Intracapsular accommodation mechanism in terms of lens curvature gradient.

The intracapsular accommodation mechanism (IAM) may be understood as an increase in the lens equivalent refractive index as the eye accommodates. Our goal was to evaluate the existence of an IAM by analysing observed changes in the inner curvature gradient of the lens. To this end, we fitted a gradient index and curvature lens model to published experimental data on external and nucleus geometry changes during accommodation. For each case analysed, we computed the refractive power and equivalent index for each accommodative state using a ray transfer matrix. All data sets showed an increase in the effective refractive index, indicating a positive IAM, which was stronger for older lenses. These results suggest a strong dependence of the lens equivalent refractive index on the inner curvature gradient.

The influence of variations in ocular biometric and optical parameters on differences in refractive error.

PURPOSE: To present a paraxial method to estimate the influence of variations in ocular biometry on changes in refractive error (S) at a population level and apply this method to literature data. METHODS: Error propagation was applied to two methods of eye modelling, referred to as the simple method and the matrix method. The simple method defines S as the difference between the axial power and the whole-eye power, while the matrix method uses more accurate ray transfer matrices. These methods were applied to literature data, containing the mean ocular biometry data from the SyntEyes model, as well as populations of premature infants with or without retinopathy, full-term infants, school children and healthy and diabetic adults. RESULTS: Applying these equations to 1000 SyntEyes showed that changes in axial length provided the most important contribution to the variations in refractive error (57%-64%), followed by lens power/gradient index power (16%-31%) and the anterior corneal radius of curvature (10%-13%). All other components of the eye contributed <4%. For young children, the largest contributions were made by variations in axial length, lens and corneal power for the simple method (67%, 23% and 8%, respectively) and by variations in axial length, gradient lens power and anterior corneal curvature for the matrix method (55%, 21% and 14%, respectively). During myopisation, the influence of variations in axial length increased from 54.5% to 73.4%, while changes in corneal power decreased from 9.82% to 6.32%. Similarly, for the other data sets, the largest contribution was related to axial length. CONCLUSIONS: This analysis confirms that the changes in ocular refraction were mostly associated with variations in axial length, lens and corneal power. The relative contributions of the latter two varied, depending on the particular population.

Impaired Bestrophin Channel Activity in an iPSC-RPE Model of Best Vitelliform Macular Dystrophy (BVMD) from an Early Onset Patient Carrying the P77S Dominant Mutation.

Best Vitelliform Macular dystrophy (BVMD) is the most prevalent of the distinctive retinal dystrophies caused by mutations in the BEST1 gene. This gene, which encodes for a homopentameric calcium-activated ion channel, is crucial for the homeostasis and function of the retinal pigment epithelia (RPE), the cell type responsible for recycling the visual pigments generated by photoreceptor cells. In BVMD patients, mutations in this gene induce functional problems in the RPE cell layer with an accumulation of lipofucsin that evolves into cell death and loss of sight. In this work, we employ iPSC-RPE cells derived from a patient with the p.Pro77Ser dominant mutation to determine the correlation between this variant and the ocular phenotype. To this purpose, gene and protein expression and localization are evaluated in iPSC-RPE cells along with functional assays like phagocytosis and anion channel activity. Our cell model shows no differences in gene expression, protein expression/localization, or phagocytosis capacity, but presents an increased chloride entrance, indicating that the p.Pro77Ser variant might be a gain-of-function mutation. We hypothesize that this variant disturbs the neck region of the BEST1 channel, affecting channel function but maintaining cell homeostasis in the short term. This data shed new light on the different phenotypes of dominant mutations in BEST1, and emphasize the importance of understanding its molecular mechanisms. Furthermore, the data widen the knowledge of this pathology and open the door for a better diagnosis and prognosis of the disease.

GRINCU lens with conicoid iso-indicial surfaces: application for modeling the crystalline lens.

We introduce a new type of lens with two gradients of refractive index (GRIN) and of curvature (GRCU) of iso-indicial surfaces, i.e., GRINCU. The inner structure of the lens resembles that of an onion. Each layer is a meniscus lens with infinitesimal thickness, which coincides with an iso-indicial surface characterized by a conicoid shape and a constant refractive index. The internal distribution automatically adapts to the external geometry. Here, we consider the simplest case of a constant gradient of the curvature radius -G, which indicates a linear decrease as we move along the optical axis. The formulation of this type of lens is presented, including its generalization to nonrotationally symmetric conicoid surfaces. The formulation is then applied to model the crystalline lens; the code corresponding to the numerical computation of the 3D refractive index distribution as well as its gradient is provided as a supplementary file. Finally, we confirmed a refractive power increase of nearly 14% when G changes from 0 to 3.

