Data Adequacy by an Extended Analytic Hierarchy Process for Inverse Uncertainty Quantification in Nuclear Safety Analysis

Data Adequacy (DA) assessment of experimental databases must be performed to control the impact of user effects on the results provided by the Thermal-Hydraulic (T-H) codes employed for the safety assessment of Nuclear Power Plants (NPPs). The activity is typically based on expert judgement, which, however, lacks a rigorous treatment of the uncertainties. With the objective to overcome this limitation, we propose a Multi-Criteria Decision Making (MCDM) approach to consider the Representativeness (R) and Completeness (C) of the databases by an Analytic Hierarchy Process (AHP) combined with Interval Analysis (IA) and Monte Carlo Simulation (MCS) to quantify the uncertainty. The approach for DA is exemplified on the databases made available to the participants of the ATRIUM (Application Tests for Realization of Inverse Uncertainty quantification and validation Methodologies in thermal hydraulics) project promoted by the WGAMA of the OECD-NEA, whose ultimate objective is the systematic application of Inverse Uncertainty Quantification (IUQ) methodologies to assess the uncertainties affecting the T-H model of an Intermediate Break Loss Of Coolant Accident (IBLOCA) of a Light Water Reactor (LWR). The outcomes of the application show that the proposed approach allows overcoming some of the limitations of expert-based approaches, reducing the reliance on subjective evaluations through the incorporation of quantitative metrics in the analysis and via the proper quantification of the uncertainty

Pre-discharge Cardiorespiratory Monitoring in Preterm Infants. the CORE Study

Objective: Ensuring cardiorespiratory (CR) stability is essential for a safe discharge. The aim of this study was to assess the impact of a new pre-discharge protocol named CORE on the risk of hospital readmission (RHR). Methods: Preterm infants admitted in our NICU between 2015 and 2018 were randomly assigned to CORE (exposed) or to standard (not-exposed) discharge protocol. CORE included 24 h-clinical observation, followed by 24 h-instrumental CR monitoring only for high-risk infants. RHR 12 months after discharge and length of stay represent the primary and secondary outcomes, respectively. Results: Three hundred and twenty three preterm infants were enrolled. Exposed infants had a lower RHR (log-rank p < 0.05). The difference was especially marked 3 months after discharge (9.09 vs. 21.6%; p = 0.004). The hospital length of stay in exposed and not-exposed infants was 39(26–58) and 43(26–68) days, respectively (p = 0.16). Conclusions: The CORE protocol could help neonatologists to define the best timing for discharge reducing RHR without lengthening hospital stay

Impact of immune parameters and immune dysfunctions on the prognosis of patients with chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is characterized by a wide spectrum of immune alterations, affecting both the innate and adaptive immunity. These immune dysfunctions strongly impact the immune surveillance, facilitate tumor progression and eventually affect the disease course. Quantitative and functional alterations involving conventional T cells, γδ T cells, regulatory T cells, NK and NKT cells, and myeloid cells, together with hypogammaglobulinemia, aberrations in the complement pathways and altered cytokine signature have been reported in patients with CLL. Some of these immune parameters have been shown to associate with other CLL‐related characteristics with a known prognostic relevance or to correlate with disease prognosis. Also, in CLL, the complex immune response dysfunctions eventually translate in clinical manifestations, including autoimmune phenomena, increased risk of infections and second malignancies. These clinical issues are overall the most common complications that affect the course and management of CLL, and they also may impact overall disease prognosis

Immune dysfunctions and immune-based therapeutic interventions in chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL) is a B-cell malignancy characterized by a wide range of tumor-induced alterations, which affect both the innate and adaptive arms of the immune response, and accumulate during disease progression. In recent years, the development of targeted therapies, such as the B-cell receptor signaling inhibitors and the Bcl-2 protein inhibitor venetoclax, has dramatically changed the treatment landscape of CLL. Despite their remarkable anti-tumor activity, targeted agents have some limitations, which include the development of drug resistance mechanisms and the inferior efficacy observed in high-risk patients. Therefore, additional treatments are necessary to obtain deeper responses and overcome drug resistance. Allogeneic hematopoietic stem cell transplantation (HSCT), which exploits immune-mediated graft-versus-leukemia effect to eradicate tumor cells, currently represents the only potentially curative therapeutic option for CLL patients. However, due to its potential toxicities, HSCT can be offered only to a restricted number of younger and fit patients. The growing understanding of the complex interplay between tumor cells and the immune system, which is responsible for immune escape mechanisms and tumor progression, has paved the way for the development of novel immune-based strategies. Despite promising preclinical observations, results from pilot clinical studies exploring the safety and efficacy of novel immune-based therapies have been sometimes suboptimal in terms of long-term tumor control. Therefore, further advances to improve their efficacy are needed. In this context, possible approaches include an earlier timing of immunotherapy within the treatment sequencing, as well as the possibility to improve the efficacy of immunotherapeutic agents by administering them in combination with other anti-tumor drugs. In this review, we will provide a comprehensive overview of main immune defects affecting patients with CLL, also describing the complex networks leading to immune evasion and tumor progression. From the therapeutic standpoint, we will go through the evolution of immune-based therapeutic approaches over time, including i) agents with broad immunomodulatory effects, such as immunomodulatory drugs, ii) currently approved and next-generation monoclonal antibodies, and iii) immunotherapeutic strategies aiming at activating or administering immune effector cells specifically targeting leukemic cells (e.g. bi-or tri-specific antibodies, tumor vaccines, chimeric antigen receptor T cells, and checkpoint inhibitors)