Selective permeation up a chemical potential gradient to enable an unusual solvent purification modality.

The need for energy-efficient recovery of organic solutes from aqueous streams is becoming more urgent as chemical manufacturing transitions toward nonconventional and bio-based feedstocks and processes. In addition to this, many aqueous waste streams contain recalcitrant organic contaminants, such as pharmaceuticals, industrial solvents, and personal care products, that must be removed prior to reuse. We observe that rigid carbon membrane materials can remove and concentrate organic contaminants via an unusual liquid-phase membrane permeation modality. Surprisingly, detailed thermodynamic calculations on the chemical potential of the organic contaminant reveal that the organic species has a higher chemical potential on the permeate side of the membrane than on the feed side of the membrane. This unusual observation challenges conventional membrane transport theory that posits that all permeating species move from high chemical potential states to lower chemical potential states. Based on experimental measurements, we hypothesize that the organic is concentrated in the membrane relative to water via favorable binding interactions between the organic and the carbon membrane. The concentrated organic is then swept through the membrane via the bulk flow of water in a modality known as "sorp-vection." We highlight via simplified nonequilibrium thermodynamic models that this "uphill" chemical potential permeation of the organic does not result in second-law violations and can be deduced via measurements of the organic and water sorption and diffusion rates into the carbon membrane. Moreover, this work identifies the need to consider such nonidealities when incorporating unique, rigid materials for the separations of aqueous waste streams.

Faricimab Treat-and-Extend for Diabetic Macular Edema: Two-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials.

PURPOSE: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME). DESIGN: Randomized, double-masked, noninferiority phase 3 trials. PARTICIPANTS: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME. METHODS: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change. MAIN OUTCOME MEASURES: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100. RESULTS: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 µm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept. CONCLUSIONS: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Efficacy and Safety of Faricimab for Macular Edema due to Retinal Vein Occlusion: 24-Week Results from the BALATON and COMINO Trials.

PURPOSE: To evaluate the 24-week efficacy and safety of the dual angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF)-A inhibitor faricimab versus aflibercept in patients with vein occlusion. DESIGN: Phase 3, global, randomized, double-masked, active comparator-controlled trials: BALATON/COMINO (ClincalTrials.gov identifiers: NCT04740905/NCT04740931; sites: 149/192). PARTICIPANTS: Patients with treatment-naïve foveal center-involved macular edema resulting from branch (BALATON) or central or hemiretinal (COMINO) RVO. METHODS: Patients were randomized 1:1 to faricimab 6.0 mg or aflibercept 2.0 mg every 4 weeks for 24 weeks. MAIN OUTCOME MEASURES: Primary end point: change in best-corrected visual acuity (BCVA) from baseline to week 24. Efficacy analyses included patients in the intention-to-treat population. Safety analyses included patients who received ≥ 1 doses of study drug. RESULTS: Enrollment: BALATON, n = 553; COMINO, n = 729. The BCVA gains from the baseline to week 24 with faricimab were noninferior versus aflibercept in BALATON (adjusted mean change, +16.9 letters [95.03% confidence interval (CI), 15.7-18.1 letters] vs. +17.5 letters [95.03% CI, 16.3-18.6 letters]) and COMINO (+16.9 letters [95.03% CI, 15.4-18.3 letters] vs. +17.3 letters [95.03% CI, 15.9-18.8 letters]). Adjusted mean central subfield thickness reductions from the baseline were comparable for faricimab and aflibercept at week 24 in BALATON (-311.4 µm [95.03% CI, -316.4 to -306.4 µm] and -304.4 µm [95.03% CI, -309.3 to -299.4 µm]) and COMINO (-461.6 µm [95.03% CI, -471.4 to -451.9 µm] and -448.8 µm [95.03% CI, -458.6 to -439.0 µm]). A greater proportion of patients in the faricimab versus aflibercept arm achieved absence of fluorescein angiography-based macular leakage at week 24 in BALATON (33.6% vs. 21.0%; nominal P = 0.0023) and COMINO (44.4% vs. 30.0%; nominal P = 0.0002). Faricimab was well tolerated, with an acceptable safety profile comparable with aflibercept. The incidence of ocular adverse events was similar between patients receiving faricimab (16.3% [n = 45] and 23.0% [n = 84] in BALATON and COMINO, respectively) and aflibercept (20.4% [n = 56] and 27.7% [n = 100], respectively). CONCLUSIONS: These findings demonstrate the efficacy and safety of faricimab, a dual Ang-2/VEGF-A inhibitor, in patients with macular edema secondary to retinal vein occlusion. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Surgical Management of Full-Thickness Macular Holes in Macular Telangiectasia Type 2: A Global Multicenter Study.

