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To reduce treatment burden and optimise patient outcomes in diabetic macular oedema, we present 1-year results from two phase 3 trials of faricimab, a novel angiopoietin-2 and vascular endothelial growth factor-A bispecific antibody.YOSEMITE and RHINE were randomised, double-masked, non-inferiority trials across 353 sites worldwide. Adults with vision loss due to centre-involving diabetic macular oedema were randomly assigned (1:1:1) to intravitreal faricimab 6·0 mg every 8 weeks, faricimab 6·0 mg per personalised treatment interval (PTI), or aflibercept 2·0 mg every 8 weeks up to week 100. PTI dosing intervals were extended, maintained, or reduced (every 4 weeks up to every 16 weeks) based on disease activity at active dosing visits. The primary endpoint was mean change in best-corrected visual acuity at 1 year, averaged over weeks 48, 52, and 56. Efficacy analyses included the intention-to-treat population (non-inferiority margin 4 Early Treatment Diabetic Retinopathy Study [ETDRS] letters); safety analyses included patients with at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (YOSEMITE NCT03622580 and RHINE NCT03622593).3247 patients were screened for eligibility in YOSEMITE (n=1532) and RHINE (n=1715). After exclusions, 940 patients were enrolled into YOSEMITE between Sept 5, 2018, and Sept 19, 2019, and 951 patients were enrolled into RHINE between Oct 9, 2018, and Sept 20, 2019. These 1891 patients were randomly assigned to faricimab every 8 weeks (YOSEMITE n=315, RHINE n=317), faricimab PTI (n=313, n=319), or aflibercept every 8 weeks (n=312, n=315). Non-inferiority for the primary endpoint was achieved with faricimab every 8 weeks (adjusted mean vs aflibercept every 8 weeks in YOSEMITE 10·7 ETDRS letters [97·52% CI 9·4 to 12·0] vs 10·9 ETDRS letters [9·6 to 12·2], difference -0·2 ETDRS letters [-2·0 to 1·6]; RHINE 11·8 ETDRS letters [10·6 to 13·0] vs 10·3 ETDRS letters [9·1 to 11·4] letters, difference 1·5 ETDRS letters [-0·1 to 3·2]) and faricimab PTI (YOSEMITE 11·6 ETDRS letters [10·3 to 12·9], difference 0·7 ETDRS letters [-1·1 to 2·5]; RHINE 10·8 ETDRS letters [9·6 to 11·9], difference 0·5 ETDRS letters [-1·1 to 2·1]). Incidence of ocular adverse events was comparable between faricimab every 8 weeks (YOSEMITE n=98 [31%], RHINE n=137 [43%]), faricimab PTI (n=106 [34%], n=119 [37%]), and aflibercept every 8 weeks (n=102 [33%], n=113 [36%]).Robust vision gains and anatomical improvements with faricimab were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for faricimab to extend the durability of treatment for patients with diabetic macular oedema.F Hoffmann-La Roche.