Pachychoroid: current concepts on clinical features and pathogenesis.

PURPOSE: The term "pachychoroid" refers to a newly described phenotype in which functional and structural choroidal changes are thought to play a key pathogenic role in a spectrum of related retinal disorders. A more detailed understanding of how the choroid is involved within this spectrum and a better knowledge of the most relevant clinical signs of the pachychoroid phenotype are important to differentiate these disorders from other retinal conditions. Our objectives are to provide a literature review of pachychoroid and the commonalities that may be present across pathologies included in the spectrum, and to provide details on the examination, monitoring, and management of these disorders. METHODS: We searched the PubMed web platform to identify relevant studies using the following keywords: pachychoroid, pachychoroid pigment epitheliopathy, pachychoroid neovasculopathy, aneurysmal type 1 neovascularization, focal choroidal excavation, peripapillary pachychoroid syndrome, vasculopathy pachysclera, pachychoroid geographic atrophy, and pachydrusen. We selected 157 publications and identified the most important features related to pachychoroid. RESULTS: The presence of hypertrophic or congested vessels in the choroid, not thickened choroid per se, under an area of reduced or absent choriocapillaris in the posterior pole seems to be the most salient feature of pachychoroid. However, other qualitative/quantitative features are needed to differentiate the uncomplicated pachychoroid from the pathological pachychoroid clinical spectrum, which may be associated with exudation, neovascularization, and/or retinal pigment epithelium and photoreceptor atrophy. CONCLUSIONS: The most salient feature of pachychoroid appears to be the presence of large vessels under an area of reduced or absent choriocapillaris. Knowledge of the features and pathogenesis of the different disorders in the pachychoroid spectrum may assist in the management of patients.

Anti-VEGF intravitreal injections in the era of COVID-19: responding to different levels of epidemic pressure.

PURPOSE: Following the first wave of the COVID-19 pandemic in early 2020, the easing of strict measures to reduce its spread has led to a resurgence of cases in many countries at both the national and local level. This article addresses how guidance for ophthalmologists on managing patients with retinal disease receiving intravitreal injections of anti-vascular endothelial growth factor (VEGF) during the pandemic should be adapted to the local epidemic pressure, with more or less stringent measures implemented according to the ebb and flow of the pandemic. METHODS: The Vision Academy's membership of international retinal disease experts analyzed guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic and graded the recommendations according to three levels of increasing epidemic pressure. The revised recommendations were discussed, refined, and voted on by the 14-member Vision Academy Steering Committee for consensus. RESULTS: Protocols to minimize the exposure of patients and healthcare staff to COVID-19, including use of personal protective equipment, physical distancing, and hygiene measures, should be routinely implemented and intensified according to local infection rates and pressure on the hospital/clinic or healthcare system. In areas with many COVID-19-positive clusters, additional measures including pre-screening of patients, postponement of non-urgent appointments, and simplification of complex intravitreal anti-VEGF regimens should be considered. Treatment prioritization for those at greatest risk of irreversible vision loss should be implemented in areas where COVID-19 cases are increasing exponentially and healthcare resources are strained. CONCLUSION: Consistency in monitoring of local infection rates and adjustment of clinical practice accordingly will be required as we move forward through the COVID-19 era. Ophthalmologists must continue to carefully weigh the risk-benefits to minimize the exposure of patients and healthcare staff to COVID-19, ensure that patients receive sight-saving treatment, and avoid the potential long-term impact of prolonged treatment postponement.

New Insights on the Genetic Basis Underlying SHILCA Syndrome: Characterization of the NMNAT1 Pathological Alterations Due to Compound Heterozygous Mutations and Identification of a Novel Alternative Isoform.

