Current Overview of Metal Nanoparticles' Synthesis, Characterization, and Biomedical Applications, with a Focus on Silver and Gold Nanoparticles.

Metal nanoparticles (NPs) have garnered considerable attention, due to their unique physicochemical properties, that render them promising candidates for various applications in medicine and industry. This article offers a comprehensive overview of the most recent advancements in the manufacturing, characterization, and biomedical utilization of metal NPs, with a primary focus on silver and gold NPs. Their potential as effective anticancer, anti-inflammatory, and antimicrobial agents, drug delivery systems, and imaging agents in the diagnosis and treatment of a variety of disorders is reviewed. Moreover, their translation to therapeutic settings, and the issue of their inclusion in clinical trials, are assessed in light of over 30 clinical investigations that concentrate on administering either silver or gold NPs in conditions ranging from nosocomial infections to different types of cancers. This paper aims not only to examine the biocompatibility of nanomaterials but also to emphasize potential challenges that may limit their safe integration into healthcare practices. More than 100 nanomedicines are currently on the market, which justifies ongoing study into the use of nanomaterials in medicine. Overall, the present review aims to highlight the potential of silver and gold NPs as innovative and effective therapeutics in the field of biomedicine, citing some of their most relevant current applications.

Privacy Enhancing and Scalable Federated Learning to Accelerate AI Implementation in Cross-Silo and IoMT Environments.

Federated Learning (FL) is a machine learning technique that enables to collaboratively learn valuable information across devices or sites without moving the data. In FL, the model is trained and shared across decentralized locations where data are privately owned. After local training, model updates are sent back to a central server, thus enabling access to distributed data on a large scale while maintaining privacy, security, and data access rights. Although FL is a well-studied topic, existing frameworks are still at an early stage of development. They encounter challenges with respect to scalability, data security, aggregation methodologies, data provenance, and production readiness. In this paper, we propose a novel FL framework that supports functionalities like scalable processing with respect of data, devices, sites and collaborators, monitoring services, privacy, and support for use cases. Furthermore, we integrate multi party computation (MPC) within the FL setup, preventing reverse engineering attacks. The proposed framework has been evaluated in diverse use cases both in cross-device and cross-silo settings. In the former case, in-device FL is leveraged in the context of an AI-driven internet of medical things (IoMT) environment. We demonstrate the framework suitability for a range of AI techniques while benchmarking with conventional centralized training. Furthermore, we prove the feasibility of developing a user-friendly pipeline that enables an efficient implementation of FL in diverse clinical use cases.

Neural gradient boosting in federated learning for hemodynamic instability prediction: towards a distributed and scalable deep learning-based solution.

Federated learning (FL) is a privacy preserving approach to learning that overcome issues related to data access, privacy, and security, which represent key challenges in the healthcare sector. FL enables hospitals to collaboratively learn a shared prediction model without moving the data outside their secure infrastructure. To do so, after having sent model updates to a central server, an update aggregation is performed, and the model is sent back to the sites for further training. Although widely applied on neural networks, the deployment of FL architectures is lacking scalability and support for machine learning techniques such as decision tree-based models. The latter, when embedded in FL, suffer from costly encryption techniques applied for sharing sensitive information such as the splitting decisions within the trees. In this work, we focus on predicting hemodynamic instability on ICU patients by enabling distributed gradient boosting in FL. We employ a clinical dataset from 25 hospitals generated based on the Philips eICU database and we design a FL pipeline that supports neural-based boosting models as well as conventional neural networks. This enhancement enables decision tree models in FL, which represent the state-of-the-art approach for classification tasks involving tabular clinical data. Comparable performances in terms of accuracy, precision, recall and F1 score have been reached when detecting hemodynamic instability in FL, and in a centralized setup. In summary, we demonstrate the feasibility of a scalable FL for detecting hemodynamic instability in ICU data, which preserves privacy and holds the deployment benefits of a neural-based architecture.

Patient empowerment for cancer patients through a novel ICT infrastructure.

