND: Men with prostate cancer face preference-sensitive decisions when choosing among treatments with similar survival outcomes but different procedures, risks and potential complications. A decision-support intervention, 'Decision Navigation' assists men with prostate cancer to prepare a question list (consultation plan) for their doctors and provides them with a consultation summary and audio recording. A randomised controlled trial of Decision Navigation showed advantages over usual care on quantitative measures including confidence in decision-making and regret. OBJECTIVE: The aim of this study was to gain a qualitative understanding of patient's and doctor's perspectives on Decision Navigation. METHODS: Six patients who received Decision Navigation were purposively selected for interview out of 62 randomised controlled trial participants. All four doctors who consulted Navigated patients were interviewed. Interview data was analysed using framework analysis. RESULTS: Patients reported that planning for the consultation helped them to frame their questions, enabling them to participate in consultations and take responsibility for making decisions. They reported feeling more confident in the decisions made, having a written report of the key information and an audio recording. Patients considered routine information relating to side effects was inadequate. Doctors reported that consultation plans made them aware of patients' concerns and ensured comprehensive responses to questions posed. Doctors also endorsed implementing Decision Navigation as part of routine care. CONCLUSION: Results suggest that Decision Navigation facilitated patients' involvement in treatment decision-making. Prostate patients engaging in preference-sensitive decision-making welcomed this approach to personalised tailored support.
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Actitud del Personal de Salud , Actitud Frente a la Salud , Técnicas de Apoyo para la Decisión , Participación del Paciente , Neoplasias de la Próstata/terapia , Anciano , Humanos , Masculino , Persona de Mediana Edad , Prioridad del Paciente , Relaciones Médico-Paciente , Neoplasias de la Próstata/psicología , Investigación Cualitativa , Derivación y ConsultaRESUMEN
We report identification of a novel genetic locus (GLC1P) for normal tension glaucoma (NTG) on chromosome 12q14 using linkage studies of an African-American pedigree (maximum non-parametric linkage score = 19.7, max LOD score = 2.7). Subsequent comparative genomic hybridization and quantitative polymerase chain reaction (PCR) experiments identified a 780 kbp duplication within the GLC1P locus that is co-inherited with NTG in the pedigree. Real-time PCR studies showed that the genes within this duplication [TBK1 (TANK-binding kinase 1), XPOT, RASSF3 and GNS] are all expressed in the human retina. Cohorts of 478 glaucoma patients (including 152 NTG patients), 100 normal control subjects and 400 age-related macular degeneration patients were subsequently tested for copy number variation in GLC1P. Overlapping duplications were detected in 2 (1.3%) of the 152 NTG subjects, one of which had a strong family history of glaucoma. These duplications defined a 300 kbp critical region of GLC1P that spans two genes (TBK1 and XPOT). Microarray expression experiments and northern blot analysis using RNA obtained from human skin fibroblast cells showed that duplication of chromosome 12q14 results in increased TBK1 and GNS transcription. Finally, immunohistochemistry studies showed that TBK1 is expressed in the ganglion cells, nerve fiber layer and microvasculature of the human retina. Together, these data link the duplication of genes on chromosome 12q14 with familial NTG and suggest that an extra copy of the encompassed TBK1 gene is likely responsible for these cases of glaucoma. However, animal studies will be necessary to rule out a role for the other duplicated or neighboring genes.
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Cromosomas Humanos Par 12/genética , Variaciones en el Número de Copia de ADN/genética , Glaucoma de Baja Tensión/genética , Proteínas Serina-Treonina Quinasas/genética , Negro o Afroamericano , Northern Blotting , Duplicación Cromosómica/genética , Estudios de Cohortes , Hibridación Genómica Comparativa , Ligamiento Genético/genética , Humanos , Análisis por Micromatrices , Linaje , Reacción en Cadena de la Polimerasa , Proteínas Serina-Treonina Quinasas/metabolismoRESUMEN
Mutations in the thrombospondin 1 ( THBS1 ) gene have been previously reported in primary congenital glaucoma (PCG) pedigrees that exhibit autosomal dominant inheritance with low penetrance. We sought to determine the role of THBS1 mutations in a cohort of 20 patients with PCG and 362 normal controls from Iowa using a combination of Sanger sequencing and whole exome sequencing. We detected 16 different THBS1 variants, including 4 rare, nonsynonymous variants (p.Thr611Met, p.Asn708Lys, p.Gln1089His, and p.Glu1166Lys). However, none of these variants were judged to be disease-causing mutations based on: 1) prevalence in cases and controls from Iowa, 2) prevalence in the public database gnomAD, 3) mutation analysis algorithms, and 4) THBS1 DNA sequence conservation. These results indicate THBS1 mutations are not a common cause of PCG in patients from Iowa and may be a rare cause of PCG overall.
