Clinical Pharmacology Perspective on Development of Adeno-Associated Virus Vector-Based Retina Gene Therapy.

Adeno-associated virus (AAV) vector-based gene therapy is an innovative modality being increasingly investigated to treat diseases by modifying or replacing defective genes or expressing therapeutic entities. With its unique anatomic and physiological characteristics, the eye constitutes a very attractive target for gene therapy. Specifically, the ocular space is easily accessible and is generally considered "immune-privileged" with a low risk of systemic side effects following local drug administration. As retina cells have limited cellular turnover, a one-time gene delivery has the potential to provide long-term transgene expression. Despite the initial success with voretigene neparvovec (Luxturna), the first approved retina gene therapy, there are still challenges to be overcome for successful clinical development of these products and scientific questions to be answered. The current review paper aims to integrate published experience learned thus far for AAV-based retina gene therapy related to preclinical to clinical translation; first-in-human dose selection; relevant bioanalytical assays and strategies; clinical development considerations including trial design, biodistribution and vector shedding, immunogenicity, transgene expression, and pediatric populations; opportunities for model-informed drug development; and regulatory perspectives. The information presented herein is intended to serve as a guide to inform the clinical development strategy for retina gene therapy with a focus on clinical pharmacology.

Pediatric orbital cellulitis: Case report of an unusual etiology and pathogen.

Orbital cellulitis is an uncommon condition with risks to sight and life. As a complication of maxillofacial injuries, the literature suggests this is only possible with fractures or direct inoculation, and there are no reports to the contrary. Here, we make the first report of a possible etiology by which orbital cellulitis developed in a 14-year-old boy even without skin breach or bony fractures; as well as a rare causative pathogen. He presented with facial abscess and progressive orbital cellulitis after blunt facial trauma, requiring functional endoscopic sinus surgery with needle aspiration of facial abscess externally. Cultures showed growth of Streptococcus constellatus/Parvimonas micra, and he received further antibiotics with full recovery.The pathophysiology of orbital cellulitis in this patient is attributed to vascular congestion and local pressure from maxillofacial contusion and maxillary hemoantrum, with impaired paranasal sinus ventilation encouraging anaerobic bacterial growth. Further progression led to facial abscess formation and intraorbital spread with orbital cellulitis. The pediatric demographic is injury-prone, and self-reporting of symptoms can be delayed. Hence, increased suspicion of complicated injuries and orbital cellulitis may be required when managing maxillofacial contusions so that prompt treatment can be given.

Research Funding, Income, and Career Satisfaction Among Clinician-Scientists in Ophthalmology in the United States.

PURPOSE: The purpose of this study was to characterize clinician-scientists in ophthalmology and identify factors associated with successful research funding, income, and career satisfaction. DESIGN: Cross-sectional study. METHODS: A survey was conducted of clinician-scientists in ophthalmology at US academic institutions between April 17, 2019, and May 19, 2019. Collected information including 1) demographic data; 2) amount, type, and source of startup funding; first extramural grant; and first R01-equivalent independent grant; 3) starting and current salaries; and 4) Likert-scale measurements of career satisfaction were analyzed using multivariate regression. RESULTS: Ninety-eight clinician-scientists in ophthalmology were surveyed across different ages (mean: 48 ± 11 years), research categories, institutional types, geographic regions, and academic ranks. Median startup funding ranged from $50-99k, and median starting salaries ranged from $150-199k. A majority of investigators (67%) received their first extramural award from the National Eye Institute, mainly through K-award mechanisms (82%). The median time to receiving their first independent grant was 8 years, mainly through an R01 award (70%). Greater institutional startup support (P = .027) and earlier extramural grant success (P = .022) were associated with earlier independent funding. Male investigators (P = .001) and MD degreed participants (P = .008) were associated with higher current salaries but not starting salaries. Overall career satisfaction increased with career duration (P = .011) but not with earlier independent funding (P = .746) or higher income (P = .300). CONCLUSIONS: Success in research funding by clinician-scientists in ophthalmology may be linked to institutional support and earlier acquisition of extramural grants but does not impact academic salaries. Nevertheless, career satisfaction among clinician-scientists improves with time, which is not necessarily influenced by research or financial success.

