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Background Investigate retinal fluid changes via a novel deep-learning algorithm in real-world patients receiving faricimab for the treatment of neovascular age-related macular degeneration (nAMD). Methods Multicenter, retrospective chart review and optical coherence tomography (OCT) image upload from participating sites was conducted on patients treated with faricimab for nAMD from February 2022 to January 2024. The Notal OCT Analyzer (NOA) algorithm provided intraretinal, subretinal and total retinal fluid for each scan. Results were segregated based on treatment history and fluid compartments, allowing for multiple cross-sections of evaluation. Results A total of 521 eyes were included at baseline. The previous treatments prior to faricimab were aflibercept, ranibizumab, bevacizumab, or treatment-naive for 52.3%, 21.0%, 13.3%, and 11.2% of the eyes, respectively. Of all 521 eyes, 49.9% demonstrated fluid reduction after one injection of faricimab. The mean fluid reduction after one injection was −60.7nL. The proportion of eyes that saw reduction in fluid compared to baseline after second, third, fourth and fifth faricimab injections were 54.4%, 51.9%, 51.4% and 52.2%, respectively. The mean (SD) retreatment interval after second, third, fourth and fifth faricimab injection were 53.4 (34.3), 56.6 (36.0), 57.1 (35.3) and 61.5 (40.2) days, respectively. Conclusion Deep-learning algorithms provide a novel tool for evaluating precise quantification of retinal fluid after treatment of nAMD with faricimab. Faricimab demonstrates reduction of retinal fluid in multiple groups after just one injection and sustains this response after multiple treatments, along with providing increases in treatment intervals between subsequent injections.

Faricimab, the first bispecific antibody designed for intraocular use, is approved for the treatment of neovascular age-related macular degeneration (nAMD), diabetic macular edema (DME), and retinal vein occlusion (RVO). Here, we report the usability of a novel faricimab 6 mg pre-filled syringe (PFS) configuration that has been designed specifically for intravitreal use. A simulated-use human factors validation study enrolling 15 retina specialists and 15 ophthalmic assistants was conducted in a market research facility configured to represent an ophthalmology clinic. Participants' ability to complete tasks related to package handling, dose preparation, and injection of a faricimab 6 mg dose into a polymer eye using the PFS was assessed. In a second Phase 3b, single-arm, actual-use study, the ability of seven retina specialists and six ophthalmic assistants to prepare and administer the PFS in accordance with the instructions for use was assessed. Injections were performed into single eyes of 35 patients with nAMD or DME in three US clinics and patients were followed for 7 days for safety reporting (ClinicalTrials.gov identifier: NCT05569148). In the simulated-use study, most retina specialists and ophthalmic assistants completed all tasks deemed essential for PFS preparation and administration correctly and without error. Of the 22 tasks, the pass rate was 86.7-100%; 16 tasks had a pass rate of 100%. No use errors were observed during the actual-use study. One patient experienced one mild adverse event of eye irritation that resolved the same day and was deemed unrelated to the study drug. Participants were able to safely and correctly prepare and administer a faricimab 6 mg dose using the PFS in accordance with the instructions for use, under realistic conditions representing the real world. The faricimab 6 mg PFS may therefore offer a more convenient, safe-handling alternative to vial administration.

PURPOSE: To describe the Port Delivery System with ranibizumab refill-exchange procedure. METHODS: Procedure based on the clinical trial program in patients with retinal diseases. RESULTS: The refill-exchange procedure is performed under topical anesthesia and strict aseptic conditions. Supplemental task lighting and magnification are recommended throughout the procedure. Ranibizumab is aseptically transferred from the vial with the filter needle and air is removed from the syringe. The filter needle is then replaced with the refill needle; any remaining air is removed from the syringe and the plunger is advanced to the 0.1-mL mark. Targeting the implant septum center, the refill needle is inserted perpendicularly to the globe until the soft stop contacts the conjunctiva (perpendicular orientation and conjunctival contact are maintained throughout the procedure); a cotton-tipped applicator is recommended for globe stabilization. The entire syringe contents are slowly injected over 5–10 seconds while existing solution fills the fluid collection reservoir. Once completed, the needle is carefully withdrawn while maintaining perpendicularity. The procedure can be successfully performed in rare, specific cases, including subconjunctival thickening or fibrous capsule formation, fluid-filled bleb formation, and corneal patch grafts. CONCLUSION: The procedure is straightforward but distinct from intravitreal injections and requires adherence to standardized techniques. With appropriate preparation, the procedure can be performed in specific cases. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:257–265.]

