Publications by authors named "Chiara Eandi"

77 Publications

Bilateral acute macular neuroretinopathy following COVID-19 infection.

Acta Ophthalmol 2021 May 26. Epub 2021 May 26.

Hôpital Ophtalmique Jules Gonin, Fondation Asile des Aveugles, Lausanne, Switzerland.

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http://dx.doi.org/10.1111/aos.14913DOI Listing
May 2021

Case Report: Central Retinal Artery Occlusion in a COVID-19 Patient.

Front Pharmacol 2020 23;11:588384. Epub 2020 Dec 23.

Department of Ophthalmology, Fondation Asile des Aveugles, Jules Gonin Eye Hospital, University of Lausanne, Lausanne, Switzerland.

We report a case of central retinal artery occlusion (CRAO) in a patient with a previous history of severe COVID-19 disease. This disease has been associated with inflammatory-induced homeostasis changes leading to endothelial dysfunction and a procoagulant state with multi-organ involvement, but the burden of thromboembolic complications in COVID-19 patients is currently unknown. The pathogenesis of retinal artery occlusions is a multifactorial process where inflammation and hypercoagulation state are established risk factors. Even if our experience may represent a coincidental relationship, it is likely that COVID-19 patients could be at risk of developing retinal vascular occlusions. A focused ophthalmological surveillance is advisable to prevent and manage this possible cause of severe vision loss that has an important impact in health care system.
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http://dx.doi.org/10.3389/fphar.2020.588384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785811PMC
December 2020

Eighteen-months results of intravitreal anti-vascular endothelial growth factor on vision and microcirculation in radiation maculopathy.

Retina 2021 Jan 4. Epub 2021 Jan 4.

Department of Ophthalmology, University of Lausanne, Jules-Gonin Eye Hospital, Fondation Asile des Aveugles, Lausanne, Switzerland Department of Surgical Science, University of Torino, Torino, Italy.

Purpose: To evaluate 18 months' results of a strict anti-VEGF protocol for radiation maculopathy (RM) following proton therapy in choroidal melanoma.

Methods: Retrospective, comparative, non-randomized study of 74 RM patients presenting macular lipid deposits, hemorrhages, microaneurysms, cystoid edema, nerve layer infarction, telangiectasia or capillary nonperfusion. The study group included 52 consecutive patients injected with intravitreal anti-VEGFs (bevacizumab/ranibizumab: 46/6) every two months for the first and every three months for the second year, with minimum 12 months' follow-up. The control group consisted of 22 patients having declined this treatment. BCVA, SD-OCT and OCTA were recorded at baseline, 6, 12 and 18 months. The foveal avascular zone (FAZ) and capillary density (CD) were measured at the superficial capillary plexus.

Results: RM was diagnosed at 2 years [1.5-3.5] after proton therapy. BCVA at baseline, 12 and 18 months improved in the study group from 0.45, 0.3 to 0.2 LogMar, but decreased in the control group from 0.5, 0.9 to 1.0 LogMar respectively (p<0.001 at 12 months). Simultaneously, FAZ enlargement was less in the study (from 0.377, 0.665 to 0.744 mm2) than control group (from 0.436, 1.463 to 2.638 mm2) (p=0.05 at 12 months). CMT (280 and 276 µm) and CD (37 and 38%, at baseline, respectively) did not evolve significantly different.

Conclusion: Intravitreal anti-VEGFs, every two months for the first and every three months for the second year, slow down, over up to 18 months, vision loss and anatomical degradation in RM following proton therapy for choroidal melanoma.
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http://dx.doi.org/10.1097/IAE.0000000000003105DOI Listing
January 2021

Treat and extend versus fixed regimen in neovascular age related macular degeneration: A systematic review and meta-analysis.

Eur J Ophthalmol 2020 Oct 29:1120672120964699. Epub 2020 Oct 29.

Department of Surgical Science, Eye Clinic, University of Torino, Torino, Piemonte, Italy.

Purpose: To compare efficacy of treat and extend (T&E) versus fixed regimen treatment protocols in neovascular age-related macular degeneration (nAMD).

Methods: Randomized clinical trials (RCTs) comparing T&E versus fixed regimen protocols for nAMD were systematically searched. Primary outcome was to compare the mean best corrected visual acuity (BCVA) change in T&E regimen versus fixed regimen. Secondary outcomes were change in the mean optical coherence tomography (OCT) central retinal thickness (CRT) and mean number of injections. Standardized mean difference (SMD) along with 95% confidence intervals (CIs) were calculated. Random-effect models were used for meta-analyses.

Results: Four RCTs were included, with a total of 649 and 621 eyes in the T&E and fixed regimen cohort at 12 months, and 267 and 249 eyes at 24 months. Pooled analysis of mean BCVA change included all four RCTs at 12 months and two RCTs at 24 months, showing no difference between the two groups (12-month: SMD = 0.08, 95% CI: -0.20 to 0.35,  = 0.55; 24-month: SMD = 0.04, 95% CI: -0.13 to 0.21,  = 0.64). Pooled analysis of OCT CRT change at 12 months included three studies, showing no difference between the two groups (SMD = 0.03, 95% CI: -0.46 to 0.51,  = 0.91). Pooled analysis of mean injection number included all four RCTs at 12 months and two RCTs at 24 months, showing significant difference between the two groups (12-month: SMD = -1.11, 95% CI: -1.67 to -0.56,  < 0.001; 24-month: SMD = -1.34, 95% CI: -1.54 to -1.15,  < 0.001).