As a result of recent advances in cancer research and "precision medicine" approaches, i.e. the idea of treating each patient with the right drug at the right time, more and more cancer patients are being cured, or might have to cope with a life with cancer. For many people, cancer survival today means living with a complex and chronic condition. Surviving and living with or beyond cancer requires the long-term management of the disease, leading to a significant need for active rehabilitation of the patients. In this paper, we present a novel methodology employed in the iManageCancer project for cancer patient empowerment in which personal health systems, serious games, psychoemotional monitoring and other novel decision-support tools are combined into an integrated patient empowerment platform. We present in detail the ICT infrastructure developed and our evaluation with the involvement of cancer patients on two sites, a large-scale pilot for adults and a small-scale test for children. The evaluation showed mixed evidences on the improvement of patient empowerment, while ability to cope with cancer, including improvement in mood and resilience to cancer, increased for the participants of the adults' pilot.

iManageMyHealth and iSupportMyPatients: mobile decision support and health management apps for cancer patients and their doctors.

Clinical decision support systems can play a crucial role in healthcare delivery as they promise to improve health outcomes and patient safety, reduce medical errors and costs and contribute to patient satisfaction. Used in an optimal way, they increase the quality of healthcare by proposing the right information and intervention to the right person at the right time in the healthcare delivery process. This paper reports on a specific approach to integrated clinical decision support and patient guidance in the cancer domain as proposed by the H2020 iManageCancer project. This project aims at facilitating efficient self-management and management of cancer according to the latest available clinical knowledge and the local healthcare delivery model, supporting patients and their healthcare providers in making informed decisions on treatment choices and in managing the side effects of their therapy. The iManageCancer platform is a comprehensive platform of interconnected mobile tools to empower cancer patients and to support them in the management of their disease in collaboration with their doctors. The backbone of the iManageCancer platform comprises a personal health record and the central decision support unit (CDSU). The latter offers dedicated services to the end users in combination with the apps iManageMyHealth and iSupportMyPatients. The CDSU itself is composed of the so-called Care Flow Engine (CFE) and the model repository framework (MRF). The CFE executes personalised and workflow oriented formal disease management diagrams (Care Flows). In decision points of such a Care Flow, rules that operate on actual health information of the patient decide on the treatment path that the system follows. Alternatively, the system can also invoke a predictive model of the MRF to proceed with the best treatment path in the diagram. Care Flow diagrams are designed by clinical experts with a specific graphical tool that also deploys these diagrams as executable workflows in the CFE following the Business Process Model and Notation (BPMN) standard. They are exposed as services that patients or their doctors can use in their apps in order to manage certain aspects of the cancer disease like pain, fatigue or the monitoring of chemotherapies at home. The mHealth platform for cancer patients is currently being assessed in clinical pilots in Italy and Germany and in several end-user workshops.

Evaluating the benefits of digital pathology implementation: time savings in laboratory logistics.

BACKGROUND: The benefits of digital pathology for workflow improvement and thereby cost savings in pathology, at least partly outweighing investment costs, are being increasingly recognised. Successful implementations in a variety of scenarios have started to demonstrate the cost benefits of digital pathology for both research and routine diagnosis, contributing to a sound business case encouraging further adoption. To further support new adopters, there is still a need for detailed assessment of the impact that this technology has on the relevant pathology workflows, with an emphasis on time-saving. AIMS: To assess the impact of digital pathology adoption on logistic laboratory tasks (i.e. not including pathologists' time for diagnosis-making) in the Laboratorium Pathologie Oost Nederland, a large regional pathology laboratory in The Netherlands. METHODS AND RESULTS: To quantify the benefits of digitisation, we analysed the differences between the traditional analogue and new digital workflows, carried out detailed measurements of all relevant steps in key analogue and digital processes, and compared the time spent. We modelled and assessed the logistic savings in five workflows: (i) routine diagnosis; (ii) multidisciplinary meeting; (iii) external revision requests; (iv) extra stainings; and (v) external consultation. On average, >19 working hours were saved on a typical day by working digitally, with the highest savings in routine diagnosis and multidisciplinary meeting workflows. CONCLUSIONS: By working digitally, a significant amount of time could be saved in a large regional pathology laboratory with a typical case mix. We also present the data in each workflow per task and concrete logistic steps to allow extrapolation to the context and case mix of other laboratories.

Cohort Selection and Management Application Leveraging Standards-based Semantic Interoperability and a Groovy DSL.