PURPOSE: To report on macular hole repair in macular telangiectasia type 2 (MacTel2). DESIGN: Global, multicenter, retrospective case series. PARTICIPANTS: Patients undergoing surgery for MacTel2-associated full-thickness macular hole (MTMH). METHODS: Standardized data collection sheet distributed to all surgeons. MAIN OUTCOME MEASURES: Anatomic closure and visual outcomes of MTMH. RESULTS: Sixty-three surgeries in 47 patients with MTMH were included from 30 surgeons. Mean age was 68.1 years, with 62% female, 72% White, 21% East or South Asian, 2% African American, and 2% Hispanic or Latino. Procedures included 34 internal limiting membrane (ILM) peeling alone, 22 ILM flaps, 5 autologous retinal transplantations (ARTs), 1 retinotomy, and 1 subretinal bleb. For ILM peeling, preoperative visual acuity (VA) was 0.667 ± 0.423 logarithm of the minimum angle of resolution (logMAR). Minimum hole diameter (MHD) was 305.5 ± 159.4 µm (range, 34-573 µm). Sixteen of 34 ILM peels (47%) resulted in MTMH closure. At postoperative month 6, VA was stable at 0.602 ± 0.516 logMAR (P = 0.65). VA improved by at least 2 lines in 43% and at least 4 lines in 24%. For ILM flaps, preoperative VA was 0.878 ± 0.552 logMAR. MHD was 440.8 ± 175.5 µm (range, 97-697 µm), which was significantly larger than for ILM peels (P < 0.01). Twenty of 22 ILM flaps (90%) resulted in MTMH closure, which was significantly higher than for ILM peels (P < 0.01). At postoperative month 6, VA improved to 0.555 ± 0.405 logMAR (P < 0.05). VA improved by at least 2 lines in 56% and at least 4 lines in 28%. For ARTs, preoperative VA was 1.460 ± 0.391 logMAR. MHD was 390.2 ± 203.7 µm (range, 132-687 µm). All 5 ARTs (100%) resulted in MTMH closure. At postoperative month 6, VA was stable at 1.000 ± 0.246 logMAR (P = 0.08). Visual acuity improved at least 2 lines in 25%. CONCLUSIONS: Surgical closure of macular holes improved VA in 57% of MTMHs. Internal limiting membrane flaps achieved better anatomic and functional outcomes than ILM peeling alone. Autologous retinal transplantation may be an option for refractory MTMHs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Predictive factors for microvascular recovery after treatments for diabetic retinopathy.

BACKGROUND: To identify factors associated with microvascular recovery after intravitreal bevacizumab or panretinal photocoagulation (PRP) in diabetic retinopathy (DR). METHODS: We retrospectively reviewed 320 eyes/patients with DR treated with intravitreal bevacizumab and/or PRP. Two consecutive fluorescein angiographies (FAs) of each eye were compared. The number of microaneurysms and the area of capillary non-perfusion were calculated automatically using ImageJ software. Microvascular recovery was defined as a marked reduction in the numbers of microaneurysms (< 20%) or a marked reduction in the area of capillary non-perfusion (< 50%) in 45-degree fields or a complete regression of new vessels in ETDRS 7 standard fields. Baseline FA findings and changes in the ocular and systemic factors were analyzed. RESULTS: Twenty-eight (8.8%) of the 320 total eyes were found to meet the criteria of microvascular recovery after the treatments. Multivariate analysis revealed the presence of diffuse capillary telangiectasis (P = .003) and late disc leaking (P = .007) on baseline FA and a reduction of glycated hemoglobin (P = .005) during the follow-up period were predictive factors of microvascular recovery after the treatments. Although the microvascular recovery group presented with a significant improvement of BCVA after the treatments, the baseline BCVA could not predict the microvascular recovery after the treatments. CONCLUSIONS: Diffuse capillary telangiectasis or late disc leaking on baseline FA and improved glycemic control positively predicted the microvascular recovery after treatments for DR.

