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Human mesenchymal stromal cells (hMSCs), whether used alone or together with three-dimensional scaffolds, are the best-studied postnatal stem cells in regenerative medicine. In this study, innovative composite scaffolds consisting of a core–shell architecture were seeded with bone-marrow-derived hMSCs (BM-hMSCs) and tested for their biocompatibility and remarkable capacity to promote and support bone regeneration and mineralization. The scaffolds were prepared by grafting three different amounts of gelatin–chitosan (CH) hydrogel into a 3D-printed polylactic acid (PLA) core (PLA-CH), and the mechanical and degradation properties were analyzed. The BM-hMSCs were cultured in the scaffolds with the presence of growth medium (GM) or osteogenic medium (OM) with differentiation stimuli in combination with fetal bovine serum (FBS) or human platelet lysate (hPL). The primary objective was to determine the viability, proliferation, morphology, and spreading capacity of BM-hMSCs within the scaffolds, thereby confirming their biocompatibility. Secondly, the BM-hMSCs were shown to differentiate into osteoblasts and to facilitate scaffold mineralization. This was evinced by a positive Von Kossa result, the modulation of differentiation markers (osteocalcin and osteopontin), an expression of a marker of extracellular matrix remodeling (bone morphogenetic protein-2), and collagen I. The results of the energy-dispersive X-ray analysis (EDS) clearly demonstrate the presence of calcium and phosphorus in the samples that were incubated in OM, in the presence of FBS and hPL, but not in GM. The chemical distribution maps of calcium and phosphorus indicate that these elements are co-localized in the same areas of the sections, demonstrating the formation of hydroxyapatite. In conclusion, our findings show that the combination of BM-hMSCs and PLA-CH, regardless of the amount of hydrogel content, in the presence of differentiation stimuli, can provide a construct with enhanced osteogenicity for clinically relevant bone regeneration.

The introduction of imatinib in 2000 opened the era of tyrosine kinase inhibitors (TKIs) for CML therapy and has revolutionized the life expectancy of CML patients, which is now quite like the one of the healthy aged population. Over the last 20 years, both the TKI therapy itself and the objectives have undergone evolutions highlighted and discussed in this review. The main objective of the CML therapy in the first 10 years after TKI introduction was to abolish the disease progression from the chronic to the blastic phase and guarantee the long-term survival of the great majority of patients. In the second 10 years (from 2010 to the present), the main objective of CML therapy moved from survival, considered achieved as a goal, to treatment-free remission (TFR). Two phenomena emerged: no more than 50–60% of CML patients could be candidates for discontinuation and over 50% of them molecularly relapse. The increased cumulative incidence of specific TKI off-target side effects was such relevant to compel to discontinue or reduce the TKI administration in a significant proportion of patients and to avoid a specific TKI in particular settings of patients. Therefore, the treatment strategy must be adapted to each category of patients. What about the patients who do not get or fail the TFR? Should they be compelled to continue the TKIs at the maximum tolerated dose? Alternative strategies based on the principle of minimal effective dose have been tested with success and they are now re-evaluated with more attention, since they guarantee survival and probably a better quality of life, too. Moving from treating the disease to treating the patient is an important change of paradigm. We can say that we are entering a personalized CML therapy, which considers the patients’ age, their comorbidities, tolerability, and specific objectives. In this scenario, the new techniques supporting the monitoring of the patients, such as the digital PCR, must be considered. In the present review, we present in deep this evolution and comment on the future perspectives of CML therapy.

Several research works propose non-textual alternatives to textual documentation and similar forms of representing information in software development. This is because of the problems that stem from writing these documents, which range from incomprehensible requirements to ambiguous user stories. The various proposals of researchers often contain some trace of oral or visual communication. In this paper, we study the implications of eliminating textual communication and substituting unnecessary writing by extracting the values of West African oral storytellers. Traditional West African communities did not make use of writing for thousands of years and yet their legends, customs, beliefs, and knowledge were effectively transmitted across several generations. How did they manage to accomplish this? What can we learn from their storytellers? How can these lessons be applied to software products? These are all questions that this paper attempts to answer. Perhaps if we fully understand how they operated, then we can target our written communication to the activities where it is needed instead of spreading writing across plenty of tasks as it is currently. To achieve this, we performed an analysis of the two domains: West African oral storytelling and software development and found similarities, then selected some key elements from oral storytelling and explained how they can have relevance in software development. The theme directly encompasses diversity and inclusion by bringing into software engineering a perspective of a region where its literacy research is scarcely being explored. The study found that traditional oral storytelling can provide insights into effective communication and audience engagement, and identified four ways in which software development can be compared to oral storytelling. The study also found that certain elements of storytelling, such as audience relationship, story structure, parables and proverbs, and community relaxation and support, can be applied to writing tasks in software development.