This paper describes a new Cohort Selection application implemented to support streamlining the definition phase of multi-centric clinical research in oncology. Our approach aims at both ease of use and precision in defining the selection filters expressing the characteristics of the desired population. The application leverages our standards-based Semantic Interoperability Solution and a Groovy DSL to provide high expressiveness in the definition of filters and flexibility in their composition into complex selection graphs including splits and merges. Widely-adopted ontologies such as SNOMED-CT are used to represent the semantics of the data and to express concepts in the application filters, facilitating data sharing and collaboration on joint research questions in large communities of clinical users. The application supports patient data exploration and efficient collaboration in multi-site, heterogeneous and distributed data environments.

Workflow-driven clinical decision support for personalized oncology.

BACKGROUND: The adoption in oncology of Clinical Decision Support (CDS) may help clinical users to efficiently deal with the high complexity of the domain, lead to improved patient outcomes, and reduce the current knowledge gap between clinical research and practice. While significant effort has been invested in the implementation of CDS, the uptake in the clinic has been limited. The barriers to adoption have been extensively discussed in the literature. In oncology, current CDS solutions are not able to support the complex decisions required for stratification and personalized treatment of patients and to keep up with the high rate of change in therapeutic options and knowledge. RESULTS: To address these challenges, we propose a framework enabling efficient implementation of meaningful CDS that incorporates a large variety of clinical knowledge models to bring to the clinic comprehensive solutions leveraging the latest domain knowledge. We use both literature-based models and models built within the p-medicine project using the rich datasets from clinical trials and care provided by the clinical partners. The framework is open to the biomedical community, enabling reuse of deployed models by third-party CDS implementations and supporting collaboration among modelers, CDS implementers, biomedical researchers and clinicians. To increase adoption and cope with the complexity of patient management in oncology, we also support and leverage the clinical processes adhered to by healthcare organizations. We design an architecture that extends the CDS framework with workflow functionality. The clinical models are embedded in the workflow models and executed at the right time, when and where the recommendations are needed in the clinical process. CONCLUSIONS: In this paper we present our CDS framework developed in p-medicine and the CDS implementation leveraging the framework. To support complex decisions, the framework relies on clinical models that encapsulate relevant clinical knowledge. Next to assisting the decisions, this solution supports by default (through modeling and implementation of workflows) the decision processes as well and exploits the knowledge embedded in those processes.

The INTEGRATE project: Delivering solutions for efficient multi-centric clinical research and trials.

The objective of the INTEGRATE project (http://www.fp7-integrate.eu/) that has recently concluded successfully was the development of innovative biomedical applications focused on streamlining the execution of clinical research, on enabling multidisciplinary collaboration, on management and large-scale sharing of multi-level heterogeneous datasets, and on the development of new methodologies and of predictive multi-scale models in cancer. In this paper, we present the way the INTEGRATE consortium has approached important challenges such as the integration of multi-scale biomedical data in the context of post-genomic clinical trials, the development of predictive models and the implementation of tools to facilitate the efficient execution of postgenomic multi-centric clinical trials in breast cancer. Furthermore, we provide a number of key "lessons learned" during the process and give directions for further future research and development.

Case Study for Integration of an Oncology Clinical Site in a Semantic Interoperability Solution based on HL7 v3 and SNOMED-CT: Data Transformation Needs.

This paper describes the data transformation pipeline defined to support the integration of a new clinical site in a standards-based semantic interoperability environment. The available datasets combined structured and free-text patient data in Dutch, collected in the context of radiation therapy in several cancer types. Our approach aims at both efficiency and data quality. We combine custom-developed scripts, standard tools and manual validation by clinical and knowledge experts. We identified key challenges emerging from the several sources of heterogeneity in our case study (systems, language, data structure, clinical domain) and implemented solutions that we will further generalize for the integration of new sites. We conclude that the required effort for data transformation is manageable which supports the feasibility of our semantic interoperability solution. The achieved semantic interoperability will be leveraged for the deployment and evaluation at the clinical site of applications enabling secondary use of care data for research. This work has been funded by the European Commission through the INTEGRATE (FP7-ICT-2009-6-270253) and EURECA (FP7-ICT-2011-288048) projects.

Enhancing reuse of structured eligibility criteria and supporting their relaxation.

