Assessment of the Predictive Ability of Theranostics for Corneal Cross-linking in Treating Keratoconus: A Randomized Clinical Trial.

PURPOSE: To validate the ability of theranostic imaging biomarkers in assessing corneal cross-linking (CXL) efficacy in flattening the maximum keratometry (Kmax) index. DESIGN: Prospective, randomized, multicenter, masked clinical trial (ClinicalTrails.gov identifier, NCT05457647). PARTICIPANTS: Fifty patients with progressive keratoconus. INTERVENTION: Participants were stratified to undergo epithelium-off (25 eyes) and epithelium-on (25 eyes) CXL protocols using an ultraviolet A (UV-A) medical device with theranostic software. The device controlled UV-A light both for performing CXL and assessing the corneal riboflavin concentration (riboflavin score) and treatment effect (theranostic score). A 0.22% riboflavin formulation was applied onto the cornea for 15 minutes and 20 minutes in epithelium-off and epithelium-on protocols, respectively. All eyes underwent 9 minutes of UV-A irradiance at 10 mW/cm2. MAIN OUTCOME MEASURES: The primary outcome measure was validation of the combined use of theranostic imaging biomarkers through measurement of their accuracy (proportion of correctly classified eyes) and precision (positive predictive value) to classify eyes correctly and predict a Kmax flattening at 1 year after CXL. Other outcome measures included change in Kmax, endothelial cell density, uncorrected and corrected distance visual acuity, manifest spherical equivalent refraction and central corneal thickness 1 year after CXL. RESULTS: Accuracy and precision of the theranostic imaging biomarkers in predicting eyes that had >0.1 diopter (D) of Kmax flattening at 1 year were 91% and 95%, respectively. The Kmax value significantly flattened by a median of -1.3 D (IQR, -2.11 to -0.49 D; P < 0.001); both the uncorrected and corrected distance visual acuity improved by a median of -0.1 logarithm of the minimum angle of resolution (logMAR; IQR, -0.3 to 0.0 logMAR [P < 0.001] and -0.2 to 0.0 logMAR [P < 0.001], respectively). No significant changes in endothelial cell density (P = 0.33) or central corneal thickness (P = 0.07) were noted 1 year after surgery. CONCLUSIONS: The study demonstrated the efficacy of integrating theranostics in a UV-A medical device for the precise and predictive treatment of keratoconus with epithelium-off and epithelium-on CXL protocols. Concentration of riboflavin and its UV-A light mediated photoactivation in the cornea are the primary factors determining CXL efficacy. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Spatial targeted delivery of riboflavin with a controlled corneal iontophoresis delivery system in theranostic-guided UV-A light photo-therapy.

Seven human donor eye globes underwent corneal cross-linking using theranostic UV-A device with accessory corneal iontophoresis system for patterned delivery of a 0.22% riboflavin solution. Theranostic-guided UV-A light illumination assessed riboflavin distribution and treated corneas at 10 mW/cm2 for 9 min with a 5.0-mm beam size. Corneal topography maps were taken at baseline and 2-h post-treatment. Analysis utilized corneal topography elevation data, with results showing controlled riboflavin delivery led to a consistent gradient, with 40% higher levels centrally (248 ± 79 µg/cm3) than peripherally (180 ± 72 µg/cm3 at ±2.5 mm from the center). Theranostic-guided UV-A light irradiation resulted in significant changes in corneal topography, with a decrease in best-fit sphere value (-0.7 ± 0.2 D; p < 0.001) and consistent downward shift in corneal elevation map (-11.7 ± 3.7 µm). The coefficient of variation was 2.5%, indicating high procedure performance in achieving significant and reliable corneal flattening.

Real-time monitoring of riboflavin concentration using different clinically available ophthalmic formulations for epi-off and epi-on corneal cross-linking.

