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This report summarizes the outcomes of the ICPR 2024 Competition on Multiple Sclerosis Lesion Segmentation (MSLesSeg). The competition aimed to develop methods capable of automatically segmenting multiple sclerosis lesions in MRI scans. Participants were provided with a novel annotated dataset comprising a heterogeneous cohort of MS patients, featuring both baseline and follow-up MRI scans acquired at different hospitals. MSLesSeg focuses on developing algorithms that can independently segment multiple sclerosis lesions of an unexamined cohort of patients. This segmentation approach aims to overcome current benchmarks by eliminating user interaction and ensuring robust lesion detection at different timepoints, encouraging innovation and promoting methodological advances.

Magnetic resonance imaging is a fundamental tool to reach a diagnosis of multiple sclerosis and monitoring its progression. Although several attempts have been made to segment multiple sclerosis lesions using artificial intelligence, fully automated analysis is not yet available. State-of-the-art methods rely on slight variations in segmentation architectures (e.g. U-Net, etc.). However, recent research has demonstrated how exploiting temporal-aware features and attention mechanisms can provide a significant boost to traditional architectures. This paper proposes a framework that exploits an augmented U-Net architecture with a convolutional long short-term memory layer and attention mechanism which is able to segment and quantify multiple sclerosis lesions detected in magnetic resonance images. Quantitative and qualitative evaluation on challenging examples demonstrated how the method outperforms previous state-of-the-art approaches, reporting an overall Dice score of 89% and also demonstrating robustness and generalization ability on never seen new test samples of a new dedicated under construction dataset.

The term "In Silico Trial" indicates the use of computer modelling and simulation to evaluate the safety and efficacy of a medical product, whether a drug, a medical device, a diagnostic product or an advanced therapy medicinal product. Predictive models are positioned as new methodologies for the development and the regulatory evaluation of medical products. New methodologies are qualified by regulators such as FDA and EMA through formal processes, where a first step is the definition of the Context of Use (CoU), which is a concise description of how the new methodology is intended to be used in the development and regulatory assessment process. As In Silico Trials are a disruptively innovative class of new methodologies, it is important to have a list of possible CoUs highlighting potential applications for the development of the relative regulatory science. This review paper presents the result of a consensus process that took place in the InSilicoWorld Community of Practice, an online forum for experts in in silico medicine. The experts involved identified 46 descriptions of possible CoUs which were organised into a candidate taxonomy of nine CoU categories. Examples of 31 CoUs were identified in the available literature; the remaining 15 should, for now, be considered speculative., Comment: Submitted to IEEE JOURNAL OF BIOMEDICAL AND HEALTH INFORMATICS

Agent-Based Models are a powerful class of computational models widely used to simulate complex phenomena in many different application areas. However, one of the most critical aspects, poorly investigated in the literature, regards an important step of the model credibility assessment: solution verification. This study overcomes this limitation by proposing a general verification framework for Agent-Based Models that aims at evaluating the numerical errors associated with the model. A step-by-step procedure, which consists of two main verification studies (deterministic and stochastic model verification), is described in detail and applied to a specific mission critical scenario: the quantification of the numerical approximation error for UISS-TB, an ABM of the human immune system developed to predict the progression of pulmonary tuberculosis. Results provide indications on the possibility to use the proposed model verification workflow to systematically identify and quantify numerical approximation errors associated with UISS-TB and, in general, with any other ABMs.

Multiple Sclerosis (MS) is a chronic and potentially highly disabling disease that can cause permanent damage and deterioration of the central nervous system. In Europe it is the leading cause of non-traumatic disabilities in young adults, since more than 700,000 EU people suffer from MS. Although recent studies on MS pathophysiology have been provided, MS remains a challenging disease. In this context, thanks to recent advances in software and hardware technologies, computational models and computer simulations are becoming appealing research tools to support scientists in the study of such disease. Thus, motivated by this consideration we propose in this paper a new model to study the evolution of MS in silico, and the effects of the administration of Daclizumab drug, taking into account also spatiality and temporality of the involved phenomena. Moreover, we show how the intrinsic symmetries of the system can be exploited to drastically reduce the complexity of its analysis., Comment: Submitted to CIBB 2019 post proceedings - LNCS

SARS-CoV-2 is a severe respiratory infection that infects humans. Its outburst entitled it as a pandemic emergence. To get a grip on this, outbreak specific preventive and therapeutic interventions are urgently needed. It must be said that, until now, there are no existing vaccines for coronaviruses. To promptly and rapidly respond to pandemic events, the application of in silico trials can be used for designing and testing medicines against SARS-CoV-2 and speed-up the vaccine discovery pipeline, predicting any therapeutic failure and minimizing undesired effects. Here, we present an in silico platform that showed to be in very good agreement with the latest literature in predicting SARS- CoV-2 dynamics and related immune system host response. Moreover, it has been used to predict the outcome of one of the latest suggested approach to design an effective vaccine, based on monoclonal antibody. UISS is then potentially ready to be used as an in silico trial platform to predict the outcome of vaccination strategy against SARS-CoV-2., Comment: 8 pages, 7 figures