BackgroundThe COVID-19 pandemic has had a significant impact on the management and care of onco-hematological patients, particularly those with lymphoproliferative disorders who are at higher risk for COVID-19 associated bacterial and fungal superinfections.Case presentationWe present the successful treatment of a 44-year-old male patient with refractory mantle cell lymphoma treated with chimeric antigen receptor T (CAR-T) cell therapy, despite concurrent COVID-19 infection. The patient developed grade II cytokine release syndrome, requiring admission to the intensive care unit. The CAR-T cells expanded effectively, and the patient achieved complete metabolic remission. During the treatment course, the patient experienced complications including COVID-19-associated pulmonary aspergillosis and a co-infection with Stenotrophomonas maltophilia and the SARS-CoV-2 omicron variant. Prompt antifungal and antibacterial therapy, along with appropriate COVID-19 treatment, led to the resolution of these infections. Dexamethasone was also administered to reduce inflammation and aid hematologic recovery. Despite the presence of multiple infections, the patient achieved complete remission of lymphoma, highlighting the effectiveness of CAR-T cell therapy in this high-risk patient.ConclusionDespite the challenges posed by concurrent infections, the decision to proceed with CAR-T cell therapy in this patient proved to be successful, resulting in complete remission of lymphoma. Early initiation of supportive therapies and the use of dexamethasone contributed to the resolution of complications. This case underscores the importance of individualized decision-making and the potential benefits of CAR-T cell therapy in similar high-risk patients.

Within the domain of managing software development teams, effective task prioritization is a critical responsibility that should not be underestimated, particularly for larger organizations with significant backlogs. Current approaches primarily rely on predicting task priority without considering information about other tasks, potentially resulting in inaccurate priority predictions. This paper presents the benefits of considering the entire backlog when prioritizing tasks. We employ an iterative approach using Particle Swarm Optimization to optimize a linear model with various preprocessing methods to determine the optimal model for task prioritization within a backlog. The findings of our study demonstrate the usefulness of constructing a task prioritization model based on complete information from the backlog. The method proposed in our study can serve as a valuable resource for future researchers and can also facilitate the development of new tools to aid IT management teams.

Software repositories contain a wealth of information about the aspects related to software development process. For this reason, many studies analyze software repositories using methods of data analytics with a focus on clustering. Software repository clustering has been applied in studying software ecosystems such as GitHub, defect and technical debt prediction, software remodularization. Although some interesting insights have been reported, the considered studies exhibited some limitations. The limitations are associated with the use of individual clustering methods and manifesting in the shortcomings of the obtained results. In this study, to alleviate the existing limitations we engage multiple cluster validity indices applied to multiple clustering methods and carry out consensus clustering. To our knowledge, this study is the first to apply the consensus clustering approach to analyze software repositories and one of the few to apply the consensus clustering to software metrics. Intensive experimental studies are reported for software repository metrics data consisting of a number of software repositories each described by software metrics. We revealed seven clusters of software repositories and relate them to developers’ activity. It is advocated that the proposed clustering environment could be useful for facilitating the decision making process for business investors and open-source community with the help of the Gartner’s hype cycle.

The effective and sensitive monitoring of Minimal Residual Disease or Measurable Residual Disease (MRD) is a very important aspect in the management of patients affected by hematologic malignancies. The recent availability of new technologies has opened to the improvement of MRD monitoring. It is particularly relevant in patients affected by Chronic Myeloid Leukemia (CML). MRD monitoring is key in the management of CML patients thanks to the efficacy of TKIs therapy. Moreover, the policies of TKIs discontinuation aimed at treatment free remission are strongly based on the good selection of patients eligible for stopping TKIs therapy. The recently described application of digital PCR in CML patients monitoring seems to improve the accuracy and precision in the identification of optimal responders. The present review reports an overview on the application of digital PCR in the monitoring of MRD in CML and its impact on TKIs discontinuation trials and, consequently, on TFR success.

We review and critically assess several issues arising from the potential -large-scale- implementation or deployment of Large Language Models (LLMs) in society. These include security, political, economic, cultural, and educational issues as well as issues concerning social biases, creativity, copyright, and freedom of speech. We argue, without a preconceived pessimism toward these tools, that they may bring about many benefits. However, we also call for a balance assessment of their downsides. While our work is only preliminary and certainly partial it nevertheless holds some value as one of the first exploratory attempts in the literature.

Over the past 20 years agile methodologies revolutionized Information Technology, offering tremendous opportunities for the development of Software Engineering as an independent discipline. More specifically, agile methodologies contributed to enhancing the effectiveness and the speed of the production process as well as to improving the productivity and motivations of software developers organized in high performing teams. The agile philosophy can be and has been applied in different contexts and across several domains. This work analyses the relationship between Agile methodologies used by software engineers and the practices pursued by musicians in their daily lives. Our findings suggests that collaborative, strongly planned software development life cycle models (such as Waterfall, V-model, iterative, and Spiral) are not adequate models to describe the daily practices of musical composers. This is because their work requires a lot of flexibility, which such models intrinsically lack, because they are oriented to ensuring some form of monitorable progress. Interestingly, our findings also show that nine out of 12 Agile Principles are consciously or unconsciously followed by musicians in their practices. This suggests that there are some deep connections between these two prima facie different fields, which are both very creative. Even though our findings await replication, possibly with larger statistical samples, they contribute to open up a new strand of research in the field.

Automated Guided Vehicles (AGVs) have become a vital part of the automation sector and a key component of a new industrial revolution that promises to: i. automate the entire manufacturing process, ii. increase productivity rates, iii. develop safer workplaces, while iv. maximising profits and reducing running costs for businesses. However, several concerns arise in the face of this very promising revolution. A major issue is how to ensure that AGVs function effectively and safely during interactions with humans. Another one concerns the ethical desirability of pervasive, continuous, and multidimensional couplings (or interactions) between humans and robots. Generally speaking, automated systems, in virtue of their vast sensing capabilities, may pose privacy challenges to their users. This is because such systems can seamlessly gather information about people' behaviors, without people's consent or awareness. To tackle the important issues abovementioned, we performed a systematic literature review [SLR] on AGVs with mounted serial manipulators. We used as an input 282 papers published in the relevant scientific literature. We analysed these papers and selected 50 papers based on certain criteria to find out trends, algorithms, performance metrics used, as well as potential ethical concerns raised by the deployment of AGVs in the industry. Our findings suggest that corporations can effectively rely on AGVs with mounted manipulators as an efficient and safe solution to production challenges.

