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Ricardo Machado Soares,&ast; Catarina Cunha Ferreira,&ast; Joana da Silva Fernandes, Carolina Madeira, Luís MA Silva, Eduardo Saraiva, Lígia Ribeiro, Sofia Fonseca Department of Ophthalmology - Centro Hospitalar Vila Nova de Gaia e Espinho, Porto, Portugal&ast;These authors contributed equally to this workCorrespondence: Ricardo Machado Soares, Department of Ophthalmology, Centro Hospitalar Vila Nova de Gaia e Espinho, EPE, Rua Conceição Fernandes, S/N, 4434-502, Vila Nova de Gaia, Porto, Portugal, Tel +351 915045174, Email ricardo.machado.soares@chvng.min-saude.ptPurpose: To report the long-term functional, anatomical and safety outcomes of 0.2 μg/day fluocinolone acetonide 0.19mg in patients with persistent or recurrent diabetic macular edema (DME).Methods: Retrospective, observational, single-center study of patients with recurrent or persistent DME. All patients received 0.2 μg/day of fluocinolone acetonide 0.19mg, and data were collected at baseline and months 1, 3, 6, 12, 24 and 36 after implantation. Outcomes measured included best-corrected visual acuity (BCVA), central macular thickness (CMT), intraocular pressure (IOP), and safety outcomes.Results: A total of 28 eyes from 28 patients were included. The mean age was 66.5 years (95% CI 62.8– 70.2) with a mean duration of DME of 8.8 years (95% CI 7.7– 10.0). Only two eyes were phakic. Mean follow-up was 25.4 months (95% CI 21.2– 29.6). Mean BCVA at baseline was 48.6 ETDRS letters (95% CI 41.3– 55.8) and improved as early as month 1 of follow-up with a mean gain in BCVA of 7.8 (95% CI 4.3– 11.3) ETDRS letters (p< 0.001). Statistically significant improvements in BCVA were also observed at months 6, 12 and 24. At baseline, patients had a mean CMT of 530.5μm (95% CI 463.0– 598.0), and a decrease in CMT was observed, starting at the first month of follow-up (mean CMT reduction of − 170.5μm, 95% CI − 223.8– − 117.1; p< 0.001). Statistically significant decreases in CMT were also observed at months 6, 12, 24, and 36, with the maximum decrease observed at month 12 (p< 0.001). Mean IOP at baseline was 16.4mmHg (95% CI 15.3– 17.5) and nine eyes (32.1%) had an IOP ≥ 21mmHg during follow-up.Conclusion: Our results support the effectiveness and safety profile of fluocinolone acetonide. Although additional long-term real-world evidence is required, fluocinolone acetonide may represent a safe strategy for daily, low-dose, sustained and localized release to the posterior segment of the eye, providing both functional and anatomical benefits in DME.Keywords: diabetic macular edema, intravitreal implant, best corrected visual acuity, intravitreal corticosteroid, sub-optimal response

