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Importance: In Medicare Advantage (MA), step therapy for physician-administered drugs is an approach to lowering drug spending. The impact of step therapy in MA on prescribing behavior and the magnitude of any changes has not been analyzed. Objective: To evaluate the impact of step therapy on macular degeneration drug prescribing patterns for 3 large MA insurers. Design, Setting, and Participants: This was a retrospective encounter-based analysis using 20% nationally representative MA outpatient and carrier encounter records for 2017 to 2019. Participants were MA beneficiaries who were 65 years or older and had received a macular degeneration drug administration. Macular degeneration drug administrations for beneficiaries of MA Aetna, Humana, and UnitedHealthcare (UHC) insurers were assessed. Humana implemented macular degeneration step therapy in 2019, setting bevacizumab as the plan-preferred drug, and aflibercept and ranibizumab as the plan-nonpreferred drugs. Aetna and UHC, which did not implement macular degeneration step therapy, served as the control group. Data analyses were performed from May 2024 to December 2024. Exposures: A macular degeneration drug administration subject to a step therapy policy. Main Outcome and Measures: A binary indicator of whether the drug administered was bevacizumab. Linear probability models and a difference-in-differences framework were used to quantify changes in prescribing patterns before and after the introduction of step therapy for MA insurers that did and did not implement step therapy. To empirically measure the impact of step therapy, the first administration of a treatment episode was assessed, followed by switching patterns. Results: A total of 18â¯331 MA beneficiaries, 21â¯683 treatment episodes, and 171â¯985 drug administrations were included across the control and treatment groups. The difference-in-differences regressions found a 7.8% (95% CI, 4.9%-10.7%; P < .001) greater probability of being prescribed bevacizumab for the first administration due to step therapy. The predicted probabilities of preferred-drug administration in the treatment group increased from 0.61 to 0.70 between the periods before and after step therapy implementation for the first administration. Step therapy was not significantly associated with an increased rate of medication switching (hazard ratio, 0.86; 95% CI, 0.71-1.06; P = .15). Conclusions and Relevance: The findings of this retrospective encounter-based analysis indicate that step therapy is associated with a greater probability of prescribing the plan-preferred drug for the first administration. The analysis failed to find a statistically significant greater rate of medication switching within a treatment episode. Step therapy changed macular degeneration prescribing patterns, but step therapy alone did not transition all administrations to the plan-preferred drug.
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Bevacizumab , Degeneração Macular , Medicare Part C , Padrões de Prática Médica , Ranibizumab , Humanos , Estados Unidos , Estudos Retrospectivos , Idoso , Masculino , Feminino , Degeneração Macular/tratamento farmacológico , Bevacizumab/uso terapêutico , Bevacizumab/administração & dosagem , Padrões de Prática Médica/estatística & dados numéricos , Ranibizumab/administração & dosagem , Ranibizumab/uso terapêutico , Idoso de 80 Anos ou mais , Proteínas Recombinantes de Fusão/uso terapêutico , Proteínas Recombinantes de Fusão/administração & dosagem , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/administração & dosagemRESUMO
Purpose: The Consortium of Student-Led Eye Clinics (CSLEC), founded in 2021, administered a comprehensive survey to document the types of services, most common diagnoses, and follow-up care protocols offered by student-led free vision screening programs (SLFVSP) in the United States. Methods: An 81-question institutional review board (IRB)-approved survey was administered to student-led vision screening eye clinics from October 1, 2022 to February 24, 2023. Results: Sixteen SLFVSPs were included in the final analysis, of which 81% (n = 13) conducted variations of fundoscopic examinations and 75% (n = 12) measured intraocular pressure. Cataracts and diabetic retinopathy were reported as the most frequent diagnoses by the majority of SLFVSPs (n = 9, 56%); non-mobile SLFVSPs more commonly reported cataract as a frequent diagnosis (P < 0.05). Most patients screened at participating programs were uninsured or met federal poverty guidelines. Prescription glasses were offered by 56% of the programs (n = 9). SLFVSPs that directly scheduled follow-up appointments reported higher attendance rates (66.5%) than those that only sent referrals (20%). Transportation was the most cited barrier for follow-up appointment attendance. Conclusions: SLFVSPs, one community vision screening initiative subtype, vary significantly in scope and capabilities of identifying vision threatening disease. The follow-up infrastructure is not uniformly robust and represents a key target for improving care delivery to at-risk populations. Translational Relevance: The CSLEC aims to develop a consensus-based standardization for the scope of screening services, offer guidelines for diagnostic criteria, promote real-time data stewardship, and identify means to improve follow-up care mechanisms in member communities.