This study aimed to examine the embodied conceptualization of hope through metaphors. We asked a group of participants to discuss their hopes in a semi-structured interview. We examined the types of hand, head, and eyebrow gestures produced when they were talking about their future hopes. The obtained results showed that when participants talked about their future hopes, they mainly used forward hand gestures, rightward head gestures, and upward eyebrow gestures. Based on these results, it is suggested that various semantic components and emotional associations of hope are metaphorically embodied in different manners in various parts of the body. The future aspect of hope is conceptualized as a forward movement and is embodied as a forward hand gesture. The good or positive emotional aspect associated with future hopes is metaphorically conceptualized as a rightward head gesture or an upward eyebrow gesture. We call this process distributed embodiment of a metaphorical concept. Our proposal is supported by the findings of past studies that have found future is metaphorically embodied as something in front of us (or forward movement), and good is metaphorically embodied as upper space (or upward movement) or right side (or rightward movement).

BackgroundMinimal residual disease (MRD) monitoring is an important tool to optimally address post-transplant management of acute myeloid leukemia (AML) patients.MethodsWe retrospectively analyzed the impact of bone marrow CD34+ molecular chimerism and WT1 on the outcome of a consecutive series of 168 AML patients submitted to allogeneic stem cell transplantation.ResultsThe cumulative incidence of relapse (CIR) was significantly lower in patients with donor chimerism on CD34+ cells ≥ 97.5% and WT1 < 213 copies/ABL x 10^4 both at 1st month (p=0.008 and p 213 showed intermediate prognosis. 12 of these patients fell in this category because of molecular chimerism < 97.5% at a time-point in which WT1 was < 213.ConclusionsOur results confirm that lineage-specific molecular chimerism and WT1 after allo-SCT (1st and 3rd month) are useful MRD markers. When considered together at 3rd month, CD34+ molecular chimerism could represent an earlier predictor of relapse compared to WT1. Further studies are necessary to confirm this preliminary observation.

Background. The conditioning regimens with different alkylators at different doses can influence the outcome of allogeneic stem cell transplantation (SCT), but conclusive data are missing. Methods. With the aim to analyze real-life allogeneic SCTs performed in Italy between 2006 and 2017 in elderly patients (aged >60 y) with acute myeloid leukemia or myelodysplastic syndrome, we collected 780 first transplants data. For analysis purposes, patients were grouped according to the type of alkylator included in the conditioning (busulfan [BU]-based; n = 618; 79%; treosulfan [TREO]-based; n=162; 21%). Results. No significant differences were observed in nonrelapse mortality, cumulative incidence of relapse, and overall survival, although in the TREO-based group, we observed a greater proportion of elderly patients (P

Purpose: With this Systematic Literature Review (SLR), we aim to discover technologies to construct a Goal-Question-Metrics (GQM) based metrics recommender for software developers. Since such a system has not yet been described in the literature, we decided to analyse the technologies used in three main components of recommender systems - data sets, algorithms, and recommendations - independently. Methods: To achieve our goal we performed - following the best norms in our discipline - a systematic literature review (SLR). We first identified, through searches aptly performed, 422 potentially relevant papers, from which we selected - after applying inclusion and exclusion criteria - 30 papers, which we eventually included in our final log. Results: Systems with textual data set preprocess information in nearly the same way and the majority use similarity scores to create recommendations. Systems with GQM-based algorithms consist of questionnaires and require users to explicitly answer questions to produce suggestions. With respect to the recommendations of reviewed systems, they range from application programming interfaces (APIs) to requirements, but no system presently recommends metrics. Conclusion: In our SLR we: (a) identified a sequence of the most popular steps for preprocessing in recommender systems; (b) proposed an optimisation strategy for such steps; (c) found out that the most promising approach includes both ranking and classification; and (d) established that there are no recommendation systems developed to date to process metrics.

Task prioritization is one of the most researched areas in software development. Given the huge number of papers written on the topic, it might be challenging for IT practitioners-software developers, and IT project managers-to find the most appropriate tools or methods developed to date to deal with this important issue. The main goal of this work is therefore to review the current state of research and practice on task prioritization in the Software Engineering domain and to individuate the most effective ranking tools and techniques used in the industry. For this purpose, we conducted a systematic literature review guided and inspired by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, otherwise known as the PRISMA statement. Based on our analysis, we can make a number of important observations for the field. Firstly, we found that most of the task prioritization approaches developed to date involve a specific type of prioritization strategy-bug prioritization. Secondly, the most recent works we review investigate task prioritization in terms of "pull request prioritization" and "issue prioritization," (and we speculate that the number of such works will significantly increase due to the explosion of version control and issue management software systems). Thirdly, we remark that the most frequently used metrics for measuring the quality of a prioritization model are f-score, precision, recall, and accuracy.