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Glaucoma , Trombospondinas , Humanos , Estados Unidos/epidemiología , Trombospondinas/genética , Citocromo P-450 CYP1B1/genética , Presión Intraocular , Mutación , Linaje , Glaucoma/epidemiología , Glaucoma/genética , Glaucoma/congénito , Análisis Mutacional de ADNRESUMEN
Importance: The p.Asp67Tyr genetic variant in the GJA3 gene is responsible for congenital cataracts in a family with a high incidence of glaucoma following cataract surgery. Objective: To describe the clinical features of a family with a strong association between congenital cataracts and glaucoma following cataract surgery secondary to a genetic variant in the GJA3 gene (NM_021954.4:c.199G>T, p.Asp67Tyr). Design, Setting, and Participants: This was a retrospective, observational, case series, genetic association study from the University of Iowa spanning 61 years. Examined were the ophthalmic records from 1961 through 2022 of the family members of a 4-generation pedigree with autosomal dominant congenital cataracts. Main Outcomes and Measures: Frequency of glaucoma following cataract surgery and postoperative complications among family members with congenital cataract due to the p.Asp67Tyr GJA3 genetic variant. Results: Medical records were available from 11 of 12 family members (7 male [63.6%]) with congenital cataract with a mean (SD) follow-up of 30 (21.7) years (range, 0.2-61 years). Eight of 9 patients with congenital cataracts developed glaucoma, and 8 of 8 patients who had cataract surgery at age 2 years or younger developed glaucoma following cataract surgery. The only family member with congenital cataracts who did not develop glaucoma had delayed cataract surgery until 12 and 21 years of age. Five of 11 family members (45.5%) had retinal detachments after cataract extraction and vitrectomy. No patients developed retinal detachments after prophylactic 360-degree endolaser. Conclusions and Relevance: The GJA3 genetic variant, p.Asp67Tyr, was identified in a 4-generation congenital cataract pedigree from Iowa. This report suggests that patients with congenital cataract due to some GJA3 genetic variants may be at especially high risk for glaucoma following cataract surgery. Retinal detachments after cataract extraction in the first 2 years of life were also common in this family, and prophylactic retinal endolaser may be indicated at the time of surgery.
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Extracción de Catarata , Catarata , Conexinas , Glaucoma , Desprendimiento de Retina , Niño , Preescolar , Humanos , Masculino , Catarata/genética , Extracción de Catarata/efectos adversos , Variación Genética , Glaucoma/genética , Retina , Estudios Retrospectivos , Conexinas/genéticaRESUMEN
PURPOSE: Analysis of mutant mouse strains and linkage analysis with human families have both demonstrated that mutations influencing the podosomal adaptor protein SH3 and PX domains 2B (SH3PXD2B) can result in a congenital form of glaucoma. Here, we use immunohistochemistry to describe localization of the SH3PXD2B protein throughout the adult human eye and test whether sequence variants in SH3PXD2B occur in multiple other forms of glaucoma. METHODS: In immunohistochemical experiments, cryosections of human donor eyes were evaluated for SH3PXD2B immunoreactivity with a polyclonal antibody. In genetic experiments, exon sequences of SH3PXD2B from patients with primary congenital glaucoma (n=21), Axenfeld-Rieger syndrome (n=30), and primary open angle glaucoma (n=127) were compared to control subjects (n=89). The frequency of non-synonymous SH3PXD2B coding sequence variants were compared between patient cohorts and controls using Fisher's exact test. RESULTS: Varying intensities of SH3PXD2B immunoreactivity were detected in almost all ocular tissues. Among tissues important to glaucoma, immunoreactivity was detected in the drainage structures of the iridocorneal angle, ciliary body, and retinal ganglion cells. Intense immunoreactivity was present in photoreceptor inner segments. From DNA analysis, a total of 11 non-synonymous variants were detected. By Fisher's Exact test, there was not a significant skew in the overall frequency of these changes in any patient cohort versus controls (p-value >0.05). Each cohort contained unique variants not detected in other cohorts or patients. CONCLUSIONS: SH3PXD2B is widely distributed in the adult human eye, including several tissues important to glaucoma pathogenesis. Analysis of DNA variants in three forms of glaucoma detected multiple variants unique to each patient cohort. While statistical analysis failed to support a pathogenic role for these variants, some of them may be rare disease-causing variants whose biologic significance warrants investigation in follow up replication studies and functional assays.
