IVI Valencia Clinic

Introduction: Chronic low-grade systemic inflammation constitutes a central biological feature of aging and a key factor in the development of multiple chronic diseases [1,2]. The soluble urokinase Plasminogen Activator Receptor (suPAR) has emerged as a robust biomarker of chronic systemic inflammation and biological vulnerability [3-5]. Nutritional strategies aimed at modulating intracellular redox balance may influence upstream inflammatory pathways involved in the regulation of suPAR [6-9]. Objective: To explore whether supplementation with a cysteine-rich whey protein isolate, a glutathione precursor, is associated with changes in circulating suPAR concentrations and health-related quality of life in adults. Methods: An exploratory, open-label, single-arm, longitudinal pre-post intervention proof-of-concept study. Twelve adult participants received oral supplementation with a cysteine-rich whey protein isolate (Immunocal®) for three months. Circulating suPAR concentrations and health-related quality of life, assessed using the SF-36 questionnaire, were measured at baseline and at the end of the intervention. Results: After three months of supplementation, mean suPAR levels decreased from 3.19 to 1.87 ng/mL (mean Δ = 1.31; p < 0.0001). Mean total SF-36 scores increased from 71.77 to 87.39 (mean Δ = 15.61; p < 0.0001). The intervention was well tolerated and no serious adverse events were reported. Conclusion: Supplementation with glutathione precursors using Immunocal® for a three-month period was associated with a significant reduction in circulating suPAR concentrations, a consolidated biomarker of chronic systemic inflammation and immune activation, as well as with concomitant improvements in health-related quality of life in adults.

Objectives: The objective of this study was to investigate choroidal structural alterations and evaluate the outcomes of switching to faricimab in patients with neovascular age-related macular degeneration (nAMD) previously treated with other anti-vascular endothelial growth factor (anti-VEGF) therapies after 12 months of follow-up. Methods: We performed a retrospective study of 30 eyes from 30 patients with nAMD who were switched to faricimab. The choroidal vascularity index (CVI), best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (CST), and the presence of subretinal fluid, intraretinal fluid, and wet macula were assessed at baseline and after 6 and 12 months. Results: CVI remained stable during follow-up (p > 0.05). BCVA improved significantly after 6 months (p = 0.041), but not at 12 months (p = 0.075). A significant reduction in CMT was observed (p < 0.05). Additionally, wet macula improved after 12 months (p < 0.05). Moreover, treatment intervals increased from 7.53 ± 2.39 to 12.47 ± 4.51 weeks. Conclusions: Switching to faricimab in patients with nAMD previously treated with other anti-VEGF therapies was associated with anatomical improvement, extended treatment intervals, and short-term visual gains, while choroidal vascular structure was maintained. Nonetheless, additional studies are warranted to more comprehensively evaluate the effectiveness of switching to faricimab, as well as the associated changes in choroidal vascular structure.

Abstract: PURPOSE: The purpose of this study was to investigate the association of different cardiometabolic factors with the asymmetry index (AI) of quantitative parameters measured with swept-source-optical coherence tomography angiography (OCTA). MATERIALS AND METHODS: We performed a retrospective study. The study enrolled 200 eyes of 100 patients. Demographic and clinical characteristics were obtained. AI of OCTA quantitative parameters (vessel density [VD] and foveal avascular zone [FAZ] area of superficial capillary plexus [SCP], deep capillary plexus [DCP], total capillary plexus (TCP), and choriocapillaris) in 4.5 mm × 4.5 mm cube were recorded in each patient. RESULTS: Dyslipidemia (DL) was associated with AI of SCP VD ( P = 0.016). Moreover, males and nondiabetic patients had a higher AI of SCP VD ( P = 0.010 and P &lt; 0.001). Regarding to AI of FAZ area, diabetes mellitus (DM) was associated with AI of FAZ area of SCP and DCP ( P &lt; 0.042 and P = 0.022), and smoking status was associated with AI of TCP FAZ area ( P = 0.012). In addition, correlation analysis revealed a weak negative correlation between systolic and diastolic blood pressure (dBP) and AI of TCP VD ( P = 0.032 and 0.026) and between dBP and AI of DCP FAZ area and TCP FAZ area ( P = 0.034 and 0.013). Finally, a weak positive correlation was found between low-density lipoprotein and AI of SCP FAZ area ( P = 0.034). CONCLUSION: In an era without built-in normative data, we demonstrated that cardiometabolic conditions (DM, hypertension, and DL) are associated with interocular asymmetry of SCP perfusion and FAZ area of retinal capillary plexus.