Bio-Templated Chiral Zeolitic Imidazolate Framework for Enantioselective Chemoresistive Sensing.

Chiral metal-organic frameworks (MOFs) have gained rising attention as ordered nanoporous materials for enantiomer separations, chiral catalysis, and sensing. Among those, chiral MOFs are generally obtained through complex synthetic routes by using a limited choice of reactive chiral organic precursors as the primary linkers or auxiliary ligands. Here, we report a template-controlled synthesis of chiral MOFs from achiral precursors grown on chiral nematic cellulose-derived nanostructured bio-templates. We demonstrate that chiral MOFs, specifically, zeolitic imidazolate framework (ZIF), unc-[Zn(2-MeIm)2 , 2-MeIm=2-methylimidazole], can be grown from regular precursors within nanoporous organized chiral nematic nanocelluloses via directed assembly on twisted bundles of cellulose nanocrystals. The template-grown chiral ZIF possesses tetragonal crystal structure with chiral space group of P41 , which is different from traditional cubic crystal structure of I-43 m for freely grown conventional ZIF-8. The uniaxially compressed dimensions of the unit cell of templated ZIF and crystalline dimensions are signatures of this structure. We observe that the templated chiral ZIF can facilitate the enantiotropic sensing. It shows enantioselective recognition and chiral sensing abilities with a low limit of detection of 39 µM and the corresponding limit of chiral detection of 300 µM for representative chiral amino acid, D- and L- alanine.

One-year follow-up of optical coherence tomography angiography microvascular findings: macular telangiectasia type 2 versus tamoxifen retinopathy.

PURPOSE: To compare microstructural and microvascular changes in eyes with macular telangiectasia type 2 (MacTel2) and in those with tamoxifen retinopathy (TR) at baseline and at the 1-year follow-up using optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: We followed up patients diagnosed with MacTel2 or TR for at least 1 year. We included 17 patients with MacTel2 (31 eyes) and 15 with TR (25 eyes) who discontinued tamoxifen use after a TR diagnosis. We performed OCT and OCTA at baseline and after 1 year. RESULTS: Patients with MacTel2 and TR showed intraretinal cavitation, ellipsoid zone (EZ) loss, and capillary telangiectasia in the superficial and deep plexuses. EZ disruption predominantly affected the temporal region in MacTel2 (32%) and was limited to the foveal center in TR (24%). Vascular density (VD) was significantly reduced within the deep temporal parafovea and superficial fovea in MacTel2 and TR eyes, respectively. After 1 year, the MacTel2 eyes showed enlarged EZ loss, proliferative vascular invasion, and increased VD (p = 0.021) in the temporal deep plexus compared with TR eyes. CONCLUSIONS: After 1-year follow-up, the MacTel2 eyes showed proliferative vascular remodeling, particularly in the temporal parafovea of the deep plexus with EZ loss progression, whereas the TR eyes maintained their baseline capillary rarefaction.

EFFECT OF ORAL CARBONIC ANHYDRASE INHIBITOR ON CYSTOID MACULAR EDEMA ASSOCIATED WITH RETINITIS PIGMENTOSA: An OCT and OCT Angiography Study.

PURPOSE: To investigate the factors associated with visual improvement in response to oral carbonic anhydrase inhibitors (CAIs) and the occurrence of microvascular changes in patients with retinitis pigmentosa-associated cystoid macular edema (RP-CME). METHODS: This retrospective cohort study included 59 eyes from 39 patients with RP-CME who underwent at least 3 months of oral CAI treatment. The eyes were divided into responding and nonresponding groups based on optical coherence tomography (OCT) criteria (resolution of cyst and reduction of foveal or parafoveal volume). All eyes were assessed before and after treatment using OCT and OCT angiography. RESULTS: Thirty-three eyes (55.9%) demonstrated a positive response to treatment, and 26 eyes (44.1%) did not. Compared with nonresponding eyes, responding eyes had a significantly higher frequency of multilayer CME than CME limited to the inner nuclear layer ( P = 0.016). Subgroup analysis within the responding group revealed that improvements in visual acuity were more likely in eyes with fovea-involving CME and a higher baseline external limiting membrane and ellipsoid zone width. Microvascular parameters showed no significant changes after treatment. CONCLUSION: Eyes with CME extending to the outer nuclear layer or central fovea, and higher initial photoreceptor integrity may be prognostic factors associated with structural and functional improvements after carbonic anhydrase inhibitors treatment. Early treatment of multilayer CME with foveal involvement seems to be crucial in preventing irreversible photoreceptor damage.