Margarida Vale,1 Francisca Leite,2,3 Catarina Madeira1,2,4 1NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, Portugal; 2Associação CoLAB TRIALS, Évora, Portugal; 3Hospital da Luz Learning Health, Lisboa, Portugal; 4CHRC, NOVA Medical School, Universidade NOVA de Lisboa, Lisboa, PortugalCorrespondence: Catarina Madeira, CoLAB TRIALS, Largo do Senhor da Pobreza, Escola Superior de Enfermagem São João de, Deus, Évora, 7000-811, Portugal, Tel +351 91 4006726, Email catarina.madeira@colabtrials.ptPurpose: Over the last years, in response to the increasing complexity and demand of clinical trials, there has been a growing concern with the application of efficient risk management methodologies. The main objective of this work is to assess the current level of implementation of risk management activities by clinical trials sites’ teams and identify points of improvement.Methods: A cross-sectional study was conducted through an original, non-validated questionnaire created to assess the risk management practices at Portuguese clinical trial sites. The web-based survey was sent by e-mail to the clinical trial sites identified, and it was available for one month. Descriptive statistics were used to summarize the findings.Results: In total, 46 clinical trial sites accepted to participate in this study. The surveys’ answers showed that although 57.0% of sites reported the use of a systematic risk management tool, only nine sites (19.6%) described a standard tool or document that captured systematically the analysis of risks at the site level. Most of the sites (87.0%) showed willing to use a risk management tool specifically tailored for their operational needs, with the lack of knowledge about risk management being the main reason against its implementation.Conclusion: This work indicates that the surveyed clinical trial sites generally recognize the importance of risk management methodologies as an opportunity to anticipate difficulties in the trial conduct and optimize the use of sites’ resources. However, mainly due to lack of experience with risk management methodologies, sites are not currently implementing these strategies in the management of their trial-related operations. The development of a risk management tool for sites can be useful in this context.Keywords: clinical research, operational risks, planning, trial feasibility, healthcare, risk assessment tool

Ana Filipa Moleiro,1,2 Gonçalo Godinho,3 Carolina Madeira,4 Ana Faria Pereira,1 Elisete Brandão,1 Fernando Falcão-Reis,1,2 João Nuno Beato,1,2 Susana Penas1,2 1Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Porto, Portugal; 2Department of Surgery and Physiology, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; 3Department of Ophthalmology, Centro Hospitalar de Leiria, Leiria, Portugal; 4Department of Ophthalmology, Centro Hospitalar Gaia-Espinho, Gaia, PortugalCorrespondence: Ana Filipa Moleiro, Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Alameda Hernani Monteiro, Porto, 4200-426, Portugal, Tel +351 915689259, Email anafomoleiro@gmail.comPurpose: This work aimed to longitudinally assess the peripapillary (PPCT) and subfoveal (SFCT) choroidal thickness (CT), in patients diagnosed with central (CRVO) or branch retinal vein occlusions (BRVO), correlating SFCT with central macular thickness (CMT) and PPCT with peripapillary retinal nerve fiber layer thickness (pRNFL).Patients and Methods: This was a retrospective longitudinal study of 71 eyes from 71 patients with treatment-naïve retinal vein occlusion (24 CRVO and 40 BRVO). Spectral-domain optical coherence tomography (SD-OCT, Spectralis HRA-OCT, Heidelberg) was used to measure PPCT, SFCT, pRNFL and CMT of the affected and fellow eyes at baseline (acute phase) and at 3 and 9 months post anti-VEGF treatment. IBM SPSS Statistics version 27.0 (IBM Corp., Armonk, NY, USA) was used for statistical analysis. A p-value ≤ 0.05 was considered statistically significant.Results: Affected eyes presented a thicker baseline PPCT and SFCT compared to their fellow eyes both in CRVO and BRVO (p < 0.05). Both groups presented a significant decrease of PPCT in the affected eyes at 3 months compared to baseline (p < 0.05). At 9 months, compared to 3 months, PPCT remained stable (p > 0.05). Similarly, affected eyes’ SFCT significantly decreased at 3 months (p < 0.05) in both groups. At 9 months, compared to 3 months, SFCT decreased in the CRVO patients (p = 0.047) but remained stable in the BRVO patients (p = 0.850). No correIations between SFCT and CMT were seen at any timepoint in both groups (p > 0.05). PPCT correlates with pRNFL in CRVO at 3 months, although no other correlations were found during the follow-up. In BRVO, PPCT did not show any significant correlation with pRNFL.Conclusion: Both in CRVO and BRVO eyes, PPCT and SFCT at diagnosis are significantly thicker compared to the fellow eye, suggesting a possible increase in CT immediately after the occlusion, which is followed by a decrease at an early follow-up stage.Keywords: biomarkers, vascular retinal diseases, retinal vein occlusions, choroidal thickness, optical coherence tomography