BILATERAL ENTEROCOCCUS FAECALIS ENDOPHTHALMITIS WITH MULTIPLE RECURRENCES.

PURPOSE: To describe the first case report of a bilateral recurrent Enterococcus faecalis endophthalmitis postcataract surgery. METHODS: Case report with a description of the timeline, diagnosis, and management of a patient with bilateral recurrent E. faecalis endophthalmitis. RESULTS: An 89-year-old man presented 6 weeks' postcataract surgery with pain, tearing, and blurred vision in the left eye. B-scan ultrasonography revealed vitritis and cultures postvitrectomy grew E. faecalis. There was gradual improvement in vision postintravitreal vancomycin administration. Four years later, the patient experienced another episode of E. faecalis endophthalmitis in the right eye postcataract extraction, followed by several additional episodes in both eyes posttreatment. CONCLUSION: Enterococcus faecalis is a rare but highly virulent cause of endophthalmitis that may remain sequestered in the capsular bag, despite aggressive treatment. Even after recurrent episodes, early vitrectomy and aggressive antibiotic therapy may prove to be effective in preventing vision loss.

Implementing the new normal in ophthalmology care beyond COVID-19.

The COVID-19 pandemic has altered the clinical landscape immeasurably. The need to physical distance requires rethinking how we deliver ophthalmic care. Within healthcare, we will need to focus our resources on the five T's: Utilising technology, multidisciplinary clinical teams with wide professional talents need to work efficiently to reduce patient contact time. With regular testing, this will allow us to reduce the risk further. We also must acknowledge the explosion of different modalities to train our future ophthalmologists and the global challenges and advantages that these bring. Finally, we must not forget the psychological impact that this pandemic will have on ophthalmologists and ancillary staff, and need to have robust mechanisms for support.

Rationale for American Society of Retina Specialists Best Practice Recommendations for Conducting Vitreoretinal Surgery during the COVID-19 Era.

PURPOSE: To detail the rationale behind recommendations recently published by the American Society of Retina Specialists (ASRS) outlining best practices for safety of vitreoretinal surgeons and staff while performing vitreoretinal surgery during the coronavirus disease (COVID)-19 pandemic. METHODS: The committee for ASRS Best Practices for Retinal Surgery during the COVID-19 Pandemic reviewed existing evidence and information on SARS-CoV-2 transmission, and risk factors during vitreoretinal surgery. Recommendations were based on best available published data, cumulative clinical experiences, and recommendations and policies from other organizations. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the strength of recommendations and confidence in the evidence. These serve as interim recommendations which are routinely updated given gaps of knowledge and lack of high-quality data on this evolving subject. RESULTS: Relevant existing literature related to methods of transmission, and ocular manifestations of SARS-CoV-2 are summarized. The data and clinical experiences driving recommendations for pre-operative, intraoperative and post-operative surgical considerations, anesthesia choice, as well as considerations for intravitreal injections are provided. CONCLUSION: Recommendations are provided with the goal of protecting vitreoretinal surgeons and associated personnel from exposure to SARS-CoV-2 during interventional vitreoretinal procedures. This is a rapidly evolving topic with numerous remaining gaps in our current knowledge. As such, recommendations will evolve and the current manuscript is intended to serve as a foundation for continued dialogue on best practices.

OCT Angiography Biomarkers for Predicting Visual Outcomes after Ranibizumab Treatment for Diabetic Macular Edema.