MACULAR MICROVASCULATURE IN X-LINKED RETINOSCHISIS: Optical Coherence Tomography and Optical Coherence Tomography Angiography Study.

PURPOSE: The study aimed to evaluate the macular microvasculature of X-linked retinoschisis (XLRS) and identify correlations between vascular changes, structural changes, and functional outcome. METHODS: Genetically confirmed XLRS patients and heathy control subjects underwent complete ophthalmic examination, dilated funduscopic examination, optical coherence tomography, and optical coherence tomography angiography. Schisis distribution, outer plexiform layer discontinuation, photoreceptor layer thickness, and photoreceptor outer segment length were reviewed using optical coherence tomography. Vascular flow density and foveal thickness at foveal and parafoveal area were measured using optical coherence tomography angiography. RESULTS: A total of 17 eyes of 9 XLRS patients and 22 eyes of 11 control subjects were examined from July 2018 to August 2020. Flow density in the deep capillary plexus at foveal and parafoveal area decreased in XLRS patients compared with control subjects (P = 0.014 and 0.001, respectively), whereas foveal avascular zone area and perimeter remarkably increased (P = 0.015 and 0.001, respectively). Although outer and total retinal layers were significantly thicker in XLRS, inner retinal layer was thinner with reduced photoreceptor layer thickness and shortened photoreceptor outer segment length (P < 0.001 and P < 0.001, respectively). Foveal flow loss in deep capillary plexus, foveal avascular zone enlargement, thinner inner retina and photoreceptor layer thickness, and shortened photoreceptor outer segment length correlated with best-corrected visual acuity. CONCLUSION: X-linked retinoschisis eyes exhibit decreased flow density in the deep capillary plexus and variable foveal avascular zone with enlarged perimeter. Structural deterioration of the photoreceptor best reflects the degenerative changes, whereas microvascular alteration shows considerable correlation with functional outcome in XLRS.

Long-Term Progression of Pericentral Hydroxychloroquine Retinopathy.

PURPOSE: To investigate the long-term progression of pericentral hydroxychloroquine retinopathy. DESIGN: Multicenter, retrospective cohort study. PARTICIPANTS: Eighty eyes (60 with pericentral pattern) of 41 Korean patients with hydroxychloroquine retinopathy followed up for 2 years or more after drug cessation. METHODS: Patients were screened for hydroxychloroquine retinopathy using spectral-domain or swept-source OCT, fundus autofluorescence (FAF), and Humphrey visual field (VF) tests. Follow-up was divided into short-term (≤2 years) and subsequent periods, and progression was evaluated in each period and severity group. Retinopathy progression on OCT was defined as increased length of the ellipsoid zone defect, decreased distance from the fovea to the photoreceptor defects, or newly developed or enlarged retinal pigment epithelium defects. On FAF, progression was defined as an increase in the area of hyperautofluorescence or hypoautofluorescence. Functional progression was defined as a regression coefficient of less than 0 dB/year for mean deviation and more than 0 dB/year for pattern standard deviation, based on linear regression analysis of 3 or more VF tests. Structural and functional progression rates were calculated using the slopes of retinal thicknesses on the Early Treatment Diabetic Retinopathy Study grid and perimetric parameters over time, respectively. MAIN OUTCOME MEASURES: Structural and functional progression of retinopathy. RESULTS: Approximately one third of eyes with early pericentral retinopathy showed limited progression during the short-term period after drug cessation, but they subsequently showed stable or improved photoreceptors. Most eyes with moderate pericentral retinopathy showed continuous progression, particularly when converted to the severe stage. Severe eyes showed progressive damage throughout the follow-up period. In all severity groups, the rates of retinal thinning decreased over time. In eyes with pericentral retinopathy showing progression, circumferential enlargement of retinal damage was prominent in earlier stages, whereas centripetal enlargement of the ring-shaped lesion was noted in advanced stages. Functional progression, noted in 58.7% of the pericentral eyes, corresponded with structural progression. CONCLUSIONS: Pericentral hydroxychloroquine retinopathy showed severity-dependent progression. Moderate pericentral retinopathy usually progressed, but centripetal progression threatening the fovea was remarkable mostly in severe retinopathy. Our results suggest that early detection of retinopathy may minimize the risk of progression to foveal involvement in pericentral retinopathy.