Conclusion: A T&E regimen proved as effective as a fixed dosage regimen throughout a 24-month follow-up and with a lower number of injections.
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http://dx.doi.org/10.1177/1120672120964699DOI Listing
October 2020

MicroRNA Expression in the Aqueous Humor of Patients with Diabetic Macular Edema.

Int J Mol Sci 2020 Oct 3;21(19). Epub 2020 Oct 3.

Ophthalmology Unit of the Department of Medicine, Surgery and Neuroscience, University of Siena, 53100 Siena, Italy.

We identified and compared secreted microRNA (miRNA) expression in aqueous humor (AH) and plasma samples among patients with: type 2 diabetes mellitus (T2D) complicated by non-proliferative diabetic retinopathy (DR) associated with diabetic macular edema (DME) (DME group: 12 patients); T2D patients without DR (D group: 8 patients); and non-diabetic patients (CTR group: 10 patients). Individual patient AH samples from five subjects in each group were profiled on TaqMan Low Density MicroRNA Array Cards. Differentially expressed miRNAs identified from profiling were then validated in single assay for all subjects. The miRNAs validated in AH were then evaluated in single assay in plasma. Gene Ontology (GO) analysis was conducted. From AH profiling, 119 mature miRNAs were detected: 86 in the DME group, 113 in the D group and 107 in the CTR group. miRNA underexpression in the DME group was confirmed in single assay for let-7c-5p, miR-200b-3p, miR-199a-3p and miR-365-3p. Of these four, miR-199a-3p and miR-365-3p were downregulated also in the plasma of the DME group. GO highlighted 54 validated target genes of miR-199a-3p, miR-200b-3p and miR-365-3p potentially implied in DME pathogenesis. Although more studies are needed, miR-200b-3p, let-7c-5p, miR-365-3p and miR-199a-3p represent interesting molecules in the study of DME pathogenesis.
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http://dx.doi.org/10.3390/ijms21197328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582592PMC
October 2020

Choroidal Structure after Half-Dose Photodynamic Therapy in Chronic Central Serous Chorioretinopathy.

J Clin Med 2020 Aug 24;9(9). Epub 2020 Aug 24.

Department of Surgical Science, University of Torino, 10126 Torino, Italy.

The study aims to analyze the changes produced by half-dose photodynamic therapy (HD-PDT) in the choroid of eyes with chronic central serous chorioretinopathy (CSC) applying the binarization method to spectral domain optical coherence tomography (SDOCT) and OCT Angiography (OCTA) images. SDOCT and OCTA were performed before, one hour, one week, and one month after HD-PDT. Binarization with a modified Niblack method and analysis by ImageJ were applied. An average ratio between luminal part and total structure was calculated. Twenty-two eyes of 21 patients (20 male and 1 female; mean age 54.8 years) were enrolled. A statistically significant reduction of the central choroidal thickness was observed one week (from 407 µm to 362 µm, = 0.034) and one month (from 407 µm to 341.5 µm, = 0.0004) after HD-PDT. The baseline average ratio between luminal part and total structure was 33.4% in SDOCT, and 61.1% in OCTA. These values were 35.3% and 61% one hour, 33.9% and 60.4% one week, and 34.5% and 60.6% one month after HD-PDT, respectively. Overall, PDT seems to produce short-term changes on the luminal component of both choriocapillaris and choroid, which return to baseline status after one month from treatment. However, choroid stays significantly thinner after one month, with both luminal and interstitial components significantly reduced.
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http://dx.doi.org/10.3390/jcm9092734DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563121PMC
August 2020

The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination.

Immunity 2020 08;53(2):429-441.e8

Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, F-75012 Paris, France. Electronic address:

A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility. We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD. HTRA1 induced the persistence of monocytes in the subretinal space and exacerbated pathogenic inflammation by hydrolyzing thrombospondin 1 (TSP1), which separated the two CD47-binding sites within TSP1 that are necessary for efficient CD47 activation. This HTRA1-induced inhibition of CD47 signaling induced the expression of pro-inflammatory osteopontin (OPN). OPN expression increased in early monocyte-derived macrophages in 10q26 risk carriers. In models of subretinal inflammation and AMD, OPN deletion or pharmacological inhibition reversed HTRA1-induced pathogenic MP persistence. Our findings argue for the therapeutic potential of CD47 agonists and OPN inhibitors for the treatment of AMD.
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http://dx.doi.org/10.1016/j.immuni.2020.07.021DOI Listing
August 2020

Intravitreal dexamethasone implant one month before versus concomitant with cataract surgery in patients with diabetic macular oedema: the dexcat study.

Acta Ophthalmol 2021 Feb 26;99(1):e74-e80. Epub 2020 Jun 26.

Department of Ophthalmology, University of Catania, Catania, Italy.

Purpose: To report clinical outcomes of two different timings of intravitreal dexamethasone (DEX) implant administration for prevention of diabetic macular oedema (DME) worsening following cataract surgery.

Methods: This multicentre, retrospective study included patients with DME who received an intravitreal DEX implant 1 month before cataract surgery, 'precataract DEX' group, or at the time of cataract surgery, 'concomitant treatments' group. Inclusion criteria were a follow-up ≥3 months and ophthalmological examination with optical coherence tomography (OCT) imaging at baseline (cataract surgery) and throughout follow-up. Anatomical improvement was considered to be a decrease in OCT central subfield (CSF) thickness ≥20% compared to baseline. The primary outcomes were anatomical and functional results at 3 months.

Results: Two hundred twenty-one patients were included: 136 in the 'precataract DEX' group and 85 in the 'concomitant treatments' group. At 3 months, a reduction of CSF thickness ≥ 20% was found in 7.3% of eyes in the 'precataract DEX group' and in 83.7% of eyes in the 'concomitant treatments' group (p < 0.001), with mean CSF thickness lower in the latter group (371 ± 52 µm versus 325 ± 57 µm, p < 0.001). At 3 months, mean best-corrected visual acuity had improved from baseline in both groups (p < 0.001), with no difference between groups (p = 0. 20). No serious systemic adverse events were reported.