PURPOSE: To correlate quantitative OCT angiography (OCTA) biomarkers with clinical features and to predict the extent of visual improvement after ranibizumab treatment for diabetic macular edema (DME) with OCTA biomarkers. DESIGN: Retrospective, longitudinal study in Taiwan. PARTICIPANTS: Fifty eyes of 50 patients with DME and 22 eyes of 22 healthy persons, with the exception of cataract and refractive error, from 1 hospital. METHODS: Each eye underwent OCT angiography (RTVue XR Avanti System with AngioVue software version 2017.1; Optovue, Fremont, CA), and 3×3-mm2 en face OCTA images of the superficial layer and the deep layer were obtained at baseline and after 3 monthly injections of ranibizumab in the study group. OCT angiography images also were acquired from the control group. MAIN OUTCOME MEASURES: Five OCTA biomarkers, including foveal avascular zone (FAZ) area (FAZ-A), FAZ contour irregularity (FAZ-CI), average vessel caliber (AVC), vessel tortuosity (VT), and vessel density (VD), were analyzed comprehensively. Best-corrected visual acuity (BCVA) and central retinal thickness (CRT) also were obtained. Student t tests were used to compare the OCTA biomarkers between the study group and the control group. Linear regression models were used to evaluate the correlations between the baseline OCTA biomarkers and the changes of BCVA and CRT after treatment. RESULTS: Eyes with DME had larger AVC, VT, FAZ-A, and FAZ-CI and lower VD than those in the control group (P < 0.001 for all). After the loading ranibizumab treatment, these OCTA biomarkers improved but did not return to normal levels. Among all biomarkers, higher inner parafoveal VD in the superficial layer at baseline correlated most significantly with visual gain after treatment in the multiple regression model with adjustment for CRT and ellipsoid zone disruption (P < 0.001). To predict visual improvement, outer parafoveal VD in the superficial layer at the baseline showed the largest area under the receiver operating characteristic curve (0.787; P = 0.004). No baseline OCTA biomarkers showed any significant correlation specifically with anatomic improvement. CONCLUSIONS: For eyes with DME, parafoveal VD in the superficial layer at baseline was an independent predictor for visual improvement after the loading ranibizumab treatment.

Real-World Trends in Intravitreal Injection Practices among American Retina Specialists.

PURPOSE: To analyze practice patterns used for intravitreal injections (IVIs) by retinal specialists in the United States. DESIGN: Cross-sectional online survey. PARTICIPANTS: Retina specialists in the United States who responded to a web-based survey. METHODS: Retinal specialists in the United States were contacted via e-mail to complete a web-based, anonymous, 24-question survey. Multivariate analysis was performed on a selected question of interest focused on choice of anesthetic used for IVI. MAIN OUTCOME MEASURES: Differences in IVI practices, such as antibiotic preferences, and different odds of anesthetic use by demographic variables with 95% confidence intervals. RESULTS: A total of 281 retinal specialists responded to the survey (17% response rate). Respondents' average age was 53 years, with an average of 20 years in practice. Respondents practiced in 42 states, with 90% practicing in an urban or suburban area. For anesthesia, 14% used a topical anesthetic with cotton swab compression, 27% used a subconjunctival anesthetic, and 31% used an anesthetic gel. Age, gender, geographic location, and practice setting did not seem to impact choice of anesthetic for IVI significantly. Sixty-six percent of respondents always use a lid speculum, 21% administer topical antibiotics before injection, 36% wear a mask, 73% wear gloves, and 45% always dilate the eyes before injection. Most respondents use a 30-gauge needle and inject in the inferior temporal quadrant (70%). Forty-five percent always perform bilateral injections the same day if indicated. After the injection, 14% administer post operative nonsteroidal anti-inflammatory drugs, 28% administer postoperative antibiotics, and 31% routinely check intraocular pressure after injection. CONCLUSIONS: This study provided real-world trends in practices for IVI among retina specialists in the United States. In addition, age, gender, practice type, and geographic location did not influence anesthetic choice for IVI.

Analysis of Patient-Reported Barriers to Diabetic Retinopathy Follow-Up.

BACKGROUND AND OBJECTIVES: Close follow-up of diabetic retinopathy (DR) has been linked to improved visual outcomes. This study elucidates patient-identified barriers to DR follow-up in a diverse urban clinic population. PATIENTS AND METHODS: Patients 18 years of age or older with DR or macular edema were interviewed using a 21-question survey on attitudes and barriers toward care. Univariate and multivariate logistic analysis identified barriers associated with non-compliance to follow-up. RESULTS: Two hundred nine patients participated with mean age of 58.2 years and hemoglobin A1c of 8.5%. The most common barriers cited were long waiting times (46.4%), other medical conditions (35.9%), forgetting (28.2%), and inability to leave work (9.1%). In a multivariate analysis, forgetting (odds ratio [OR]: 4.35) and other medical conditions (OR: 1.91) were barriers independently associated with non-compliance. Having proliferative DR was associated with other medical conditions in univariate (OR: 4.60) and multivariate analysis (OR: 4.35). CONCLUSION: Patients with DR who report other medical conditions or forgetting have a higher risk of non-compliance to follow-up. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:99-105.].