BackgroundChimeric antigen receptor (CAR) T-cell therapy represents the most advanced immunotherapy against relapsed/refractory B cell malignancies. While cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome are distinctive, known CAR T-cell acute adverse events, hematological toxicity has been increasingly reported. Cytopenia following CAR T-cell treatment is attributed in most cases to lymphodepletion regimens, bridging chemotherapy, or radiotherapy. However, when cytopenia becomes prolonged, the development of myelodysplastic syndrome (MDS) should be considered.Case presentationWe report a case of high risk (HR)-MDS following CAR T-cell therapy in a patient with relapsed diffuse large B cell lymphoma. Eight months after CAR T-cell infusion, the blood count showed progressive, worsening cytopenia and the bone marrow biopsy revealed multilineage dysplasia without excess of blasts associated with chromosome 7 deletion and RUNX1 mutation. Next generation sequencing analysis, retrospectively performed on stored samples, showed a germ line CSF3R mutation, CEBPA clonal hematopoiesis, but no RUNX1 lesion.ConclusionWe describe a case of HR-MDS, with deletion of chromosome 7 and acquisition of RUNX1 mutation, developing after CAR T-cell therapy in a patient with clonal hematopoiesis (CH). Previous chemotherapy favored MDS onset; however, we could not exclude the fact that the impairment of immunosurveillance related to either lymphodepletion or CAR T-cell infusion may play a role in MDS development. Thus, we designed a multicenter prospective study (ClonHema-CAR-T-Study) to investigate if cytopenia after CAR T-cell treatment may be due to underling CH as well as the presence of secondary myeloid malignancies.

Modeling and understanding users interests has become an essential part of our daily lives.A variety of business processes and a growing number of companies employ various tools to such an end. The outcomes of these identification strategies are beneficial for both companies and users: the former are more likely to offer services to those customers who really need them, while the latter are more likely to get the service they desire.Several works have been carried out in the area of user interests identification. As a result, it might not be easy for researchers, developers, and users to orient themselves in the field; that is, to find the tools and methods that they most need, to identify ripe areas for further investigations, and to propose the development and adoption of new research plans.In this study, to overcome these potential shortcomings, we performed a systematic literature review on user interests identification. We used as input data browsing tab titles. Our goal here is to offer a service to the readership, which is capable of systematically guiding and reliably orienting researchers, developers, and users in this very vast domain.Our findings demonstrate that the majority of the research carried out in the field gathers data from either social networks (such as Twitter, Instagram and Facebook) or from search engines, leaving open the question of what to do when such data is not available.

BackgroundInfectious complications are a significant cause of morbidity and mortality in patients undergoing allogeneic haematopoietic stem cell transplantation (Allo-SCT). The BATMO (Best-Antimicrobial-Therapy-TMO) is an innovative program for infection prevention and management and has been used in our centre since 2019. The specific features of the BATMO protocol regard both prophylaxis during neutropenia (abandonment of fluoroquinolone, posaconazole use in high-risk patients, aerosolized liposomal amphotericin B use until engraftment or a need for antifungal treatment, and letermovir use in CMV-positive recipients from day 0 to day +100) and therapy (empirical antibiotics based on patient clinical history and colonization, new antibiotics used in second-line according to antibiogram with the exception of carbapenemase-producing K pneumoniae for which the use in first-line therapy is chosen).MethodsData on the infectious complications of 116 transplant patients before BATMO protocol (Cohort A; 2016 - 2018) were compared to those of 84 transplant patients following the introduction of the BATMO protocol (Cohort B; 2019 - 2021). The clinical and transplant characteristics of the 2 Cohorts were comparable, even though patients in Cohort B were at a higher risk of developing bacterial, fungal, and CMV infections, due to a significantly higher proportion of myeloablative regimens and haploidentical donors.ResultsNo change in the incidence of infections with organ localization was observed between the two Cohorts. A significant reduction in Clostridioides difficile infections by day +100 was observed in Cohort B (47% vs. 15%; p=0.04). At day +30, a higher incidence of Gram-negative bloodstream infections (BSIs) was observed in Cohort B (12% vs. 23%; p=0.05). By day +100 and between days +100 and +180, the incidence of BSIs and of the various etiological agents, the mortality from Gram-negative bacteria, and the incidence of invasive fungal infections were not different in the two Cohorts. The incidence of CMV reactivations by day +100 dropped drastically in patients of Cohort B, following letermovir registration (51% vs. 15%; p=0.00001).DiscussionThe results of this study suggest that the BATMO program is safe. In particular, the choice to avoid prophylaxis with fluoroquinolone was associated with an increase in Gram-negative BSIs by day +30, but this did not translate into higher levels of mortality. Moreover, this strategy was associated with a significant reduction of Clostridiodes difficile infections. The efficacy of anti-CMV prophylaxis with letermovir was confirmed by a significant reduction in CMV reactivations. Even though patients in Cohort B were at higher risk of developing fungal infections (more haploidentical transplants with more myeloablative regimens), the extensive use of posaconazole for prophylaxis balanced this risk, and no increase in the incidence of fungal-associated complications was observed.