Conclusion: Both approaches prevented a worsening of DME, showing a comparable visual outcome. Dexamethasone (DEX) implant given at the same time as cataract surgery provided a better anatomical outcome.
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http://dx.doi.org/10.1111/aos.14516DOI Listing
February 2021

New Brilliant Blue G Derivative as Pharmacological Tool in Retinal Surgery.

Front Pharmacol 2020 25;11:708. Epub 2020 May 25.

Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy.

Our study was aimed at assessing the retinal binding of a new synthetic Brilliant Blue G (BBG) derivative (pure benzyl-Brilliant Blue G; PBB) ophthalmic formulation, to improve vitreoretinal surgery procedure. Protein affinity of the new molecule was evaluated (cell-free assay) and . Furthermore, an model of vitreoretinal surgery was developed by using porcine eyes to assess the pharmacological profile of PBB, compared to commercial formulations based on BBG and methyl-BBG (Me-BBG). PBB showed a higher affinity for proteins (p < 0.05), compared to BBG and Me-BBG. and studies demonstrated that the high selectivity of PBB could be related to high lipophilicity and binding affinity to fibronectin, the main component of the retinal internal limiting membrane (ILM). The PBB staining capabilities were evaluated in porcine eyes in comparison with BBG and Me-BBG. Forty microliters of each formulation were slowly placed over the retinal surface and removed after 30 s. After that, ILM peeling was carried out, and the retina collected. BBG, Me-BBG, and PBB quantification in ILM and retina tissues was carried out by HPLC analysis. PBB levels in the ILM were significantly (p < 0.05) higher compared to BBG and Me-BBG formulations. On the contrary, PBB showed a much lower (p < 0.05) distribution in retina (52 ng/mg tissue) compared to BBG and Me-BBG, in particular PBB levels were significantly (p < 0.05) lower. Therefore, the new synthetic Brilliant Blue derivative (PBB) showed a great ILM selectivity in comparison to underneath retinal layers. In conclusion, these findings had high translational impact with a tangible improving in model of retinal surgery, suggesting a future use during surgical practice.
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http://dx.doi.org/10.3389/fphar.2020.00708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7261835PMC
May 2020

Baseline SD-OCT characteristics of diabetic macular oedema patterns can predict morphological features and timing of recurrence in patients treated with dexamethasone intravitreal implants.

Acta Diabetol 2020 Jul 29;57(7):867-874. Epub 2020 Feb 29.

IRCCS - Fondazione Bietti, Rome, Italy.

Aims: To evaluate the timing and spectral-domain optical coherence tomography (SD-OCT) features of diabetic macular oedema (DME) recurrence according to baseline OCT patterns in patients treated with dexamethasone implant (DEX-I).

Methods: This is a retrospective observational study (72 eyes/65 patients). Best-corrected visual acuity, timing of DME recurrence, and SD-OCT pattern [intraretinal cysts (IRC), IRC plus subretinal fluid (mixed), external limiting membrane (ELM), ellipsoid (IS/OS) layer integrity] were assessed at baseline and monthly until first DME recurrence.

Results: Forty-two (58.3%) and 30 (41.6%) DME eyes had an IRC and mixed DME pattern at baseline, respectively. Twenty-four out of thirty mixed eyes (80%) relapsed without subretinal fluid. At baseline, mixed eyes showed similar changes in ELM and IS/OS (60 and 76.6% of eyes, respectively) versus IRC eyes (42.8 and 80.9% of eyes). After DME recurrence, more mixed eyes at baseline showed ELM and IS/OS changes (63.3 and 86.6%) than IRC eyes (50 and 76.2%). 33.3% of mixed eyes had DME recurrence at ≥ 6 months from first DEX-I implant versus 19% of IRC eyes.

Conclusions: Mixed DME eyes were treated with DEX-I relapse later and more frequently without subretinal fluid than IRC eyes. SD-OCT characteristics of different DME patterns at baseline can predict morphological features and timing of DME recurrence.
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http://dx.doi.org/10.1007/s00592-020-01504-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7311372PMC
July 2020

Hypertensive choroidopathy in atypical hemolytic-uremic syndrome.

Eur J Ophthalmol 2021 Mar 25;31(2):NP63-NP66. Epub 2019 Dec 25.

Department of Surgical Sciences, Eye Clinic, University of Torino, Torino, Italy.

Purpose: We present the case of a 22-year-old woman, diagnosed as having atypical hemolytic uremic syndrome with a hypertensive crisis, who presented a bilateral serous retinal detachment.

Case Description: A 22-year-old woman, diagnosed as having atypical hemolytic uremic syndrome, was referred for blurred vision in both eyes, evolving over 7 days. Treatment including hemodialysis, plasma exchange, systemic steroids, antihypertensive medications and eculizumab was started 1 month prior to referral. At presentation, best-corrected visual acuity was 20/40 in the right eye and 20/25 in the left eye. Retinal examination revealed bilateral serous retinal detachment in the posterior pole and some small, flat, variably pigmented lesions. Optical coherence tomography confirmed marked serous retinal detachment in both eyes. Fluorescein and indocyanine green angiography was performed. Treatment for systemic hypertension was changed. Seven days later, dilated fundus examination and optical coherence tomography demonstrated a significant regression of the serous retinal detachment. Her visual acuity improves in both eyes at the last control, showing at fundus examination a complete resolution of the exudative detachment but a persistence of variable flat pigmented lesion.