PURPOSE: To assess the feasibility of theranostics to determine the riboflavin concentration in the cornea using clinically available ophthalmic formulations during epithelium-off (epi-off) and transepithelial (epi-on) corneal cross-linking procedures. METHODS: Thirty-two eye bank human donor corneas were equally randomized in eight groups; groups 1 to 3 and groups 4 to 8 underwent epi-off and epi-on delivery of riboflavin respectively. Riboflavin ophthalmic solutions were applied onto the cornea according to the manufacturers' instructions. The amount of riboflavin into the cornea was estimated, at preset time intervals during imbibition time, using theranostic UV-A device (C4V CHROMO4VIS, Regensight srl, Italy) and expressed as riboflavin score (d.u.). Measurements of corneal riboflavin concentration (expressed as µg/cm3) were also performed by spectroscopy absorbance technique (AvaLight-DH-S-BAL, Avantes) for external validation of theranostic measurements. RESULTS: At the end of imbibition time in epi-off delivery protocols, the average riboflavin score ranged from 0.77 ± 0.38 (the average corneal riboflavin concentration was 213 ± 190 µg/cm3) to 1.79 ± 0.07 (554 ± 103 µg/cm3). In epi-on delivery protocols, the average riboflavin score ranged from 0.17 ± 0.01 to 0.67 ± 0.19 (corneal riboflavin concentration ranged from 6 ± 5 µg/cm3 to 122 ± 39 µg/cm3) at the end of imbibition time. A statistically significant linear correlation (P ≤ 0.05) was found between the theranostic and spectrophotometry measurements in all groups. CONCLUSIONS: Real-time theranostic imaging provided an accurate strategy for assessing permeation of riboflavin into the human cornea during the imbibition phase of corneal cross-linking, regardless of delivery protocol. A large variability in corneal riboflavin concentration exists between clinically available ophthalmic formulations both in epi-off and epi-on delivery protocols.

Accuracy of an Air-Puff Dynamic Tonometry Biomarker to Discriminate the Corneal Biomechanical Response in Patients With Keratoconus.

PURPOSE: The aim of this study was to assess accuracy of the mean corneal stiffness ( kc , N/m) parameter to discriminate between patients with keratoconus and age-matched healthy subjects. METHODS: Dynamic Scheimpflug imaging tonometry was performed with Corvis ST (Oculus Optikgeräte GmbH, Germany) in patients with keratoconus (n = 24; study group) and age-matched healthy subjects (n = 32; control). An image processing algorithm was developed to analyze the video sequence of the Corvis ST air-puff event and to determine the geometric and temporal parameters that correlated with the corneal tissue biomechanical properties. A modified 3-element viscoelastic model was used to derive the kc parameter, which represented the corneal tissue resistance to deformation under load. Receiver operating characteristic curves were used to assess the overall diagnostic performance for determining the area under the curve, sensitivity, and specificity of the kc in assessing the corneal tissue deformation to the Corvis ST air-puff event in keratoconus and control eyes. The Corvis Biomechanical Index ( CBI ) was analyzed for external validation. RESULTS: The kc parameter was significantly different between keratoconus and controls ( P < 0.001), ranging from 24.9 ±3.0 to 34.2 ±3.5 N/m, respectively. It was highly correlated with CBI (r = -0.69; P < 0.001); however, the kc parameter had greater specificity (94%) than CBI (75%), whereas the 2 biomarkers had similar area under the curve (0.98 vs. 0.94) and sensitivity (96% vs. 92%) in predicting the occurrence of keratoconus. CONCLUSIONS: The kc parameter extracted by video processing analysis of dynamic Scheimpflug tonometry data was highly accurate in discriminating patients with clinically manifest keratoconus compared with controls.

Predicting corneal cross-linking treatment efficacy with real-time assessment of corneal riboflavin concentration.