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Proteínas Adaptadoras Transductoras de Señales/genética , Segmento Anterior del Ojo/patología , Anomalías del Ojo/genética , Glaucoma de Ángulo Abierto/genética , Glaucoma/genética , Polimorfismo Genético , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Segmento Anterior del Ojo/anomalías , Segmento Anterior del Ojo/metabolismo , Autopsia , Estudios de Casos y Controles , Exones , Anomalías del Ojo/patología , Enfermedades Hereditarias del Ojo , Glaucoma/congénito , Glaucoma/patología , Glaucoma de Ángulo Abierto/patología , Humanos , Inmunohistoquímica , Masculino , Ratones , Análisis de Secuencia de ADN , Estados UnidosRESUMEN
The purpose of this study was to determine and compare the prevalence of glaucoma therapy escalation (GTE) after penetrating keratoplasty (PKP) and Descemet's stripping automated endothelial keratoplasty (DSAEK) in eyes with a surgical indication of pseudophakic corneal edema. A retrospective review was conducted of the medical records of all patients who underwent PKP or DSAEK to treat pseudophakic corneal edema at a tertiary eye care center from January 1 2003 to December 31, 2006. Eyes that were treated with PKP from January 1, 2003 to December 31, 2004 and with DSAEK from January 1, 2005 to December 31, 2006 were included in the statistical analysis. Inclusion criteria included satisfactory preoperative control of intraocular pressure (IOP) and follow-up of at least 12 months. The main outcome measure was GTE, which was defined as a sustained requirement for escalation of topical medical therapy or the need to provide surgical intervention to maintain a satisfactory postoperative IOP. Among 54 eyes that met the inclusion criteria, GTE occurred in 7 (35.0%) of 20 eyes after PKP and in 14 (41.2%) of 34 eyes after DSAEK (P = 0.78) during a mean follow-up period of 27.6 and 28.6 months, respectively. Surgical escalation occurred in 2 (10.0%) eyes after PKP and 2 (5.9%) eyes after DSAEK (P = 0.62), and was associated with late-onset endothelial graft failure in all four eyes. Glaucoma therapy escalation is relatively common and occurs with comparable frequency in eyes with pseudophakic corneal edema after PKP and DSAEK.