Conclusion: Although multiple organ systems are commonly affected in hemolytic uremic syndrome, ocular involvement has only been described in very few cases. Ocular manifestations in atypical hemolytic uremic syndrome include retinal, choroidal and vitreal hemorrhages, retina and/or ischemic signs. Bilateral serous retinal detachment may also be a sign of atypical hemolytic uremic syndrome or even the first manifestation of a hypertensive event.
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http://dx.doi.org/10.1177/1120672119896286DOI Listing
March 2021

Chronic Neovascular Central Serous Chorioretinopathy: A Stress/Rest Optical Coherence Tomography Angiography Study.

Am J Ophthalmol 2020 03 9;211:63-75. Epub 2019 Nov 9.

Fondazione per la Macula Onlus, Dipartimento di Neuroscienze Riabilitazione, Oftalmologia, Genetica e Scienze Materno-Infantili (DINOGMI), University Eye Clinic, Genova, Italy. Electronic address:

Purpose: To compare optical coherence tomography-angiography (OCT-A) performed during physical exercise (stress OCT-A) to the basal examination (rest OCT-A) in the imaging of choroidal neovascularization (CNV) in patients with chronic central serous chorioretinopathy (CSCR).

Design: Prospective, cohort study.

Methods: This multicenter study included 29 consecutive patients with chronic CSCR and flat irregular pigment epithelium detachments (FIPEDs). All patients underwent rest and stress OCT-A (i.e., hand-grip test [HGT]). Systemic hemodynamic data were recorded during the examinations. Rest and stress OCT-A in the en-face and cross-sectional views were qualitatively compared to establish the degree of evidence of flow signals due to CNVs. The en-face angiograms underwent additional automated quantitative analysis to assess the rate of change in neovascular parameters during the stress condition.

Results: Blood pressure significantly increased during the HGT (P = 0.001). Considering both the en-face and the cross-sectional images, CNV was identified in 13 eyes with the rest OCT-A and in 22 eyes with the stress OCT-A (P = 0.001). Cross-sectional imaging was more sensitive than en-face imaging in detecting neovascular blood flow signals under both rest (P = 0.125) and stress (P = 0.001) conditions. The quantitative analysis showed a significantly greater neovascular area and fractal dimension on the stress OCT-A (P = 0.002).

Conclusions: Performing OCT-A during HGT enhances the sensitivity of the examination in detecting CNV in chronic CSCR. The increased neovascular perfusion following the induced increase of blood pressure is consistent with choroidal blood flow dysregulation in patients with CSCR and indicates new areas of discussion about CNV in this disease.
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http://dx.doi.org/10.1016/j.ajo.2019.10.033DOI Listing
March 2020

Aflibercept regulates retinal inflammation elicited by high glucose via the PlGF/ERK pathway.

Biochem Pharmacol 2019 10 25;168:341-351. Epub 2019 Jul 25.

Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy; Center for Research in Ocular Pharmacology-CERFO, University of Catania, Catania, Italy. Electronic address:

Diabetic retinopathy (DR) is a secondary complication of diabetes. DR can cause irreversible blindness, and its pathogenesis is considered multifactorial. DR can progress from non-proliferative DR to proliferative DR, characterized by retinal neovascularization. The main cause of vision loss in diabetic patients is diabetic macular edema, caused by vessel leakage and blood retinal barrier breakdown. Currently, aflibercept is an anti-VEGF approved for diabetic macular edema. Aflibercept can bind several members of vascular permeability factors, namely VEGF-A, B, and PlGF. We analyzed the aflibercept-PlGF complex at molecular level, through an in silico approach. In order to explore the role of PlGF in DR, we treated primary human retinal endothelial cells (HRECs) and mouse retinal epithelial cells (RPEs) with aflibercept and an anti-PlGF antibody. We explored the hypothesis that aflibercept has anti-inflammatory action through blocking of PlGF signaling and the ERK axis in an in vitro and in vivo model of DR. Both aflibercept and the anti-PlGF antibody exerted protective effects on retinal cells, by inhibition of the ERK pathway. Moreover, aflibercept significantly decreased (p < 0.05) the expression of TNF-α in an in vitro and in vivo model of DR. Therefore, our data suggest that inhibition of PlGF signaling, or a selective blocking, may be useful in the management of early phases of DR when the inflammatory process is largely involved.
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http://dx.doi.org/10.1016/j.bcp.2019.07.021DOI Listing
October 2019

[Highlights in the field of ophthalmology].

Rev Med Suisse 2019 Feb;15(637):355-357

Hôpital ophtalmique Jules-Gonin, Université de Lausanne, Fondation Asile des Aveugles, Avenue de France 15, 1000 Lausanne 7.

Technological advances in ophthalmology are becoming more and more important. New imaging instruments and software analysis allow ultra-wide field visualization of the retina non-invasively. This creates important clinical advantages for an aging population affected by chronic pathologies such as cataract, age related macular degeneration, and diabetic retinopathy. In particular, it will be possible to organize screening programs and an individualized approach and follow up of the patients. While new retinal implants are under development a new drug is now available for the treatment of corneal scars.
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February 2019

OLIMPIC: a 12-month study on the criteria driving retreatment with ranibizumab in patients with visual impairment due to myopic choroidal neovascularization.

Graefes Arch Clin Exp Ophthalmol 2019 Apr 24;257(4):759-768. Epub 2019 Jan 24.

Novartis Farma SpA, Largo Umberto Boccioni 1, 21040, Origgio, VA, Italy.

Purpose: To evaluate criteria driving retreatment with ranibizumab in Italian patients with myopic choroidal neovascularization (mCNV).