Two-Year Results of the Phase 3 Randomized Controlled Study of Abicipar in Neovascular Age-Related Macular Degeneration.

PURPOSE: To report the 2-year efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) compared with monthly ranibizumab in patients with treatment-naïve neovascular age-related macular degeneration (nAMD). DESIGN: Two multicenter, randomized, phase 3 clinical trials with identical protocols (CEDAR and SEQUOIA). Analyses used pooled trial data. PARTICIPANTS: The trials enrolled 1888 patients (1 eye/patient) with active choroidal neovascularization secondary to age-related macular degeneration and best-corrected visual acuity (BCVA) of 24 to 73 Early Treatment Diabetic Retinopathy Study letters. METHODS: At enrollment, patients were assigned to study eye treatment with abicipar 2 mg every 8 weeks after initial doses at baseline and weeks 4 and 8 (abicipar Q8, n = 630), abicipar 2 mg every 12 weeks after initial doses at baseline and weeks 4 and 12 (abicipar Q12, n = 628), or ranibizumab 0.5 mg every 4 weeks (ranibizumab Q4, n = 630). MAIN OUTCOME MEASURES: Efficacy measures included stable vision (<15-letter loss in BCVA from baseline) and change from baseline in BCVA and central retinal thickness (CRT). Safety measures included adverse events (AEs). RESULTS: For patients who completed the study, efficacy of abicipar after initial doses was maintained through week 104. At week 104, the proportion of patients with stable vision was 93.0% (396/426), 89.8% (379/422), and 94.4% (470/498); mean change in BCVA from baseline was +7.8 letters, +6.1 letters, and +8.5 letters, and mean change in CRT from baseline was -147 µm, -146 µm, and -142 µm in the abicipar Q8 (14 injections), abicipar Q12 (10 injections), and ranibizumab Q4 (25 injections) groups, respectively. The overall incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3% from baseline through week 52 and 16.2%, 17.6%, and 1.3% from baseline through week 104 in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. CONCLUSIONS: Two-year results show efficacy of abicipar Q8 and Q12 in nAMD. First onset of IOI events with abicipar was much reduced in the second year and comparable with ranibizumab (0.8% and 2.3% vs. 1.0%). The extended duration of effect of abicipar allows for quarterly dosing and reduced treatment burden.

CENTRAL RETINAL VEIN OCCLUSION IN YOUNG PATIENTS: Clinical Characteristics and Prognostic Factors.

PURPOSE: To investigate the clinical characteristics and prognostic factors of young patients with central retinal vein occlusion (CRVO). METHODS: This retrospective cohort study involved treatment-naïve patients with CRVO. Medical records regarding basic demographics, predisposing factors, ocular characteristics, and treatments were reviewed and compared according to age at CRVO onset. RESULTS: We enrolled 263 patients, of whom 69 were younger patients. Younger patients had higher prevalence of nontraditional risk factors including physical or psychological stress (P = 0.032), hematologic abnormalities (P = 0.003), and better visual acuity at baseline and last visit (all P < 0.001) and were unlikely to undergo intravitreal injections (47.8 vs. 68.6%, P < 0.001) during follow-up. Younger patients had higher prevalence of paracentral acute middle maculopathy (28.1 vs. 4.7%, P < 0.001). Older age (odds ratio = 1.165, P = 0.028), male sex (odds ratio = 7.074, P = 0.034), coexisting renal disease (odds ratio = 7.845, P = 0.050), and poor baseline visual acuity (odds ratio = 16.069, P = 0.002) were significant risk factors for poor visual outcomes in young CRVO patients. CONCLUSION: Younger CRVO patients had a milder clinical course with fewer treatments and were more likely to have nontraditional risk factors than older patients.

One-Year Anatomical and Functional Outcomes of the Argus II Implantation in Korean Patients with Late-Stage Retinitis Pigmentosa: A Prospective Case Series Study.