OBJECTIVES: To describe conjunctiva and Tenon's capsule handling during the Port Delivery System with ranibizumab (PDS) implant insertion procedure including up-front assessments, planning, and instrumentation, with emphasis placed on the peritomy, scleral dissection, and closure steps. METHODS: Surgical pearls based on experience accumulated in the PDS clinical trial program in patients with retinal diseases. RESULTS: Preoperative preparation, specific instruments, and meticulous techniques are key to optimizing surgical outcomes. Before surgery, assessment of factors that affect conjunctival integrity and an in-office conjunctiva examination are conducted. Gentle, purposeful conjunctiva and Tenon's capsule handling with nontoothed forceps and suturing with a BV needle are recommended to prevent tissue damage. The peritomy is 6 mm by 6 mm, centered around the planned implant location in the superotemporal quadrant. A complete sub-Tenon's capsule dissection is achieved using a wide, robust lateral and posterior dissection technique to free tissue from the sclera and minimize tension. The globe is stabilized during scleral cutdown by grasping the sclera with fine-toothed forceps away from the incision edge to prevent tissue delamination. When closing the peritomy, both the conjunctiva and Tenon's capsule are completely captured and sutured with scleral anchoring at the apex of the peritomy to help prevent conjunctival retraction and erosion. Mitigation and detection of adverse events is critical to successful surgical outcomes. CONCLUSIONS: The PDS implant insertion procedure is straightforward, but it requires planned preoperative preparation, specific instruments, and meticulous techniques. The surgical pearls described here offer insights for optimizing outcomes. [Ophthalmic Surg Lasers Imaging Retina. 2022;53:266–273.]

Purpose: To investigate the tensile and elastic properties of both commercially available and experimental human amniotic membrane preparations. Method: Nine preparations of human amniotic membrane were studied. The four dry preparations were untreated (nonirradiated, n = 20), and gamma (n = 25), low-dose (AmbioDry ® , Okto Ophtho Inc., Costa Mesa, Calif., USA, n = 20) and high-dose (n = 20) electron beam sterilized. The same dry membranes were moistened with balanced salt solution (n = 20, 34, 20 and 20, respectively). The ninth group consisted of thawed medium-frozen amniotic membrane (AmnioGraft ® , Bio-Tissue Inc., Miami, Fla., USA, n = 20). The membranes were cut into thin strips, loaded on a gram range load sensor, and stretched incrementally to the point of rupture. The modulus of elasticity, displacement until rupture and maximum tolerated stress were recorded and compared. Results: The dry preparations exhibited higher moduli of elasticity when compared with the moist samples, with the low-dose electron beam-irradiated samples having the greatest mean modulus of elasticity overall and maintaining a high modulus of elasticity as a moist sample (p < 0.05). Moist nonirradiated preparations and thawed medium-frozen preparations stretched the farthest before rupture and experienced the greatest mean stresses at the point of rupture. While 3 of 4 membranes had greater stretch when moistened as compared to their dry counterparts, there was no difference in the membrane stiffness between dry and moistened low-dose electron beam-irradiated samples (p > 0.8). Conclusions: Low-dose electron beam-irradiated amnion appeared to maintain desirable elastic characteristics in transition from a dry to rehydrated state and may thus provide an easy-to-manipulate transplant tissue for ocular surface reconstruction. Moist nonirradiated and thawed medium-frozen tissues, however, may provide surgical advantages as they required greater forces to rupture.