Methods: OLIMPIC was a 12-month, phase IIIb, open-label study. Patients with active mCNV were treated with ranibizumab 0.5 mg according to the European label. The study assessed local criteria in Italy driving retreatment decisions with ranibizumab; and the efficacy, safety, and tolerability of ranibizumab.

Results: The mean (standard deviation [SD]) age of treated patients (N = 200) was 61.8 (12.7) years; range 22-85 years. The multivariate regression model indicated that presence of active leakage (odds ratio [OR] 95% confidence interval [CI]: 11.30 [1.03-124.14]), presence of intraretinal fluid (OR [95%CI]: 28.21 [1.55-513.73]), and an improvement in best-corrected visual acuity (BCVA) from baseline < 10 letters (OR [95%CI]: 17.60 [1.39-222.75]) were the factors with the greatest effect on retreatment with ranibizumab. The mean (SD) BCVA gain from baseline to month 12 was 8.4 (12.8) letters (P < 0.0001). The mean (SD) number of injections was 2.41 (1.53); range 1-9. Ocular and non-ocular adverse events were reported in 41 (20.5%) and 30 (15.0%) patients, respectively.

Conclusions: Individualized treatment with ranibizumab was effective in improving BCVA in patients with mCNV over 12 months. Both anatomical and functional variables had significant effects on causing retreatment. There were no new safety findings.

Trial Registration: www.ClinicalTrials.Gov (NCT No: NCT02034006).
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http://dx.doi.org/10.1007/s00417-019-04248-8DOI Listing
April 2019

Clinical Course of Autosomal Recessive Bestrophinopathy Complicated by Choroidal Neovascularization.

Ophthalmic Surg Lasers Imaging Retina 2018 11;49(11):888-892

The authors report the clinical course of two cases of autosomal recessive bestrophinopathy (ARB) complicated by choroidal neovascularization (CNV). One patient presenting with a novel BEST1 mutation (c.658 C>T, p.Gln220*) underwent anti-vascular endothelial growth factor therapy. Response to treatment was documented on optical coherence tomography angiography (OCTA). Despite initial response to treatment, recurrent CNV exudation with progressive subretinal fibrosis was observed. In the second patient, the CNV was not treated and spontaneous regression was observed. This report indicates that the clinical course of CNV in ARB may vary considerably, ranging from spontaneous regression to progressive subretinal fibrosis despite intervention. [Ophthalmic Surg Lasers Imaging Retina. 2018;49:888-892.].
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http://dx.doi.org/10.3928/23258160-20181101-10DOI Listing
November 2018

Retinal Vascular Reactivity in Central Serous Chorioretinopathy.

Invest Ophthalmol Vis Sci 2018 09;59(11):4425-4433

Fondazione per la Macula Onlus, Di.N.O.G.Mi., University Eye Clinic, Genova, Italy.

Purpose: To investigate the retinal vascular response to the isometric exercise in patients with central serous chorioretinopathy (CSCR) by using optical coherence tomography angiography (OCT-A).

Methods: This was a multicenter case-control study including 35 CSCR patients and 25 age-matched healthy controls. All subjects underwent macular OCT-A scans in resting conditions and during a handgrip isometric exercise. Hemodynamic data, such as systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and ocular perfusion pressure (OPP), were recorded at baseline and during the stress test. Qualitative and quantitative assessments of the retinal superficial capillary plexus (SCP) and deep capillary plexus (DCP) were performed on OCT angiograms. The results obtained in CSCR patients were then compared with those of healthy subjects.

Results: At baseline and during the isometric exercise, SBP, DBP, MAP, and OPP were significantly higher (P < 0.05) in CSCR patients than controls. Under stress conditions, the hemodynamic values significantly increased both in patients and controls. The qualitative and quantitative analyses of OCT angiograms evidenced an increased blood flow during exercise only in CSCR patients. Baseline vascular perfusion density (VPD) values of SCP and DCP were significantly lower (P < 0.05) in CSCR cases than in healthy subjects. A significant increase (P < 0.05) of VPD values was obtained during the exercise in CSCR patients and not in controls.

Conclusions: Unlike healthy subjects, retinal blood flow in patients with CSCR seems affected by rapid increases in BP and OPP. Our study suggests that the autoregulatory mechanisms controlling retinal microcirculation are not entirely able to counteract overperfusion in patients with CSCR.
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http://dx.doi.org/10.1167/iovs.18-24475DOI Listing
September 2018

Choroidal Vascular Reactivity in Central Serous Chorioretinopathy.

Invest Ophthalmol Vis Sci 2018 08;59(10):3897-3905

Fondazione per la Macula Onlus, Di.N.O.G.Mi, University Eye Clinic, Università di Genova, Genova, Italy.

Purpose: To investigate by optical coherence tomography angiography (OCT-A) the choroidal vascular response to experimentally increased blood pressure in patients with central serous chorioretinopathy (CSCR).

Methods: For this multicenter, observational, case-control study, we enrolled 35 patients with an established diagnose of CSCR and 25 age-matched healthy controls. All subjects underwent a handgrip isometric exercise to obtain elevation of blood pressure (BP). In the resting phase and during the physical effort, macular OCT-angiograms were acquired. Systemic hemodynamic data were recorded at baseline and during stress conditions using an electronic sphygmomanometer. The analysis of vascular density (VD) of the choriocapillaris (CC) was performed on OCT-angiograms. The results obtained in CSCR patients, both at baseline and during the stress test, were compared with those of healthy subjects.