PURPOSE: To assess predictability of tissue biomechanical stiffening induced by UV-A light-mediated real-time assessment of riboflavin concentration during corneal crosslinking (CXL) of human donor tissues. SETTING: Studio Italiano di Oftalmologia, Rome, Italy. DESIGN: Laboratory study. METHODS: 20 sclerocorneal tissues were randomly stratified to undergo CXL with either the epithelium intact (n = 12) or removed (n = 8). Samples underwent corneal soaking with 0.22% riboflavin formulation (RitSight) with dosing time of t = 10 minutes and t = 20 minutes in epithelium-off and epithelium-on protocols, respectively. All tissues underwent 9-minute UV-A irradiance at 10 mW/cm 2 using theranostic device (C4V CHROMO4VIS). The device used controlled UV-A light irradiation to induce both imaging and treatment of the cornea, providing a real-time measure of corneal riboflavin concentration and treatment efficacy (ie, theranostic score) during surgery. Tissue biomechanics were assessed with an air-puff device (Corvis), which was performed before and after treatment. A 3-element viscoelastic model was developed to fit the corneal deformation response to air-puff excitation and to calculate the mean corneal stiffness parameter (k c ). RESULTS: Significant corneal tissue stiffening ( P < .05) was induced by the theranostic UV-A device in either CXL treatment protocol. Significant correlation was found between the theranostic score and the increase in k c ( R = 0.75; P = .003). The score showed high accuracy (94%) and precision (94%) to predict correctly samples that had improved tissue biomechanical strengthening. CONCLUSIONS: Real-time assessment of corneal riboflavin concentration provided a predictive and precise approach for significant improvement of tissue strength on individual corneas, regardless of CXL treatment protocol.

A randomized clinical trial assessing theranostic-guided corneal cross-linking for treating keratoconus: the ARGO protocol.

The Assessment of theranostic guided riboflavin/UV-A corneal cross-linking for treatment of keratoconus (ARGO; registration number NCT05457647) clinical trial tests the hypothesis that theranostic-guided riboflavin/UV-A corneal cross-linking (CXL) can provide predictable clinical efficacy for halting keratoconus progression, regardless of treatment protocol, i.e., either with or without epithelial removal. Theranostics is an emerging therapeutic paradigm of personalized and precision medicine that enables real-time monitoring of image-guided therapy. In this trial, the theranostic software module of a novel UV-A medical device will be validated in order to confirm its accuracy in estimating corneal cross-linking efficacy in real time. During CXL procedure, the theranostic UV-A medical device will provide the operator with an imaging biomarker, i.e., the theranostic score, which is calculated by non-invasive measurement of corneal riboflavin concentration and its UV-A light mediated photo-degradation. ARGO is a randomized multicenter clinical trial in patients aged between 18 and 40 years with progressive keratoconus aiming to validate the theranostic score by assessing the change of the maximum keratometry point value at 1-year postoperatively. A total of 50 participants will be stratified with allocation ratio 1:1 using a computer-generated stratification plan with blocks in two treatment protocols, such as epithelium-off or epithelium-on CXL. Following treatment, participants will be monitored for 12 months. Assessment of safety and performance of theranostic-guided corneal cross-linking treatment modality will be determined objectively by corneal tomography, corneal endothelial microscopy, visual acuity testing and slit-lamp eye examination.

Theranostic-guided corneal cross-linking: Preclinical evidence on a new treatment paradigm for keratoconus.

Theranostics is an emerging therapeutic paradigm of personalized medicine; the term refers to the simultaneous integration of therapy and diagnostics. In this work, theranostic-guided corneal cross-linking was performed on 10 human sclero-corneal tissues. The samples were soaked with 0.22% riboflavin formulation and underwent 9 minutes UV-A irradiance at 10 mW/cm2 using theranostic device, which provided both a measure of corneal riboflavin concentration and a theranostic score estimating treatment efficacy in real time. A three-element viscoelastic model was developed to fit the deformation response of the cornea to air-puff excitation of dynamic tonometry and to calculate the mean corneal stiffness parameter before and after treatment. Significant correlation was found between the theranostic score and the increase in mean corneal stiffness (R = 0.80; P < .001). Accuracy and precision of the theranostic score in predicting the induced corneal tissue stiffening were both 90%. The riboflavin concentration prior to starting the UV-A photo-therapy phase was the most important variable to allow corneal cross-linking to be effective. Theranostic UV-A light mediated imaging and therapy enables the operator to adopt a precise approach for achieving highly predictable biomechanical strengthening on individual corneas.

Video-Based Automatic Baby Motion Analysis for Early Neurological Disorder Diagnosis: State of the Art and Future Directions.