The efficacy and safety of propranolol for retinopathy of prematurity (ROP) remain under debate. This network meta-analysis (NMA) focuses on whether a ranking may be established for different dose levels of propranolol as treatment of ROP in terms of stage progression as the primary outcome, with appearance of plus disease and need for anti-vascular endothelial growth factors (anti-VEGFs) or laser therapy as secondary endpoints. Fourteen studies (10 randomised controlled trials, three single-arm trials and one retrospective observational study) of 474 patients treated with oral or ocular propranolol were retrieved from databases up to April 2024. Meta-insight and model-based NMA were undertaken to evaluate the propranolol dose-response relationship. Studies were evaluated for model fit, risk of bias and Confidence of evidence In Network Meta-Analysis (CINeMA). Effect sizes were determined as odds ratio (OR) with 95% credible interval (CrI). Bayesian analysis showed a trend towards improved effects for propranolol given at late stages (stages 2-3; S23) of ROP progression compared with its administration at earlier stages (stages 0-1; S01). OR values for oral propranolol 1.5 and 2mg/kg/day given at S23 were 0.13 (95% CrI 0.04-0.37) and 0.16 (95% CrI 0.04-0.61), respectively, while given at S01 were 0.28 (95% CrI 0.02-2.96) and 0.78 (95% CrI 0.14-4.43), respectively. Similarly, OR of eye propranolol 0.2% at S23 was 0.37 (95% CrI 0.09-1.00) versus an S01 OR of 0.64 (95% CrI 0.21-2.04). Surface under the cumulative ranking curve (SUCRA) analyses confirmed best probability values for oral propranolol 1.5-2mg/kg followed by eye propranolol 0.2%, all at S23. Model-based NMA showed nonlinearity in the dose-response for oral propranolol with a trend to greater maximal effect for its administration at late versus early stages. For secondary endpoints, lower risk values were found with oral propranolol 1.5mg/kg/day at S23 for progression to plus disease (OR 0.14; 95% CrI 0.02-0.84) and need for anti-VEGFs (OR 0.23; 95% CrI 0.05-0.93) and laser (OR 0.16; 95% CrI 0.02-1.10) therapies also followed by eye propranolol 0.2%, and a similar profile was obtained with SUCRA analysis. Lower doses (0.5-1.0mg/kg/day) of oral propranolol retained efficacy. Threat of adverse events was estimated as risk difference versus control with no difference for eye propranolol 0.2% and oral propranolol 0.5mg/kg/day, modest increases of risk for oral propranolol 1.0 and 1.5mg/kg/day and the highest risk difference for oral propranolol 2.0mg/kg/day (0.06; 95% CI -0.01 to 0.13). A diminished risk of disease progression and need for additional treatment was obtained with propranolol in ROP, but safety is a potential concern. Propranolol eye micro-drops (0.2%) can be as efficacious as oral propranolol. Nonetheless, the evidence is limited due to the paucity and quality of the available studies.

To describe the clinical characteristics, multimodal imaging features, and anatomic basis of a distinctive pattern of deep retinal hemorrhages located in the central fovea, a presentation referred to as "central bouquet hemorrhage." Retrospective, observational, multicenter case series of eyes with central bouquet hemorrhage. Multimodal imaging features were reviewed and analyzed. Ten eyes from 10 patients (4 women and 6 men), with a mean age of 55.6 ± 21.7 years (range 25-84 years) were included. Underlying etiologies were neovascular age-related macular degeneration (40%), lacquer cracks in pathological myopia (30%), macular telangiectasia Type 2 (10%), proliferative diabetic retinopathy (10%), and ocular trauma associated with angioid streaks (10%). On ophthalmoscopy, all eyes with central bouquet hemorrhage displayed a deep retinal hemorrhage with round margins in the central fovea and associated with petaloid hemorrhages radiating in the surrounding Henle fiber layer. Cross-sectional optical coherence tomography showed a well-delineated round hyperreflective lesion involving the central foveal Henle fiber layer/outer nuclear layer in all cases. Accompanying hyperreflective hemorrhages tracking along the obliquely oriented Henle fiber layer were present in all eyes. Resolution occurred in all patients, either spontaneously (30%) or after treatment with intravitreal anti-vascular endothelial growth factor injections (70%), and was associated with partial visual acuity improvement (from 20/113 to 20/36). "Central bouquet hemorrhage" is a novel descriptive term describing a characteristic round pattern of intraretinal blood in the fovea associated with Henle fiber layer hemorrhage and encountered in a spectrum of macular disease.