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Antihipertensivos/administración & dosificación , Edema Corneal/cirugía , Queratoplastia Endotelial de la Lámina Limitante Posterior/efectos adversos , Glaucoma/terapia , Queratoplastia Penetrante/efectos adversos , Seudofaquia/cirugía , Anciano , Anciano de 80 o más Años , Edema Corneal/diagnóstico , Queratoplastia Endotelial de la Lámina Limitante Posterior/métodos , Progresión de la Enfermedad , Femenino , Estudios de Seguimiento , Glaucoma/etiología , Glaucoma/fisiopatología , Humanos , Presión Intraocular , Queratoplastia Penetrante/métodos , Masculino , Persona de Mediana Edad , Soluciones Oftálmicas , Complicaciones Posoperatorias , Seudofaquia/diagnóstico , Estudios Retrospectivos , Factores de Tiempo , Resultado del Tratamiento , Agudeza VisualRESUMEN
BACKGROUND CONTEXT: Musculoskeletal (MSK) pain presents a global challenge. Individual and group pain management programmes (PMPs) are recommended approaches for patients with chronic MSK disorders. With advances in remote healthcare capability, telehealth, and the recent COVID-19 pandemic, the importance of telehealth PMPs has become even more evident. Nevertheless, it is not known how patients perceive PMPs for their MSK complaint when delivered via telehealth. OBJECTIVE: To synthesise the evidence of patients' experiences of group and individual telehealth PMPs for chronic MSK pain. DESIGN: A scoping review informed by the PRISMA extension for scoping reviews. DATA SOURCES: Based on a planned search strategy, modified following initial searches, an electronic search was conducted of key databases: Cochrane Library, Medline, CINAHL, EMBASE, AMED, SportDiscus and APA PsychInfo from 2010 until 11 May 2021. STUDY SELECTION: Any qualitative or mixed methods study reporting patient experiences of telehealth PMPs for patients with MSK disorders. DATA EXTRACTION AND DATA SYNTHESIS: Data were extracted and synthesised using thematic analysis. RESULTS: From 446 identified studies, 10 were included. Just two studies investigated group telehealth PMPs for patients with MSK disorders, with eight delivered individually. Four main themes emerged: (1) Usability of the technology, (2) Tailored care, (3) Therapeutic alliance and (4) Managing behaviour. The findings highlight patient acceptability of telehealth to support self-management for chronic MSK disorders, with appropriate clinical and technical support. Group telehealth has the potential to empower patients with peer support. Remote delivery of PMPs also impacts on how patients and providers interact, communicate and develop a therapeutic relationship. CONCLUSIONS AND IMPLICATIONS: Barriers and enablers to engagement in telehealth PMPs for patients with chronic MSK disorders have been identified. Peer support and group cohesiveness can be achieved remotely to enhance the patient experience. There is a critical need for further research in this area.
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COVID-19 , Dolor Crónico , Dolor Musculoesquelético , Telemedicina , Dolor Crónico/terapia , Humanos , Dolor Musculoesquelético/terapia , PandemiasRESUMEN
BACKGROUND: There are over 1 million adults with a learning disability in the UK, of whom approximately 20% displaying behaviours that challenge others. Two thirds of people with learning disabilities live in the family home. As they and their family carers age, both are likely to face particular difficulties and stresses, but there is little understanding of their experiences and needs. To address this evidence gap, our main objective is to undertake two rapid scoping reviews that will collectively focus on the health and social care needs, experiences, service interventions and resources of older people with learning disabilities and behaviours that challenge others, and their family carers. Both reviews will focus on issues relating to forward planning and transitions to different care contexts. The study is part of a research project funded by the National Institute for Health Research No.129491. METHODS: We propose to address the need for evidence via two rapid scoping reviews. We will include published and unpublished (grey) literature, encompassing empirical research, policy and practice guidance and lay resources to support decision-making. We will search multiple electronic databases, hand search references lists, and use expert guidance to identify potential evidence. The following databases were used for research and grey literature: CINAHL; Healthcare Management Information Consortium (HMIC); NHS Evidence; Scopus; Turning Evidence Into Practice (TRIP); Web of Science (WoS); Google (first 5 pages); and Google Scholar (first 5 pages). For RR2, additional intended databases are the Carer Research Knowledge Exchange Network (CAREN) and Social Care Institute for Excellence (SCIE). Two reviewers will independently screen all citations and full-text articles for inclusion. One reviewer will extract data, with an independent review undertaken by the research team. Critical appraisal will depend on the nature of included evidence. Narrative synthesis will be collaboratively developed, with descriptive information presented in tables summarising study characteristics and thematic analysis of findings presented in the main text. Dissemination will be through journal publication, conference presentations and written short-form, easy-read versions of articles and audio-video clips for lay audiences. DISCUSSION: We will consider the strengths and limitations of our reviews, considering their impact on findings. We will summarise the main findings and provide an interpretation linked to the review questions and objectives. We will consider the implications of our findings for policy and practice, as well as future research addressing the support of older people with learning difficulties and behaviours that challenge others, and their family carers, in the context of transition to different care contexts in the UK. The protocol has been registered as Vseteckova, J., Jordan, J., Tilley, E., Larkin, M., Ryan, S., and Wallace, L. (2021, December 4). Transitions for older people with learning disabilities and behaviours that challenge others, and their family carers: a merged protocol for two rapid scoping reviews of evidence. Retrieved from osf.io/jzrn9.