Background Total tau protein (T-Tau) and neurofilament light chain (NfL) have emerged as candidate plasma biomarkers of neurodegeneration, but studies have not compared how these biomarkers cross-sectionally or longitudinally associate with cognitive and neuroimaging measures. We therefore compared plasma T-Tau and NfL as cross-sectional and longitudinal markers of (1) global and domain-specific cognitive decline and (2) neuroimaging markers of cortical thickness, hippocampal volume, white matter integrity, and white matter hyperintensity volume. Methods We included 995 participants without dementia who were enrolled in the Mayo Clinic Study of Aging cohort. All had concurrent plasma NfL and T-tau, cognitive status, and neuroimaging data. Follow-up was repeated approximately every 15 months for a median of 6.2 years. Plasma NfL and T-tau were measured on the Simoa-HD1 Platform. Linear mixed effects models adjusted for age, sex, and education examined associations between baseline z -scored plasma NfL or T-tau and cognitive or neuroimaging outcomes. Analyses were replicated in Alzheimer’s Disease Neuroimaging Initiative (ADNI) among 387 participants without dementia followed for a median of 3.0 years. Results At baseline, plasma NfL was more strongly associated with all cognitive and neuroimaging outcomes. The combination of having both elevated NfL and T-tau at baseline, compared to elevated levels of either alone, was more strongly associated at cross-section with worse global cognition and memory, and with neuroimaging measures including temporal cortex thickness and increased number of infarcts. In longitudinal analyses, baseline plasma T-tau did not add to the prognostic value of baseline plasma NfL. Results using ADNI data were similar. Conclusions Our results indicate plasma NfL had better utility as a prognostic marker of cognitive decline and neuroimaging changes. Plasma T-tau added cross-sectional value to NfL in specific contexts. Trial registration Not applicable

Abstract Rationale Cystic fibrosis (CF) is characterized by dietary antioxidant deficiencies, which may contribute to an oxidant–antioxidant imbalance and oxidative stress. Objectives Evaluate the effects of an oral antioxidant-enriched multivitamin supplement on antioxidant concentrations, markers of inflammation and oxidative stress, and clinical outcomes. Methods In this investigator-initiated, multicenter, randomized, double-blind, controlled trial, 73 pancreatic-insufficient subjects with CF 10 years of age and older with an FEV1 between 40% and 100% predicted were randomized to 16 weeks of an antioxidant-enriched multivitamin or control multivitamin without antioxidant enrichment. Endpoints included systemic antioxidant concentrations, markers of inflammation and oxidative stress, clinical outcomes (pulmonary exacerbations, anthropometric measures, pulmonary function), safety, and tolerability. Measurements and Main Results Change in sputum myeloperoxidase concentration over 16 weeks, the primary efficacy endpoint, was not significantly different between the treated and control groups. Systemic antioxidant (β-carotene, coenzyme Q10, γ-tocopherol, and lutein) concentrations significantly increased in the antioxidant-treated group (P < 0.001 for each), whereas circulating calprotectin and myeloperoxidase decreased in the treated group compared with the control group at Week 4. The treated group had a lower risk of first pulmonary exacerbation requiring antibiotics than the control group (adjusted hazard ratio, 0.50; P = 0.04). Lung function and growth endpoints did not differ between groups. Adverse events and tolerability were similar between groups. Conclusions Antioxidant supplementation was safe and well tolerated, resulting in increased systemic antioxidant concentrations and modest reductions in systemic inflammation after 4 weeks. Antioxidant treatment was also associated with a lower risk of first pulmonary exacerbation. Clinical trial registered with www.clinicaltrials.gov (NCT01859390).