RESOLUTION, DEPTH OF FIELD, AND PHYSICIAN SATISFACTION DURING DIGITALLY ASSISTED VITREORETINAL SURGERY.

PURPOSE: To evaluate depth of field, lateral resolution, and image quality of a heads-up 3D visualization system for vitreoretinal surgery using physician survey and optical measurement outcomes. METHODS: Depth of field and lateral resolution were compared between the standard ocular viewing system and the digital 3D system at ×5, ×13, and ×18 magnification by 6 retinal surgeons. Optical techniques were used as well as a survey of surgeon impression. Surgeon impression surveys were performed after 6 weeks of surgical use of the device. RESULTS: Physician questionnaire survey scores for depth of field at high magnification were better for the digital 3D system and equivalent for all other categories. Measured lateral resolution was 36.7 mm and 16.6 mm at ×5 magnification (P < 0.001), 14.3 mm and 6.4 mm at ×13 magnification (P < 0.001), and 9.8 mm and 4.2 mm (P < 0.001) at ×18 magnification for the digital 3D and oculars, respectively. Measured depth of field was 4.00 mm and 6.78 mm at ×5 magnification (P = 0.027), 0.72 mm and 0.86 mm at ×13 (P = 0.311), and 0.28 mm and 0.40 mm at ×18 magnification (P = 0.235) for the oculars and digital 3D, respectively. CONCLUSION: Lateral resolution of the digital 3D system was half that of the ocular viewing system and there was some improvement in depth of field with the digital system. Surgeon impression suggested that the digital system was superior when evaluating depth of field at high magnification.

Especial y marginal: hacia una problematización de la intervención estatal en la salud de los veteranos de Malvinas (1984-2000) / Special and marginal: towards a problematization of the state intervention regarding the health of Malvinas veterans (1984-2000)

RESUMEN El objetivo de este artículo es dar cuenta de las modalidades en que fue instituida la salud del veterano argentino de la guerra de Malvinas como un problema de intervención estatal entre 1984 y 2000. Para ello nos centramos en el concepto de problematización como un modo de análisis de las prácticas y el pensamiento político. El texto consta de tres apartados: en el primero se presentan las bases metodológicas para el análisis de las políticas públicas, mientras que el segundo y el tercero están destinados al análisis de una serie de leyes, proyectos de ley, decretos, informes, etc., producidos por diferentes esferas estatales en torno al veterano de guerra y su situación sanitaria. La hipótesis de lectura que proponemos es que el veterano o excombatiente de Malvinas fue problematizado como un segmento poblacional marginal, aunque la estabilización de un tratamiento específico tardó más de quince años en materializarse.

ABSTRACT The aim of this paper is to account for the modalities in which Malvinas veterans' health was constituted as a problem requiring state intervention between 1984 and 2000. In order to do so, we have focused on the concept of problematization as a way to analyze practices and political thought. The text consists of three sections: the first one presents the methodological basis of the analysis of public policies, whereas the second and third ones intend to analyze a series of laws, bills, decrees, reports and other documents produced by different state spheres about war veterans and their health situation. The hypothesis that we propose is that the Malvinas veterans were problematized as a marginal segment of the population, although the stabilization of a specific treatment took more than fifteen years to materialize

Success in Attaining Independent Funding Among National Institutes of Health K Grant Awardees in Ophthalmology: An Extended Follow-up.

