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Novice surgeons had impaired simulated dexterity after alcohol and caffeine consumption and increased agility and slower performance following propranolol intake and sleep deprivation, respectively. Alcohol and sleep deprivation also increased tremor in novice surgeons. Conversely, only alcohol negatively altered senior surgeons' skills.

This study aimed to evaluate the image quality assessment (IQA) and quality criteria employed in publicly available datasets for diabetic retinopathy (DR). A literature search strategy was used to identify relevant datasets, and 20 datasets were included in the analysis. Out of these, 12 datasets mentioned performing IQA, but only eight specified the quality criteria used. The reported quality criteria varied widely across datasets, and accessing the information was often challenging. The findings highlight the importance of IQA for AI model development while emphasizing the need for clear and accessible reporting of IQA information. The study suggests that automated quality assessments can be a valid alternative to manual labeling and emphasizes the importance of establishing quality standards based on population characteristics, clinical use, and research purposes. In conclusion, image quality assessment is important for AI model development; however, strict data quality standards must not limit data sharing. Given the importance of IQA for developing, validating, and implementing deep learning (DL) algorithms, it’s recommended that this information be reported in a clear, specific, and accessible way whenever possible. Automated quality assessments are a valid alternative to the traditional manual labeling process, and quality standards should be determined according to population characteristics, clinical use, and research purpose.

Background/Objectives: Tremor and expertise are potentially influenced variables in vitreoretinal surgery. We investigated whether surgeon experience impacts the association of microsurgical performance with caffeine and β-blockers weight-adjusted intake. Subjects/Methods: Novice and senior surgeons (<2 and >10 practice years, respectively) were recruited in this self-controlled, cross-sectional study. A simulator’s task sequence was repeated over 2 days, 30 min after the following exposures: day 1, placebo, 2.5 mg/kg caffeine, 5.0 mg/kg caffeine, and 0.6 mg/kg propranolol; and day 2, placebo, 0.2 mg/kg propranolol, 0.6 mg/kg propranolol, and 5.0 mg/kg caffeine. Outcomes were total score (0–700, worst-best), simulation time (minutes), intraocular trajectory (centimeters), and tremor-specific score (0–100, worst-best). Results: We recruited 15 novices (9 men [60%], 1.33 ± 0.49 practice years) and 11 seniors (8 men [72.7%], 16.00 ± 4.24 practice years). Novices performed worse after 2.5 mg/kg caffeine and improved following 0.2 mg/kg propranolol in total score (557 vs. 617, p= 0.009), trajectory (229.86 vs. 208.07, p= 0.048), time (14.9 vs. 12.7, p= 0.048), and tremor-score (55 vs. 75, p= 0.009). Surgical performance improved with propranolol post-caffeine but remained worse than 0.2 mg/kg propranolol in total score (570 vs. 617, p= 0.014), trajectory (226.59 vs. 208.07, p= 0.033), and tremor-score (50 vs. 75, p= 0.029). Seniors’ tremor-score was lower after 2.5 mg/kg caffeine compared to 0.2 mg/kg propranolol (8 vs. 37, p= 0.015). Tremor-score following propranolol post-caffeine remained inferior to 0.6 mg/kg propranolol alone (17 vs. 38, p= 0.012). Conclusion: While caffeine and propranolol were associated with performance changes among novices, only tremor was affected in seniors, without dexterity changes. The pharmacologic exposure impact on surgical dexterity seems to be offset by increased experience.

Supplemental Digital Content is Available in the Text.Safety assessment of subretinal implantation of human embryonic stem cell–derived retinal pigment epithelium to repopulate the retinal pigment epithelium cells in the submacular area in Stargardt disease.

A rare case of subretinal migration of an intravitreal dexamethasone implant in a vitrectomized eye, and the surgical outcome performed to remove the implant and restore vision.

Purpose To evaluate the occurrence of transient central retinal artery occlusion following intravitreal anti-vascular endothelial growth factor injection.Methods Prospective, observational study of 807 patients (807 eyes) who were given intravitreal injections of ranibizumab or aflibercept to treat any cause of retinal vascular diseases between 1 January 2017 and 30 November 2018 at the Federal Fluminense University Hospital in Niteroi, and a private facility in Rio de Janeiro, Brazil. Patients who did not present transient central retinal artery occlusion were excluded.Results Among 4069 injections, only 18 patients (0.44%) presented transient central retinal artery occlusion, 14 mild cases (77.7%), and 4 severe cases (22.3%). The clinical factors associated with more severe cases of transient central retinal artery occlusion were the duration of the transient central retinal artery occlusion (p= 0.001), number of prior injections (p= 0.01), and a positive carotid Doppler test (p= 0.01). Twelve cases (66.6%) had positive carotid artery obstruction (atheroma plaque size ≥70%) while 6 cases (33.3%) had negative carotid artery obstruction (atheroma plaque size <70%). The age group >60 years old (p= 0.06), cup/disc ratio >0.6 (p= 0.06), and pseudophakic lens status were also factors with association with transient central retinal artery occlusion, although did not meet criteria for statistical significance. The only patient who experienced a recurrent episode of transient central retinal artery occlusion had diabetic macular edema, positive carotid Doppler test, and cup/optic disc ratio >0.6.Conclusion Transient central retinal artery occlusion is a rare adverse event that can appear in patients with retinal vascular disease receiving anti-vascular endothelial growth factor therapy. The atheroma plaque size and the number of prior injections can be associated with the severity of the event.