Background: Melanoma is a disease that primarily arises in the skin but is a derivative of the neural crest. Eukaryotic translation initiation factor 4E (eIF4E) regulates translation of multiple malignancy-associated mRNAs and is overexpressed in many epithelial tumours. However, expression in human tumours derived from the neural crest is unknown. Here, we determined the association of eIF4E and phospho-eIF4E expression in melanocytic lesions with malignant conversion, metastatic potential and patient survival. Methods: Archived formalin-fixed, paraffin-embedded surgical specimens from 114 patients with melanocytic lesions were stained immunohistochemically for eIF4E and phospho-eIF4E and evaluated semiquantitatively. The relationship between cytoplasmic and nuclear eIF4E and phospho-eIF4E protein expression, melanocytic lesion subtype and tumour progression was determined. Kaplan–Meier survival analyses and Cox proportional hazard regression were performed. Results: Increased eIF4E and phospho-eIF4E expression was highly associated with malignancy ( P <0.0001). High nuclear phospho-eIF4E was associated with synchronous or future metastasis ( P =0.0059). Kaplan–Meier analyses demonstrated highly significant associations between high histoscores for cytoplasmic and nuclear phospho-eIF4E and reduced survival in all patients ( P =0.0003 and 0.0009, respectively). Conclusions: Increased melanoma expression of eIF4E and phospho-eIF4E is associated with metastatic potential, reduced survival and increased risk of death.

Corticobasal degeneration (CBD) is a neurodegenerative disorder affecting movement and cognition, definitively diagnosed only at autopsy. Here, we conduct a genome-wide association study (GWAS) in CBD cases ( n =152) and 3,311 controls, and 67 CBD cases and 439 controls in a replication stage. Associations with meta-analysis were 17q21 at MAPT ( P =1.42 × 10 −12 ), 8p12 at lnc-KIF13B-1 , a long non-coding RNA (rs643472; P =3.41 × 10 −8 ), and 2p22 at SOS1 (rs963731; P =1.76 × 10 −7 ). Testing for association of CBD with top progressive supranuclear palsy (PSP) GWAS single-nucleotide polymorphisms (SNPs) identified associations at MOBP (3p22; rs1768208; P =2.07 × 10 −7 ) and MAPT H1c (17q21; rs242557; P =7.91 × 10 −6 ). We previously reported SNP/transcript level associations with rs8070723/ MAPT , rs242557/ MAPT , and rs1768208/ MOBP and herein identified association with rs963731/ SOS1 . We identify new CBD susceptibility loci and show that CBD and PSP share a genetic risk factor other than MAPT at 3p22 MOBP (myelin-associated oligodendrocyte basic protein). Corticobasal degeneration is a rare neurodegenerative disorder that can only be definitively diagnosed by autopsy. Here, Kouri et al. conduct a genome-wide-association study and identify two genetic susceptibility loci 17q21 ( MAPT ) and 3p12 ( MOBP ), and a novel susceptibility locus at 8p12.

Background The COVID‐19 pandemic underscored the need for rapid and accurate diagnostic tools. In August 2020, the Abbott BinaxNOW COVID‐19 Antigen Card test became available as a timely and affordable alternative for SARS‐CoV‐2 molecular testing, but its performance may vary due to factors including timing and symptomatology. This study evaluates BinaxNOW diagnostic performance in diverse epidemiological contexts. Methods Using RT‐PCR as reference, we assessed performance of the BinaxNOW COVID‐19 test for SARS‐CoV‐2 detection in anterior nasal swabs from participants of two studies in Puerto Rico from December 2020 to May 2023. Test performance was assessed by days post symptom onset, collection strategy, vaccination status, symptomatology, repeated testing, and RT‐PCR cycle threshold (Ct) values. Results BinaxNOW demonstrated an overall sensitivity of 84.1% and specificity of 98.8%. Sensitivity peaked within 1–6 days after symptom onset (93.2%) and was higher for symptomatic (86.3%) than asymptomatic (67.3%) participants. Sensitivity declined over the course of infection, dropping from 96.3% in the initial test to 48.4% in testing performed 7–14 days later. BinaxNOW showed 99.5% sensitivity in participants with low Ct values (≤ 25) but lower sensitivity (18.2%) for participants with higher Cts (36–40). Conclusions BinaxNOW demonstrated high sensitivity and specificity, particularly in early‐stage infections and symptomatic participants. In situations where test sensitivity is crucial for clinical decision‐making, nucleic acid amplification tests are preferred. These findings highlight the importance of considering clinical and epidemiological context when interpreting test results and emphasize the need for ongoing research to adapt testing strategies to emerging SARS‐CoV‐2 variants.