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Catarata , Retinopatia Diabética , Seleção Visual , Humanos , Estados Unidos/epidemiologia , Exame Físico , Catarata/diagnóstico , Catarata/epidemiologia , Pressão IntraocularRESUMO
PURPOSE: To determine early endophthalmitis incidence and risk factors after glaucoma surgeries in the Medicare population. DESIGN: Retrospective, longitudinal study. PARTICIPANTS: Medicare Fee-for-Service (FFS) and Medicare Advantage beneficiaries in the United States aged 65 years or older undergoing glaucoma surgery. METHODS: Medicare claims were used to identify all patients who underwent glaucoma, cataract, or combined cataract/glaucoma surgery from 2016 to 2019. Endophthalmitis cases within 42 days of the index surgery were identified using the diagnostic codes. Multivariable logistic regression models were used to evaluate factors associated with postoperative endophthalmitis. MAIN OUTCOME MEASURES: The 42-day postoperative endophthalmitis incidence and risk factors associated with endophthalmitis after glaucoma surgery. RESULTS: There were 466 928 glaucoma surgeries, of which 310 823 (66.6%) were combined with cataract surgery. Cataract surgeries alone (n = 8 460 360) served as a reference group. Microinvasive glaucoma surgeries constituted most glaucoma procedures performed (67.8%), followed by trabeculectomy (14.0%), tube shunt (10.9%), and other procedures (7.3%). There were 572 cases of endophthalmitis identified after all glaucoma surgeries. Endophthalmitis incidence after glaucoma, combined cataract/glaucoma, and cataract surgeries alone was 1.5 (95% confidence interval [CI], 1.3-1.7), 1.1 (95% CI, 1.0-1.2), and 0.8 (95% CI, 0.8-0.8) per 1000 procedures, respectively. The median day of diagnosis of endophthalmitis was later for glaucoma surgeries (16.5 days) compared with combined cataract/glaucoma or cataract surgeries alone (8 and 6 days, respectively). Compared with microinvasive glaucoma surgery (MIGS), tube shunts were the only surgery type to be a significant risk factor for endophthalmitis for both stand-alone (adjusted odds ratio [aOR], 1.8, P = 0.002) and combined surgery (aOR 1.8, P = 0.047). The other risk factor for both stand-alone (aOR 1.1, P = 0.001) and combined (aOR 1.06, P = 0.049) surgeries was the Charlson Comorbidity Index (CCI). Age (aOR 1.03, P = 0.004) and male gender (1.46, P = 0.001) were significant risk factors for combined cataract and glaucoma surgeries. CONCLUSIONS: Compared with cataract surgery, early endophthalmitis incidence was higher for both glaucoma and combined cataract/glaucoma surgeries, with the highest incidence among tube shunts. 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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Extração de Catarata , Catarata , Endoftalmite , Glaucoma , Humanos , Idoso , Masculino , Estados Unidos/epidemiologia , Medicare , Estudos Retrospectivos , Incidência , Estudos Longitudinais , Endoftalmite/epidemiologia , Endoftalmite/etiologia , Endoftalmite/diagnóstico , Extração de Catarata/efeitos adversos , Fatores de Risco , Catarata/complicações , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Glaucoma/epidemiologia , Glaucoma/cirurgia , Glaucoma/complicaçõesRESUMO
This document discusses preprocedural planning for transcatheter aortic valve replacement, evaluating the imaging modalities used in initial imaging for preprocedure planning under two variants 1) Preintervention planning for transcatheter aortic valve replacement: assessment of aortic root; and 2) Preintervention planning for transcatheter aortic valve replacement: assessment of supravalvular aorta and vascular access. US echocardiography transesophageal, MRI heart function and morphology without and with IV contrast, MRI heart function and morphology without IV contrast and CT heart function and morphology with IV contrast are usually appropriate for assessment of aortic root. CTA chest with IV contrast, CTA abdomen and pelvis with IV contrast, CTA chest abdomen pelvis with IV contrast are usually appropriate for assessment of supravalvular aorta and vascular access. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.