EC funded STriTuVaD project aims to test, through a phase IIb clinical trial, two of the most advanced therapeutic vaccines against tuberculosis. In parallel, we have extended the Universal Immune System Simulator to include all relevant determinants of such clinical trial, to establish its predictive accuracy against the individual patients recruited in the trial, to use it to generate digital patients and predict their response to the HRT being tested, and to combine them to the observations made on physical patients using a new in silico-augmented clinical trial approach that uses a Bayesian adaptive design. This approach, where found effective could drastically reduce the cost of innovation in this critical sector of public healthcare. One of the most challenging task is to develop a methodology to reproduce biological diversity of the subjects that have to be simulated, i.e., provide an appropriate strategy for the generation of libraries of digital patients. This has been achieved through the the creation of the initial immune system repertoire in a stochastic way, and though the identification of a "vector of features" that combines both biological and pathophysiological parameters that personalize the digital patient to reproduce the physiology and the pathophysiology of the subject., Comment: 5 pages

Tuberculosis (TB) is one of the deadliest diseases worldwide, with 1,5 million fatalities every year along with potential devastating effects on society, families and individuals. To address this alarming burden, vaccines can play a fundamental role, even though to date no fully effective TB vaccine really exists. Current treatments involve several combinations of antibiotics administered to TB patients for up to two years, leading often to financial issues and reduced therapy adherence. Along with this, the development and spread of drug-resistant TB strains is another big complicating matter. Faced with these challenges, there is an urgent need to explore new vaccination strategies in order to boost immunity against tuberculosis and shorten the duration of treatment. Computational modeling represents an extraordinary way to simulate and predict the outcome of vaccination strategies, speeding up the arduous process of vaccine pipeline development and relative time to market. Here, we present EU - funded STriTuVaD project computational platform able to predict the artificial immunity induced by RUTI and ID93/GLA-SE, two specific tuberculosis vaccines. Such an in silico trial will be validated through a phase 2b clinical trial. Moreover, STriTuVaD computational framework is able to inform of the reasons for failure should the vaccinations strategies against M. tuberculosis under testing found not efficient, which will suggest possible improvements., Comment: 5 pages

Thyroid cancer is the commonest endocrine malignancy. Mutation in the BRAF serine/threonine kinase is the most frequent genetic alteration in thyroid cancer. Target therapy for advanced and poorly differentiated thyroid carcinomas include BRAF pathway inhibitors. Here, we evaluated the role of MAP3K8 expression as a potential driver of resistance to BRAF inhibition in thyroid cancer. By analyzing Gene Expression Omnibus data repository, across all thyroid cancer histotypes, we found that MAP3K8 is up-regulated in poorly differentiated thyroid carcinomas and its expression is related to a stem cell like phenotype and a poorer prognosis and survival. Taken together these data unravel a novel mechanism for thyroid cancer progression and chemo-resistance and confirm previous results obtained in cultured thyroid cancer stem cells, Comment: 5 pages

Different research communities have developed various approaches to assess the credibility of predictive models. Each approach usually works well for a specific type of model, and under some epistemic conditions that are normally satisfied within that specific research domain. Some regulatory agencies recently started to consider evidences of safety and efficacy on new medical products obtained using computer modelling and simulation (which is referred to as In Silico Trials); this has raised the attention in the computational medicine research community on the regulatory science aspects of this emerging discipline. But this poses a foundational problem: in the domain of biomedical research the use of computer modelling is relatively recent, without a widely accepted epistemic framing for problem of model credibility. Also, because of the inherent complexity of living organisms, biomedical modellers tend to use a variety of modelling methods, sometimes mixing them in the solution of a single problem. In such context merely adopting credibility approaches developed within other research community might not be appropriate. In this position paper we propose a theoretical framing for the problem of assessing the credibility of a predictive models for In Silico Trials, which accounts for the epistemic specificity of this research field and is general enough to be used for different type of models., Comment: 11 pages

The main results in the paper are the weighted multipolar Hardy inequalities \begin{equation*} c\int_{\R^N}\sum_{i=1}^n\frac{u^2}{|x-a_i|^2}\,d\mu \leq\int_{\R^N}|\nabla u |^2d\mu+ K\int_{\R^N} u^2d\mu, \end{equation*} in $\R^N$ for any $u$ in a suitable weighted Sobolev space, with $0

\begin{abstract} We state the following weighted Hardy inequality \begin{equation*} c_{o, \mu}\int_{{\R}^N}\frac{\varphi^2 }{|x|^2}\, d\mu\le \int_{{\R}^N} |\nabla\varphi|^2 \, d\mu + K \int_{\R^N}\varphi^2 \, d\mu \quad \forall\, \varphi \in H_\mu^1 %\qquad c\le c_\mu, \end{equation*} in the context of the study of the Kolmogorov operators \begin{equation*} Lu=\Delta u+\frac{\nabla \mu}{\mu}\cdot\nabla u \end{equation*} perturbed by inverse square potentials and of the related evolution problems. The function $\mu$ in the drift term is a probability density on $\R^N$. We prove the optimality of the constant $c_{o, \mu}$ and state existence and nonexistence results following the Cabr\'e-Martel's approach \cite{CabreMartel} extended to Kolmogorov operators. \end{abstract}