Purpose: To assess the variability of silicone oil (SO) particles released across syringes from the same lot and the role of different needle gauges.Materials and methods: Four syringe models and six needle models were assessed for SO release. About 50 microliters of a buffer solution were loaded into the syringe, needle or syringe/needle setup. The data were analyzed by imaging flow cytometry with fluorescently labeling for SO.Results: All syringe models had a high coefficient of variation in SO release across syringes from the same lot. The amount of SO was significantly greater in the syringe when the needle was attached. SO particles with the BD 30G needle attached to the syringe were statistically greater than the 27G counterpart (p= 0.005). None of the other comparisons was statistically different. Finally, the number of SO particles was higher in the syringe/needle setup than in needles only (p= 0.0024).Conclusion: We found a high variability in SO content across syringes from the same lot. Additionally, there was no clear association between needle gauge and the number of SO particles, as well as their coefficient of variation. Finally, the needles accounted for a small number of SO particles in comparison to the combined syringe-needle setup.

Alcohol intake was the only analyzed exposure associated with a dose-dependent alteration in novice surgeons' performance. Simulated vitreoretinal surgical dexterity deteriorated after 2.5 mg/kg caffeine ingestion and improved after 0.2 mg/kg propranolol ingestion. A short-term session of physical exercise or acute sleep deprivation was not associated with performance.

IMPORTANCE: Vitreoretinal surgery can be technically challenging and is limited by physiologic characteristics of the surgeon. Factors that improve accuracy and precision of the vitreoretinal surgeon are invaluable to surgical performance. OBJECTIVES: To establish weight-adjusted cutoffs for caffeine and β-blocker (propranolol) intake and to determine their interactions in association with the performance of novice vitreoretinal microsurgeons. DESIGN, SETTINGS, AND PARTICIPANTS: This single-blind cross-sectional study of 15 vitreoretinal surgeons who had less than 2 years of surgical experience was conducted from September 19, 2018, to September 25, 2019, at a dry-laboratory setting. Five simulations were performed daily for 2 days. On day 1, performance was assessed after sequential exposure to placebo, low-dose caffeine (2.5 mg/kg), high-dose caffeine (5.0 mg/kg), and high-dose propranolol (0.6 mg/kg). On day 2, performance was assessed after sequential exposure to placebo, low-dose propranolol (0.2 mg/kg), high-dose propranolol (0.6 mg/kg), and high-dose caffeine (5.0 mg/kg). INTERVENTIONS: Surgical simulation tasks were repeated 30 minutes after masked ingestion of placebo, caffeine, or propranolol pills during the 2 days. MAIN OUTCOMES AND MEASURES: An Eyesi surgical simulator was used to assess surgical performance, which included surgical score (range, 0 [worst] to 700 [best]), task completion time, intraocular trajectory, and tremor rate (range, 0 [worst] to 100 [best]). The nonparametric Friedman test followed by Dunn-Bonferroni post hoc test was applied for multiple comparisons. RESULTS: Of 15 vitreoretinal surgeons, 9 (60%) were male, with a mean (SD) age of 29.6 (1.4) years and mean (SD) body mass index (calculated as weight in kilograms divided by height in meters squared) of 23.15 (2.9). Compared with low-dose propranolol, low-dose caffeine was associated with a worse total surgical score (557.0 vs 617.0; difference, –53.0; 95% CI, –99.3 to –6.7; P = .009), a lower antitremor maneuver score (55.0 vs 75.0; difference, –12.0; 95% CI, –21.2 to –2.8; P = .009), longer intraocular trajectory (2298.6 vs 2080.7 mm; difference, 179.3 mm; 95% CI, 1.2-357.3 mm; P = .048), and increased task completion time (14.9 minutes vs 12.7 minutes; difference, 2.3 minutes; 95% CI, 0.8-3.8 minutes; P = .048). Postcaffeine treatment with propranolol was associated with performance improvement; however, surgical performance remained inferior compared with low-dose propranolol alone for total surgical score (570.0 vs 617.0; difference, –51.0; 95% CI, –77.6 to –24.4; P = .01), tremor-specific score (50.0 vs 75.0; difference, –16.0; 95% CI, –31.8 to –0.2; P = .03), and intraocular trajectory (2265.9 mm vs 2080.7 mm; difference, 166.8 mm; 95% CI, 64.1-269.6 mm; P = .03). CONCLUSIONS AND RELEVANCE: The findings suggest that performance of novice vitreoretinal surgeons was worse after receiving low-dose caffeine alone but improved after receiving low-dose propranolol alone. Their performance after receiving propranolol alone was better than after the combination of propranolol and caffeine. These results may be helpful for novice vitreoretinal surgeons to improve microsurgical performance.