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Substituição da Valva Aórtica Transcateter , Humanos , Imageamento por Ressonância Magnética , Sociedades Médicas , Tomografia Computadorizada por Raios X/métodos , Estados UnidosRESUMO
Purpose: The strain response of the mouse astrocytic lamina (AL) to an ex vivo mechanical test was compared between two protocols: eyes that underwent sustained intraocular pressure (IOP) increase and eyes after optic nerve crush. Methods: Chronic IOP elevation was induced by microbead injection or the optic nerve was crushed in mice with widespread green fluorescence. After 3 days or 6 weeks, eyes were inflation tested by a published method of two-photon fluorescence to image the AL. Digital volume correlation was used to calculate strains. Optic nerve axon damage was also evaluated. Results: In the central AL but not the peripheral AL, four strains were greater in eyes at the 3-day glaucoma time point than control (P from 0.029 to 0.049, n = 8 eyes per group). Also, at this time point, five strains were greater in the central AL compared to the peripheral AL (P from 0.041 to 0.00003). At the 6-week glaucoma time point, the strains averaged across the specimen, in the central AL, and the peripheral AL were indistinguishable from the respective controls. Strains were not significantly different between controls and eyes 3 days or 6 weeks after crush (n = 8 and 16). Conclusions: We found alterations in the ex vivo mechanical behavior in eyes from mice with experimental glaucoma but not in those with crushed optic nerves. The results of this study demonstrate that significant axon injury does not directly affect mechanical behavior of the astrocytic lamina.
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Glaucoma , Traumatismos do Nervo Óptico , Camundongos , Animais , Fenômenos Biomecânicos , Pressão Intraocular , Nervo Óptico , EscleraRESUMO
To evaluate how well outcomes following cataract extraction and microinvasive glaucoma surgery in one eye predict outcomes in sequential second eye. Retrospective study of 78 patients who underwent cataract extraction and microinvasive glaucoma surgery in both eyes. Linear regressions using Pearson correlation coefficients were used to evaluate correlations in intraocular pressure and glaucoma medication change between eyes. Multivariable logistic regression models were used to evaluate the associations between first-eye variables and the likelihood of second-eye surgical success at 6 months. Surgical success was defined as meeting target intraocular pressure without additional medications compared to baseline or secondary surgical interventions. Baseline ocular characteristics were comparable between fellow eyes, with the majority having mild glaucoma. Intraocular pressure changes between fellow eyes at 6 months were modestly correlated between eyes (Râ =â 0.48; Pâ <â .001). Changes in glaucoma medications were strongly correlated between eyes at all time points, and month 6 demonstrated the most significant correlation (Râ =â 0.80; Pâ <â .001). First and second eye cohorts achieved 82% and 83% surgical success. Multivariate analysis for predictive factors of successful second eye surgery showed patients with successful first eye surgery at 6 months were significantly more likely to have successful second eye surgery (odds ratio, 20.67; Pâ <â .001). Reductions in intraocular pressure and glaucoma medications at 6 months following surgery in first eyes are correlated to second eye reductions. Successful surgical outcomes at 6 months following first eye surgeries are strongly associated with successful sequential second eye outcomes.
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Extração de Catarata , Glaucoma , Humanos , Estudos Retrospectivos , Glaucoma/cirurgia , Pressão Intraocular , Olho , Resultado do TratamentoRESUMO
Purpose: The Retinal Ganglion Cell (RGC) Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) consortium was founded in 2021 to help address the numerous scientific and clinical obstacles that impede development of vision-restorative treatments for patients with optic neuropathies. The goals of the RReSTORe consortium are: (1) to define and prioritize the most critical challenges and questions related to RGC regeneration; (2) to brainstorm innovative tools and experimental approaches to meet these challenges; and (3) to foster opportunities for collaborative scientific research among diverse investigators. Design and Participants: The RReSTORe consortium currently includes > 220 members spanning all career stages worldwide and is directed by an organizing committee comprised of 15 leading scientists and physician-scientists of diverse backgrounds. Methods: Herein, we describe the structure and organization of the RReSTORe consortium, its activities to date, and the perceived impact that the consortium has had on the field based on a survey of participants. Results: In addition to helping propel the field of regenerative medicine as applied to optic neuropathies, the RReSTORe consortium serves as a framework for developing large collaborative groups aimed at tackling audacious goals that may be expanded beyond ophthalmology and vision science. Conclusions: The development of innovative interventions capable of restoring vision for patients suffering from optic neuropathy would be transformative for the ophthalmology field, and may set the stage for functional restoration in other central nervous system disorders. By coordinating large-scale, international collaborations among scientists with diverse and complementary expertise, we are confident that the RReSTORe consortium will help to accelerate the field toward clinical translation. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.