Faricimab is a bispecific antibody that acts through dual inhibition of both angiopoietin-2 and vascular endothelial growth factor A. We report primary results of two phase 3 trials evaluating intravitreal faricimab with extension up to every 16 weeks for neovascular age-related macular degeneration (nAMD).TENAYA and LUCERNE were randomised, double-masked, non-inferiority trials across 271 sites worldwide. Treatment-naive patients with nAMD aged 50 years or older were randomly assigned (1:1) to intravitreal faricimab 6·0 mg up to every 16 weeks, based on protocol-defined disease activity assessments at weeks 20 and 24, or aflibercept 2·0 mg every 8 weeks. Randomisation was performed through an interactive voice or web-based response system using a stratified permuted block randomisation method. Patients, investigators, those assessing outcomes, and the funder were masked to group assignments. The primary endpoint was mean change in best-corrected visual acuity (BCVA) from baseline averaged over weeks 40, 44, and 48 (prespecified non-inferiority margin of four letters), in the intention-to-treat population. Safety analyses included patients who received at least one dose of study treatment. These trials are registered with ClinicalTrials.gov (TENAYA NCT03823287 and LUCERNE NCT03823300).Across the two trials, 1329 patients were randomly assigned between Feb 19 and Nov 19, 2019 (TENAYA n=334 faricimab and n=337 aflibercept), and between March 11 and Nov 1, 2019 (LUCERNE n=331 faricimab and n=327 aflibercept). BCVA change from baseline with faricimab was non-inferior to aflibercept in both TENAYA (adjusted mean change 5·8 letters [95% CI 4·6 to 7·1] and 5·1 letters [3·9 to 6·4]; treatment difference 0·7 letters [-1·1 to 2·5]) and LUCERNE (6·6 letters [5·3 to 7·8] and 6·6 letters [5·3 to 7·8]; treatment difference 0·0 letters [-1·7 to 1·8]). Rates of ocular adverse events were comparable between faricimab and aflibercept (TENAYA n=121 [36·3%] vs n=128 [38·1%], and LUCERNE n=133 [40·2%] vs n=118 [36·2%]).Visual benefits with faricimab given at up to 16-week intervals demonstrates its potential to meaningfully extend the time between treatments with sustained efficacy, thereby reducing treatment burden in patients with nAMD.F Hoffmann-La Roche.

Thyrocytes secrete CXC chemokines, particularly (C-X-C motif) ligand (CXCL)8 and CXCL10; its physiopathological significance remains unclear. This study investigates the modulation of the secretion of CXCL8 vs. CXCL10, in human primary cells cultures of thyroid follicular cells (TFC) in Graves' disease (GD), and fibroblasts (OF) or preadipocytes (OP) from Graves' ophthalmopathy (GO).Cells were initially incubated with different concentrations of tumor necrosis factor (TNF)α (1, 5, 10 ng/mL). Then, CXCL8 and CXCL10 were measured in the supernatants of TFC, OF or OP cells basally and after 24 h of treatment with interferon (IFN)γ (1000 IU/mL) and/or TNFα (10 ng/mL), in presence/absence of the peroxisome proliferator activated receptor (PPAR)γ agonist pioglitazone (0, 0.1, 1, 5, 10, 20 μM), or the PPARα agonist fenofibrate (5, 10, 50, 100 μM).CXCL8, not CXCL10, was detected in basal conditions in TFC, OF and OP. CXCL8 secretion increased dose-dependently with increasing concentrations of TNFα. CXCL10 secretion was significantly stimulated by IFNγ (P 0.01) and not by TNFα, whereas CXCL8 was induced by TNFα (P 0.01), and inhibited by IFNγ (P 0.01) in TFC, OF and OP. Combining TNFα and IFNγ, the IFNγ-induced CXCL10 secretion was synergistically increased (P 0.01) while the TNFα-induced CXCL8 secretion (P 0.01) was reversed in all cell types. Pioglitazone had no significant effect on the secretion of CXCL8 stimulated by TNFα, while inhibited CXCL10. Fenofibrate, in presence of IFNγ plus TNFα, dose-dependently inhibited both CXCL10 and CXCL8 release.We first show that TFC, OF, and OP secrete CXCL8 and CXCL10 differentially, sustained by specific proinflammatory cytokines or their combination. This could reflect a different role of the two chemokines in the course of the disease, as CXCL10 could be associated with the initial phase of the disease when IFNγ is preponderant, while CXCL8 could be associated with a later chronic phase of the disease, when TNFα prevails.