BACKGROUND AND OBJECTIVE:To evaluate the retinal and vasculature changes in infants with congenital Zika syndrome (CZS) using fluorescein angiography (FA).PATIENTS AND METHODS:This consecutive case series included six infants with CZS. FA and color fundus imaging were performed under general anesthesia in both eyes of all infants using a contact widefield digital imaging system. All color fundus images were obtained using a 130° field of view lens, and the FA images were captured using either a 130° or 80° field of view lens. The immunoglobulin M antibody capture enzyme-linked immunosorbent assay was positive for Zika virus in the cerebrospinal fluid samples of all infants. Other congenital infections were ruled out.RESULTS:The mean ± standard deviation age of the infants at the time of examination was 1.4 years ± 0.1 years (range: 1.3 years to 1.5 years). Contact fundus photographs showed macular abnormalities in seven eyes (58%) and retinal vasculature changes in two eyes (17%). FA detected macular abnormalities in all 12 eyes (100%) and retinal vasculature changes in five eyes (42%). The main retinal vasculature changes were peripheral avascularity in five eyes (42%) and microvasculature abnormalities in three eyes (25%).CONCLUSION:FA may be an important tool for detecting subtle macular and retinal vasculature changes in CZS.[[Ophthalmic Surg Lasers Imaging Retina.2019;50:702–708.]

Pars plana vitrectomy is a challenging, minimally invasive microsurgical procedure due to its intrinsic manoeuvres and physiological limits that constrain human capability. An important human limitation is physiological hand tremor, which can significantly increase the risk of iatrogenic retinal damage resulting from unintentional manoeuvres that affect anatomical and functional surgical outcomes. The limitations imposed by normal physiological tremor are more evident and challenging during ‘micron-scale’ manoeuvres such as epiretinal membrane and internal limiting membrane peeling, and delicate procedures requiring coordinated bimanual surgery such as tractional retinal detachment repair. Therefore, over the previous three decades, attention has turned to robot-assisted surgical devices to overcome these challenges. Several systems have been developed to improve microsurgical accuracy by cancelling hand tremor and facilitating faster, safer and more effective microsurgeries. By markedly reducing tremor, microsurgical precision is improved to a level beyond present human capabilities. In conclusion, robotics offers potential advantages over free-hand microsurgery as it is currently performed during ophthalmic surgery and opens the door to a new class of revolutionary microsurgical modalities. The skills transfer that is beyond human capabilities to robotic technology is a logical next step in microsurgical evolution.

BACKGROUND AND OBJECTIVE:To report the efficacy, safety, and benefits of femtosecond laser-assisted cataract surgery (FLACS) combined with sutureless 23-gauge pars plana vitrectomy (PPV).PATIENTS AND METHODS:This multicenter, retrospective study evaluated patient records and videos of 43 cases with retinal pathologies and cataract who underwent the combined procedure.RESULTS:In 44.2% and 55.8% of cases, respectively, the LenSx Laser (femtosecond machine; Alcon, Fort Worth, TX) and the Constellation (vitreous cutter; Alcon, Fort Worth, TX), and the Victus (femtosecond machine; Bausch + Lomb, Rochester, NY) and Stellaris PC (vitreous cutter; Bausch + Lomb, Rochester, NY) were used. No complications developed during capsulorrhexis, even without a red fundus reflex, retrobulbar block, or scleral indentation. Foldable intraocular lenses remained stable in the capsular bag during the vitreoretinal surgeries and postoperative visits. The mean times of femtosecond phacoemulsification, vitreoretinal surgery, and total surgery were 22.9 minutes ± 4.7 minutes, 43.1 minutes ± 9.8 minutes, and 65.3 minutes ± 8.6 minutes, respectively.CONCLUSION:This emerging technology is safe and offers several potential benefits for the success of the combined procedure.[[Ophthalmic Surg Lasers Imaging Retina. 2018;49:374–379.]

PurposeTo report the long-term anatomical and visual outcomes of intravitreal bevacizumab (IVB) monotherapy in naive choroidal neovascularisation (CNV) caused by myopia.MethodsRetrospective analysis of naive CNV secondary to myopia that underwent antivascular endothelial growth factor monotherapy was performed. Collected data included demographic details, clinical examination details including visual acuity at presentation and follow-up with imaging and treatment details. Main outcome measures were resolution of CNV activity at the last visit. Secondary outcomes included change in visual acuity, number of injections and adverse events.ResultsThirty-three eyes of 31 subjects with a mean age of 51.48±16.4 years were included. The mean follow-up was 66.47 months. 27 eyes had type 2 CNV and the rest seven eyes had type 1 CNV. The mean number of IVB injections per eye was 4.9. Mean visual acuity at baseline reduced from 0.65±0.33 logMAR units (Snellen equivalent=20/89) to 0.73±0.50 logMAR units (20/107) at final follow-up (p=0.003). The mean central macular thickness decreased from 309.31±86 µm at baseline to 267.5±70.89 µm at the last visit (p=0.03). However, visual acuity was maintained (±1 line of baseline) in 13 eyes (39.4%), ≥2 line improvement in nine (27.3%) eyes and more than two lines worsening in 11 eyes (33.3%). Foveal atrophy was observed at baseline and last visit in 6 (12.5%) and 14 (29.1%), respectively (p=0.007). No systemic adverse events were observed.ConclusionIVB monotherapy is safe and effective for long-term treatment of CNV secondary to myopia in real life.