Abstract Background Intermittent treatment with TKIs is an option for the great majority (70%–80%) of CML patients who do not achieve a stable deep molecular response and are not eligible for treatment discontinuation. For these patients, the only alternative is to assume TKI continuously, lifelong. Methods The Italian phase III multicentric randomized OPTkIMA study started in 2015, with the aim to evaluate if a progressive de‐escalation of TKIs (imatinib, nilotinib, and dasatinib) is able to maintain the molecular response (MR3.0) and to improve Health Related Quality of Life (HRQoL). Results Up to December 2018, 166/185 (90%) elderly CML patients in stable MR3.0/MR4.0 completed the first year of any TKI intermittent schedule 1 month ON and 1 month OFF. The first year probability of maintaining the MR3.0 was 81% and 23.5% of the patients who lost the molecular response regained the MR3.0 after resuming TKI continuously. Patients’ HRQoL at baseline was better than that of matched peers from healthy population. Women was the only factor independently associated with worse baseline HRQoL (p > 0.0001). Overall, global HRQoL worsened at 6 (p

Communication among humans consists of both verbal and non verbal components. The latter may sometimes express concepts or ideas not conveyable by the former. This is also true in Software Engineering. This paper first analyses theoretically the role of non verbal communication in software development teams, using the framework provided by distributed cognition as a conceptual palette and as a point of reference. Then, it presents an empirical investigation involving 38 IT professionals from Russia, sharing their experiences in communicating and interacting when developing software artifacts. The results of this empirical investigation are consistent with many of the ideas underlying a distributed approach to cognition. In addition, our findings provide valuable insights to make communication more effective in software development teams, while defining a new framework for follow-up studies.

Software development is a complex process that requires skills in mathematics and physics. Moreover, it usually includes collaboration with other people. To get a precise understanding of the way such a process is organized, we need to understand its essence. Technical knowledge is crucially important for any developer; however, another important characteristic of any software engineer is creativity. In this article, we look at one particular artistic practice [filmmaking] that involves both these latter characteristics to determine whether insights from such a practice can be applied in the IT industry and vice versa.

While research to improve memory or counter decay caused by neurodegenerative diseases has a fairly long history, scientific attempts to erase memories are very recent. The use of non-invasive brain stimulation for memory modulation represents a new and promising application for the treatment of certain disorders [such as Post-Traumatic Stress Disorder (PTSD)]. However, numerous ethical issues are related to memory intervention. In particular, the possibility of using forms of non-invasive brain stimulation requires to distinguish treatment interventions from the enhancement of the healthy. Furthermore, a range of important societal and legal concerns arise when manipulating memories. In this short contribution, we address some of the most significant ethical, social, and legal implications surrounding the application of memory-modulation techniques and offer a series of reflections and considerations, which we hope can be of use to guide -and perhaps regulate- their potential, future implementation in society.

Real-time quantitative PCR (RT-qPCR) is the gold standard to quantify the BCR-ABL1 transcript for molecular response monitoring in chronic myeloid leukemia (CML) patients, and it plays a pivotal role in clinical decision-making process, even if it presents technical limits. Increasing data suggest that digital PCR (dPCR) is more accurate and reliable than RT-qPCR in CML minimal residual disease monitoring and in patients’ selection for treatment discontinuation. But what about the identification of treatment discontinuation failures? We present the case of a CML patient enrolled both in a study aiming to comparatively assess molecular response by RT-qPCR and dPCR and in the progressive arm of the OPTkIMA trial. This is a phase III trial including CML patients randomized to receive a fixed versus a progressive intermittent tyrosine kinase inhibitor regimen. At 24 months, because of two consecutive detections of MR2.0 by RT-qPCR, the patient resumed daily treatment. Conversely, dPCR revealed a stability of molecular response and even a slight decreasing of transcript over time. An additional specimen was sampled one month after the first MR2.0 detection because of clinical decision: RT-qPCR resulted MR3.0 and dPCR confirmed the transcript’s stability. Nowadays, the resumption of therapy is RT-qPCR-driven despite its limits in detection and robustness. In this case, according to dPCR, the patient could have continued intermittent treatment and the stability of response was then confirmed by RT-qPCR. So, dPCR could be able to better identify peculiar clinical response to therapy.

Objectives: Many countries recently approved a number of SARS-CoV-2 vaccines. There is therefore growing optimism around the world about their future availability and effectiveness. However, supplies are likely to be limited and restricted to certain categories of individuals, at least initially. Thus, governments have suggested prioritization schemes to allocate such limited supplies. The majority of such schemes are said to be developed to safeguard the weakest sections of society; that is, healthcare personnel and the elderly.Methods: In this work, we analyse three case studies (incarcerated people; homeless people, asylum seekers and undocumented migrants). We propose a bioethical argument that frames the discussion by describing the salient facts about each of the three populations and then argue that these characteristics entail inclusion and prioritization in the queue for vaccination in their country of residence.Results: Through an analysis informed by ethical considerations revolving around the concepts of fairness and equality, we try to raise awareness of these important issues among decision makers.Conclusion: Our goal is to advocate for the development of more inclusive policies and frameworks in SARS-CoV-2 vaccine allocation and, in general, in all scenarios in which there is a shortage of optimal care and treatments.