This study aims to genetically characterize a two-year-old patient suffering from multiple systemic abnormalities, including skeletal, nervous and developmental involvements and Leber congenital amaurosis (LCA). Genetic screening by next-generation sequencing identified two heterozygous pathogenic variants in nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1) as the molecular cause of the disease: c.439+5G>T and c.299+526_*968dup.This splice variant has never been reported to date, whereas pathogenic duplication has recently been associated with cases displaying an autosomal recessive disorder that includes a severe form of spondylo-epiphyseal dysplasia, sensorineural hearing loss, intellectual disability and LCA (SHILCA), as well as some brain anomalies. Our patient presented clinical manifestations which correlated strongly with this reported syndrome. To further study the possible transcriptional alterations resulting from these mutations, mRNA expression assays were performed in the patient and her father. The obtained results detected aberrant alternative transcripts and unbalanced levels of expression, consistent with severe systemic involvement. Moreover, these analyses also detected a novel NMNAT1 isoform, which is variably expressed in healthy human tissues. Altogether, these findings represent new evidence of the correlation of NMNAT1 and SHILCA syndrome, and provide additional insights into the healthy and pathogenic expression of this gene.

Natural occurrence of asbestos in serpentinite quarries from Southern Spain.

The nevado-filábride complex (NFC) (southern Spain) is well known for its widespread mining and quarrying activities. Serpentinite and metabasite rocks are extracted, processed and traded as building and ornamental stones. Due to the possible presence of natural occurrence of asbestos (NOA) in these rocks, the aim of this paper is to conduct an in-depth characterisation of fibrous minerals. To this aim, seven serpentinite rock samples were collected in four quarries located in the Sierra Nevada and Sierra de los Filabres (South-eastern Spain), which were then analysed by X-ray powder diffraction (XRPD), scanning electron microscopy combined with energy-dispersive spectrometry (SEM/EDS), differential scanning calorimetry (DSC), derivative thermogravimetry (DTG) and X-ray synchrotron microtomography (SR-µCT). It is essential to investigate asbestos minerals from both scientific and legal perspective, especially for public health officials that implement occupational health and safety policies, in order to safeguard the health of workers (e.g. quarry excavations, road yards, civil constructions, building stones).

Guidance for anti-VEGF intravitreal injections during the COVID-19 pandemic.

PURPOSE: There is an urgent need to address how to best provide ophthalmic care for patients with retinal disease receiving intravitreal injections with anti-vascular endothelial growth factor agents during the ongoing global COVID-19 pandemic. This article provides guidance for ophthalmologists on how to deliver the best possible care for patients while minimizing the risk of infection. METHODS: The Vision Academy's Steering Committee of international retinal disease experts convened to discuss key considerations for managing patients with retinal disease during the COVID-19 pandemic. After reviewing the existing literature on the issue, members put forward recommendations that were systematically refined and voted on to develop this guidance. RESULTS: The considerations focus on the implementation of steps to minimize the exposure of patients and healthcare staff to COVID-19. These include the use of personal protective equipment, adherence to scrupulous hygiene and disinfection protocols, pre-screening to identify symptomatic patients, and reducing the number of people in waiting rooms. Other important measures include triaging of patients to identify those at the greatest risk of irreversible vision loss and prioritization of treatment visits over monitoring visits where possible. In order to limit patient exposure, ophthalmologists should refrain from using treatment regimens that require frequent monitoring. CONCLUSION: Management of patients with retinal disease receiving intravitreal injections during the COVID-19 pandemic will require adjustment to regular clinical practice to minimize the risk of exposure of patients and healthcare staff, and to prioritize those with the greatest medical need. The safety of patients and healthcare staff should be of paramount importance in all decision-making.

CURRENT CONCEPTS AND MODALITIES FOR MONITORING THE FELLOW EYE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: An Expert Panel Consensus.

PURPOSE: The presence of neovascular age-related macular degeneration (nAMD) in one eye is a major risk factor for the development of disease in the fellow eye. Several methods exist to help physicians monitor the fellow eye, with new technologies becoming increasingly available. METHODS: We provide an overview of modalities for nAMD monitoring, including advances in home-based options, and review their utility for fellow-eye monitoring, based on a review of the literature and a consensus of retinal experts. RESULTS: Studies demonstrate the importance of early detection of nAMD in the fellow eye so that interventions can be made before significant vision loss occurs. A series of techniques exist for the early detection of nAMD including chart-based methods and imaging devices. The increased availability of home-based methods has presented an opportunity for patients to monitor their vision at home. CONCLUSION: Frequent monitoring of the fellow eye in patients with unilateral nAMD is of critical importance to prevent vision loss and maintain quality of life. Patients should be examined every 3 to 4 months from the time of choroidal neovascularization diagnosis and encouraged to monitor their vision at home using home-based technologies where available, to provide the best opportunity for early detection.