IMPORTANCE: A better pathophysiologic understanding of the neurodevelopmental abnormalities observed in neonates exposed in utero to Zika virus (ZIKV) is needed to develop treatments. The retina as an extension of the diencephalon accessible to in vivo microcopy with spectral-domain optical coherence tomography (SD-OCT) can provide an insight into the pathophysiology of congenital Zika syndrome (CZS). OBJECTIVE: To quantify the microstructural changes of the retina in CZS and compare these changes with those of cobalamin C (cblC) deficiency, a disease with potential retinal maldevelopment. DESIGN, SETTING, AND PARTICIPANTS: This case series included 8 infants with CZS and 8 individuals with cblC deficiency. All patients underwent ophthalmologic evaluation at 2 university teaching hospitals and SD-OCT imaging in at least 1 eye. Patients with cblC deficiency were homozygous or compound heterozygotes for mutations in the methylmalonic aciduria and homocystinuria type C (MMACHC) gene. Data were collected from January 1 to March 17, 2016, for patients with CZS and from May 4, 2015, to April 23, 2016, for patients with cblC deficiency. MAIN OUTCOMES AND MEASURES: The SD-OCT cross-sections were segmented using automatic segmentation algorithms embedded in the SD-OCT systems. Each retinal layer thickness was measured at critical eccentricities using the position of the signal peaks and troughs on longitudinal reflectivity profiles. RESULTS: Eight infants with CZS (5 girls and 3 boys; age range, 3-5 months) and 8 patients with cblC deficiency (3 girls and 5 boys; age range, 4 months to 15 years) were included in the analysis. All 8 patients with CZS had foveal abnormalities in the analyzed eyes (8 eyes), including discontinuities of the ellipsoid zone, thinning of the central retina with increased backscatter, and severe structural disorganization, with 3 eyes showing macular pseudocolobomas. Pericentral retina with normal lamination showed a thinned (&lt;30% of normal thickness) ganglion cell layer (GCL) that colocalized in 7 of 8 eyes with a normal photoreceptor layer. The inner nuclear layer was normal or had borderline thinning. The central retinal degeneration was similar to that of cblC deficiency. CONCLUSIONS AND RELEVANCE: Congenital Zika syndrome showed a central retinal degeneration with severe GCL loss, borderline inner nuclear layer thinning, and less prominent photoreceptor loss. The findings provide the first, to date, in vivo evidence in humans for possible retinal maldevelopment with a predilection for retinal GCL loss in CZS, consistent with a murine model of the disease and suggestive of in utero depletion of this neuronal population as a consequence of Zika virus infection.

After monthly intravitreal injections, the systemic exposures of aflibercept, bevacizumab, and ranibizumab were distinct and correlated with different reductions in plasma free–vascular endothelial growth factor, which could provide biologic plausibility for potential differences in systemic adverse events.

Long-term intravitreal bevacizumab may result in marked regression of retinal neovascularization in patients with proliferative diabetic retinopathy and previous panretinal photocoagulation. On treatment-naive eyes, primary intravitreal bevacizumab injections resulted in either control or regression of 42.1% of proliferative diabetic retinopathy eyes over 24 months of follow-up. There were no serious complications.

IMPORTANCE: Zika virus (ZIKV) can cause severe changes in the retina and choroid that may result in marked visual impairment in infants with congenital Zika syndrome (CZS), the term created for a variety of anomalies associated with intrauterine ZIKV infection. OBJECTIVE: To evaluate the affected retinal layers in infants with CZS and associated retinal abnormalities using optical coherence tomography (OCT). DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional, consecutive case series included 8 infants (age range, 3.0-5.1 months) with CZS. Optical coherence tomographic images were obtained in the affected eyes of 7 infants with CZS who had undergone previous ophthalmologic examinations on March 17, 2016, and in 1 infant on January 1, 2016. An IgM antibody-capture enzyme-linked immunosorbent assay for ZIKV was performed on the cerebrospinal fluid samples of 7 of the 8 infants (88%), and other congenital infections were ruled out. MAIN OUTCOMES AND MEASURES: Observation of retinal and choroidal findings in the OCT images. RESULTS: Among the 8 infants included in the study (3 male; 5 female; mean [SD] age at examination, 4.1 [0.7] months), 7 who underwent cerebrospinal fluid analysis for ZIKV had positive findings for IgM antibodies. Eleven of the 16 eyes (69%) of the 8 infants had retinal alterations and OCT imaging was performed in 9 (82%) of them. Optical coherence tomography was also performed in 1 unaffected eye. The main OCT findings in the affected eyes included discontinuation of the ellipsoid zone and hyperreflectivity underlying the retinal pigment epithelium in 9 eyes (100%), retinal thinning in 8 eyes (89%), choroidal thinning in 7 eyes (78%), and colobomatouslike excavation involving the neurosensory retina, retinal pigment epithelium, and choroid in 4 eyes (44%). CONCLUSIONS AND RELEVANCE: Zika virus can cause severe damage to the retina, including the internal and external layers, and the choroid. The colobomatouslike finding seen in the OCT images relate to the excavated chorioretinal scar observed clinically.