Patient recruitment is one of the most important barriers to successful completion of clinical trials and thus to obtaining evidence about new methods for prevention, diagnostics and treatment. The reason is that recruitment is effort consuming. It requires the identification of candidate patients for the trial (the population under study), and verifying for each patient whether the eligibility criteria are met. The work we describe in this paper aims to support the comparison of population under study in different trials, and the design of eligibility criteria for new trials. We do this by introducing structured eligibility criteria, that enhance reuse of criteria across trials. We developed a method that allows for automated structuring of criteria from text. Additionally, structured eligibility criteria allow us to propose suggestions for relaxation of criteria to remove potentially unnecessarily restrictive conditions. We thereby increase the recruitment potential and generalizability of a trial. Our method for automated structuring of criteria enables us to identify related conditions and to compare their restrictiveness. The comparison is based on the general meaning of criteria, comprised of commonly occurring contextual patterns, medical concepts and constraining values. These are automatically identified using our pattern detection algorithm, state of the art ontology annotators and semantic taggers. The comparison uses predefined relations between the patterns, concept equivalences defined in medical ontologies, and threshold values. The result is a library of structured eligibility criteria which can be browsed using fine grained queries. Furthermore, we developed visualizations for the library that enable intuitive navigation of relations between trials, criteria and concepts. These visualizations expose interesting co-occurrences and correlations, potentially enhancing meta-research. The method for criteria structuring processes only certain types of criteria, which results in low recall of the method (18%) but a high precision for the relations we identify between the criteria (94%). Analysis of the approach from the medical perspective revealed that the approach can be beneficial for supporting trial design, though more research is needed.

Enabling semantic interoperability in multi-centric clinical trials on breast cancer.

BACKGROUND AND OBJECTIVES: Post-genomic clinical trials require the participation of multiple institutions, and collecting data from several hospitals, laboratories and research facilities. This paper presents a standard-based solution to provide a uniform access endpoint to patient data involved in current clinical research. METHODS: The proposed approach exploits well-established standards such as HL7 v3 or SPARQL and medical vocabularies such as SNOMED CT, LOINC and HGNC. A novel mechanism to exploit semantic normalization among HL7-based data models and biomedical ontologies has been created by using Semantic Web technologies. RESULTS: Different types of queries have been used for testing the semantic interoperability solution described in this paper. The execution times obtained in the tests enable the development of end user tools within a framework that requires efficient retrieval of integrated data. CONCLUSIONS: The proposed approach has been successfully tested by applications within the INTEGRATE and EURECA EU projects. These applications have been deployed and tested for: (i) patient screening, (ii) trial recruitment, and (iii) retrospective analysis; exploiting semantically interoperable access to clinical patient data from heterogeneous data sources.

Semantic Normalization and Query Abstraction Based on SNOMED-CT and HL7: Supporting Multicentric Clinical Trials.

Advances in the use of omic data and other biomarkers are increasing the number of variables in clinical research. Additional data have stratified the population of patients and require that current studies be performed among multiple institutions. Semantic interoperability and standardized data representation are a crucial task in the management of modern clinical trials. In the past few years, different efforts have focused on integrating biomedical information. Due to the complexity of this domain and the specific requirements of clinical research, the majority of data integration tasks are still performed manually. This paper presents a semantic normalization process and a query abstraction mechanism to facilitate data integration and retrieval. A process based on well-established standards from the biomedical domain and the latest semantic web technologies has been developed. Methods proposed in this paper have been tested within the EURECA EU research project, where clinical scenarios require the extraction of semantic knowledge from biomedical vocabularies. The aim of this paper is to provide a novel method to abstract from the data model and query syntax. The proposed approach has been compared with other initiatives in the field by storing the same dataset with each of those solutions. Results show an extended functionality and query capabilities at the cost of slightly worse performance in query execution. Implementations in real settings have shown that following this approach, usable interfaces can be developed to exploit clinical trial data outcomes.

Supporting patient screening to identify suitable clinical trials.

To support the efficient execution of post-genomic multi-centric clinical trials in breast cancer we propose a solution that streamlines the assessment of the eligibility of patients for available trials. The assessment of the eligibility of a patient for a trial requires evaluating whether each eligibility criterion is satisfied and is often a time consuming and manual task. The main focus in the literature has been on proposing different methods for modelling and formalizing the eligibility criteria. However the current adoption of these approaches in clinical care is limited. Less effort has been dedicated to the automatic matching of criteria to the patient data managed in clinical care. We address both aspects and propose a scalable, efficient and pragmatic patient screening solution enabling automatic evaluation of eligibility of patients for a relevant set of trials. This covers the flexible formalization of criteria and of other relevant trial metadata and the efficient management of these representations.

Computational Horizons In Cancer (CHIC): Developing Meta- and Hyper-Multiscale Models and Repositories for In Silico Oncology - a Brief Technical Outline of the Project.