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Intercellular cytoplasmic material transfer (MT) occurs between transplanted and developing photoreceptors and ambiguates cell origin identification in developmental, transdifferentiation, and transplantation experiments. Whether MT is a photoreceptor-specific phenomenon is unclear. Retinal ganglion cell (RGC) replacement, through transdifferentiation or transplantation, holds potential for restoring vision in optic neuropathies. During careful assessment for MT following human stem cell-derived RGC transplantation into mice, we identified RGC xenografts occasionally giving rise to labeling of donor-derived cytoplasmic, nuclear, and mitochondrial proteins within recipient Müller glia. Critically, nuclear organization is distinct between human and murine retinal neurons, which enables unequivocal discrimination of donor from host cells. MT was greatly facilitated by internal limiting membrane disruption, which also augments retinal engraftment following transplantation. Our findings demonstrate that retinal MT is not unique to photoreceptors and challenge the isolated use of species-specific immunofluorescent markers for xenotransplant identification. Assessment for MT is critical when analyzing neuronal replacement interventions.
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Retina , Neurônios Retinianos , Animais , Humanos , Camundongos , Retina/metabolismo , Células Ganglionares da Retina , Neuroglia/metabolismo , Células FotorreceptorasRESUMO
A major risk factor for glaucomatous optic neuropathy is the level of intraocular pressure (IOP), which can lead to retinal ganglion cell axon injury and cell death. The optic nerve has a rostral unmyelinated portion at the optic nerve head followed by a caudal myelinated region. The unmyelinated region is differentially susceptible to IOP-induced damage in rodent models and human glaucoma. While several studies have analyzed gene expression changes in the mouse optic nerve following optic nerve injury, few were designed to consider the regional gene expression differences that exist between these distinct areas. We performed bulk RNA-sequencing on the retina and separately micro-dissected unmyelinated and myelinated optic nerve regions from naïve C57BL/6 mice, mice after optic nerve crush, and mice with microbead-induced experimental glaucoma (total = 36). Gene expression patterns in the naïve unmyelinated optic nerve showed significant enrichment of the Wnt, Hippo, PI3K-Akt, and transforming growth factor ß pathways, as well as extracellular matrix-receptor and cell membrane signaling pathways, compared to the myelinated optic nerve and retina. Gene expression changes induced by both injuries were more extensive in the myelinated optic nerve than the unmyelinated region, and greater after nerve crush than glaucoma. Changes present three and fourteen days after injury largely subsided by six weeks. Gene markers of reactive astrocytes did not consistently differ between injury states. Overall, the transcriptomic phenotype of the mouse unmyelinated optic nerve was significantly different from immediately adjacent tissues, likely dominated by expression in astrocytes, whose junctional complexes are inherently important in responding to IOP elevation.
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Glaucoma , Disco Óptico , Humanos , Camundongos , Animais , Disco Óptico/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos C57BL , Glaucoma/genética , Glaucoma/metabolismo , Retina/metabolismo , Nervo Óptico/metabolismo , Pressão Intraocular , Compressão Nervosa , Expressão Gênica , Modelos Animais de DoençasRESUMO
Retinal ganglion cell (RGC) death in glaucoma and other optic neuropathies results in irreversible vision loss due to the mammalian central nervous system's limited regenerative capacity. RGC repopulation is a promising therapeutic approach to reverse vision loss from optic neuropathies if the newly introduced neurons can reestablish functional retinal and thalamic circuits. In theory, RGCs might be repopulated through the transplantation of stem cell-derived neurons or via the induction of endogenous transdifferentiation. The RGC Repopulation, Stem Cell Transplantation, and Optic Nerve Regeneration (RReSTORe) Consortium was established to address the challenges associated with the therapeutic repair of the visual pathway in optic neuropathy. In 2022, the RReSTORe Consortium initiated ongoing international collaborative discussions to advance the RGC repopulation field and has identified five critical areas of focus: (1) RGC development and differentiation, (2) Transplantation methods and models, (3) RGC survival, maturation, and host interactions, (4) Inner retinal wiring, and (5) Eye-to-brain connectivity. Here, we discuss the most pertinent questions and challenges that exist on the path to clinical translation and suggest experimental directions to propel this work going forward. Using these five subtopic discussion groups (SDGs) as a framework, we suggest multidisciplinary approaches to restore the diseased visual pathway by leveraging groundbreaking insights from developmental neuroscience, stem cell biology, molecular biology, optical imaging, animal models of optic neuropathy, immunology & immunotolerance, neuropathology & neuroprotection, materials science & biomedical engineering, and regenerative neuroscience. While significant hurdles remain, the RReSTORe Consortium's efforts provide a comprehensive roadmap for advancing the RGC repopulation field and hold potential for transformative progress in restoring vision in patients suffering from optic neuropathies.
