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Abstract This study aimed at predicting the filtration surgery (FS) outcome using a machine learning (ML) approach. 102 glaucomatous patients undergoing FS were enrolled and underwent ocular surface clinical tests (OSCTs), determination of surgical site-related biometric parameters (SSPs) and conjunctival vascularization. Break-up-time, Schirmer test I, corneal fluorescein staining, Meibomian gland expressibility; conjunctival hyperemia, upper bulbar conjunctiva area of exposure, limbus to superior eyelid distance; and conjunctival epithelial and stromal (CET, CST) thickness and reflectivity (ECR, SCR) at AS-OCT were considered. Successful FS required a 30% baseline intraocular pressure reduction, with values ≤ 18 mmHg with or without medications. The classification tree (CT) was the ML algorithm used to analyze data. At the twelfth month, FS was successful in 60.8% of cases, whereas failed in 39.2%. At the variable importance ranking, CST and SCR were the predictors with the greater relative importance to the CART tree construction, followed by age. CET and ECR showed less relative importance, whereas OSCTs and SSPs were not important features. Within the CT, CST turned out the most important variable for discriminating success from failure, followed by SCR and age, with cut-off values of 75 µm, 169 on gray scale, and 62 years, respectively. The ROC curve for the classifier showed an AUC of 0.784 (0.692–0.860). In this ML approach, CT analysis found that conjunctival stroma thickness and reflectivity, along with age, can predict the FS outcome with good accuracy. A pre-operative thick and hyper-reflective stroma, and a younger age increase the risk of FS failure.

Abstract Anomalous aortic origin of the coronary artery (AAOCA) is a rare disease associated with sudden cardiac death, usually related to physical effort in young people. Clinical routine tests fail to assess the ischemic risk, calling for novel diagnostic approaches. To this aim, some recent studies propose to assess the coronary blood flow (CBF) in AAOCA by computational simulations but they are limited by the use of data from literature retrieved from normal subjects. To overcome this limitation and obtain a reliable assessment of CBF, we developed a fully patient-specific lumped parameter model based on clinical imaging and in-vivo data retrieved during invasive coronary functional assessment of subjects with AAOCA. In such a way, we can estimate the CBF replicating the two hemodynamic conditions in-vivo analyzed. The model can mimic the effective coronary behavior with high accuracy and could be a valuable tool to quantify CBF in AAOCA. It represents the first step required to move toward a future clinical application with the aim of improving patient care. The study was registered at Clinicaltrial.gov with (ID: NCT05159791, date 2021-12-16).

To analyze in vivo scleral changes induced by MicroPulse transscleral laser therapy (MP-TLT) in refractory glaucoma using anterior segment–optical coherence tomography (AS-OCT). Forty-two candidate patients for MP-TLT were consecutively enrolled and underwent AS-OCT at baseline and after six months. MP-TLT success was defined as an intraocular pressure (IOP) reduction by one-third. The main outcome measures were the mean superior (S-), inferior (I-), and total (T-) intra-scleral hypo-reflective space area (MISHA: mm2) and scleral reflectivity (S-SR, I-SR, T-SR; arbitrary scale) as in vivo biomarkers of uveoscleral aqueous humor (AH) outflow. The IOP was the secondary outcome. The relations between the baseline-to-six months differences (D) of DS-MISHA, DI-MISHA, and DT-MISHA and DS-SR, DI-SR, DT-SR, and DIOP, were investigated. At 6 months, the median IOP reduction was 21% in the failures and 38% in the successes. The baseline S-MISHA, I-MISHA, and T-MISHA did not differ between the groups, while S-SR and T-SR were higher in the successes (p < 0.05). At six months, successful and failed MP-TLTs showed a 50% increase in S-MISHA (p < 0.001; p = 0.037), whereas I-SR and T-SR reduced only in the successes (p = 0.002; p = 0.001). When comparing DS-MISHA, DI-MISHA, and DT-MISHA and DS-SR, DI-SR, and DT-SR, there were no significant differences between the groups. In the successful procedures, DIOP was positively correlated with DT-MISHA and DI-MISHA (ρ = 0.438 and ρ = 0.490; p < 0.05). MP-TLT produced potentially advantageous modifications of the sclera in refractory glaucoma. Given the partial correlation between these modifications and post-treatment IOP reduction, our study confirmed that the activation of the uveoscleral AH outflow route could significantly contribute to the IOP lowering after MP-TLT.

