Mophological analysis of the human vasculature from medical imaging. Application to cerebral and coranary arteries

In this project, we have investigated new ways of modelling and analysis of human vasculature from Medical images. The research was divided in two main areas: cerebral vasculature analysis and coronary arteries modeling. Regarding cerebral vasculature analysis, we have studed cerebral aneurysms, internal carotid and the Circle of Willis (CoW). Aneurysms are abnormal vessel enlargements that can rupture causing important cerebral damages or death. The understanding of this pathology, together with its virtual treatment, and image diagnosis and prognosis, includes identification and detailed measurement of the aneurysms. In this context, we have proposed two automatic aneurysm isolation method, to separate the abnormal part of the vessel from the healthy part, to homogenize and speed-up the processing pipeline usually employed to study this pathology, [Cardenes2011TMI, arrabide2011MedPhys]. The results obtained from both methods have been also compared and validatied in [Cardenes2012MBEC]. A second important task here the analysis of the internal carotid [Bogunovic2011Media] and the automatic labelling of the CoW, Bogunovic2011MICCAI, Bogunovic2012TMI]. The second area of research covers the study of coronary arteries, specially coronary bifurcations because there is where the formation of atherosclerotic plaque is more common, and where the intervention is more challenging. Therefore, we proposed a novel modelling method from Computed Tomography Angiography (CTA) images, combined with Conventional Coronary Angiography (CCA), to obtain realistic vascular models of coronary bifurcations, presented in [Cardenes2011MICCAI], and fully validated including phantom experiments in [Cardene2013MedPhys]. The realistic models obtained from this method are being used to simulate stenting procedures, and to investigate the hemodynamic variables in coronary bifurcations in the works submitted in [Morlachi2012, Chiastra2012]. Additionally, another preliminary work has been done to reconstruct the coronary tree from rotational angiography, and published in [Cardenes2012ISBI].

Toward integrated management of cerebral aneurysms

In the last few years, some of the visionary concepts behind the virtual physiological human began to be demonstrated on various clinical domains, showing great promise for improving healthcare management. In the current work, we provide an overview of image- and biomechanics-based techniques that, when put together, provide a patient-specific pipeline for the management of intracranial aneurysms. The derivation and subsequent integration of morphological, morphodynamic, haemodynamic and structural analyses allow us to extract patient-specific models and information from which diagnostic and prognostic descriptors can be obtained. Linking such new indices with relevant clinical events should bring new insights into the processes behind aneurysm genesis, growth and rupture. The development of techniques for modelling endovascular devices such as stents and coils allows the evaluation of alternative treatment scenarios before the intervention takes place and could also contribute to the understanding and improved design of more effective devices. A key element to facilitate the clinical take-up of all these developments is their comprehensive validation. Although a number of previously published results have shown the accuracy and robustness of individual components, further efforts should be directed to demonstrate the diagnostic and prognostic efficacy of these advanced tools through large-scale clinical trials.

Computational fluid dynamics modelling in cardiovascular medicine.

This paper reviews the methods, benefits and challenges associated with the adoption and translation of computational fluid dynamics (CFD) modelling within cardiovascular medicine. CFD, a specialist area of mathematics and a branch of fluid mechanics, is used routinely in a diverse range of safety-critical engineering systems, which increasingly is being applied to the cardiovascular system. By facilitating rapid, economical, low-risk prototyping, CFD modelling has already revolutionised research and development of devices such as stents, valve prostheses, and ventricular assist devices. Combined with cardiovascular imaging, CFD simulation enables detailed characterisation of complex physiological pressure and flow fields and the computation of metrics which cannot be directly measured, for example, wall shear stress. CFD models are now being translated into clinical tools for physicians to use across the spectrum of coronary, valvular, congenital, myocardial and peripheral vascular diseases. CFD modelling is apposite for minimally-invasive patient assessment. Patient-specific (incorporating data unique to the individual) and multi-scale (combining models of different length- and time-scales) modelling enables individualised risk prediction and virtual treatment planning. This represents a significant departure from traditional dependence upon registry-based, population-averaged data. Model integration is progressively moving towards 'digital patient' or 'virtual physiological human' representations. When combined with population-scale numerical models, these models have the potential to reduce the cost, time and risk associated with clinical trials. The adoption of CFD modelling signals a new era in cardiovascular medicine. While potentially highly beneficial, a number of academic and commercial groups are addressing the associated methodological, regulatory, education- and service-related challenges.