PURPOSE: To report the anatomical and functional outcomes of Argus II retinal prosthesis implantation in Korean patients. METHODS: We included 5 consecutive patients with end-stage retinitis pigmentosa (RP) who underwent Argus II retinal prosthesis implantation and were followed for at least 12 months. The transcorneal electrical evoked response was utilized for patient selection. We used intraoperative optical coherence tomography (OCT) for optimal placement of the array and provided specialized vision rehabilitation training. A morphological evaluation using SD-OCT and a functional evaluation using computer-based visual function tests, a letter-reading ability test, and the Functional Low-Vision Observer Rated Assessment (FLORA) were conducted. RESULTS: Postoperatively, the array was completely apposed to the retinal surface in all eyes, except for one eye which had a preexisting macular concavity. Fibrosis-like tissues of ≥50-µm thickness developed at the interface in 2 eyes. All of the patients showed improvement in computer-based visual function tests and could read ETDRS letters at a distance of 50 cm. Three patients could read Korean words. FLORA was improved in all patients, mainly in tasks of visual mobility, daily activities, and social interactions. CONCLUSIONS: Along with good anatomical outcomes and specialized rehabilitation practices, recipients of the Argus II implant showed profound improvements in functional vision and mobility.

Efficacy and Safety of Abicipar in Neovascular Age-Related Macular Degeneration: 52-Week Results of Phase 3 Randomized Controlled Study.

PURPOSE: To compare the efficacy and safety of abicipar every 8 weeks and quarterly (after initial doses) versus ranibizumab every 4 weeks in treatment-naïve patients with neovascular age-related macular degeneration (AMD). DESIGN: Two randomized, multicenter, double-masked, parallel-group, active-controlled, phase 3 clinical trials (CEDAR, SEQUOIA) with identical protocols were conducted. Data from both trials were pooled for analysis. PARTICIPANTS: Patients with active choroidal neovascularization secondary to AMD and best-corrected visual acuity (BCVA) of 24-73 Early Treatment Diabetic Retinopathy Study letters in the study eye were enrolled. METHODS: Patients (n = 1888) were randomized in a 1:1:1 ratio to study eye treatment with abicipar 2 mg every 8 weeks after 3 initial doses at baseline and weeks 4 and 8 (Q8), abicipar 2 mg every 12 weeks after 3 initial doses at baseline and weeks 4 and 12 (Q12), or ranibizumab 0.5 mg every 4 weeks (Q4). MAIN OUTCOME MEASURES: The primary efficacy end point was proportion of patients with stable vision (defined as <15-letter loss in BCVA from baseline) in the study eye at week 52. Secondary end points included change from baseline in BCVA and central retinal thickness (CRT) at week 52. Safety measures included adverse events (AEs). RESULTS: The proportion of patients with stable vision at week 52 was 93.2%, 91.3%, and 95.8% in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively, with both abicipar Q8 and Q12 noninferior to ranibizumab Q4. Week 52 mean change from baseline in BCVA was 7.5, 6.4, and 8.4 letters and in CRT was -144, -145, and -144 µm in the abicipar Q8, abicipar Q12, and ranibizumab Q4 groups, respectively. Incidence of intraocular inflammation (IOI) AEs was 15.4%, 15.3%, and 0.3%, respectively. The IOI AEs were typically mild or moderate in severity and treated with topical corticosteroids; 62 of 192 patients (32.3%) received oral and/or injectable corticosteroids. CONCLUSIONS: Abicipar Q8 and Q12 were both noninferior to ranibizumab Q4 in the primary end point of stable vision at week 52. Intraocular inflammation was more frequent with abicipar. Quarterly and Q8 abicipar reduce nAMD disease and treatment burden compared with monthly treatment.

Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE.

EVIDENCE, an automated variant prioritization system, has been developed to facilitate whole exome sequencing analyses. This study investigated the diagnostic yield of EVIDENCE in patients with suspected genetic disorders. DNA from 330 probands (age range, 0-68 years) with suspected genetic disorders were subjected to whole exome sequencing. Candidate variants were identified by EVIDENCE and confirmed by testing family members and/or clinical reassessments. EVIDENCE reported a total 228 variants in 200 (60.6%) of the 330 probands. The average number of organs involved per patient was 4.5 ± 5.0. After clinical reassessment and/or family member testing, 167 variants were identified in 141 probands (42.7%), including 105 novel variants. These variants were confirmed as being responsible for 121 genetic disorders. A total of 103 (61.7%) of the 167 variants in 95 patients were classified as pathogenic or probably to be pathogenic before, and 161 (96.4%) variants in 137 patients (41.5%) after, clinical assessment and/or family member testing. Factor associated with a variant being regarded as causative includes similar symptom scores of a gene variant to the phenotype of the patient. This new, automated variant interpretation system facilitated the diagnosis of various genetic diseases with a 42.7% diagnostic yield.