Abstract Management of congenital coronary artery anomalies (CAA) is not standardized due to the variety of conditions included and their rare prevalence. Detection of CAA during myocardial infarction with non‐obstructive coronary arteries (MINOCA) may induce clinicians to address the patient for surgery as CAA is not included in any algorithm1,2 for the management of MINOCA and American Association for Thoracic Surgery evidence‐based guidelines suggest surgical repair for patients with anomalous aortic origin of a coronary artery and symptoms compatible with myocardial ischaemia.3 We present the case of a 35‐year‐old man with an anomalous origin of left coronary artery from right Valsalva sinus with pre‐pulmonic course detected during urgent coronary angiography for suspected myocardial infarction. Stress cardiac magnetic resonance did not show signs of ischaemia at high‐dose dobutamine but did reveal a recent myocarditis. This clinical case highlights the need for accurate risk stratification in CAA especially when confounding clinical scenarios co‐exist.

Abstract Neurotrophic Keratopathy (NK), classified as an orphan disease (ORPHA137596), is a rare degenerative corneal disease characterized by epithelial instability and decreased corneal sensitivity caused by the damage to the corneal nerves. The administration of human recombinant nerve growth factor (rhNGF) eye drops, as a licensed-in-Europe specific medication for treatment of moderate and severe NK, has added promising perspectives to the management of this disorder by providing a valid alternative to the neurotization surgery. However, few studies have been conducted to the molecular mechanism underlying the response to the treatment. Here, we carried out tears proteomics to highlight the protein expression during pharmacological treatment of NK (Data are available via ProteomeXchange with identifier PXD025408).Our data emphasized a proteome modulation during rhNGF treatment related to an increase in DNA synthesis, an activation of both BDNF signal and IL6 receptor. Furthermore, the amount of neuronal Extracellular Vesicles EVs (CD171+) correlated with the EVs carrying IL6R (CD126+) together associated to the inflammatory EVs (CD45+) in tears. Such scenario determined drug response, confirmed by an in vivo confocal microscopy analysis, showing an increase in length, density and number of nerve fiber branches during treatment. In summary, rhNGF treatment seems to determine an inflammatory micro-environment, mediated by functionalized EVs, defining the drug response by stimulating protein synthesis and fiber regeneration.

BackgroundA severe prosthesis-patient mismatch (PPM) is associated with adverse outcomes following transcatheter aortic valve replacement (TAVR) for de novo aortic stenosis or a failed surgical bioprosthesis. The impact of severe PPM in patients undergoing TAV-in-TAVR is unknown.AimWe sought to investigate the incidence and 1-year outcomes of different grades of PPM in patients undergoing TAV-in-TAVR.Materials and methodsThe TRANSIT-PPM is an international registry, including cases of degenerated TAVR treated with a second TAVR. PPM severity, as well as in-hospital, 30-day, and 1-year outcomes were defined according to the Valve Academic Research Consortium-3 (VARC-3) criteria.ResultsAmong 28 centers, 155 patients were included. Severe PPM was found in 6.5% of patients, whereas moderate PPM was found in 14.2% of patients. The rate of severe PPM was higher in patients who underwent TAV-in-TAVR with a second supra-annular self-expanding (S-SE) TAVR (10%, p = 0.04). Specifically, the rate of severe PPM was significantly higher among cases of a SE TAVR implanted into a balloon-expandable (BE) device (19%, p = 0.003). At 1-year follow-up, the rate of all-cause mortality, and the rate of patients in the New York Heart Association (NYHA) class III/IV were significantly higher in the cohort of patients with severe PPM (p = 0.016 and p = 0.0001, respectively). Almost all the patients with a severe PPM after the first TAVR had a failed < 23 mm BE transcatheter heart valve (THV): the treatment with an S-SE resolved the severe PPM in the majority of the cases.ConclusionAfter TAV-in-TAVR, in a fifth of the cases, a moderate or severe PPM occurred. A severe PPM is associated with an increased 1-year all-cause mortality.Clinical trial registration[https://clinicaltrials.gov], identifier [NCT04500964].