Myeloproliferative neoplasms (MPN) are chronic, clonal hematologic malignancies characterized by myeloproliferation and a high incidence of vascular complications (thrombotic and bleeding). Although MPN-specific driver mutations have been identified, the underlying events that culminate in these clinical manifestations require further clarification. We reviewed the numerous studies performed during the last decade identifying endothelial cell (EC) dysregulation as a factor contributing to MPN disease development. The JAK2V617F MPN mutation and other myeloid-associated mutations have been detected not only in hematopoietic cells but also in EC and their precursors in MPN patients, suggesting a link between mutated EC and the high incidence of vascular events. To date, however, the role of EC in MPN continues to be questioned by some investigators. In order to further clarify the role of EC in MPN, we first describe the experimental strategies used to study EC biology and then analyze the available evidence generated using these assays which implicate mutated EC in MPN-associated abnormalities. Mutated EC have been reported to possess a pro-adhesive phenotype as a result of increased endothelial Pselectin exposure, secondary to degranulation of Weibel-Palade bodies, which is further accentuated by exposure to pro-inflammatory cytokines. Additional evidence indicates that MPN myeloproliferation requires JAK2V617F expression by both hematopoietic stem cells and EC. Furthermore, the reports of JAK2V617F and other myeloid malignancy- associated mutations in both hematopoietic cells and EC in MPN patients support the hypothesis that MPN driver mutations may first appear in a common precursor cell for both EC and hematopoietic cells.

Abstract Treatment‐free remission (TFR) by tyrosine kinase inhibitors (TKI) discontinuation in patients with deep molecular response (DMR) is a paramount goal in the current chronic myeloid leukemia (CML) therapeutic strategy. The best DMR level by real‐time quantitative PCR (RT‐qPCR) for TKI discontinuation is still a matter of debate. To compare the accuracy of digital PCR (dPCR) and RT‐qPCR for BCR‐ABL1 transcript levels detection, 142 CML patients were monitored for a median time of 24 months. Digital PCR detected BCR‐ABL1 transcripts in the RT‐qPCR undetectable cases. The dPCR analysis of the samples, grouped by the MR classes, revealed a significant difference between MR4.0 and MR4.5 (P = 0.0104) or MR5.0 (P = 0.0032). The clinical and hematological characteristics of the patients grouped according to DMR classes (MR4.0 vs MR4.5‐5.0) were superimposable. Conversely, patients with dPCR values

Malnutrition is common after allogeneic Hematopoietic Stem Cell Transplantation (alloHSCT), and interventions directed to correct nutritional status are warranted to improve transplant outcomes. In this prospective study, an oral polymeric formulation enriched with TGF-β2 (TE-OPF) was explored to correct malnutrition according to Patient-Generated Subjective Global Assessment (PG-SGA). TE-OPF was proposed to 51 consecutive patients who received transplants at our institution for hematological malignancies, and sufficient dose intake was established per protocol as at least 50% of the prescribed dose of TE-OPF: group A received adequate nutritional support; group B, inadequate. The study met the primary outcomes in terms of safety (no adverse events reported during TE-OPF intake except for its disgusting taste) and malnutrition (PG-SGA C 28 days after transplant): severely malnourished patients (PG-SGA C) accounted for 13% in group A and 88.9% in group B (p = 0.000). At the end of the study, after a median follow-up of 416 days, the estimated median Overall Survival (OS) was 734 days for well or moderately nourished patients (PG-SGA A/B) in comparison to 424 for malnourished patients (p = 0.03). Inadequate TE-OPF intake was associated with an increase in acute gastrointestinal Graft Versus Host Disease (GVHD) cumulative incidence (38% vs. 0% p = 0.006). A higher incidence of pneumonia was reported in group B (p = 0.006). IGF-1 levels at 14 and 28 days after transplant were significantly higher in group A and were associated with a lower incidence of acute GVHD (aGVHD). Higher subsets of B, T, and NK cells were found in group A, and a higher number of CD16+ NK cells was associated with a lower incidence of acute GVHD (p = 0.005) and increased survival at the end of the study (p = 0.023). Artificial neural network analysis suggested that inadequate TE-OPF intake, pneumonia, and sepsis significantly affected malnutrition 28 days after alloHSCT and survival 365 days after alloHSCT (normalized importance 100%, 82%, and 68%, respectively). In this exploratory and preliminary study, the use of TE-OPF appeared to reduce the incidence of malnutrition after alloHSCT, but larger and controlled studies are required.

CMV infection is a major challenge in allogeneic stem cell transplantation (allo-SCT). The changing landscape in CMV management includes the introduction of letermovir in prophylaxis of high-risk patients and the source of CMV DNA monitoring (plasma—PL vs. whole blood—WB), for pre-emptive therapy (PET) initiation. We report here how our real-life experience in CMV management evolved, following letermovir registration. We focus on: (i) the effects of systematic use of letermovir for CMV prophylaxis in high-risk patients, (ii) the results of a longitudinal comparison of CMV DNAemia monitoring in PL and WB. From December 2018 to April 2020, 60 allo-SCTs have been performed in our center (LET ERA), of whom 45 received letermovir in prophylaxis from day 0 to day + 100, because of recipient positivity of anti CMV IgG. These patients were compared with a cohort of 41 allo-SCTs performed between November 2017 and November 2018 (NO LET ERA). Firstly, the incidence of CMV clinically significant infections, CMV disease, bacterial infections, proven/probable fungal infections, hospital re-admissions after allo-SCT by day + 100 in the two ERA were 8 vs. 44% (p = 0.0006), 2 vs. 12% (p = 0.02), 37 vs. 56% (p = 0.05), 8 vs. 19% (p = 0.09), and 23 vs. 39% (p = 0.09), respectively. By day + 180 these differences were 17 vs. 68% (p < 0.00001), 2 vs. 12% (p = 0.02), 45 vs. 78% (p = 0.09), 8 vs. 22% (p = 0.05), and 40 vs. 66% (p = 0.01), respectively. Secondly, from February to May 2019, we comparatively measured CMV DNA from WB and PL and we confirmed that there is a linear correlation between CMV DNA level in WB and PL (Spearman’s test r = 0.86). Moreover, CMV DNAemia at the time of PET in the 12 patients with a clinically significant CMV infection was higher in WB vs. PL (5.202 vs. 4.981 copies/ml, p = 0.1). Our real-life experience confirms that: (i) letermovir is highly effective, leading to a significant drop in CMV clinically significant infections and CMV-related complications by day + 100 and + 180 after allo-SCT; (ii) WB may be an effective alternative to PL as a source for CMV DNA monitoring, as a linear correlation of DNAemia was confirmed between WB and PL, even if the CMV DNAemia at PET initiation was comparable in the two sources.