Results: Baseline and under stress values of systolic BP, diastolic BP, and mean arterial pressure were significantly higher (P < 0.05) in CSCR patients compared to controls, reaching values in the range of hypertension during the exercise. Baseline VD values of the CC were significantly lower (P < 0.05) in CSCR cases compared to healthy subjects. We noticed a significant increase (P < 0.05) in these values under stress condition in CSCR patients and not in controls.

Conclusions: The present study suggests that choroidal blood flow is dysregulated in CSCR. During physical stress, CSCR patients easily reach critical values of BP that are not dampened by compensatory mechanisms in the choroidal vessels, as it happens in healthy subjects. The CC in CSCR could be particularly vulnerable to variations of systemic hemodynamics.
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http://dx.doi.org/10.1167/iovs.18-23995DOI Listing
August 2018

Expanding the Mutation Spectrum in : Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort.

Int J Mol Sci 2018 Jul 27;19(8). Epub 2018 Jul 27.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France.

Here we report novel mutations in with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment ( = 0.002) and an earlier age of onset ( = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of underlying Stargardt disease.
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http://dx.doi.org/10.3390/ijms19082196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121640PMC
July 2018

Publisher Correction: TGF-β concentrations and activity are down-regulated in the aqueous humor of patients with neovascular age-related macular degeneration.

Sci Rep 2018 Jun 29;8(1):10141. Epub 2018 Jun 29.

University of Siena, Department of Biotechnology, Chemistry and Pharmacy, Siena, 53100, Italy.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-28203-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6023889PMC
June 2018

TGF-β concentrations and activity are down-regulated in the aqueous humor of patients with neovascular age-related macular degeneration.

Sci Rep 2018 05 23;8(1):8053. Epub 2018 May 23.

University of Siena, Department of Biotechnology, Chemistry and Pharmacy, Siena, 53100, Italy.

Controversy still exists regarding the role of the TGF-β in neovascular age-related macular degeneration (nAMD), a major cause of severe visual loss in the elderly in developed countries. Here, we measured the concentrations of active TGF-β1, TGF-β2, and TGF-β3 by ELISA in the aqueous humor of 20 patients affected by nAMD, who received 3 consecutive monthly intravitreal injections of anti-VEGF-A antibody. Samples were collected at baseline (before the first injection), month 1 (before the second injection), and month 2 (before the third injection). The same samples were used in a luciferase-based reporter assay to test the TGF-β pathway activation. Active TGF-β1 concentrations in the aqueous humor were below the minimum detectable dose. Active TGF-β2 concentrations were significantly lower at baseline and at month 1, compared to controls. No significant differences in active TGF-β3 concentration were found among the sample groups. Moreover, TGF-β pathway activation was significantly lower at baseline compared to controls. Our data corroborate an anti-angiogenic role for TGF-β2 in nAMD. This should be considered from the perspective of a therapy using TGF-β inhibitors.
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http://dx.doi.org/10.1038/s41598-018-26442-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5966430PMC
May 2018

Uncovering genetic and non-genetic biomarkers specific for exudative age-related macular degeneration: significant association of twelve variants.

Oncotarget 2018 Jan 12;9(8):7812-7821. Epub 2017 Dec 12.

Molecular Genetics Laboratory UILDM, Santa Lucia Foundation, Rome, Italy.

Age-related Macular Degeneration (AMD) represents one of the most sight-threatening diseases in developed countries that substantially impacts the patients' lifestyle by compromising everyday activities, such as reading and driving. In this context, understanding the prevalence, burden, and population-specific risk/protective factors of AMD is essential for adequate health care planning and provision. Our work aimed to characterize exudative AMD in Italian population and to identify the susceptibility/protective factors (genetic variants, age, sex, smoking and dietary habits) which are specific for the onset of disease. Our study involved a cohort of 1976 subjects, including 976 patients affected with exudative AMD and 1000 control subjects. In particular, the sample cohort has been subjected to a large genotyping analysis of 20 genetic variants which are known to be associated with AMD among European and Asiatic populations. This analysis revealed that 8 genetic variants ( and ) were significantly associated with AMD susceptibility. Successively, we performed a multivariate analysis, considering both genetic and non-genetic data available for our sample cohort. The multivariate analysis showed that age, smoking, dietary habits and sex, together with the genetic variants, were significantly associated with AMD in our population. Altogether, these data represent a starting point for the set-up of adequate preventive and personalized strategies aimed to decrease the burden of disease and improve the patients' quality of life.
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http://dx.doi.org/10.18632/oncotarget.23241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814260PMC
January 2018

Short-Term Choriocapillaris Changes in Patients with Central Serous Chorioretinopathy after Half-Dose Photodynamic Therapy.

Int J Mol Sci 2017 Nov 20;18(11). Epub 2017 Nov 20.

Department of Surgical Science, University of Torino, 10126 Torino, Italy.

Background: Although photodynamic therapy (PDT) has become the standard treatment for central serous chorioretinopathy (CSC), its mechanism of action remains unclear. It is assumed that PDT induces short-term choriocapillaris (CC) occlusion and long-term choroidal vascular remodeling. In this paper, we describe the short-term CC changes induced by Half-Dose PDT (HD-PDT) in chronic CSC using optical coherence tomography-angiography (OCTA).

Methods: This is a prospective interventional case series. Chronic CSC eyes underwent Spectral-Domain OCT, Fundus Autofluorescence, FA, ICGA (Heidelberg Spectralis, Heidelberg, Germany) and OCTA (RTVue XR Avanti with AngioVue; Optovue Inc., Fremont, CA, USA) before HD-PDT, with follow-up after one hour, one week, and one month. Vascular changes after PDT were analyzed within the CC layer. The CC vessel density was defined as the percentage of an area occupied by flow pixels, using Image J software to obtain measurements by applying a grey level threshold. All pixels with a grey level above the threshold were considered as indicators of blood flow.