Neurodevelopmental disorders (NDD) are impairments of the growth and development of the brain and/or central nervous system. In the light of clinical findings on early diagnosis of NDD and prompted by recent advances in hardware and software technologies, several researchers tried to introduce automatic systems to analyse the baby's movement, even in cribs. Traditional technologies for automatic baby motion analysis leverage contact sensors. Alternatively, remotely acquired video data (e.g., RGB or depth) can be used, with or without active/passive markers positioned on the body. Markerless approaches are easier to set up and maintain (without any human intervention) and they work well on non-collaborative users, making them the most suitable technologies for clinical applications involving children. On the other hand, they require complex computational strategies for extracting knowledge from data, and then, they strongly depend on advances in computer vision and machine learning, which are among the most expanding areas of research. As a consequence, also markerless video-based analysis of movements in children for NDD has been rapidly expanding but, to the best of our knowledge, there is not yet a survey paper providing a broad overview of how recent scientific developments impacted it. This paper tries to fill this gap and it lists specifically designed data acquisition tools and publicly available datasets as well. Besides, it gives a glimpse of the most promising techniques in computer vision, machine learning and pattern recognition which could be profitably exploited for children motion analysis in videos.

Development of SaraHome: A novel, well-accepted, technology-based assessment tool for patients with ataxia.

BACKGROUND AND OBJECTIVE: Early onset ataxias (EOAs) are a heterogeneous group of neurological conditions, responsible for severe motor disability in paediatric age, which still lack reliable outcome measures. Available scales to assess ataxia, such as the Scale for Assessment and Rating of Ataxia (SARA), are based on subjective assessment of specific motor and language tasks by an examiner, and therefore is age dependent and lacks accuracy in detecting small variations in disease severity. In last years, novel technologies, including computer interfaces and videogames, have emerged for clinical applications and the advent of Internet of Medical Things and of Information Communication Technology have allowed the remote control of such technologies. This pilot study describes a newly developed tool (SaraHome) for the assessment at home of EOA evaluating its feasibility and acceptability on a small sample of children. METHODS: Ten EOA children and ten caregivers have been enrolled for a preliminary outpatient evaluation. The Microsoft Kinect 2.0 and Leap Motion Controller (LMC) connected to a personal computer with an ad hoc software have been set-up, for the acquisition of standardized motor tasks performed by the patients with the caregivers' assistance. Acceptance and practicability have been tested by QUEST 2.0 and IMI questionnaires in caregivers and patients respectively. RESULTS: The SaraHome software was developed, based on a collection of services provided by a complex architecture that consists of a Restful interface, which enables to access a series of plugins for the execution of different tasks. A graphical user interface allows the acquisition of the patient movements while performing a motor task. A protocol of standard tasks inspired by SARA was established, and a system of video-assisted instruction provided. The set-up for the optimal acquisition of such protocol by Kinect and LMC has been defined. Both patients and caregivers accomplished the SaraHome assessment with good feedback at the technology acceptance questionnaires. CONCLUSIONS: SaraHome represents a newly developed tool for the assessment of ataxia in patients, resulting from the integration of low-cost and easy-accessible technologies. This pilot application highlighted the feasibility and the acceptability of the system, suggesting the potential use in clinical practice.

Reduced preference for social rewards in a novel tablet based task in young children with Autism Spectrum Disorders.

Atypical responsivity to social rewards has been observed in young children with or at risk of Autism Spectrum Disorders (ASD). These observations contributed to the hypothesis of reduced social motivation in ASD. In the current study we develop a novel task to test social reward preference using a tablet computer (iPad), where two differently coloured buttons were associated with a social and a nonsocial rewarding image respectively. 63 young children, aged 14-68 months, with and without a diagnosis of ASD took part in the study. The experimental sessions were also recorded on video, using an in-built webcam on the tablet as well as an external camera. Children with ASD were found to show a reduced relative preference for social rewards, indexed by a lower proportion of touches for the button associated with the social reward image. Greater social preference as measured using the tablet-based task was associated with increased use of social communicative behaviour such as eye contact with the experimenter and social smile in response to the social reward image. These results are consistent with earlier findings from eye-tracking studies, and provide novel empirical insights into atypical social reward responsivity in ASD.