BackgroundMyelodysplastic syndromes and acute leukemias after allogeneic stem cell transplantation (allo-SCT) are mainly caused by recurrence of the primitive leukemic clones. More rarely, they originate from donor hematopoietic stem cells, developing the so-called donor cell leukemia (DCL) or myelodysplastic syndromes (DC-MDSs). DCL and DC-MDS can be considered as an in vivo model of leukemogenesis, and even if the pathogenetic mechanisms remain speculative, a genetic predisposition of donor progenitor cells, an altered host microenvironment, and the impairment of immune surveillance are considered the main causes.Case PresentationWe report a case of DC-MDS diagnosed 5 years after an allo-SCT from a matched related donor (patient’s sister) in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia (Ph+ B-ALL). The sex-mismatch allowed us to identify the donor cell origin. At the onset, the DC-MDS was characterized by chromosome seven monosomy and NRAS, RUNX1, and BCOR mutations. Because of a familiar history of colorectal neoplasia and the variant allele frequency (VAF) of NRAS mutation at the onset, this mutation was searched on germline DNA in both the donor and the recipient, but the result was negative. Moreover, after transplant (+4 months), the patient developed severe and long-lasting chronic graft-versus-host disease (cGVHD), requiring multiple lines of treatments. Because of the severe immunosuppression, recurrent infections occurred and, lately, the patient died due to septic shock.ConclusionThis case report highlights the need, whenever possible, to evaluate the donor origin of the posttransplant myelodysplasia and acute leukemias. The potential key role of the impaired immune surveillance and of long-lasting immunosuppression appears to be emerging in the development of this case of DC-MDS. Finally, this case reminds the importance to investigate the familiar genetic predisposition in donors with a familiar history of neoplasia.

We start (section The COVID-19 Pandemic and Italy's Response to It) by focusing on Italy's “tough” response to COVID-19 pandemic, which included total lockdown with very limited possibility of movement for over 60 million individuals. We analyse (section Sweden's Softer Approach) Sweden's softer approach, which is based on relatively lax measures and tends to safeguard fundamental constitutional rights. We problematise (section General Disagreement Among Experts: A Pressing Epistemic Problem) around the stalemate that arises as a consequence of the implementation of these different approaches, both epistemically grounded and equally justified, in the face of an unknown virus, in society. We point out that in some cases, like the one we discuss here, the epistemic justification that underlies scientific expertise is not enough to direct public debates and that politicians shouldn't exclusively focus on it. We claim that, especially in situations of emergency when experts disagree, decision makers ought to promote broad discussions, with attention to public reason as well as to constitutional rights, in the attempt to find a shared procedural and democratic agreement on how to act. On these grounds (section The Need of More Public Discourse in Fighting Covid-19) we call for an increase role of different types of expertise in public debates thus for the inclusion of ethicists, bioethicists, economists, psychologists, moral and legal philosophers in any scientific committee responsible for taking important decisions for public health, especially during situations like pandemics. Likewise, in the interest of public reason and representativeness, we also claim that it may be fruitful to bring in non-experts, or experts whose expertise is not based solely on “epistemic status,” but rather on either experience or political advocacy, of either the homeless, the immigrant, or other disenfranchised groups. This, in expanding the epistemic-expert pool, may also make it “more representative of society as a whole.”

In the 2020 Covid-19 pandemic, medical experts (virologists, epidemiologists, public health scholars, and statisticians alike) have become instrumental in suggesting policies to counteract the spread of coronavirus. Given the dangerousness and the extent of the contagion, almost no one has questioned the suggestions that these experts have advised policymakers to implement. Quite often the latter explicitly sought experts' advice and justified unpopular measures (e.g., restricting people's freedom of movement) by referring to the epistemic authority attributed to experts. The main goal of this paper is to analyze the basis of this epistemic authority and the reasons why in this case it has not been challenged, contrary to the widespread tendency to devalue expertise that has been observed in recent years. In addition, in relation to the fact that experts' recommendations are generally technical and supposedly neutral, we note that in the COVID-19 crisis different experts have suggested different public health policies. We consider the British case of herd immunity and the US case of the exclusion of disabled people from medical care. These decisions have strong axiological implications and affect people profoundly in very sensitive domains. Another goal is, therefore, to argue that in such cases experts should justify their recommendations-which effectively become obligations-by the canons of public reason within the political process because when values are involved it is no longer just a matter of finding the “best technical solution,” but also of making discretionary choices that affect citizens and that cannot be imposed solely on the basis of epistemic authority.