Importance: Understanding factors associated with attaining independent research funding by ophthalmology clinician-scientists receiving National Eye Institute career development awards (K08 or K23) in ophthalmology can be important to maintaining the pipeline of clinician-scientists. Objective: To provide continued follow-up of a cohort of ophthalmology clinician-scientists who received National Institutes of Health (NIH) K career development grants. Design, Setting, and Participants: Cohort study from an electronic database review of ophthalmologists who have received either a K08 or K23 career development grant from the NIH. Data were analyzed between December 30, 2015, and December 30, 2017. Main Outcomes and Measures: Receipt of an NIH R01 grant. Results: We previously characterized a group of more than 100 ophthalmologists who received K awards from 1996 to 2010, of whom 29 were awarded R01 grants. In follow-up of this cohort in 2017, 27 additional K awardees of this initial cohort were awarded an R01 from 2011 to 2017, leading to a total of 62 of 128 ophthalmologists receiving an R01. The mean time to receiving an R01 grant after the K award ended was 2.8 years. The data did not identify a definitive association with sex, having a PhD degree, or research tier of university in obtaining an R01 grant in this cohort. Conclusions and Relevance: In comparison with our previous report of the same cohort, there was a 93% increase in the number of K awardees who have received an R01 award, with the mean time to award being nearly 3 years after completing their K grant. This suggests that most K awardees in ophthalmology are successful in obtaining R01 grants, but one should recognize this may be several years after their K grant has ended.

Nonisolated Small Bowel Gastrointestinal Angiodysplasias are Associated With Higher Rebleeding Rates When Compared With Isolated Small Bowel Gastrointestinal Angiodysplasia on Video Capsule Endoscopy.

BACKGROUND: Gastrointestinal angiodysplasias (GIAD) are commonly diagnosed in the small bowel but can be located in other areas of the gastrointestinal tract. About half of patients diagnosed with GIAD have more than 1 lesion and 20% of patients have GIAD in both the small bowel and a source outside of the small bowel (nonisolated to small bowel GIAD or NISGIAD). The remaining patients with GIAD have lesions isolated to the small bowel (ISGIAD). Complications including rebleeding, hospitalization and mortality rates have not been previously analyzed between these 2 groups. AIM: To compare rebleeding, hospitalization and mortality rates between ISGIAD and NISGIAD. The secondary goals were to evaluate comorbidities that may be associated with ISGIAD and/or NISGIAD, and to determine if any of these comorbidities are associated with a higher risk of rebleeding from GIAD. MATERIALS AND METHODS: This was a retrospective study that included 425 patients who underwent video capsule endoscopy between 2006 and 2013. Patients underwent esophagogastroduodenoscopy and colonoscopy before video capsule endoscopy. The primary indications for workup included obscure gastrointestinal bleeding. After exclusion criteria, 87 patients diagnosed with GIAD remained, 57 patients with ISGIAD and 30 with NISGIAD. Categorical variables were compared by the Fisher exact test or χ test and continuous data were compared using the Student T test. RESULTS: Risk factors associated with rebleeding rates included coronary artery disease, chronic kidney disease, and congestive heart failure on multivariate analysis. Odds ratios for rebleeding was found in patients with NISGIAD (odds ratio, 4.222; P=0.036). There was no difference in hospitalization rates between patients with ISGIAD and NISGIAD. There was no statistically significant difference in mortality from any cause at 30, 60, and 90 days in patients with ISGIAD and NISGIAD. CONCLUSIONS: In this retrospective analysis of GIAD at a single institution, patients with NISGIAD compared with ISGIAD had a 4 times odds of rebleeding within 1 year after capsule endoscopy. This is a novel study, as the distribution of GIAD has not been previously described as being a risk factor for rebleeding.

Prognostic Implications of Tumor Diameter in Association With Gene Expression Profile for Uveal Melanoma.