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Doenças do Nervo Óptico , Células Ganglionares da Retina , Animais , Humanos , Retina , Encéfalo , Diferenciação Celular , MamíferosRESUMO
OBJECTIVE: To compare outcomes following Ahmed-FP7 (AGI-FP7), Baerveldt-250mm2 (BGI-250), or Baerveldt-350mm2 (BGI-350) implantation. METHODS AND ANALYSIS: Retrospective cohort study comprising 800 eyes from 800 individuals who underwent surgery 1 January 2016-31 December 2020 at a tertiary-care institution. Data were extracted from standardised fields in the electronic health record. Primary outcome was failure (defined as intraocular pressure (IOP) ≤5 mm Hg or >18 mm Hg or reduction <20% at two consecutive visits from month 3 onwards; or visual acuity (VA) loss ≥3 lines; or return to the operating room (OR)). Secondary outcomes were IOP, VA, number of follow-up visits and return to the OR. RESULTS: A total of 523 AGI-FP7, 133 BGI-250 and 144 BGI-350 cases were analysed. The AGI-FP7 group was more likely to be younger and diagnosed with secondary glaucoma, with a higher mean baseline IOP (28.5±12.2 vs 22.0±7.7 mm Hg in BGI-250 and 23.4±9.0 in BGI-350, p<0.001). Cumulative failure rate at month 12 was 30% (AGI-FP7) vs 39% (BGI-250) vs 33% (BGI-350, p=0.159). Mean IOP at month 12 was lower in the BGI-350 group compared with AGI-FP7 (12.4±4.4 vs 14.8±5.6 mm Hg, p=0.003) but not BGI-250 (vs 13.1±4.6, p=0.710). Target IOP was achieved in 71% of AGI-FP7, 66% BGI-250, and 76% BGI-350. VA loss and rates of return to the OR did not differ between groups. Both BGI-250 and BGI-350 had more follow-up visits than AGI-FP7 (p<0.001). CONCLUSION: These three glaucoma drainage devices performed similarly within 1 year, with no difference in failure rates despite differing baseline patient characteristics.
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Implantes para Drenagem de Glaucoma , Glaucoma , Humanos , Registros Eletrônicos de Saúde , Estudos Retrospectivos , Resultado do Tratamento , Seguimentos , Implantação de Prótese/métodos , Complicações Pós-Operatórias/cirurgia , Acuidade Visual , Glaucoma/cirurgia , Pressão IntraocularRESUMO
PRCIS: Compared with phacoemulsification and microstent alone, we observed that phacoemulsification with combined microstent and canaloplasty resulted in a significantly greater reduction in glaucoma medications while maintaining similar rates of intraocular pressure reduction and low complications. PURPOSE: The purpose of this study was to compare the outcomes of phacoemulsification combined with Hydrus Microstent (Alcon Inc.) implantation alone or in combination with canaloplasty (OMNI Surgical System, Sight Sciences Inc.). MATERIALS AND METHODS: Retrospective study of mild-to-moderate primary open angle glaucoma patients who underwent phacoemulsification with microstent alone (42 eyes of 42 patients) or in combination with canaloplasty (canaloplasty-microstent, 32 eyes of 32 patients). The mean number of ocular hypotensive medications and intraocular pressure were assessed preoperatively and postoperatively at 1 week and at 1, 3, and 6 months. Complications and secondary surgical interventions were recorded. Outcomes measures included the percentage of unmedicated eyes and surgical success at 6 months. Surgical success was defined as reaching the target intraocular pressure without medications or secondary surgical interventions. RESULTS: Mean intraocular pressure at 6 months was 14.1±3.5 mm Hg (13% reduction) after microstent alone and 13.6±3.1 mm Hg (17% reduction) after canaloplasty-microstent. Mean medications at 6 months were 0.57±0.9 (67% reduction) after microstent alone and 0.16±0.4 (88% reduction) after canaloplasty-microstent ( P< 0.05). At 6 months, 64.3% of microstent alone and 87.3% of canaloplasty-microstent were off all medications ( P =0.02). Success probabilities at 6 months were 44.5% for microstent alone and 70.0% for canaloplasty-microstent ( P =0.04). No secondary surgical interventions occurred in either group. CONCLUSIONS: Microstent combined with canaloplasty resulted in a significantly higher rate of medication-free status compared with microstent alone through 6 months.