Spontaneous resolution of VMT occurred in 21.4% (36 of 168) of eyes after a mean follow-up of 11.4 ± 12.6 months. An unfavorable anatomical outcome occurred in 7.7% (13 of 168) of eyes. The baseline SD-OCT grade may predict the progression to fullthickness macular hole.

We have developed a tool Fab fragment of a rabbit monoclonal antibody that is useful for early evaluation in rabbit models of technologies for long acting delivery (LAD) of proteins to the eye. Using this Fab we show that vitreal clearance can be slowed through increased hydrodynamic size. Fab (G10rabFab) and Fab′ (G10rabFab′) fragments of a rabbit monoclonal antibody (G10rabIgG) were expressed in Chinese hamster ovary (CHO) cells and purified using antigen-based affinity chromatography. G10rabFab retains antigen-binding upon thermal stress (37 °C) for 8 weeks in phosphate-buffered saline (PBS) and can be detected in rabbit tissues using an antigen-based ELISA. Hydrodynamic radius, measured using quasi-elastic light scattering (QELS), was increased through site-specific modification of the G10rabFab′ free cysteine with linear methoxy-polyethylene glycol(PEG)-maleimide of 20000 or 40000 molecular weight. Pharmacokinetic studies upon intravitreal dosing in New Zealand white rabbits were conducted on the G10rabFab and PEGylated G10rabFab′. Results of single and multidose pharmacokinetic experiments yield reproducible results and a vitreal half-life for G10rabFab of 3.2 days. Clearance from the eye is slowed through increased hydrodynamic size, with vitreal half-life showing a linear dependence on hydrodynamic radius (RH). A linear dependence of vitreal half-life on RHsuggests that molecule diffusivity makes an important contribution to vitreal clearance. A method for prediction of vitreal half-life from RHmeasurements is proposed.

IMPORTANCE: The Zika virus (ZIKV) might cause microcephaly and ophthalmoscopic findings in infants of mothers infected during pregnancy. OBJECTIVE: To assess and identify possible risk factors for ophthalmoscopic findings in infants born with microcephaly and a presumed clinical diagnosis of ZIKV intrauterine infection. DESIGN, SETTING, AND PARTICIPANTS: We conducted a cross-sectional study at the Altino Ventura Foundation in Recife, Brazil, that included 40 infants with microcephaly born in Pernambuco state, Brazil, between May and December 2015. Toxoplasmosis, rubella, cytomegalovirus, syphilis, and human immunodeficiency virus were ruled out in all of them. Testing of cerebrospinal fluid for ZIKV using IgM antibody-capture enzyme-linked immunosorbent assay was performed in 24 of 40 infants (60.0%). The infants and mothers underwent ocular examinations. The infants were divided into 2 groups, those with and without ophthalmoscopic alterations, for comparison. MAIN OUTCOMES AND MEASURES: Identification of risk factors for ophthalmoscopic findings in infants born with microcephaly and ZIKV intrauterine infection. RESULTS: Among the 40 infants, the mean (SD) age was 2.2 (1.2) months (range, 0.1-7.3 months). Of the 24 infants tested, 100% had positive results for ZIKV infection: 14 of 22 infants (63.6%) from the group with ophthalmoscopic findings and 10 of 18 infants (55.6%) from the group without ophthalmoscopic findings. The major symptoms reported in both groups were rash by 26 mothers (65.0%), fever by 9 mothers (22.5%), headache by 9 mothers (22.5%), and arthralgia by 8 mothers (20.0%). No mothers reported conjunctivitis or other ocular symptoms during pregnancy or presented signs of uveitis at the time of examination. Thirty-seven eyes (46.3%) of 22 infants (55.0%) had ophthalmoscopic alterations. Ten mothers (71.4%) of infants with ocular findings reported symptoms during the first trimester (frequency, 0.48; 95% CI, 0.02-0.67; P = .04). A difference was also observed between the groups of infants with and without ocular findings regarding the cephalic perimeter: mean (SD) of 28.8 (1.7) and 30.3 (1.5), respectively (frequency, −1.50; 95% CI, −2.56 to −0.51; P = .004). CONCLUSIONS AND RELEVANCE: Ocular involvement in infants with presumed ZIKV congenital infection were more often seen in infants with smaller cephalic diameter at birth and in infants whose mothers reported symptoms during the first trimester.