Relationship between Aflibercept Efficacy and Genetic Variants of Genes Associated with Neovascular Age-Related Macular Degeneration: The BIOIMAGE Trial.

PURPOSE: To identify the genetic variants of the vascular endothelial growth factor (VEGF) pathway genes and other genes associated with neovascular age-related macular degeneration (nAMD) as possible predictive biomarkers of a favorable treatment response to aflibercept. DESIGN: A 52-week (with extension phase: 104-week), prospective, open-label, single-arm, multicenter, phase IV trial was conducted in Spain. PARTICIPANTS: Patients with nAMD were enrolled. METHODS: Aflibercept was administered every 8 weeks until week 48 (after 1-monthly loading doses over 3 months). After week 48, the interval between visits for aflibercept administration was extended by 2 weeks per visit to a maximum of 12 weeks if no evidence of disease activity was observed. A total of 338 SNPs in 90 genes associated with nAMD were analyzed. MAIN OUTCOME MEASURES: Efficacy was evaluated mainly with best-corrected visual acuity (BCVA), and adverse events (AEs) were reported. Treatment efficacy was defined as an increase in BCVA ≥15 letters versus the baseline visit. Univariate and multivariate logistic regressions were used to associate single-nucleotide polymorphisms (SNPs) and treatment efficacy. RESULTS: 194 nonconsecutive patients were enrolled, 170 completed the 52-week follow-up, and of the 85 patients who started the extension phase, 77 completed this phase. Mean BCVA increased from baseline to weeks 52 and 104 by 9 and 10 letters (p = 0.0001 for both), respectively. The percentages of patients gaining ≥15 letters in weeks 52 and 104 were 33 and 31%, respectively. Multivariate logistic regression showed significant associations of 6 SNPs (in 6 genes) with treatment efficacy: rs12366035 (VEGFB; TT; odds ratio [OR] 217), rs25681 (C5; AA/AG; OR 19.7/8.3), rs17793056 (CX3CR1; CT/CC; OR 8.1/6.2), rs1800775 (CETP; CC; OR 6.6), rs2069845 (IL6; GG/AA; OR 5.6/3.3), and rs13900 (CCL2; CT; OR 4.0). One percent of the patients reported arteriothrombolic events related to aflibercept (cerebrovascular accident) according to the Antiplatelet Trialist Collaboration, and 2% reported serious ocular (retinal pigment epithelial tear, retinal tear, and endophthalmitis) and systemic (cardiac failure, hypersensitivity, and transient ischemic attack) AEs related to aflibercept. CONCLUSIONS: Results suggest strong pharmacogenetic associations between one genetic variant of VEGFB (TT, rs12366035) and C5 (AA, rs12366035) genes and the BCVA response after 52-week aflibercept treatment in patients with nAMD. Likewise, the results support the efficacy of aflibercept observed in phase III studies and a good safety profile.

Induced Gamma-Band Activity during Actual and Imaginary Movements: EEG Analysis.

The purpose of this paper is to record and analyze induced gamma-band activity (GBA) (30-60 Hz) in cerebral motor areas during imaginary movement and to compare it quantitatively with activity recorded in the same areas during actual movement using a simplified electroencephalogram (EEG). Brain activity (basal activity, imaginary motor task and actual motor task) is obtained from 12 healthy volunteer subjects using an EEG (Cz channel). GBA is analyzed using the mean power spectral density (PSD) value. Event-related synchronization (ERS) is calculated from the PSD values of the basal GBA (GBAb), the GBA of the imaginary movement (GBAim) and the GBA of the actual movement (GBAac). The mean GBAim and GBAac values for the right and left hands are significantly higher than the GBAb value (p = 0.007). No significant difference is detected between mean GBA values during the imaginary and actual movement (p = 0.242). The mean ERS values for the imaginary movement (ERSimM (%) = 23.52) and for the actual movement (ERSacM = 27.47) do not present any significant difference (p = 0.117). We demonstrated that ERS could provide a useful way of indirectly checking the function of neuronal motor circuits activated by voluntary movement, both imaginary and actual. These results, as a proof of concept, could be applied to physiology studies, brain-computer interfaces, and diagnosis of cognitive or motor pathologies.

Characterization of the cone-rod dystrophy retinal phenotype caused by novel homozygous DRAM2 mutations.