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Catarata , Glaucoma de Ângulo Aberto , Limbo da Córnea , Facoemulsificação , Humanos , Pressão Intraocular , Glaucoma de Ângulo Aberto/complicações , Glaucoma de Ângulo Aberto/cirurgia , Estudos Retrospectivos , Facoemulsificação/métodos , Limbo da Córnea/cirurgia , Catarata/complicaçõesRESUMO
Neuronal repopulation achieved through transplantation or transdifferentiation from endogenous sources holds tremendous potential for restoring function in chronic neurodegenerative disease or acute injury. Key to the evaluation of neuronal engraftment is the definitive discrimination of new or donor neurons from preexisting cells within the host tissue. Recent work has identified mechanisms by which genetically encoded donor cell reporters can be transferred to host neurons through intercellular material transfer. In addition, labeling transplanted and endogenously transdifferentiated neurons through viral vector transduction can yield misexpression in host cells in some circumstances. These issues can confound the tracking and evaluation of repopulated neurons in regenerative experimental paradigms. Using the retina as an example, we discuss common reasons for artifactual labeling of endogenous host neurons with donor cell reporters and suggest strategies to prevent erroneous conclusions based on misidentification of cell origin.
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A major risk factor for glaucomatous optic neuropathy is the level of intraocular pressure (IOP), which can lead to retinal ganglion cell axon injury and cell death. The optic nerve has a rostral unmyelinated portion at the optic nerve head followed by a caudal myelinated region. The unmyelinated region is differentially susceptible to IOP-induced damage in rodent models and in human glaucoma. While several studies have analyzed gene expression changes in the mouse optic nerve following optic nerve injury, few were designed to consider the regional gene expression differences that exist between these distinct areas. We performed bulk RNA-sequencing on the retina and on separately micro-dissected unmyelinated and myelinated optic nerve regions from naïve C57BL/6 mice, mice after optic nerve crush, and mice with microbead-induced experimental glaucoma (total = 36). Gene expression patterns in the naïve unmyelinated optic nerve showed significant enrichment of the Wnt, Hippo, PI3K-Akt, and transforming growth factor ß pathways, as well as extracellular matrix-receptor and cell membrane signaling pathways, compared to the myelinated optic nerve and retina. Gene expression changes induced by both injuries were more extensive in the myelinated optic nerve than the unmyelinated region, and greater after nerve crush than glaucoma. Changes three and fourteen days after injury largely subsided by six weeks. Gene markers of reactive astrocytes did not consistently differ between injury states. Overall, the transcriptomic phenotype of the mouse unmyelinated optic nerve was significantly different from immediately adjacent tissues, likely dominated by expression in astrocytes, whose junctional complexes are inherently important in responding to IOP elevation.
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Tight glycemic control (TGC), the cornerstone of diabetic management, reduces the incidence and progression of diabetic microvascular disease. However, TGC can also lead to transient episodes of hypoglycemia, which have been associated with adverse outcomes in patients with diabetes. Here, we demonstrate that low glucose levels result in hypoxia-inducible factor (HIF)-1-dependent expression of the glucose transporter, Glut1, in retinal cells. Enhanced nuclear accumulation of HIF-1α was independent of its canonical post-translational stabilization but instead dependent on stimulation of its translation and nuclear localization. In the presence of hypoxia, this physiologic response to low glucose resulted in a marked increase in the secretion of the HIF-dependent vasoactive mediators that promote diabetic retinopathy. Our results provide a molecular explanation for how early glucose control, as well as glycemic variability (i.e., oscillating serum glucose levels), contributes to diabetic eye disease. These observations have important implications for optimizing glucose management in patients with diabetes.