Mário Lima-Fontes,1 Gonçalo Godinho,2 Ana Maria Cunha,1 Carolina Madeira,3 Manuel Falcão,1,4 Fernando Falcão-Reis,1,4 Ângela Carneiro1,4 1Department of Ophthalmology, Centro Hospitalar Universitário São João, Porto, Portugal; 2Department of Ophthalmology, Centro Hospitalar de Leiria, Leiria, Portugal; 3Department of Ophthalmology, Centro Hospitalar Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal; 4Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, PortugalCorrespondence: Mário Lima-Fontes, Department of Ophthalmology, Centro Hospitalar Universitário São João, Alameda Professor Hernâni Monteiro, Porto, 4200-319, Portugal, Tel +351 918420563, Fax +351 225513669, Email marioruifontes@gmail.comPurpose: To describe a case of hypotony maculopathy following anti-VEGF intravitreal injection (IVI) in a patient with pseudoxanthoma elasticum (PE).Methods: Clinical case report.Results: A 52-year-old male complained of right eye (OD) vision loss 2 days after an uncomplicated anti-VEGF IVI for the treatment of choroidal neovascularization secondary to angioid streaks. Relevant medical history included PE, pathologic myopia, and a previous pars plana vitrectomy (PPV) due to a retinal detachment. OD best-corrected visual acuity (BCVA) dropped from 6/12 to 6/18 after the IVI. Intraocular pressure (IOP) was 3 mmHg and chorioretinal folds were evident in the posterior pole. Topical dexamethasone and atropine were prescribed, and full recovery was noticed after 3 days. Four months later, the patient developed a new episode of vision loss after another IVI. His BCVA was counting fingers, IOP was 2mmHg, and more noticeable chorioretinal folds were found. This time, an open scleral wound at the injection site was evident and a scleral suture was necessary. Once again, the patient recovered well.Conclusion: Hypotony maculopathy following intravitreal injection is a rare condition. However, the described patient presented several conditions which could be related with poor scleral wound closure: intrinsic scleral fragility due to myopia and pseudoxanthoma elasticum; repeated IVI procedures; and absence of vitreous in the posterior segment due to prior vitrectomy. Despite the good outcome, hypotony maculopathy may be a sight-threatening condition, and special attention is necessary for specific patients with risk factors.Keywords: hypotony maculopathy, intravitreal injection, anti-VEGF, pseudoxanthoma elasticum, angioid streaks

Ana Filipa Moleiro,1,2 Gonçalo Godinho,3 Carolina Madeira,4 Ana Faria Pereira,1 Elisete Brandão,1 Fernando Falcão-Reis,1,2 João Nuno Beato,1,2 Susana Penas1,2 1Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Porto, Portugal; 2Department of Surgery and Physiology, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; 3Department of Ophthalmology, Centro Hospitalar de Leiria, Leiria, Portugal; 4Department of Ophthalmology, Centro Hospitalar Gaia-Espinho, Gaia, PortugalCorrespondence: Ana Filipa Moleiro, Department of Ophthalmology, Centro Hospitalar e Universitário de São João, Alameda Hernani Monteiro, Porto, 4200-426, Portugal, Tel +351 915689259, Email anafomoleiro@gmail.com