Nowadays, ocular drug delivery still remains a challenge, since the conventional dosage forms used for anterior and posterior ocular disease treatments, such as topical, systemic, and intraocular administration methods, present important limitations mainly related to the anatomical complexity of the eye. In particular, the blood–ocular barrier along with the corneal barrier, ocular surface, and lacrimal fluid secretion reduce the availability of the administered active compounds and their efficacy. These limitations have increased the need to develop safe and effective ocular delivery systems able to sustain the drug release in the interested ocular segment over time. In the last few years, thanks to the innovations in the materials and technologies employed, different ocular drug delivery systems have been developed. Therefore, this review aims to summarize the synthetic and natural drug-loaded ocular inserts, contacts, and intraocular lenses that have been recently developed, emphasizing the characteristics that make them promising for future ocular clinical applications.

Background: The impact of nodular calcifications in left ventricular outlow tract (LVOT) and aortic annulus on the procedural outcome of transcatheter aortic valve implantation (TAVI) with new-generation devices is yet to be elucidated. Similarly, computational simulations may provide a novel insight into the biomechanical features of TAVI devices and their interaction with nodular calcifications. Methods: This retrospective single-center study included 232 patients submitted to TAVI with Evolut-R (53.4%), Portico (33.6%) and Lotus (13.0%) devices with available preoperative computed tomography (CT) angiography and evidence of nodular calcifications in aortic annulus and/or LVOT. Calcification severity was defined ≥moderate in presence of at least two nodules or one nodule ≤5 mm. Three virtual simulation models of aortic root presenting a nodular calcification of increasing size were implemented. Stress distribution, stent-root contact area and paravalvular orifice area were computed. Results: At least moderate calcifications were found in 123 (53.0%) patients, with no sex differences. Among the ≥moderate calcification group, lower device success rate was evident (87.8% vs. 95.4%; p = 0.039). Higher rates of ≥moderate paravalvular leak (PVL) (11.4% vs. 3.7%; p = 0.028) and vascular complications (9.8% vs. 2.8%; p = 0.030) were also observed. Among the Evolut-R group, higher rates of at ≥moderate PVL (12.1%) were observed compared to Portico (3.8%; p = 0.045) and Lotus (0.0%; p = 0.044) groups. Calcification of both annulus and LVOT (odds ratio [OR] 0.105; p = 0.023) were independent predictors of device success. On computational simulations, Portico exhibited homogeneous stress distribution by increasing calfications and overall a larger paravalvular orifice areas compared to Evolut-R and Lotus. Evolut-R showed higher values of average stress than Portico, although with a more dishomogeneous distribution leading to greater paravalvular orifice areas by severe calcifications. Lotus showed overall small paravalvular orifice areas, with no significant increase across the three models. Conclusions: At least moderate nodular calcifications in the annulus/LVOT region significantly affected TAVI outcome, as they were independent predictors of device success. Lotus and Portico seemed to perform better than Evolut-R as for device success and ≥moderate PVL. Computational simulations revealed unique biomechanical features of the investigated devices in terms of stent compliance and radial force.