ABSTRACTMHAA4549A is a human immunoglobulin G1 (IgG1) monoclonal antibody that binds to a highly conserved epitope on the stalk of influenza A hemagglutinin and blocks the hemagglutinin-mediated membrane fusion in the endosome, neutralizing all known human influenza A strains. Pharmacokinetics (PK) of MHAA4549A and its related antibodies were determined in DBA/2J and Balb-c mice at 5 mg/kg and in cynomolgus monkeys at 5 and 100 mg/kg as a single intravenous dose. Serum samples were analyzed for antibody concentrations using an ELISA and the PK was evaluated using WinNonlin software. Human PK profiles were projected based on the PK in monkeys using species-invariant time method. The human efficacious dose projection was based on in vivo nonclinical pharmacological active doses, exposure in mouse infection models and expected human PK. The PK profiles of MHAA4549A and its related antibody showed a linear bi-exponential disposition in mice and cynomolgus monkeys. In mice, clearance and half-life ranged from 5.77 to 9.98 mL/day/kg and 10.2 to 5.76 days, respectively. In cynomolgus monkeys, clearance and half-life ranged from 4.33 to 4.34 mL/day/kg and 11.3 to 11.9 days, respectively. The predicted clearance in humans was ∼2.60 mL/day/kg. A single intravenous dose ranging from 15 to 45 mg/kg was predicted to achieve efficacious exposure in humans. In conclusion, the PK of MHAA4549A was as expected for a human IgG1 monoclonal antibody that lacks known endogenous host targets. The predicted clearance and projected efficacious doses in humans for MHAA4549A have been verified in a Phase 1 study and Phase 2a study, respectively.

ABSTRACTHospitalized patients with severe influenza are at significant risk for morbidity and mortality. MHAA4549A is a human monoclonal immunoglobulin (Ig) G1 antibody that binds to a highly conserved stalk region of the influenza A virus hemagglutinin protein and neutralizes all tested seasonal human influenza A virus strains. Two phase 1 trials examined the safety, tolerability, and pharmacokinetics of MHAA4549A in healthy volunteers. Both single ascending-dose trials were randomized, double blinded, and placebo controlled. Trial 1 randomized 21 healthy adults into four cohorts receiving a single intravenous dose of 1.5, 5, 15, or 45 mg/kg MHAA4549A or placebo. Trial 2 randomized 14 healthy adults into two cohorts receiving a single intravenous fixed dose of 8,400 mg or 10,800 mg of MHAA4549A or placebo. Subjects were followed for 120 days after dosing. No subject was discontinued in either trial, and no serious adverse events were reported. The most common adverse event in both studies was mild headache (trial 1, 4/16 subjects receiving MHAA4549A and 1/5 receiving placebo; trial 2, 4/8 subjects receiving MHAA4549A and 2/6 receiving placebo). MHAA4549A produced no relevant time- or dose-related changes in laboratory values or vital signs compared to those with placebo. No subjects developed an antitherapeutic antibody response following MHAA4549A administration. MHAA4549A showed linear serum pharmacokinetics, with a mean half-life of 22.5 to 23.7 days. MHAA4549A is safe and well tolerated in healthy volunteers up to a single intravenous dose of 10,800 mg and demonstrates linear serum pharmacokinetics consistent with those of a human IgG1 antibody lacking known endogenous targets in humans. (These trials have been registered at ClinicalTrials.gov under registration no. NCT01877785 and NCT02284607).

Neovascular age-related macular degeneration is a chronic condition that requires aggressive monitoring and treatment if early functional gains are to be maintained. Pro re nata treatment of exudative AMD is not sufficient to maximize the long-term visual outcomes.

BACKGROUND AND OBJECTIVE:To develop a safe and efficient surgical procedure for subretinal implantation into porcine eyes of a human embryonic stem cell-derived retinal pigmented epithelium (hESC-RPE) monolayer seeded onto a Parylene-C scaffold. This implant is referred to as CPCB-RPE1.MATERIALS AND METHODS:Ultrathin Parylene-C scaffolds were seeded with hESC-RPE and surgically implanted into the subretinal space of Yucatan mini pigs (n = 8). The surgery consisted of pars plana vitrectomy, induction of a limited retinal detachment, and peripheral retinotomy for insertion of the monolayer using a novel tissue injector, followed by silicone oil tamponade injection, laser photocoagulation around the retinotomy site, and inferior iridectomy. Oral cyclosporine was administered from day 1 and during the entire follow-up period. Three months later, the animals were euthanized and the eyes and major organs were submitted for histological analysis. Adjacent sections underwent immunohistochemical analysis to detect human cells using anti-TRA-1-85 (human blood group antigen) antibody and DAPI antibodies.RESULTS:The cell monolayer was immunopositive for TRA-1-85 3 months after implantation and migration from the Parylene-C scaffold was not detected. One eye had a mild inflammatory reaction around the implant that was negative for human biomarkers. No intraocular or systemic tumors were detected.CONCLUSION:The hESC-RPE cells survived for 3 months in this animal model. The surgical procedure for subretinal implantation of CPCB-RPE1 is feasible and safe, without cell migration off the scaffold or development of ocular or systemic tumors.[[Ophthalmic Surg Lasers Imaging Retina. 2016;47:342–351.]