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Cuidadores , Discapacidades para el Aprendizaje , Adulto , Anciano , Atención a la Salud , Humanos , Discapacidades para el Aprendizaje/terapia , Proyectos de Investigación , Literatura de Revisión como Asunto , Apoyo SocialRESUMEN
PURPOSE: Accurate identification of iridocorneal structures on gonioscopy is difficult to master, and errors can lead to grave surgical complications. This study aimed to develop and train convolutional neural networks (CNNs) to accurately identify the trabecular meshwork (TM) in gonioscopic videos in real time for eventual clinical integrations. DESIGN: Cross-sectional study. PARTICIPANTS: Adult patients with open angle were identified in academic glaucoma clinics in both Taipei, Taiwan, and Irvine, California. METHODS: Neural Encoder-Decoder CNNs (U-nets) were trained to predict a curve marking the TM using an expert-annotated data set of 378 gonioscopy images. The model was trained and evaluated with stratified cross-validation grouped by patients to ensure uncorrelated training and testing sets, as well as on a separate test set and 3 intraoperative gonioscopic videos of ab interno trabeculotomy with Trabectome (totaling 90 seconds long, 30 frames per second). We also evaluated our model's performance by comparing its accuracy against ophthalmologists. MAIN OUTCOME MEASURES: Successful development of real-time-capable CNNs that are accurate in predicting and marking the TM's position in video frames of gonioscopic views. Models were evaluated in comparison with human expert annotations of static images and video data. RESULTS: The best CNN model produced test set predictions with a median deviation of 0.8% of the video frame's height (15.25 µm) from the human experts' annotations. This error is less than the average vertical height of the TM. The worst test frame prediction of this model had an average deviation of 4% of the frame height (76.28 µm), which is still considered a successful prediction. When challenged with unseen images, the CNN model scored greater than 2 standard deviations above the mean performance of the surveyed general ophthalmologists. CONCLUSIONS: Our CNN model can identify the TM in gonioscopy videos in real time with remarkable accuracy, allowing it to be used in connection with a video camera intraoperatively. This model can have applications in surgical training, automated screenings, and intraoperative guidance. The dataset developed in this study is one of the first publicly available gonioscopy image banks (https://lin.hs.uci.edu/research), which may encourage future investigations in this topic.
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Aprendizaje Profundo , Malla Trabecular , Adulto , Estudios Transversales , Gonioscopía , Humanos , Presión Intraocular , Malla Trabecular/cirugíaRESUMEN
PURPOSE: This series describes the immunopathologic features of posterior embryotoxon (PE) and demonstrates that it is not an anterior displaced Schwalbe's line as commonly described, but a peripheral corneal stromal nub variable in location with abnormal extracellular matrix. DESIGN: Case series. PARTICIPANTS: Archived specimens from patients with PE. METHODS: Sections from archived formalin-fixed, paraffin-embedded specimens (n = 9; 7 autopsy and 2 trabeculectomy specimens) were examined by light microscopy. Immunohistochemistry was performed on 5 specimens to characterize the extracellular matrix composition of PE. RESULTS: Posterior embryotoxon appeared as nubs of whorled collagen extending from the corneal stroma, lined in some instances, by Descemet membrane. These nubs were located anterior to Schwalbe's line (n = 4), posteriorly (n = 1), partially embedded in the trabecular meshwork (n = 1), or at Schwalbe's line (n = 2). Qualitatively, collagen I labeling of the PE stroma was similar or weaker than the corneal stroma, whereas collagen III staining was focal and slightly more intense compared with the corneal stroma. Lumican and keratan sulfate staining was similar or less intense in PE compared with the corneal stroma. MAIN OUTCOME MEASURES: Identify location of PE and its immunohistochemical features. CONCLUSIONS: In contrast to the widely accepted definition of PE as a prominent, anteriorly displaced Schwalbe line, histologic evidence suggests that it is a direct extension of the corneal stroma with variable locations that may displace the attenuated Descemet membrane when located anterior to or at Schwalbe's line. Immunohistochemical examination revealed that the composition of PE's extracellular matrix was similar to corneal stroma but with some variability in staining intensity.