Background: The present study aimed to investigate the rationale and efficacy of using a citicoline, coenzyme Q10 (CAVAQ10) and vitamin B3 fixed combination in combating inflammation and oxidation in neuronal cells exposed to oxidative stress. Methods: HypoE22 cells and isolated hypothalamic specimens were selected as in vitro models to conduct the experiments. The efficacy of citicoline, CAVAQ10, and vitamin B3, with their fixed combination, were assayed after the exposure of hypothalamic cells to hydrogen peroxide (concentration range 1 nM–10 µM), in order to evaluate the biocompatibility of treatments. The activity of neuroprotective and pro-inflammatory factors, namely, brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), involved in the neuronal cell damage in neurodegenerative diseases, were assayed in isolated hypothalamus. Results: Neither citicoline, CAVAQ10, nor vitamin B3 significantly altered hypothalamic cell viability, thus suggesting the biocompatibility of single ingredients and fixed combination in the concentration range considered for the study. In the same condition, citicoline and CAVAQ10 were also effective in reducing the gene expression of monoaminoxidase-B, involved in dopamine degradation. However, only citicoline demonstrated an ability to reduce dopamine levels. Conversely, all compounds were effective in reducing the gene expression of IL-6, and TNFα, and in inducing the gene expression of BDNF, with the co-administration of citicoline/CAVAQ10/vitamin B3 being generally more effective than single ingredients. Conclusions: The present findings support the beneficial and synergistic effects of citicoline, CAVAQ10, and vitamin B3 in fixed combination in reducing inflammation and oxidation, and in stimulating neurotrophin production in neuronal cells.

Glaucoma patients often suffer from ocular surface disease (OSD) caused by the chronic administration of topical anti-glaucoma medications, especially in cases of long-term therapy with preserved or multiple drugs. Additionally, glaucoma surgery may determine ocular surface changes related to the formation and location of the filtering bleb, the application of anti-mitotic agents, and the post-operative wound-healing processes within the conjunctiva. Recently, several studies have evaluated the role of advanced diagnostic imaging technologies such as in vivo confocal microscopy (IVCM) and anterior segment-optical coherence tomography (AS-OCT) in detecting microscopic and macroscopic features of glaucoma therapy-related OSD. Their clinical applications are still being explored, with recent particular attention paid to analyzing the effects of new drug formulations and of minimally invasive surgical procedures on the ocular surface status. In this review, we summarize the current knowledge about the main changes of the ocular surface identified at IVCM and AS-OCT in glaucoma patients under medical therapy, or after surgical treatment.

PURPOSE:To evaluate the presence and concentration of citicoline and its metabolites (choline, cytidine and uridine) in the vitreous body in human eyes after topical application of an ophthalmic solution of citicoline 2%, in vivo. METHODS:Twenty-one subjects affected by epiretinal membrane with surgical indication for pars-plana vitrectomy underwent treatment with 1 drop 3 times/day of a solution of citicoline 2%, 0.2% high molecular weight hyaluronic acid and 0.01% benzalkonium chloride (OMK1, Omikron Italia s.r.l., Rome, Italy) 14 days before surgery and 2 hours prior to surgery. Five additional patients served as controls and received an OMK1 vehicle solution without citicoline. The vitreous samples were taken at the beginning of the pars-plana vitrectomy and analyzed for qualitative/quantitative determination of vitreous concentration of citicoline and its metabolites by means of high performance liquid chromatography. RESULTS:The overall mean concentration of citicoline in patients treated with citicoline 2% solution was 406.72 ± 52.99 μg/mL, while the mean concentration of choline, cytidine and uridine was 180.88 ± 41.49 μg/mL, 44.45 ± 10.19 μg/mL and 330.41 ± 75.8 μg/mL, respectively. The concentration of citicoline in phakic eyes (n = 13, 366.61 ± 129.61 μg/mL) was lower compared to that found in pseudophakic eyes (n = 8, 435.89 ± 131.42 μg/mL) and the difference was not statistically significant. The concentration of citicoline in the control eyes was 45.66 ± 26.36 μg/mL, while the concentration of choline, cytidine and uridine were 17.21 ± 9.93 μg/mL, 6.24 ± 3.6 μg/mL and 172.80 ± 99.76 μg/mL, respectively. CONCLUSION:Citicoline can reach the human vitreous in high concentration when administered in ophthalmic solution. This evidence contributes to the build-up of the pyramid of the evidences required for determining the role of citicoline administered in ophthalmic formulation in retinal and optic nerve neurodegenerative diseases.