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Diabetes Mellitus , Retinopatia Diabética , Hipoglicemia , Humanos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Retinopatia Diabética/metabolismo , Glucose/metabolismo , Hipoglicemia/complicações , Hipóxia , Subunidade alfa do Fator 1 Induzível por HipóxiaRESUMO
To identify changes in response to experimental intraocular pressure (IOP) elevation associated with the laminin α1 nmf223 mutation in mice. Laminin mutant (LM) mice (Lama1nmf223) and C57BL/6J (B6) mice in two age groups each (4-5 months and >1 year) underwent intracameral microbead injections to produce unilaterally elevated IOP. We assessed axonal transport block of immunofluorescently labeled amyloid precursor protein (APP) after 3 days and retinal ganglion cell (RGC) axon loss after 6 weeks. Light, electron and fluorescent microscopy was used to study baseline anatomic differences and effects of 3-day IOP elevation in younger LM mice. In younger mice of both LM and B6 strains, elevated IOP led to increased APP block in the retina, prelaminar optic nerve head (preONH), unmyelinated optic nerve (UON), and myelinated optic nerve (MON). APP blockade not significantly different between younger B6 and LM mouse strains. Older LM mice had greater APP accumulation in both control and glaucoma eyes compared to older B6, however, accumulation was not significantly greater in LM glaucoma eyes compared to LM controls. Axon loss at 6 weeks was 12.2% in younger LM and 18.7% in younger B6 mice (difference between strains, p = 0.22, Mann Whitney test). Untreated LM optic nerve area was lower compared to B6 (nerve area, p < 0.0001, t-test). Aberrant axon bundles, as well as defects, thickening and reduplication of pia mater, were seen in the optic nerves of younger LM mice. Axonal transport blockade significantly differed between old B6 and old LM mice in control and glaucoma eyes, and younger LM mice had abnormal axon paths and lower optic nerve area.
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Glaucoma , Nervo Óptico , Animais , Camundongos , Axônios/patologia , Modelos Animais de Doenças , Glaucoma/genética , Pressão Intraocular , Camundongos Endogâmicos C57BL , Disco Óptico/patologia , Nervo Óptico/patologia , Laminina/genéticaRESUMO
The advent of the first-ever retinal gene therapy product, involving subretinal administration of a virus-based gene delivery platform, has garnered hope that this state-of-the-art therapeutic modality may benefit a broad spectrum of patients with diverse retinal disorders. On the other hand, clinical studies have revealed limitations of the applied delivery strategy that may restrict its universal use. To this end, intravitreal administration of synthetic gene-delivery platforms, such as polymer-based nanoparticles (PNPs), has emerged as an attractive alternative to the current mainstay. To achieve success, however, it is imperative that synthetic platforms overcome key biological barriers in human eyes encountered following intravitreal administration, including the vitreous gel and inner limiting membrane (ILM). Here, we introduce a series of experiments, from the fabrication of PNPs to a comprehensive evaluation in relevant experimental models, to determine whether PNPs overcome these barriers and efficiently deliver therapeutic gene payloads to retinal cells. We conclude the article by discussing a few important considerations for successful implementation of the strategy. © 2022 Wiley Periodicals LLC. Basic Protocol 1: Preparation and characterization of PNPs Basic Protocol 2: Evaluation of in vitro transfection efficacy Basic Protocol 3: Evaluation of PNP diffusion in vitreous gel Basic Protocol 4: Ex vivo assessment of PNP penetration within vitreoretinal explant culture Basic Protocol 5: Assessment of in vivo transgene expression mediated by intravitreally administered PNPs.
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Nanopartículas , Polímeros , Humanos , Polímeros/metabolismo , Técnicas de Transferência de Genes , Terapia Genética/métodos , Retina/metabolismoRESUMO
Purpose: To describe twelve cases in which home intraocular pressure (IOP) monitoring complimented clinical decision-making in glaucoma management. Observations: Home IOP monitoring elucidated peaks and amplitudes of variation that were not captured by in-clinic IOP measurements during the pre- or post-interventional period. Conclusions & Importance: Home monitoring can establish pre-treatment IOP patterns that are not evident during in-clinic measurements. Home monitoring can also demonstrate response to treatment more quickly than in-clinic monitoring, and provide more information about nyctohemoral fluctuations than is ascertained by in-clinic tonometry.