Use of virtual screening, flexible docking, and molecular interaction fields to design novel HMG-CoA reductase inhibitors for the treatment of hypercholesterolemia

Dietary changes associated with drug therapy can reduce high serum cholesterol levels and dramatically decrease the risk of coronary artery disease, stroke, and overall mortality. Statins are hypolipemic drugs that are effective in the reduction of cholesterol serum levels, attenuating cholesterol synthesis in liver by competitive inhibition regarding the substrate or molecular target HMG-CoA reductase. We have herewith used computer-aided molecular design tools, i.e., flexible docking, virtual screening in large data bases, molecular interaction fields to propose novel potential HMG-CoA reductase inhibitors that are promising for the treatment of hypercholesterolemia.

Virtual reality in assessment and treatment of schizophrenia: a systematic review

Objective To conduct a systematic review about the use of virtual reality (VR) for evaluation, treatment and/or rehabilitation of patients with schizophrenia, focused on: areas, fields and objectives; methodological issues; features of the VR used; viability and efficiency of this resource. Methods Searches were performed about schizophrenia and virtual reality in PsycINFO, Academic Search Complete, MEDLINE Complete, CINAHL with Full Text, Web of Science and Business Source Premier databases, using the following keywords: [“schizophrenia”] AND [“virtual reality” OR “serious game”] AND [“treatment” OR “therapy” OR “rehabilitation”]. The search was carried out between November 2013 and June 2014 without using any search limiters. Results A total of 101 papers were identified, and after the application of exclusion criteria, 33 papers remained. The studies analysed focused on the use of VR for the evaluation of cognitive, social, perceptual and sensory skills, and the vast majority were experimental studies, with virtual reality specifically created for them. All the reviewed papers point towards a reliable and safe use of VR for evaluating and treating cognitive and social deficits in patients with schizophrenia, with different results in terms of generalisation, motivation, assertiveness and task participation rate. Some problems were highlighted, such as its high cost and a constant need for software maintenance. Conclusion The studies show that using the virtual reality may streamline traditional evaluation/rehabilitation programmes, allowing to enhance the results achieved, both in the cognitive and in the social field, helping for the legitimisation of this population’s psycho-social inclusion.

IMRT credentialing for prospective trials using institutional virtual phantoms: results of a joint European Organization for the Research and Treatment of Cancer and Radiological Physics Center project.

BACKGROUND AND PURPOSE: Intensity-modulated radiotherapy (IMRT) credentialing for a EORTC study was performed using an anthropomorphic head phantom from the Radiological Physics Center (RPC; RPCPH). Institutions were retrospectively requested to irradiate their institutional phantom (INSTPH) using the same treatment plan in the framework of a Virtual Phantom Project (VPP) for IMRT credentialing. MATERIALS AND METHODS: CT data set of the institutional phantom and measured 2D dose matrices were requested from centers and sent to a dedicated secure EORTC uploader. Data from the RPCPH and INSTPH were thereafter centrally analyzed and inter-compared by the QA team using commercially available software (RIT; ver.5.2; Colorado Springs, USA). RESULTS: Eighteen institutions participated to the VPP. The measurements of 6 (33%) institutions could not be analyzed centrally. All other centers passed both the VPP and the RPC ±7%/4 mm credentialing criteria. At the 5%/5 mm gamma criteria (90% of pixels passing), 11(92%) as compared to 12 (100%) centers pass the credentialing process with RPCPH and INSTPH (p = 0.29), respectively. The corresponding pass rate for the 3%/3 mm gamma criteria (90% of pixels passing) was 2 (17%) and 9 (75%; p = 0.01), respectively. CONCLUSIONS: IMRT dosimetry gamma evaluations in a single plane for a H&N prospective trial using the INSTPH measurements showed agreement at the gamma index criteria of ±5%/5 mm (90% of pixels passing) for a small number of VPP measurements. Using more stringent, criteria, the RPCPH and INSTPH comparison showed disagreement. More data is warranted and urgently required within the framework of prospective studies.

