CASE-BASED REASONING FOR MANAGING NONCOMPLIANCE WITH CLINICAL GUIDELINES

Despite the recognized advantages that can be obtained in clinical practice when following clinical guidelines (GL), situations of noncompliance with them may emerge. Keeping track of such deviations from the default GL execution, and documenting the physician's motivations, would clearly be an added value. Moreover, repeated alterations of GL actions (or flow) may highlight the need for an adaptation of the GL itself to the local reality, or may even indicate an improper or weak initial GL definition.
In this article, we propose an approach for managing noncompliance with GL, based on the case-based reasoning methodology. In front of a new noncompliance case, our tool allows the physician to retrieve past situations similar to the current one, and to decide whether to reapply the same GL modifications adopted in them. Moreover, the tool is able to learn indications from the ground noncompliance cases that can be deployed for local adaptation, and possibly, for suggesting more formal GL revisions to be carried out by a committee of expert physicians.     

Hyper-arc consistency of polynomial constraints over finite domains using the modified Bernstein form

This paper describes an algorithm to enforce hyper-arc consistency of polynomial constraints defined over finite domains. First, the paper describes the language of so called polynomial constraints over finite domains, and it introduces a canonical form for such constraints. Then, the canonical form is used to transform the problem of testing the satisfiability of a constraint in a box into the problem of studying the sign of a related polynomial function in the same box, a problem which is effectively solved by using the modified Bernstein form of polynomials. The modified Bernstein form of polynomials is briefly discussed, and the proposed hyper-arc consistency algorithm is finally detailed. The proposed algorithm is a subdivision procedure which, starting from an initial approximation of the domains of variables, removes values from domains to enforce hyper-arc consistency.     

IRS-III: A broker-based approach to semantic Web services

A factor limiting the take up of Web services is that all tasks associated with the creation of an application, for example, finding, composing, and resolving mismatches between Web services have to be carried out by a software developer. Semantic Web services is a combination of semantic Web and Web service technologies that promise to alleviate these problems. In this paper we describe IRS-III, a framework for creating and executing semantic Web services, which takes a semantic broker-based approach to mediating between service requesters and service providers. We describe the overall approach and the components of IRS-III from an ontological and architectural viewpoint. We then illustrate our approach through an application in the eGovernment domain.     

Morphological patterns of angiogenesis in ovarian follicle capillary networks. A scanning electron microscopy study of corrosion cast

To describe the morphological characteristics of the ovarian follicle (F) capillary neoformation and regression, the angiogenic figures were studied by means of scanning electron microscopy of corrosion casts in developing and mature F of rabbit, pig, and cow. Developing F showed gradual neoformation of thecal capillaries characterized by budding and then sprouting, likely from preexisting interstitial vessels. Postcapillary venules frequently showed vasoconstriction rings (sphincters). Vasodilation followed capillary elongation. Mature F, in addition to vessel elongation and dilation, also presented infolding of dilated capillary walls, followed by capillary duplication and sinusoidalization. Periovulatory F mainly showed functional changes, such as capillary dilation, signs of iperpermeabilization, and ischemia, the latter being limited to the apical follicular area. Vessel regression was characterized by thinning of capillaries and presence of avascular areas within the atretic F wall at any stage. This study showed two main types of angiogenic patterns. (a) longitudinal elongation (in series, sprouting angiogenesis) characterizing the initial phase of F development and (b) parallel duplication (in parallel, infolding or intussusceptive angiogenesis), ending in capillary lateral replication or splitting, secondary to functional microvascular changes. Indirect evidence of the establishment of postcapillary resistances contributing to capillary remodeling, was also shown. It is concluded that the sequence of capillary neoformation in mammalian ovarian F occurs in six steps: (1) budding, (2) sprouting (and elongation), (3) dilation, (4) infolding (intussusception), (5) duplication (splitting and elongation), and (6) sinusoidalization. Capillary regression hits F at any stage and characterizes F atresia.     

GANAB and N-Glycans Substrates Are Relevant in Human Physiology,Polycystic Pathology and Multiple Sclerosis: A Review

Glycans are one of the four fundamental macromolecular components of living matter, and they are highly regulated in the cell. Their functions are metabolic, structural and modulatory. In particular, ER resident N-glycans participate with the Glc₃Man₉GlcNAc₂ highly conserved sequence, in protein folding process, where the physiological balance between glycosylation/deglycosylation on the innermost glucose residue takes place, according GANAB/UGGT concentration ratio. However, under abnormal conditions, the cell adapts to the glucose availability by adopting an aerobic or anaerobic regimen of glycolysis, or to external stimuli through internal or external recognition patterns, so it responds to pathogenic noxa with unfolded protein response (UPR). UPR can affect Multiple Sclerosis (MS) and several neurological and metabolic diseases via the BiP stress sensor, resulting in ATF6, PERK and IRE1 activation. Furthermore, the abnormal GANAB expression has been observed in MS, systemic lupus erythematous, male germinal epithelium and predisposed highly replicating cells of the kidney tubules and bile ducts. The latter is the case of Polycystic Liver Disease (PCLD) and Polycystic Kidney Disease (PCKD), where genetically induced GANAB loss affects polycystin-1 (PC1) and polycystin-2 (PC2), resulting in altered protein quality control and cyst formation phenomenon. Our topics resume the role of glycans in cell physiology, highlighting the N-glycans one, as a substrate of GANAB, which is an emerging key molecule in MS and other human pathologies.     