Cone-rod dystrophies (CRD) are a group of Inherited Retinal Dystrophies (IRD) characterized by the primary involvement of cone photoreceptors, resulting in the degeneration of the central retina, or macula. Although there are more than 55 CRD genes, a considerable percentage of cases remain unsolved. In this context, the present study aimed to describe and characterize the phenoptype and the genetic cause of 3 CRD families from a cohort of IRD cases. Clinical evaluation in each patient was supported by a complete ophthalmological examination, including visual acuity measurement, fundus retinography, fundus autofluorescence imaging, optical coherence tomography and full-field electroretinography. Molecular diagnoses were performed by whole exome sequencing analyzing a group of 279 IRD genes, and cosegregation of the identified pathogenic variants was confirmed by Sanger sequencing. Three novel homozygous mutations in the autophagy gene DRAM2 were identified as the molecular cause of disease in the three families: c.518-1G>A, c.628_629insAG and c.693+2T>A. Clinical data revealed that the 3 patients presented a shared CRD phenotype with adult-onset macular involvement and later peripheral degeneration, although the age of onset, evolution and severity were variable. In order to characterize the transcription effects of these variants, mRNA expression studies were performed. The results showed alterations in the DRAM2 transcription, including alternative splicing forms and lower levels of mRNA, which correlated with the phenotypic variability observed between patients. For instance, frameshift mutations were related to a less severe phenotype, with circumscribed mid-peripheral involvement, and lower levels of mRNA, suggesting an activation of the nonsense-mediated decay (NMD) pathway; while a more severe and widespread retinal degeneration was associated to the inframe alternative splicing variant reported, possibly due to a malfunctioning or toxicity of the resulting protein. Following these findings, DRAM2 expression was assessed in several human tissues by semi-quantitative RT-PCR and two isoforms were detected ubiquitously, yet with a singular tissue-specific pattern in retina and brain. Altogether, although the unique retinal phenotype described did not correlate with the ubiquitous expression, the retinal-specific expression and the essential role of autophagy in the photoreceptor survival could be key arguments to explain this particular DRAM2 phenotype.

Average biometry of the cornea in a large population of Iranian school children.

This work establishes the average Scheimpflug corneal tomography for a population of 4953 healthy Iranian primary school children. These data were transformed to determine the corneal position and orientation in three-dimensional space, followed by a model fit that combines a biconic with a Zernike expansion. Girls were found to have slightly steeper corneas than boys. Both corneal surfaces show negative conic constants and significant higher-order aspheric Zernike terms. The corneal surfaces are decentered and misaligned with respect to each other and to the line of sight. Consequently, the average corneal surfaces may be considered as decentered and misaligned higher-order aspheres.

Is gestational diabetes mellitus in obese women predicted by oxidative damage in red blood cells?

Obesity in pregnant women has been associated with an increased risk of maternal complications, including gestational diabetes mellitus (GDM), a process that is related to oxidative stress (OS). To evaluate the biomarkers of OS in red blood cells (RBCs), we assigned 80 pregnant women to one of three groups: control (n = 28), overweight (n = 26) and obese (n = 26). Then, we measured in plasma, the levels of glucose, triacylglycerol (TAG), insulin, free fatty acids (FFAs), leptin and cytokines (e.g. interleukin-6 [IL-6] and tumor necrosis factor-alpha [TNF-alpha]) and OS biomarkers, such as lipohydroperoxides (LHP), malondialdehyde (MDA) and protein carbonylation (PC) in RBCs. We found significant positive correlations between OS biomarkers, body mass index (BMI) and pregnancy progression. Seven (26.9%) obese women who were diagnosed with GDM at 24-28 weeks of pregnancy showed significantly increased concentrations of FFAs, insulin, leptin, TNF-alpha and biomarkers of OS measured at 12-13 weeks of gestation. We propose to quantify LHP, MDA and PC in membranes of erythrocytes as possible markers to diagnose GDM from weeks 12-14.

Clinical Decision-Making when Treating Diabetic Macular Edema Patients with Dexamethasone Intravitreal Implants.