Alzheimer's disease (AD) is a severe neurodegenerative disorder still in search of effective methods of diagnosis. Altered levels of the NMDA receptor co-agonist, d-serine, have been associated with neurological disorders, including schizophrenia and epilepsy. However, whether d-serine levels are deregulated in AD remains elusive. Here, we first measured D-serine levels in post-mortem hippocampal and cortical samples from nondemented subjects (n=8) and AD patients (n=14). We next determined d-serine levels in experimental models of AD, including wild-type rats and mice that received intracerebroventricular injections of amyloid-β oligomers, and APP/PS1 transgenic mice. Finally, we assessed d-serine levels in the cerebrospinal fluid (CSF) of 21 patients with a diagnosis of probable AD, as compared with patients with normal pressure hydrocephalus (n=9), major depression (n=9) and healthy controls (n=10), and results were contrasted with CSF amyloid-β/tau AD biomarkers. d-serine levels were higher in the hippocampus and parietal cortex of AD patients than in control subjects. Levels of both d-serine and serine racemase, the enzyme responsible for d-serine production, were elevated in experimental models of AD. Significantly, d-serine levels were higher in the CSF of probable AD patients than in non-cognitively impaired subject groups. Combining d-serine levels to the amyloid/tau index remarkably increased the sensitivity and specificity of diagnosis of probable AD in our cohort. Our results show that increased brain and CSF d-serine levels are associated with AD. CSF d-serine levels discriminated between nondemented and AD patients in our cohort and might constitute a novel candidate biomarker for early AD diagnosis.

Carolina Madeira,1 Ana Vasques,2 João Beato,1 Gonçalo Godinho,1 Luís Torrão,1 Manuel Falcão,1,3 Fernando Falcão-Reis,1,3 João Pinheiro-Costa1,4 1Department of Ophthalmology, Centro Hospitalar de São João, Porto, Portugal; 2Faculty of Medicine, University of Porto, Porto, Portugal; 3Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal; 4Department of Biomedicine, Faculty of Medicine, University of Porto, Porto, Portugal Purpose: To systematically compare the efficacy of transepithelial accelerated corneal collagen crosslinking (TE-ACXL) with conventional corneal collagen crosslinking (C-CXL) in patients with progressive keratoconus. Methods: Eyes of patients with progressive keratoconus who were treated with C-CXL (3 mW/cm2 for 30 minutes) were compared with those who underwent TE-ACXL (6 mW/cm2 for 15 minutes). Best-corrected visual acuity (BCVA), keratometry values, corneal thickness, and topometric indexes were compared before CXL, and at 2 months, 6 months, and 12 months postoperatively. Results: The study enrolled 26 eyes of which 16 had TE-ACXL and 10 had C-CXL. Both groups were comparable at baseline and 12 months in terms of BCVA (P=0.16 and P=0.57), Kmax (maximum keratometry) (P=0.31 and P=0.73), pachymetry (P=0.75 and P=0.37), index of surface variance (ISV) (P=0.45 and P=0.86), index of vertical asymmetry (IVA) (P=0.26 and P=0.61), and index of height decentration (IHD) (P=0.27 and P=0.86, respectively). We did not observe significant differences between preoperative and 12-month postoperative readings in within-group analysis: ΔKmax (TE-ACXL, -2.13±5.41, P=0.25 vs C-CXL, 0.78±1.65, P=0.17), Δpachymetry (TE-ACXL, 4.10±14.83, P=0.41 vs C-CXL, -8.90±22.09, P=0.24), ΔISV (TE-ACXL, -8.50±21.26, P=0.24 vs C-CXL, 3.80±12.43, P=0.36), ΔIVA (TE-ACXL, -0.12±0.31, P=0.26 vs C-CXL, 0.03±0.18, P=0.61), and ΔIHD (TE-ACXL, -0.03±0.07, P=0.18 vs C-CXL, -0.01±0.03, P=0.88). Conclusion: Both TE-ACXL and C-CXL were similarly effective. Further follow-up is required to determine whether these techniques are comparable in the long-term. Keywords: cornea, keratoconus, crosslinking, transepithelial, riboflavin, ultraviolet radiation, keratometry

The trace metal vanadium is important in many physiological effects. VIVO forms highly stable complexes with ligands containing O-donor atoms, although binding to N- or S-donor containing biogenic ligands in solution is weaker. The first VIVO complexes of dipeptides have recently been isolated containing a deprotonated peptide-N-group. The terminal -NH(sub2) group has been replaced by a hard phenolate, to make VIVO binding more favourable.