This paper briefly outlines the aim, the objectives, the architecture and the main building blocks of the ongoing large scale integrating transatlantic research project CHIC (http://chic-vph.eu/).

Improving the implementation of clinical decision support systems.

Clinical decision support (CDS) systems promise to improve the quality of clinical care by helping physicians to make better, more informed decisions efficiently. However, the design and testing of CDS systems for practical medical use is cumbersome. It has been recognized that this may easily lead to a problematic mismatch between the developers' idea of the system and requirements from clinical practice. In this paper, we will present an approach to reduce the complexity of constructing a CDS system. The approach is based on an ontological annotation of data resources, which improves standardization and the semantic processing of data. This, in turn, allows to use data mining tools to automatically create hypotheses for CDS models, which reduces the manual workload in the creation of a new model. The approach is implemented in the context of EU research project p-medicine. A proof of concept implementation on data from an existing Leukemia study is presented.

Analyzing SNOMED CT and HL7 terminology binding for semantic interoperability on post-genomic clinical trials.

Current post-genomic clinical trials in cancer involve the collaboration of several institutions. Multi-centric retrospective analysis requires advanced methods to ensure semantic interoperability. In this scenario, the objective of the EU funded INTEGRATE project, is to provide an infrastructure to share knowledge and data in post-genomic breast cancer clinical trials. This paper presents the process carried out in this project, to bind domain terminologies in the area, such as SNOMED CT, with the HL7 v3 Reference Information Model (RIM). The proposed terminology binding follow the HL7 recommendations, but should also consider important issues such as overlapping concepts and domain terminology coverage. Although there are limitations due to the large heterogeneity of the data in the area, the proposed process has been successfully applied within the context of the INTEGRATE project. An improvement in semantic interoperability of patient data from modern breast cancer clinical trials, aims to enhance the clinical practice in oncology.

ACGT: advancing clinico-genomic trials on cancer - four years of experience.

The challenges regarding seamless integration of distributed, heterogeneous and multilevel data arising in the context of contemporary, post-genomic clinical trials cannot be effectively addressed with current methodologies. An urgent need exists to access data in a uniform manner, to share information among different clinical and research centers, and to store data in secure repositories assuring the privacy of patients. Advancing Clinico-Genomic Trials (ACGT) was a European Commission funded Integrated Project that aimed at providing tools and methods to enhance the efficiency of clinical trials in the -omics era. The project, now completed after four years of work, involved the development of both a set of methodological approaches as well as tools and services and its testing in the context of real-world clinico-genomic scenarios. This paper describes the main experiences using the ACGT platform and its tools within one such scenario and highlights the very promising results obtained.

Alignment method for spectrograms of DNA sequences.

DNA spectrograms express the periodicities of each of the four nucleotides A, T, C, and G in one or several genomic sequences to be analyzed. DNA spectral analysis can be applied to systematically investigate DNA patterns, which may correspond to relevant biological features. As opposed to looking at nucleotide sequences, spectrogram analysis may detect structural characteristics in very long sequences that are not identifiable by sequence alignment. Alignment of DNA spectrograms can be used to facilitate analysis of very long sequences or entire genomes at different resolutions. Standard clustering algorithms have been used in spectral analysis to find strong patterns in spectra. However, as they use a global distance metric, these algorithms can only detect strong patterns coexisting in several frequencies. In this paper, we propose a new method and several algorithms for aligning spectra suitable for efficient spectral analysis and allowing for the easy detection of strong patterns in both single frequencies and multiple frequencies.

Service-oriented architecture for grid-enabling medical applications.

Grid technologies have the potential to enable healthcare organizations to efficiently use powerful tools, applications and resources, many of which were so far inaccessible to them. This paper introduces a service-oriented architecture meant to Grid-enable several classes of computationally intensive medical applications for improved performance and cost-effective access to resources. We apply this architecture to fiber tracking [1,2], a computationally intensive medical application suited for parallelization through decomposition, and carry out experiments with various sets of parameters, in realistic environments and with standard network solutions. Furthermore, we deploy and assess our solution in a hospital environment, at the Amsterdam Medical Center, as part of our cooperation in the Dutch VL-e project. Our results show that parallelization and Grid execution may bring significant performance improvements and that the overhead introduced by making use of remote, distributed resources is relatively small.