Diabetes mellitus (DM) is a metabolic disease frequently associated with comorbidities that include diabetic macular edema (DME). The current medical approach to treating DME involves intravitreal injections with either anti-vascular endothelial growth factors or steroids. However, the burden associated with intravitreal injections and DM-derived complications is high, underlining the need to find optimal treatment regimens. In this article we describe the considerations we apply when treating DME patients with dexamethasone intravitreal implants (Ozurdex®), particularly those that influence the clinical decision-making process during the follow-up period. These considerations are based both on the available medical literature and on our clinical experience following the use of these implants in this type of patient, the goal being to optimize the number of injections and the clinical outcome of this therapy. We also provide a general overview of the pathophysiology of DME, highlighting the inflammatory component as a rationale to use steroids in these patients.

Bigaussian Wavefront Model for Normal and Keratoconic Eyes.

PURPOSE: To report bigaussian multivariate wavefront models capable of stochastically generating an unlimited amount of plausible wavefront data for either normal or keratoconic eyes. METHODS: The models use centroid wavefront data measured previously with an iTrace in 330 healthy right eyes and 122 keratoconic right eyes. These centroids were fitted to an 11th-order Zernike series, followed by principal component analysis to reduce dimensionality and remove correlations. The remaining parameters were then fitted to a sum of two multivariate Gaussian distributions. This fit then forms the core of the stochastic model, which may be used to generate synthetic data. Finally, the agreement between the original and synthetic data was tested using two one-sided t tests. RESULTS: For normal eyes, the first eigenvectors mostly represent pure Zernike polynomials, with a decreasing degree of purity with increasing order. For keratoconic eyes, eigenvector purity was considerably lower than for normal eyes. Depending on the data set, series of 22 to 29 eigenvectors were found sufficient for accurate wavefront reconstruction (i.e., root-mean-square errors below 0.05 µm). These eigenvectors were then used as a base for the stochastic models. In all models and all Zernike coefficients, the mean of the synthetic data was significantly equal to that of the original data (two one-sided t test, P > .05/75), but the variability of the synthetic data is often significantly lower (F test, P < .05/75). CONCLUSIONS: This synthetic wavefront model may be safely used in calculations as an alternative to actual measurements should such data not be available.

SyntEyes KTC: higher order statistical eye model for developing keratoconus.

PURPOSE: To present and validate a stochastic eye model for developing keratoconus to e.g. improve optical corrective strategies. This could be particularly useful for researchers that do not have access to original keratoconic data. METHODS: The Scheimpflug tomography, ocular biometry and wavefront of 145 keratoconic right eyes were collected. These data were processed using principal component analysis for parameter reduction, followed by a multivariate Gaussian fit that produces a stochastic model for keratoconus (SyntEyes KTC). The output of this model is filtered to remove the occasional incorrect topography patterns by either an automatic or manual procedure. Finally, the output of this keratoconus model is matched to that of the original model for normal eyes using the non-corneal biometry to obtain a description of keratoconus development. RESULTS: The synthetic data generated by the model were found to be significantly equal to the original data (non-parametric Mann-Whitney equivalence test; 145/154 passed). The variability of the synthetic data, however, was often significantly less than that of the original data, especially for the higher order Zernike terms of corneal elevation (non-parametric Levene test; p < 0.05/154). These results remained generally the same after applying either filter procedure to remove the synthetic eyes with incorrect topographies. Interpolation between matched pairs of normal and keratoconic SyntEyes appears to provide an adequate model for keratoconus progression. CONCLUSION: The synthetic data provided by the proposed keratoconus model closely resembles actual clinical data and may be used for a range of research applications when (sufficient) real data is not available.

Development of imaging biomarkers and generation of big data.

Several image processing algorithms have emerged to cover unmet clinical needs but their application to radiological routine with a clear clinical impact is still not straightforward. Moving from local to big infrastructures, such as Medical Imaging Biobanks (millions of studies), or even more, Federations of Medical Imaging Biobanks (in some cases totaling to hundreds of millions of studies) require the integration of automated pipelines for fast analysis of pooled data to extract clinically relevant conclusions, not uniquely linked to medical imaging, but in combination to other information such as genetic profiling. A general strategy for the development of imaging biomarkers and their integration in the cloud for the quantitative management and exploitation in large databases is herein presented. The proposed platform has been successfully launched and is being validated nowadays among the early adopters' community of radiologists, clinicians, and medical imaging researchers.

Orthogonal basis with a conicoid first mode for shape specification of optical surfaces: reply.

We present some comments to the paper "Orthogonal basis with a conicoid first mode for shape specification of optical surfaces: comment."