Optical coherence tomography angiography findings of type 1 diabetic patients with diabetic retinopathy, in comparison with type 2 patients.

PURPOSE: To compare optical coherence tomography angiography (OCT-A) parameters between type 1 and type 2 diabetic patients with diabetic retinopathy (DR). METHODS: A total of 70 patients with type 1 diabetes and 70 with type 2 diabetes were retrospectively analyzed. DR was graded as no DR, mild nonproliferative DR (NPDR), moderate NPDR, severe NPDR, and proliferative DR (PDR). Using OCT-A, the foveal avascular zone (FAZ) area (mm2) and vascular density (VD) (%) were calculated in the superficial capillary plexus (SCP) and deep capillary plexus (DCP). RESULTS: In both type 1 and 2 diabetes patients, the FAZ area (mm2) in both capillary plexuses (CP) increased with DR progression, whereas the VD (%) progressively decreased. The changes in the FAZ area and the VD were significantly greater in the DCP than in the SCP in both types of diabetes patients(p < 0.001). In the analysis of decreasing slope of the VD in the DCP, attenuation was not significant until severe NPDR stage but then abruptly decreased when it progressed to PDR stage in type 1 diabetes. In type 2 diabetes, the DCP VD decreased gradually as DR stage progressed. CONCLUSIONS: As DR progression, the increasing in FAZ area and the decreasing in VD are more severe in the DCP than in the SCP in both types of diabetes. In type 1 diabetes eyes, they were remained in relatively healthy until it gets to the advanced stage of DR, while the gradual deterioration of FAZ area and VD was found from the early stage to the advanced stage of DR in type 2 diabetes.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN PATIENTS WITH RETINITIS PIGMENTOSA-ASSOCIATED CYSTOID MACULAR EDEMA.

PURPOSE: To investigate the microstructure of cystoid macular edema (CME) in retinitis pigmentosa (RP) and the associated vascular changes using optical coherence tomography (OCT) angiography. METHODS: In this retrospective study, we included 42 eyes of 21 patients with RP and age-similar normally sighted controls who underwent both OCT and optical coherence tomography angiography. Using OCT, spatial distribution of CME and the retinal layer, which CME located, was examined. Optical coherence tomography angiography images of the superficial capillary plexus and deep capillary plexus were obtained. Foveal and parafoveal flow densities in each layer and foveal avascular zone area were measured. RESULTS: Of the 42 eyes with RP, 32 had CME. All CMEs were located in the inner nuclear layer and limited to the parafovea. The outer nuclear layer/ganglion cell layer was involved in 12 eyes (37.5%). Compared with RP without CME, RP with CME (RP-CME) did not show significant differences in flow density or extent of vascular disruption within the superficial capillary plexus, deep capillary plexus, or foveal avascular zone areas. CONCLUSION: RP-CME was mostly located in the inner nuclear layer of the parafoveal macula, without vascular disruption in optical coherence tomography angiography. Our findings may support the hypothesis that the pathogenesis of RP with CME differs from retinal vascular CME triggered by compromised deep capillary plexus.

COMBINED VITRECTOMY WITH INTRAVITREAL DEXAMETHASONE IMPLANT FOR REFRACTORY MACULAR EDEMA SECONDARY TO DIABETIC RETINOPATHY, RETINAL VEIN OCCLUSION, AND NONINFECTIOUS POSTERIOR UVEITIS.