The supraciliary space is a physiological route for aqueous humor outflow located anteriorly between the outer surface of the ciliary body and the internal surface of the sclera. Posteriorly, the suprachoroidal space is located between the choroid and the internal surface of the sclera. These spaces have been targeted as suitable and helpful pathways for glaucoma treatment, alternatives to the traditional subconjunctival space. The subconjunctival surgical pathway is affected by several limitations such as poor cosmesis, a lifetime risk for endophthalmitis, and an unpredictable wound healing response. Because of these limitations, the supraciliary space has gained growing interest as a possible target for new glaucoma drainage devices such as: Gold Micro Shunt (SOLX Inc.; Waltham, MA, USA), iStent Supra (Glaukos Corporation, Laguna Hills, CA, USA), CyPass Micro-Stent (Transcend Medical Inc., Menlo Park, CA, USA), Aquashunt (OPKO health Inc., Miami, FL, USA), STARflo (iSTAR Medical, Isnes, Belgium), and Esnoper-Clip implant (AJL Ophthalmics, Álava, Spain). We review the current literature concerning the supraciliary space to evaluate its safety and efficacy as a suitable pathway for glaucoma surgical treatment.

Intravenous (iv) glucocorticoids (GC) (ivGC) are used for active Graves orbitopathy (GO), but factors affecting GO outcome are poorly understood. We performed a retrospective study to investigate the variables affecting GO after ivGC.We evaluated 83 consecutive GO patients treated with ivGC but not orbital radiotherapy (ORT) and re-examined them after a median of 47 months. The endpoints were the relationships between GO outcome or additional treatments with age, sex, smoking habits, thyroid volume, thyroid treatment, time since thyroid treatment, antithyroid-stimulating hormone receptor antibodies (TRAb), GO duration, GO features, and follow-up time.GO features improved after treatment, resulting in moderate and marked amelioration in ~75% and ~41% of patients respectively. By multivariate analysis, a moderate GO improvement correlated with diplopia at first observation, which was more severe in responders. A marked GO improvement correlated with time between first and last observation and time after thyroid treatment, which were longer in responders. This likely reflected the combination of an early effect of GC and a late, spontaneous improvement of GO, as shown by analyses of GO outcome at various time points. Additional treatments after ivGC correlated by multivariate analysis with eyelid aperture, diplopia and NOSPECS score (NOSPECS stands for no GO signs [N], only eyelid sign [O], soft tissue involvement [S], proptosis [P], extraocular motility restriction [E], corneal involvement [C], and sight loss [S]) at first observation, which were more severe in responders.Our study shows that response to ivGC increases with time, likely reflecting the known tendency of GO to improve spontaneously, and is more pronounced when GO is more severe to begin with, which is associated with more additional treatments.ANOVA = analysis of variance CAS = clinical activity score GC = glucocorticoids GO = Graves orbitopathy

Introduction Amblyopia is a neurodevelopmental disorder characterized by visual acuity and contrast sensitivity loss, refractory to pharmacological and mechanical treatments in adulthood. In animal models, the corpus callosum (CC) plays a critical role in the development of the ocular dominance, thus strengthening the hypothesis of an involvement of both striate and extrastriate areas in the pathogenesis of amblyopia. To investigate the role of interhemispheric pathways in amblyopia, we studied the response of the visual cortex to transcranial Direct Current Stimulation (tDCS) applied over the primary visual area (V1) contralateral to the amblyopic eye. Methods Visual evoked potentials (VEPs) triggered by grating stimuli of different contrasts (K90%, K50%, K20%) were recorded in both hemispheres before and after inactivation of the occipital cortex of one side via cathodal tDCS (2.0 mA, 20′). VEPs were recorded before (T0), immediately after (T1) and 60′ following tDCS (T2). The display was either centered on the vertical meridian (central stimulation) or positioned in the right hemifield (with its inner edge at a distance of 1 degree from the fixation point). Visual acuity was tested at each time interval, to assess behavioral changes between active and sham stimulation. Results Cathodal tDCS improved visual acuity respect to baseline (recovery of 8.4 ± 3.3 letters, Holm-Sidak post hoc method p Conclusion tDCS is a promising treatment for amblyopia in adults. The rapid recovery of excitability and the persistent transcallosal disinhibition following perturbation of cortical activity strongly supports a critical role of interhemispheric balance in the pathophysiology of amblyopia.