Results: 20 eyes of 19 patients were included. At baseline the mean CC vessel density was 94.87 ± 2.32%. It significantly differed from the density at 1 week and 1 month (92.79 ± 3.16% and 95.55 ± 2.05%, < 0.001, respectively), but not with values at 1 h (94.8 ± 2.28%, = 0.516).

Conclusions: CC vessel density was significantly reduced at 1 week as compared with baseline, suggesting a possible short-term effect of PDT on CC perfusion. After 1 month however, the CC vessel density was even higher than the baseline, probably due to a CC recovery. OCTA seems to be useful in the visualization of CC vessels and in confirming the mechanism of action of PDT treatment in eyes with chronic CSC.
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http://dx.doi.org/10.3390/ijms18112468DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713434PMC
November 2017

Targeted next generation sequencing in Italian patients with Usher syndrome: phenotype-genotype correlations.

Sci Rep 2017 11 15;7(1):15681. Epub 2017 Nov 15.

Inherited retinal dystrophies Unit, Azienda Ospedaliera Ordine Mauriziano Torino, Torino, 10128, Italy.

We report results of DNA analysis with next generation sequencing (NGS) of 21 consecutive Italian patients from 17 unrelated families with clinical diagnosis of Usher syndrome (4 USH1 and 17 USH2) searching for mutations in 11 genes: MYO7A, CDH23, PCDH15, USH1C, USH1G, USH2A, ADGVR1, DFNB31, CLRN1, PDZD7, HARS. Likely causative mutations were found in all patients: 25 pathogenic variants, 18 previously reported and 7 novel, were identified in three genes (USH2A, MYO7A, ADGRV1). All USH1 presented biallelic MYO7A mutations, one USH2 exhibited ADGRV1 mutations, whereas 16 USH2 displayed USH2A mutations. USH1 patients experienced hearing problems very early in life, followed by visual impairment at 1, 4 and 6 years. Visual symptoms were noticed at age 20 in a patient with homozygous novel MYO7A missense mutation c.849G > A. USH2 patients' auditory symptoms, instead, arose between 11 months and 14 years, while visual impairment occurred later on. A homozygous c.5933_5940del;5950_5960dup in USH2A was detected in one patient with early deafness. One patient with homozygous deletion from exon 23 to 32 in USH2A suffered early visual symptoms. Therefore, the type of mutation in USH2A and MYO7A genes seems to affect the age at which both auditory and visual impairment occur in patients with USH.
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http://dx.doi.org/10.1038/s41598-017-16014-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5688149PMC
November 2017

Vitreous Substitutes: Old and New Materials in Vitreoretinal Surgery.

J Ophthalmol 2017 13;2017:3172138. Epub 2017 Jul 13.

Department of Surgical Sciences, Eye Clinic, University of Turin, Turin, Italy.

Recent developments in vitreoretinal surgery have increased the need for suitable vitreous substitutes. A successful substitute should maintain all the physical and biochemical properties of the original vitreous, be easy to manipulate, and be long lasting. Substitutes can be gaseous or liquid, both of which have associated advantages and disadvantages related to their physical properties and use. Furthermore, new surgical techniques with smaller vitreoretinal instruments have driven the use of more viscous substitutes. In this review, we analyze and discuss the most frequently used vitreous substitutes and look ahead to future alternatives. We classify these compounds based on their composition and structure, discuss their clinical use with respect to their associated advantages and disadvantages, and analyze how new vitreoretinal surgical techniques have modified their use.
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http://dx.doi.org/10.1155/2017/3172138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5530429PMC
July 2017

Indocyanine Green Angiography and Optical Coherence Tomography Angiography of Choroidal Neovascularization in Age-Related Macular Degeneration.

Invest Ophthalmol Vis Sci 2017 07;58(9):3690-3696

Department of Surgery and Experimental Medicine, University Tor Vergata, Rome, Italy.

Purpose: To compare the capability of indocyanine green angiography (ICGA) and optical coherence tomography angiography (OCTA) in detecting choroidal neovascularization (CNV).

Methods: In this prospective study, patients with CNV detected with fluorescein angiography (FA) underwent ICGA and OCTA, spectral domain OCT (SD-OCT), and infrared or fundus color photographs. CNV lesions were outlined on ICGA and OCTA images, and the composition and size of the CNV was documented.

Results: One hundred eighty-two eyes were included. With ICGA, well-defined lesions were observed in 37.9%, partly defined in 44.5%, and undefined in 17% of eyes. On OCTA, well-defined, partly defined, and undefined vessels were observed in 53.8%, 27.5%, and 18.7% of eyes, respectively. There was a good correlation between CNV size measured with the two instruments (r = 0.84). However, OCTA underestimated CNV area by about 4.5% (slope coefficient with linear regression: 0.55, 95% confidence interval [CI]: 0.46 to 0.65; intercept: 0.27, 95% CI: -0.2 to 0.56). On ICGA, CNV composition was capillary in 28%, mature in 14.3%, and mixed (capillary and major neovascular complex) in 57.7% of eyes. Similarly, OCTA revealed capillary, mature, and mixed CNV in 28.9%, 15.9%, and 55.5% of eyes, respectively.

Conclusions: OCTA provides the clinician the ability to perform precise structural and vascular assessment of CNV noninvasively. Our study is, to our knowledge, the largest OCTA analysis to date of CNV secondary to neovascular AMD analyzed simultaneously by ICGA and OCTA.
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http://dx.doi.org/10.1167/iovs.17-21941DOI Listing
July 2017

Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway in human retinal endothelial cells by blocking the effect of AGE/RAGE.