To describe the clinical characteristics and multimodal imaging (MMI) features of a distinctive subtype of active idiopathic multifocal choroiditis (iMFC) lesions with grey-yellow chorioretinal lesions surrounded by smaller satellite dots, a presentation referred to as "chrysanthemum lesions". Retrospective, observational, multi-center case series of eyes with active iMFC and chrysanthemum lesions. Multimodal imaging features were reviewed and presented. Twenty-five eyes from 20 patients (12 women and 8 men), with a mean age of 35.8±17.0 years (range, 7 - 78 years) were included. Chrysanthemum lesions were equally located in the macula (48.0%) or the mid/far-periphery (52.0%). The number of lesions per eye varied from 1 (16.0%) to more than 20 (56.0%). On optical coherence tomography (OCT), chrysanthemum lesions showed typical features of iMFC, including subretinal hyperreflective material splitting the retinal pigment epithelium/Bruch's membrane (RPE/BrM). Chrysanthemum lesions were hypoautofluorescent on fundus autofluorescence imaging, hyperfluorescent on fluorescein angiography, hypofluorescent on indocyanine green angiography, and associated with choriocapillaris flow signal deficit on OCT-angiography. Active iMFC may present with findings resembling chrysanthemum lesions. The distinctive lesion morphology on ophthalmoscopic examination, the high number of lesions, and the high prevalence of exclusive mid- and far-peripheral involvement may represent a distinctive phenotype of iMFC.

Abstract Study question Do segmental aneuploid (SA) embryos display unique morpho-kinetic patterns at early developmental stages? Summary answer The first three cell division cycles of embryos carrying segmental aneuploidies are significantly slower than euploid and whole-chromosome aneuploid (WCA) embryos. What is known already Segmental aneuploidies in blastocyst-stage human embryos prevalently originate (i.e., 70% of cases) from mitotic errors. Their clinical management is challenging because it is impossible to establish their meiotic/mitotic origin from PGT-A analysis of a single trophectoderm biopsy. Morpho-kinetic analysis based on Time-lapse microscopy (TLM) has been proposed as a valuable tool for systematic embryo evaluation, although it is unclear whether this approach alone can predict chromosomal abnormalities. This study aims to pinpoint morphokinetic patterns associated with the occurrence of segmental aneuploidies and/or mitotic errors, possibly improving DNA-based diagnostic interpretation and their clinical management. Study design, size, duration This is a retrospective multicenter study including a total of 7,693 embryos from 2,370 IVF cycles and 2,127 couples, cultured between 2016 and 2021 in 4 European IVF centers. Embryos with no more than 4 chromosomal alterations were considered in the analysis, resulting in 3,288 euploids, 3,155 WCA, 715 SA, and 535 complex aneuploids (CA). Overall, the dataset contained 3,742 distinct euploid-SA embryo sibling pairs. Participants/materials, setting, methods Standard morpho-kinetic features were annotated using various TLM systems. Blastocysts were subjected to comprehensive chromosomal screening via PGT-A. Morpho-kinetic timings across different embryo groups were compared using Kolmogorov-Smirnov (KS) test and binomial test, and associations with cleavage features were assessed via two-sided Fisher Exact (FS) test. Multi-center and center-specific logistic regression models were calibrated using a subset of data (70%), and their predictive performance was evaluated on independent test data using Area-Under-ROC curve (AUROC) metrics. Main results and the role of chance SA embryos cleaved at significantly slower rate than their euploid siblings in the first 3 cell cycles, from the appearance of the second blastomere t2 (average delay delta=0.49h, KS p = 0.006, fraction of pairs in which SA was delayed compared to euploid sibling F = 54.2%, binomial p = 0.002) up to t8 (delta=2.16h, KS p = 4e-4, F = 57.9%, binomial p = 1e-8). The developmental delay was partially compensated at full blastocyst stage tB (delta=1.71h, KS = 0.0008, F = 57.5%, binomial p = 5e-8). SA timings also differed from WCA ones: SA embryos were significantly slower than their WCA siblings during early cell cycles, with maximum delay reached at t8 (delta=1.67h, KS p = 0.009, F = 55.4%, binomial p = 0.003), but they fully caught-up at tB, with no significant difference observed. These morpho-kinetic patterns were consistently observed in each center separately, but with different effect sizes. The presence of segmental aneuploidies was significantly associated with multinucleation (OR = 1.99, FS test p = 0.05) and morula cell exclusion (OR = 2.69, p = 0.006). A logistic model based on morpho-kinetic data and cleavage features from a single center dataset and regressed against embryo aneuploidy class (euploid vs. SA embryos) displayed adequate predictive performance on independent data from the same center (AUROC=0.70), although predictivity diminished when tested on data from other centers (AUROC=0.52-0.55). Limitations, reasons for caution We cannot rule out inter-center variability in the annotation procedures of morpho-kinetic parameters. Standardized and automated annotation would increase the performance of predictive models and their transferability. Further work is needed to assess whether the morpho-kinetic signal is driven by mitotic errors and if an association with clinical outcomes exists. Wider implications of the findings These findings might help uncovering biological events contributing to preimplantation mosaicism. Moreover, the developed predictive framework might help improving decision-making in PGT-A cycles, providing interpretation for segmental aneuploidies and possibly helping in the evaluation of embryos showing intermediate copy number values for whole chromosomes that are suggestive of mosaicism. Trial registration number Not applicable