Background. The identification of germline mutations in familial leukemia predisposition genes by next generation sequencing is of pivotal importance. Lately, some “blend pedigrees” characterized by both solid and hematologic malignancies have been described. Some genes were recognized as related to this double predisposition, while the involvement of others is still a matter of debate. ETV6 was associated with hematologic malignancies, in particular myeloid malignancies, and recently described as mutated also in oncologic patients. No clear evidences in its involvement in blend pedigrees are known. Case Presentation. We present our recent experience in the identification of an ETV6-mutated “blend pedigree,” suggesting the involvement of ETV6 in the predisposition to both solid and hematologic neoplasia. The pedigree recognition started with a MDS case enrolled in the NEXT-Famly protocol. The patient presented 9 relatives affected by solid tumors and hematological malignancies. Following the clinical trial protocol, the patient underwent NGS analysis, which confirmed the presence of a mutation on the noncoding region of ETV6 both on tumor and on germline DNA. The mutation resulted was shared by the still alive affected relatives. Conclusion. This evidence supports the involvement of ETV6 in the predisposition to both solid and hematologic neoplasia and the importance of the investigation of the noncoding regions of the genes as recently suggested by different expert groups.

Moving from indication to transplantation is a critical process in myelofibrosis. Most of guidelines specifically focus on either myelofibrosis disease or transplant procedure, and, currently, no distinct indication for the management of MF candidates to transplant is available. Nevertheless, this period of time is crucial for the transplant outcome because engraftment, non-relapse mortality, and relapse incidence are greatly dependent upon the pre-transplant management. Based on these premises, in this review, we will go through the path of identification of the MF patients suitable for a transplant, by using disease-specific prognostic scores, and the evaluation of eligibility for a transplant, based on performance, comorbidity, and other combined tools. Then, we will focus on the process of donor and conditioning regimens’ choice. The pre-transplant management of splenomegaly and constitutional symptoms, cytopenias, iron overload and transplant timing will be comprehensively discussed. The principal aim of this review is, therefore, to give a practical guidance for managing MF patients who are potential candidates for allo-HCT.

A role of endothelial cells (ECs) in Primary Myelofibrosis (PMF) was supposed since JAK2 mutation was found in endothelial precursor cells (EPCs) and in ECs captured by laser microdissection. By Cell Search method, the circulating endothelial cells (CECs) from 14 PMF patients and 5 healthy controls have been isolated and compared by NGS with CD34+Hematopoietic stem and progenitors cells (HSPCs) for panel of 54 myeloid-associated mutations. PMF patients had higher levels of CECs. No mutation was found in HSPCs and CECs from controls, while CECs from PMF patients presented several somatic mutations. 72% of evaluable patients shared at least one mutation between HSPCs and CECs. 2 patients shared the JAK2 mutation, together with ABL1, IDH1, TET2 and ASXL1, KMT2A, respectively. 6 out of 8 shared only NON MPN-driver mutations: TET2 and NOTCH1 in one case; individual paired mutations in TP53, KIT, SRSF2, NOTCH1 and WT1, in the other cases. In conclusion, 70% of PMF patients shared at least one mutation between HSPCs and CECs. These latter harbored several myeloid-associated mutations, besides JAK2V617F mutation. Our results support a primary involvement of EC in PMF and provide a new methodological approach for further studies exploring the role of the “neoplastic” vascular niche.

Extracellular vesicles (exosomes, in particular) are essential in multicellular organisms because they mediate cell-to-cell communication via the transfer of secreted molecules. They are able to shuttle different cargo, from nucleic acids to proteins. The role of exosomes has been widely investigated in solid tumors, which gave us surprising results about their potential involvement in pathogenesis and created an opening for liquid biopsies. Less is known about exosomes in oncohematology, particularly concerning the malignancies deriving from myeloid lineage. In this review, we aim to present an overview of immunomodulation and the microenvironment alteration mediated by exosomes released by malicious myeloid cells. Afterwards, we review the studies reporting the use of exosomes as disease biomarkers and their influence in response to treatment, together with the recent experiences that have focused on the use of exosomes as therapeutic tools. The further development of new technologies and the increased knowledge of biological (exosomes) and clinical (myeloid neoplasia) aspects are expected to change the future approaches to these malignancies.

Zebrafish has proven to be a versatile and reliable experimental in vivo tool to study human hematopoiesis and model hematological malignancies. Transgenic technologies enable the generation of specific leukemia types by the expression of human oncogenes under specific promoters. Using this technology, a variety of myeloid and lymphoid malignancies zebrafish models have been described. Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR-ABL1 fusion gene, derived from the t (9;22) translocation causing the Philadelphia Chromosome (Ph). The BCR-ABL1 protein is a constitutively activated tyrosine kinas inducing the leukemogenesis and resulting in an accumulation of immature leukemic cells into bone marrow and peripheral blood. To model Ph+ CML, a transgenic zebrafish line expressing the human BCR-ABL1 was generated by the Gal4/UAS system, and then crossed with the hsp70-Gal4 transgenic line. The new line named (BCR-ABL1pUAS:CFP/hsp70-Gal4), presented altered expression of hematopoietic markers during embryonic development compared to controls and transgenic larvae showed proliferating hematopoietic cells in the caudal hematopoietic tissue (CHT). The present transgenic zebrafish would be a robust CML model and a high-throughput drug screening tool.