Biochem Pharmacol 2017 10 23;142:145-154. Epub 2017 Jun 23.

Department of Biomedical and Biotechnological Sciences, School of Medicine, Catania, Italy; Center for Research in Ocular Pharmacology - CERFO, University of Catania, Catania, Italy. Electronic address:

Diabetic retinopathy is characterized by the breakdown of endothelial blood-retinal barrier. We tested the hypothesis that sulodexide (SDX), a highly purified glycosaminoglycan composed of 80% iduronylglycosaminoglycan sulfate and 20% dermatan sulfate, protects human retinal endothelial cells (HREC) from high glucose (HG)-induced damage, through the suppression of inflammatory ERK/cPLA2/COX-2/PGE pathway, by blocking the effect of advanced glycation end-products (AGEs). HREC were treated with HG (25mM) or AGEs (glycated-BSA, 2mg/ml) for 48h, with or without SDX (60μg/ml) or aflibercept (AFL, 40μg/ml), a VEGF-trap. SDX protected HREC from HG-induced damage (MTT and LDH release) and preserved their blood-retinal barrier-like properties (Trans Endothelial Electrical Resistance and junction proteins, claudin-5, VE-cadherin and occludin, immunofluorescence and immunoblot) as well as their angiogenic potential (Tube Formation Assay). Both HG and AGEs increased phosphoERK and phospho-cPLA, an effect counteracted by SDX and, less efficiently, by AFL. Both HG and exogenous VEGF (80ng/ml) increased PGE release, an effect partially reverted by SDX for HG and by AFL for VEGF. Analysis of NFκB activity revealed that HG increased the abundance of p65 in the nuclear fraction (nuclear translocation), an effect entirely reverted by SDX, but only partially by AFL. SDX, AFL and SDX+AFL protected HREC even when added 24h after HG. These data show that SDX protects HREC from HG damage and suggest that it counteracts the activation of ERK/cPLA2/COX-2/PGE pathway by reducing AGE-related signaling and downstream NFκB activity. This mechanism, partially distinct from VEGF blockade, may contribute to the therapeutic effect of SDX.
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http://dx.doi.org/10.1016/j.bcp.2017.06.130DOI Listing
October 2017

On phagocytes and macular degeneration.

Prog Retin Eye Res 2017 Nov 7;61:98-128. Epub 2017 Jun 7.

Institut de la Vision, 17 rue Moreau, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 75012, Paris, France. Electronic address:

Age related macular degeneration (AMD) is a complex multifactorial disease caused by the interplay of age and genetic and environmental risk factors. A common feature observed in early and both forms of late AMD is the breakdown of the physiologically immunosuppressive subretinal environment and the protracted accumulation of mononuclear phagocytes (MP). We here discuss the origin and nature of subretinal MPs, the mechanisms that lead to their accumulation, the inflammatory mediators they produce as well as the consequences of their chronic presence on photoreceptors, retinal pigment epithelium and choroid. Recent advances highlight how both genetic and environmental risk factors directly promote subretinal inflammation and tip the balance from a beneficial inflammation that helps control debris accumulation to detrimental chronic inflammation and destructive late AMD. Finally, we discuss how changes in life style or pharmacological intervention can help to break the vicious cycle of inflammation and degeneration, restore the immunosuppressive properties of the subretinal space, and reestablish homeostasis.
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http://dx.doi.org/10.1016/j.preteyeres.2017.06.002DOI Listing
November 2017

Macular Pigment Density and Quantitative Fundus Autofluorescence in Young Healthy Subjects.

Invest Ophthalmol Vis Sci 2017 04;58(4):2284-2290

Department of Surgical Sciences, Eye Clinic, University of Torino, Torino, Italy.

Purpose: To measure macular pigment (MP) and find possible correlation between heterochromatic flicker photometry (HFP) and quantitative autofluorescence (qAF) in young healthy subjects.

Methods: We enrolled 80 eyes of 40 young healthy subjects. Macular pigment optical density (MPOD) was automatically calculated with a macular pigment screener (MPS; MPODHFP). We calculated qAF comparing gray levels (GL) of qAF images with GL of internal reference of a confocal scanning laser ophthalmoscopy. A raster of concentric rings was used to automatically calculate foveal qAF (qAFF) values (0°-1.2°); inner ring (1.3°-4.3°; qAF3); middle ring (4.5°-7°; qAF6); and outer ring (7.2°-9.7°; qAF8). The test-retest coefficient of repeatability was calculated with Bland-Altman method. The between-eyes coefficient of agreement and correlation between the two techniques were calculated. Finally, an estimation of MPOD from qAF was performed (MPOD-AF), to find possible direct correlations with MPODHFP obtained with the MPS II.

Results: Paired data sets of repeated measurements were not statistically different for MPS II (P = 0.66); log qAFF (P = 0.95); log qAF3 (P = 0.48); log qAF6 (P = 0.4); and log qAF8 (P = 0.56). Stepwise regression analysis showed negative correlation between MPS II and log qAFF values (R2 = 0.35) with Spearman coefficient (ρ) of -0.60 (P < 0.01) and log qAF3 (R2 = 0.18; ρ = -0.38.; P < 0.01). No correlation was found between MPS II and log qAF6 (ρ = 0.01, P = 0.93), neither with log qAF8 (ρ = -0.05, P = 0.66).

Conclusions: In young healthy subjects, a negative correlation between qAF values and MPODHFP was found in the central degrees. However, qAF and HFP do not seem to be interchangeable: they represent two opposite ways of estimating MP.
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http://dx.doi.org/10.1167/iovs.16-20510DOI Listing
April 2017