IMPORTANCE: Uveal melanoma (UM) can be divided into prognostically significant subgroups based on a prospectively validated and widely used 15-gene expression profile (GEP) test. Class 1 UMs have a low risk and class 2 UMs have a high risk for metastasis. OBJECTIVE: To determine whether any clinicopathologic factors provide independent prognostic information that may enhance the accuracy of the GEP classification. DESIGN, SETTING, AND PARTICIPANTS: This retrospective observational study performed at 2 ocular oncology referral centers included 339 patients in a primary cohort and 241 patients in a validation cohort. Both cohorts had a diagnosis of UM arising from the ciliary body and/or choroid. All patients underwent tumor biopsy for GEP prognostic testing. Clinicopathologic variables included patient age and sex, tumor thickness, largest basal tumor diameter (LBD), ciliary body involvement, and pathologic cell type. Patients from the primary cohort were enrolled from November 1, 1998, to March 16, 2012; from the validation cohort, from November 4, 1996, to November 7, 2013. Follow-up for the primary cohort was completed on August 18, 2013; for the validation cohort, December 10, 2013. Data were analyzed from November 12, 2013, to November 25, 2015. MAIN OUTCOME AND MEASURES: Progression-free survival (PFS). The secondary outcome was overall survival. RESULTS: The primary cohort included 339 patients (175 women [51.6%]; mean [SD] age, 61.8 [13.6] years). The most significant prognostic factor was GEP classification (exp[b], 10.33; 95% CI, 4.30-24.84; P < .001). The only other variable that provided independent prognostic information was LBD (exp[b], 1.13; 95% CI, 1.02-1.26; P = .02). Among class 2 UMs, LBD showed a modest but significant association with PFS (exp[b], 1.13; 95% CI, 1.04-1.24; P = .005). The 5-year actuarial metastasis-free survival estimates (SE) were 97% (3%) for class 1 UMs with LBD of less than 12 mm, 90% (4%) for class 1 UMs with LBD of at least 12 mm, 90% (9%) for class 2 UMs with LBD of less than 12 mm, and 30% (7%) for class 2 UMs with LBDs of at least 12 mm. The independent prognostic value of LBD and the 12-mm LBD cutoff were corroborated in the independent validation 241-patient cohort. CONCLUSIONS AND RELEVANCE: Class 2 UMs had better prognosis when the LBD was less than 12 mm at the time of treatment. These findings could have important implications for patient counseling, primary tumor treatment, clinical trial enrollment, metastatic surveillance, and adjuvant therapy.

Hydroxyapatite versus polyethylene orbital implants for patients undergoing enucleation for uveal melanoma.

OBJECTIVE: Clinical outcomes for enucleation vary widely, depending on surgical technique, implant choice, and indications for enucleation. The goal of this study was to compare complications of enucleation using hydroxyapatite versus polyethylene orbital implants for 1 indication: uveal melanoma in adults. DESIGN: Retrospective chart review PARTICIPANTS: Consecutive case series of patients who were enucleated for uveal melanoma by a single surgeon (J.W.H.) from 1999-2009. METHODS: A retrospective chart review was performed to record clinical and histopathologic features, surgical technique, orbital implant characteristics, and outcomes in a consecutive series of patients with uveal melanoma who were treated by enucleation by a single surgeon (J.W.H.) between 1999 and 2009. RESULTS: This study included 139 patients; 64 received hydroxyapatite implants, and 75 received polyethylene implants wrapped in donor sclera. Complications included blepharoptosis in 4 (2.9%), conjunctival cyst in 2 (1.4%), volume deficit in 2 (1.4%), implant exposure in 1 (0.7%), and conjunctival erosion in 1 (0.7%) patient. There were no significant differences in the clinicopathologic features or complications between the 2 groups. CONCLUSIONS: Few complications were encountered using this enucleation technique, and there was no difference in complication rates between patients receiving hydroxyapatite and polyethylene implants.

Stability of macular traction in involutional diabetic retinopathy over a 5-year course.

Involutional diabetic retinopathy is a descriptive term for an end-stage phase of proliferative diabetic retinopathy (PDR), which is often non-progressive. Two patients with involutional PDR with nonprogressive macular traction documented by spectral-domain optical coherence tomography (SD-OCT) over a 5-year period are described in this report.

Safety of bilateral intravitreal injections delivered in a teaching institution.

Intravitreal injection is one of the most common in-office procedures performed in ophthalmic practices. In teaching institutions such as the Veterans Affairs (VA) Hospitals, patient care is delivered by physicians-in-training, while mastering intravitreal injection technique. Infectious endophthalmitis and visual loss are the most feared complications of intravitreal injections, especially in the context of recent outbreaks caused by contaminated compounded medications. Ophthalmologists and ophthalmic educators increasingly face the dilemma of timing as well as balancing the risks and benefits of bilateral treatments required by many patients. In this editorial, we discuss published reports of bilateral injections, summarize our experience with bilateral intravitreal injections in a teaching setting at the Miami VA Hospital and list our recommendations for minimizing the risk of infectious endophthalmitis.