Geographic atrophy is an advanced form of dry age-related macular degeneration that can lead to irreversible vision loss and high burden of disease. We aimed to assess efficacy and safety of avacincaptad pegol 2 mg in reducing geographic atrophy lesion growth.

To assess the impact of a 3-hour polysomnography (PSG)-recorded night of sleep deprivation on next-morning simulated microsurgical skills among vitreoretinal surgeons with different levels of surgical experience and to associate the sleep parameters obtained by PSG with Eyesi-generated performance.

ABSTRACTCytomegalovirus can cause debilitating and life-threatening disease in newborns infected in uteroand immunocompromised individuals, including transplant recipients. RG7667 is a unique combination of two monoclonal antibodies that binds glycoprotein complexes on the surface of cytomegalovirus and inhibits its entry into host cells. A phase 1 first-in-human, randomized, double-blind, placebo-controlled, dose-escalation study of RG7667 given intravenously was conducted in 181 healthy adults. The study involved a single ascending dose stage (1, 3, 5, and 10 mg/kg each antibody; n= 21), a multiple ascending dose stage (5 and 10 mg/kg each antibody monthly for 3 doses; n= 10), and a multiple dose expansion stage (10 mg/kg each antibody monthly for 3 doses; n= 150). Subjects were followed for 85 to 141 days to evaluate safety, tolerability, pharmacokinetics, and immunogenicity. Most adverse events were mild, and the incidence of adverse events was similar among the RG7667 and placebo groups. RG7667 had dose-proportional pharmacokinetics in all three dosing stages, a mean terminal half-life of 20 to 30 days, and an overall pharmacokinetic profile consistent with that of a human monoclonal antibody that lacks endogenous host targets. The proportion of subjects developing an antitherapeutic antibody response was not higher in the RG7667 group than in the placebo group. In summary, single and multiple doses of RG7667 were found to be safe and well-tolerated in healthy adults and had a favorable pharmacokinetic and immunogenicity profile. This study supports further development of RG7667 as a therapy for the prevention and treatment of cytomegalovirus infection in susceptible populations. (This study has been registered at ClinicalTrials.gov under registration no. NCT01496755.)

BACKGROUND AND OBJECTIVE:To evaluate the preoperative and intraoperative findings as prognostic indicators of functional and anatomic results of idiopathic epiretinal membrane (ERM) surgery.PATIENTS AND METHODS:Vitrectomies included ERM and internal limiting membrane (ILM) removal with vital dyes. Best corrected visual acuity (BCVA), optical coherence tomography (OCT), fluorescein angiography, and autofluorescence were performed at baseline and postoperatively. Intraoperative ILM status after ERM removal was also evaluated.RESULTS:Thirty-one eyes were monitored for a mean of 16.78 months. BCVA and central foveal thickness (CFT) improved significantly (Thirty-one eyes were monitored for a mean of 16.78 months. BCVA and central foveal thickness (CFT) improved significantly (P< .001) from baseline at 3 and 12 months. Preoperative hyperautofluorescence was associated with greater CFT reduction (P< .005). ILM status after ERM peeling did not influence visual recovery but was associated with anatomical results as measured by OCT.CONCLUSION:Preoperative poor initial BCVA and RPE defects by FAF may not be bad prognostic factors. Preoperative hyperautofluorescence was associated with greater CFT reduction. Intraoperative classification of ILM status after ERM and ILM staining/peeling was reported and may be useful for future studies, though it was not associated neither with preoperative nor postoperative BCVA.[[Ophthalmic Surg Lasers Imaging Retina. 2015;46:457–462.]

To compare the incident rates of sustained elevation of intraocular pressure (IOP) after uncomplicated pars plana vitrectomy for idiopathic epiretinal membrane and the unoperated fellow eye.