Using virtual environments for trigger identification in addiction treatment

This paper presents a novel application of virtual environments to assist in encouraging behavior change in individuals who misuse drugs or alcohol. We describe the user-centered design of a series of scenes to engage users in the identification of triggers and to encourage discussions about relevant coping skills. Results from the initial testing of this application with six service users showed variation in user responses. Results also suggested that the system should encourage group discussion and that it was linked to a small improvement in users’ confidence in understanding and identifying triggers.

IMRT credentialing for prospective trials using institutional virtual phantoms: results of a joint European Organization for the Research and Treatment of Cancer and Radiological Physics Center project.

BACKGROUND AND PURPOSE Intensity-modulated radiotherapy (IMRT) credentialing for a EORTC study was performed using an anthropomorphic head phantom from the Radiological Physics Center (RPC; RPC(PH)). Institutions were retrospectively requested to irradiate their institutional phantom (INST(PH)) using the same treatment plan in the framework of a Virtual Phantom Project (VPP) for IMRT credentialing. MATERIALS AND METHODS CT data set of the institutional phantom and measured 2D dose matrices were requested from centers and sent to a dedicated secure EORTC uploader. Data from the RPC(PH) and INST(PH) were thereafter centrally analyzed and inter-compared by the QA team using commercially available software (RIT; ver.5.2; Colorado Springs, USA). RESULTS Eighteen institutions participated to the VPP. The measurements of 6 (33%) institutions could not be analyzed centrally. All other centers passed both the VPP and the RPC ±7%/4 mm credentialing criteria. At the 5%/5 mm gamma criteria (90% of pixels passing), 11(92%) as compared to 12 (100%) centers pass the credentialing process with RPC(PH) and INST(PH) (p = 0.29), respectively. The corresponding pass rate for the 3%/3 mm gamma criteria (90% of pixels passing) was 2 (17%) and 9 (75%; p = 0.01), respectively. CONCLUSIONS IMRT dosimetry gamma evaluations in a single plane for a H&N prospective trial using the INST(PH) measurements showed agreement at the gamma index criteria of ±5%/5 mm (90% of pixels passing) for a small number of VPP measurements. Using more stringent, criteria, the RPC(PH) and INST(PH) comparison showed disagreement. More data is warranted and urgently required within the framework of prospective studies.

Novel Virtual Environment for Alternative Treatment of Children with Cerebral Palsy

Cerebral palsy is a severe condition usually caused by decreased brain oxygenation during pregnancy, at birth or soon after birth. Conventional treatments for cerebral palsy are often tiresome and expensive, leading patients to quit treatment. In this paper, we describe a virtual environment for patients to engage in a playful therapeutic game for neuropsychomotor rehabilitation, based on the experience of the occupational therapy program of the Nucleus for Integrated Medical Assistance (NAMI) at the University of Fortaleza, Brazil. Integration between patient and virtual environment occurs through the hand motion sensor “Leap Motion,” plus the electroencephalographic sensor “MindWave,” responsible for measuring attention levels during task execution. To evaluate the virtual environment, eight clinical experts on cerebral palsy were subjected to a questionnaire regarding the potential of the experimental virtual environment to promote cognitive and motor rehabilitation, as well as the potential of the treatment to enhance risks and/or negatively influence the patient’s development. Based on the very positive appraisal of the experts, we propose that the experimental virtual environment is a promising alternative tool for the rehabilitation of children with cerebral palsy.

Virtual reality rehabilitation as a treatment approach for older women with mixed urinary incontinence : a feasibility study