PURPOSE: To compare the efficacy of intraoperative intravitreal dexamethasone implant for macular edema secondary to diabetic retinopathy (DME), retinal vein occlusion (RVO), and noninfectious posterior uveitis. METHODS: A retrospective review of 62 patients (29 men and 33 women; mean age 51.19 ± 14.41 years; 65 eyes) was performed. Best-corrected visual acuity (in logarithm of the minimal angle of resolution), central foveal thickness, intraocular pressure, and postoperative edema-free period were postoperatively assessed up to 1 year. The preoperative and postoperative numbers of other intravitreal injections needed were compared. RESULTS: Best-corrected visual acuity gradually improved in the DME group (from 0.87 to 0.51) but failed to improve from Month 3 onward in the RVO and uveitis groups. Central foveal thickness decreased in all groups, especially in the DME group (from 550.93 to 338.10 µm). Edema-free period was longest in the DME group (19.34 ± 15.12 months), followed by the uveitis (12.91 ± 7.85 months) and RVO (8.50 ± 8.76 months) groups. Subjects in the uveitis group used more intraocular pressure-lowering agents (1.00 ± 1.27) than those in the DME (0.13 ± 0.49) and RVO (0.36 ± 0.79) groups. Increased intraocular pressure events were most frequent in postoperative Week 1, especially in the uveitis group. CONCLUSION: Vitrectomy combined with intravitreal dexamethasone implant for DME, RVO, and noninfectious posterior uveitis had a favorable clinical outcome.

ADVERSE EVENTS OF THE ARGUS II RETINAL PROSTHESIS: Incidence, Causes, and Best Practices for Managing and Preventing Conjunctival Erosion.

PURPOSE: To analyze and provide an overview of the incidence, management, and prevention of conjunctival erosion in Argus II clinical trial subjects and postapproval patients. METHODS: This retrospective analysis followed the results of 274 patients treated with the Argus II Retinal Prosthesis System between June 2007 and November 2017, including 30 subjects from the US and European clinical trials, and 244 patients in the postapproval phase. Results were gathered for incidence of a serious adverse event, incidence of conjunctival erosion, occurrence sites, rates of erosion, and erosion timing. RESULTS: Overall, 60% of subjects in the clinical trial subjects versus 83% of patients in the postapproval phase did not experience device- or surgery-related serious adverse events. In the postapproval phase, conjunctival erosion had an incidence rate of 6.2% over 5 years and 11 months. In 55% of conjunctival erosion cases, erosion occurred in the inferotemporal quadrant, 25% in the superotemporal quadrant, and 20% in both. Sixty percent of the erosion events occurred in the first 15 months after implantation, and 85% within the first 2.5 years. CONCLUSION: Reducing occurrence of conjunctival erosion in patients with the Argus II Retinal Prosthesis requires identification and minimization of risk factors before and during implantation. Implementing inverted sutures at the implant tabs, use of graft material at these locations as well as Mersilene rather than nylon sutures, and accurate Tenon's and conjunctiva closure are recommended for consideration in all patients.

Natural history of diabetic macular edema and factors predicting outcomes in sham-treated patients (MEAD study).

PURPOSE: To describe the natural history of diabetic macular edema (DME) with respect to best-corrected visual acuity (BCVA) and central retinal thickness (CRT) outcomes and to identify baseline patient characteristics and systemic factors associated with improvement or worsening of outcomes in sham-treated patients. METHODS: The study population was sham-treated patients (n = 350) in the 3-year MEAD registration study of dexamethasone intravitreal implant for treatment of DME. Patients had center-involved DME and received sham intravitreal injections in the study eye at ≥ 6-month intervals. Potential prognostic factors for outcomes were evaluated using multiple linear regression analysis. RESULTS: Visual and anatomic outcomes were poorer in patients who left the study early (n = 198) than in study completers (n = 152). Mean change in BCVA from baseline at the last visit with available data was + 0.9 letters; 37.5% of patients had no change in BCVA, 23.2% had gained > 10 letters, and 16.0% had lost > 10 letters. Older age and baseline diabetic retinopathy score > 6 were associated with worse BCVA outcomes; thicker baseline CRT and larger number of hypertension medications used were associated with larger reductions in CRT during the study. CONCLUSIONS: BCVA and CRT outcomes were variable in this population of DME patients with generally good glycemic control. In DME patients without active treatment, older age and baseline diabetic retinopathy score > 6 were associated with less improvement in BCVA; thicker baseline CRT and a larger number of antihypertensive medications used predicted better improvement in CRT. TRIAL REGISTRATION: The MEAD study trials are registered at ClinicalTrials.gov with the identifiers NCT00168337 and NCT00168389.