To evaluate the efficacy of three commercially available lubricant eye drops for the treatment of mild, dry, irritated eyes.Randomized, investigator-masked evaluation of 60 patients in which 20 patients used carboxymethylcellulose sodium (CMC), 0.5% (Cellufresh), Allergan Inc., Irvine, CA) (group 1); 20 patients used a drop containing polyethylene glycol 400, 2.5% and sodium hyaluronate (Blink Intensive Tears, Abbott Medical Optics Inc., Santa Ana, CA) (group 2); and 20 patients used HP Guar 0.18% (Systane, Alcon Laboratories Inc., Ft. Worth, TX) (group 3). Study visits were at baseline and 1 month. Tests performed at both visits included Schirmer, tear-film break-up time (TBUT), visual acuity, fluorescein staining, tear osmolarity and wavefront aberrometry. Osmolarity testing was performed prior to instillation of the lubricant eye drops and then a final time 5min after instillation of the drop at both day 1 and day 30. Tear osmolarity was performed only in the right eye and only one time before and after instillation of lubricant eye drops.At day 1 the mean reduction in osmolarity 5min after instillation of the lubricant eye drop was, -5.0+/-1.9 in group 1, -9.0+/-4.2 in group 2 and -5.0+/-2.2 in group 3. At day 30 the mean reduction in osmolarity 5min after instillation of the lubricant eye drop was, -5.6+/-2.3mOsm/L in group 1; -9.9+/-2.8mOsm/L in group 2 and -4.5+/-1.8mOsm/L in group 3. The differences were statistically significant between groups 1 and 2, and 2 and 3. There was a reduction of osmolarity from day 1 to day 30 but the differences were not statistically significant. We feel that after a 30-day treatment with the lubricant eye drops, the lower osmolarity values could indicate that the tear film is progressing towards a more normal osmolarity value. A future study could examine the tear osmolarity value after 60 or 90 days of usage. LogMAR best-corrected visual acuity (BCVA) results showed an improvement in group 2 compared with baseline with no change in BCVA in groups 1 and 3. There was no statistically significant change from day 1 to 1 month in TBUT, while the Schirmer test showed an improvement in all groups at 1 month.Assessment of tear osmolarity provides the most objective, measurable test for determining improvement in dry eye patients. The instillation of any artificial tear or lubricant eye drop should decrease the tear-film osmolarity. The results found that polyethylene glycol 400, 0.25% and sodium hyaluronate (Blink Intensive Tears) significantly improved tear osmolarity compared with carboxymethylcellulose sodium (CMC), 0.5% (Cellufresh) and HP Guar 0.18% (Systane after instillation.

Increasing anatomical evidence indicates that large retinal ganglion cells (M-cells) are preferentially damaged in primary open angle glaucoma (OAG), while the smaller ganglion cells (P-cells) are relatively spared. In 13 patients with defined OAG and modest visual field defects, we evaluated the responses to stimuli that are expected to involve primarily the function of the P-pathway and compared them with those of control subjects. The psychophysical contrast sensitivity (CS), the PERG and VEPs were measured for red-green gratings of pure chromatic contrast, as well as yellow-black gratings of pure luminance contrast. As compared with controls, OAG patients had reduced CS for both luminance and chromatic contrast stimuli by about 6 dB. PERGs and VEPs to luminance stimuli were little affected, whereas those to chromatic stimuli were both reduced in amplitude and delayed. These results indicate that visual dysfunction in glaucoma is not selective for the M-pathway, and that responses to equiluminant colour-contrast stimuli may be of diagnostic value.

INTENSE concern regarding the growing costs of health care has naturally drawn special attention to expensive treatments that are devoted to the care of relatively few patients; organ and tissue transplantation exemplifies both of these characteristics. We assessed the quality process and use of resources in the context of Pisa Hospital’s program of corneal tissue procurement from non–heart-beating donors by constructing and analyzing a database containing detailed donor, recipient, and clinical information.