Background Motivated patients are more likely to adhere to treatment resulting in better outcomes. Virtual reality rehabilitation (VRR) is a treatment approach that includes video gaming to enhance motivation and functional training. Aims The study objectives were (1) to evaluate the feasibility of using a combination of pelvic floor muscles (PFM) exercises and VRR (PFM/VRR) to treat mixed urinary incontinence (MUI) in older women, (2) to evaluate the effectiveness of the PFM/VRR program on MUI symptoms, quality of life (QoL), and (3) gather quantitative information regarding patient satisfaction with this new combined training program. Methods Women 65 years and older with at least 2 weekly episodes of MUI were recruited. Participants were evaluated two times before and one time after a 12-week PFM/VRR training program. Feasibility was defined as the participants' rate of participation in and completion of both the PFM/VRR training program and the home exercise. Effectiveness was evaluated through a bladder diary, pad test, symptom and QoL questionnaire, and participant's satisfaction through a questionnaire. Results Twenty-four women (70.5 ± 3.6 years) participated. The participants complied with the study demands in terms of attendance at the weekly treatment sessions (91%), adherence to home exercise (92%) and completion of the three evaluations (96%). Post-intervention, the frequency and quantity of urine leakage decreased and patientreported symptoms and QoL improved significantly. Most participants were very satisfied with treatment (91%). Conclusion A combined PFM/VRR program is an acceptable, efficient, and satisfying functional treatment for older women with MUI and should be explore through further RCTs.

Virtual reality rehabilitation as a treatment approach for older women with mixed urinary incontinence : a feasibility study

Background Motivated patients are more likely to adhere to treatment resulting in better outcomes. Virtual reality rehabilitation (VRR) is a treatment approach that includes video gaming to enhance motivation and functional training. Aims The study objectives were (1) to evaluate the feasibility of using a combination of pelvic floor muscles (PFM) exercises and VRR (PFM/VRR) to treat mixed urinary incontinence (MUI) in older women, (2) to evaluate the effectiveness of the PFM/VRR program on MUI symptoms, quality of life (QoL), and (3) gather quantitative information regarding patient satisfaction with this new combined training program. Methods Women 65 years and older with at least 2 weekly episodes of MUI were recruited. Participants were evaluated two times before and one time after a 12-week PFM/VRR training program. Feasibility was defined as the participants' rate of participation in and completion of both the PFM/VRR training program and the home exercise. Effectiveness was evaluated through a bladder diary, pad test, symptom and QoL questionnaire, and participant's satisfaction through a questionnaire. Results Twenty-four women (70.5 ± 3.6 years) participated. The participants complied with the study demands in terms of attendance at the weekly treatment sessions (91%), adherence to home exercise (92%) and completion of the three evaluations (96%). Post-intervention, the frequency and quantity of urine leakage decreased and patientreported symptoms and QoL improved significantly. Most participants were very satisfied with treatment (91%). Conclusion A combined PFM/VRR program is an acceptable, efficient, and satisfying functional treatment for older women with MUI and should be explore through further RCTs.

Molecular dynamics, density functional, ADMET predictions, virtual screening, and molecular interaction field studies for identification and evaluation of novel potential CDK2 inhibitors in cancer therapy

In this work, we have used molecular dynamics, density functional theory, virtual screening, ADMET predictions, and molecular interaction field studies to design and propose eight novel potential inhibitors of CDK2. The eight molecules proposed showed interesting structural characteristics that are required for inhibiting the CDK2 activity and show potential as drug candidates for the treatment of cancer. The parameters related to the Rule of Five were calculated, and only one of the molecules violated more than one parameter. One of the proposals and one of the drug-like compounds selected by virtual screening indicated to be promising candidates for CDK2-based cancer therapy.

Computer-aided Drug Design of Novel PLA(2) Inhibitor Candidates for Treatment of Snakebite

Phospholipases A(2) (PLA(2)) are enzymes commonly found in snake venoms from Viperidae and Elaphidae families, which are major components thereof. Many plants are used in traditional medicine its active agents against various effects induced by snakebite. This article presents the PLA(2) BthTX-I structure prediction based on homology modeling. In addition, we have performed virtual screening in a large database yielding a set of potential bioactive inhibitors. A flexible docking program was used to investigate the interactions between the receptor and the new ligands. We have performed molecular interaction fields (MIFs) calculations with the phospholipase model. Results confirm the important role of Lys49 for binding ligands and suggest three additional residues as well. We have proposed a theoretically nontoxic, drug-like, and potential novel BthTX-I inhibitor. These calculations have been used to guide the design of novel phospholipase inhibitors as potential lead compounds that may be optimized for future treatment of snakebite victims as well as other human diseases in which PLA(2) enzymes are involved.