BACKGROUND AND OBJECTIVE:To investigate whether the confocal near-infrared reflectance (NIR) imaging modality could detect the in vivo presence of retinal pigment epithelium cells derived from embryonic human stem cells (hESC-RPE) implanted into the subretinal space of the Royal College of Surgeons (RCS) rat.MATERIALS AND METHODS:Monthly NIR images were obtained from RCS rats implanted with either hESC-RPE seeded on a parylene membrane (n = 14) or parylene membrane without cells (n = 14). Two independent, masked investigators graded the images. Histology and immunohistochemistry were performed at different time points (150, 210, and 270 postnatal days of age).RESULTS:NIR images revealed that an average of 20.53% of the parylene membrane area was covered by hESC-RPE. RPE-65 and TRA-1-85 confirmed the presence of human-specific RPE cells in those animals. No areas corresponding to cells were found in the group implanted with membrane only. Intergrader agreement was high (NIR images revealed that an average of 20.53% of the parylene membrane area was covered by hESC-RPE. RPE-65 and TRA-1-85 confirmed the presence of human-specific RPE cells in those animals. No areas corresponding to cells were found in the group implanted with membrane only. Intergrader agreement was high (r= 0.89–0.92).CONCLUSION:The NIR mode was suitable to detect the presence of hESC-RPE seeded on a membrane and implanted into the subretinal space of the RCS rat.[[Ophthalmic Surg Lasers Imaging Retina.2013;44:380–384.]

Pharmacokinetic (PK) and immunohistochemistry (IHC) assays are essential to the evaluation of the safety and efficacy of therapeutic monoclonal antibodies (mAb) during drug development. These methods require reagents with a high degree of specificity because low concentrations of therapeutic antibody need to be detected in samples containing high concentrations of endogenous human immunoglobulins. Current assay reagent generation practices are labor-intensive and time-consuming. Moreover, these practices are molecule-specific and so only support one assay for one program at a time. Here, we describe a strategy to generate a unique assay reagent, 10C4, that preferentially recognizes a panel of recombinant human mAbs over endogenous human immunoglobulins. This “panel-specific” feature enables the reagent to be used in PK and IHC assays for multiple structurally-related therapeutic mAbs. Characterization revealed that the 10C4 epitope is conformational, extensive and mainly composed of non-CDR residues. Most key contact residues were conserved among structurally-related therapeutic mAbs, but the combination of these residues exists at low prevalence in endogenous human immunoglobulins. Interestingly, an indirect contact residue on the heavy chain of the therapeutic appears to play a critical role in determining whether or not it can bind to 10C4, but has no affect on target binding. This may allow us to improve the binding of therapeutic mAbs to 10C4 for assay development in the future. Here, for the first time, we present a strategy to develop a panel-specific reagent that can expedite the development of multiple clinical assays for structurally-related therapeutic mAbs.

Diabetic retinopathy (DR) remains the major threat to sight in the working age population. Diabetic macular edema (DME) is a manifestation of DR that produces loss of central vision. Proliferative diabetic retinopathy (PDR) is a major cause of visual loss in diabetic patients. In PDR, the growth of new vessels is thought to occur as a result of vascular endothelial growth factor (VEGF) release into the vitreous cavity as a response to ischemia. Furthermore, VEGF increases vessel permeability leading to deposition of proteins in the interstitium that facilitate the process of angiogenesis and macular edema. This review demonstrates multiple benefits of intravitreal bevacizumab (IVB) on DR including DME and PDR at 24 months of follow up. The results indicate that IVB injections may have a beneficial effect on macular thickness and visual acuity (VA) in diffuse diabetic macular edema. Therefore, in the future this new therapy could replace or complement focal/grid laser photocoagulation in DME. In PDR, this new option could be an adjuvant agent to pan-retina photocoagulation so that more selective therapy may be applied. In addition, we report a series of patients in which tractional retinal detachment developed or progressed after adjuvant preoperative IVB in severe PDR.

Diabetic macular edema (DME) is the most frequent cause of severe vision impairment in patients with non-proliferative diabetic retinopathy. Even though patients should achieve optimal glycemic control, normalization of blood pressure and serum lipids, as well as improvement of cardiac and renal status, these measures alone will not prevent every patient from developing visual loss caused by DME. The goal of local treatment for DME is vision improvement, usually achieved after reducing leakage on fluorescein angiography (FA) and retinal thickness on optical coherence tomography (OCT). Laser photocoagulation is still the standard treatment for clinically significant DME. However, laser photocoagulation rarely provides major visual improvement, especially in patients with diffuse DME. Thus, a therapeutic intervention that restores visual acuity impaired by DME more often remains a significant unmet medical need. This review aims to present the most important emerging drug technologies for therapy of DME at present, including corticosteroids, vascular endothelial growth factor inhibitors, protein kinase C inhibitors, small interfering RNA, hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors and non-hormonal anti-inflammatory agents. Recent progress in this field suggests that local management of DME may change rapidly in the near future. Novel emerging drugs should enable better anatomical and functional outcomes for therapy of this sight-threatening disease.

HuM291 is a humanized anti-CD3 monoclonal antibody engineered to reduce binding to Fc receptors and complement fixation.HuM291 has a long serum half-life and mediated profound depletion of circulating T cells in chimpanzees; HuM291 also has significantly less mitogenic and cytokine-releasing activity than OKT3 in vitro.

To determine the practice pattern for treating giant retinal tear (GRT) related detachments, and their anatomic and visual outcomes with pars plana vitrectomy (PPV) with or without scleral buckling (SB).