Genomic and Immunological Characterization of Hypermucoviscous Carbapenem-Resistant Klebsiella pneumoniae ST25 Isolates from Northwest Argentina

In recent years, an increase in the prevalence hypermucoviscous carbapenem-resistant Klebsiella pneumoniae with sequence type 25 (ST25) was detected in hospitals of Tucuman (Northwest Argentina). In this work, the virulence and the innate immune response to two K. pneumoniae ST25 strains (LABACER 01 and LABACER 27) were evaluated in a murine model after a respiratory challenge. In addition, comparative genomics was performed with K. pneumoniae LABACER01 and LABACER27 to analyze genes associated with virulence. Both LABACER01 and LABACER27 were detected in the lungs of infected mice two days after the nasal challenge, with LABACER01 counts significantly higher than those of LABACER27. Only LABACER01 was detected in hemocultures. Lactate dehydrogenase (LDH) and albumin levels in bronchoalveolar lavage (BAL) samples were significantly higher in mice challenged with LABACER01 than in LABACER27-infected animals, indicating greater lung tissue damage. Both strains increased the levels of neutrophils, macrophages, TNF-α, IL-1β, IL-6, KC, MCP-1, IFN-γ, and IL-17 in the respiratory tract and blood, with the effect of LABACER01 more marked than that of LABACER27. In contrast, LABACER27 induced higher levels of IL-10 in the respiratory tract than LABACER01. Genomic analysis revealed that K. pneumoniae LABACER01 and LABACER27 possess virulence factors found in other strains that have been shown to be hypervirulent, including genes required for enterobactin (entABCDEF) and salmochelin (iroDE) biosynthesis. In both strains, the genes of toxin–antitoxin systems, as well as regulators of the expression of virulence factors and adhesion genes were also detected. Studies on the genetic potential of multiresistant K. pneumoniae strains as well as their cellular and molecular interactions with the host are of fundamental importance to assess the association of certain virulence factors with the intensity of the inflammatory response. In this sense, this work explored the virulence profile based on genomic and in vivo studies of hypermucoviscous carbapenem-resistant K. pneumoniae ST25 strains, expanding the knowledge of the biology of the emerging ST25 clone in Argentina.     

Enhancing augmented reality with cognitive and knowledge perspectives: a case study in museum exhibitions

ABSTRACT

In this paper, we present our results related to the definition of a methodology that combines augmented reality (AR) with semantic techniques for the creation of digital stories associated with museum exhibitions. In contrast to traditional AR approaches, we augment real-world elements by supplementing contents of a museum exhibition with additional inputs that provide new and different meanings. In this way we augment a cultural resource with respect to both its presentation and meaning. The methodology is framed in the cultural re-mediation theory and is grounded on a set of ontologies aimed at modelling a cultural resource and correlating it with external multimedia objects and resources. To provide an easy tool for the creation of museum narratives, the methodology makes use of a set of recognised practices widely adopted by museum curators that have been formalised through inference rules. The defined methodology has been experimented in a scenario related to Flemish paintings to validate the augmentation of cultural objects with two different approaches, the first basing on similarities and the second on dissimilarities.     

Trastuzumab and Doxorubicin Sequential Administration Increases Oxidative Stress and Phosphorylation of Connexin 43 on Ser368

Human epidermal growth factor receptor-2 (HER2) is overexpressed in up to 30% of breast cancer cases, causing a more aggressive tumour growth and poor prognosis. Trastuzumab, the humanized antibody targeted to HER2, increased the life expectancy of patients, but severe cardiotoxicity emerged as a long-term adverse effect. Clinical evidence highlights that Trastuzumab-induced cardiotoxicity drastically increases in association with Doxorubicin; however, the exact mechanisms involved remain incompletely understood. In order to analyse the molecular mechanisms involved and the possible adaptative responses to Trastuzumab and Doxorubicin treatment, in this study, H9c2 cardiomyoblasts were used. Results showed that Trastuzumab and Doxorubicin sequential administration in cardiomyoblast increased cytosolic and mitochondrial ROS production, intracellular calcium dysregulation, mitochondrial membrane depolarization, and the consequent apoptosis, induced by both Trastuzumab and Doxorubicin alone. Furthermore, in these conditions, we observed increased levels of Connexin43 phosphorylated on Ser368 (pCx43). Since phosphorylation on Ser368 decreases gap junction intracellular communication, thus reducing the spread of death signals to adjacent cells, we hypothesized that the increase in pCx43 could be an adaptative response implemented by cells to defend neighbouring cells by Trastuzumab and Doxorubicin sequential administration. However, the other side of the coin is the resulting conduction abnormalities.     

Unraveling the Immune Microenvironment of Thymic Epithelial Tumors: Implications for Autoimmunity and Treatment

Thymic Epithelial Tumors (TETs) represent a rare tumor family, originating from the epithelial component of the thymus gland. Clinicopathologically, they are segregated into six major subtypes, associated with distinct histological features and clinical outcomes. Their emergence and evolution are accompanied by the generation of a complex tumor microenvironment (TME), dominated by phenotypically and functionally divergent immune cellular subsets, in different maturation states and in analogies that vary significantly among different subtypes. These heterogenous leukocyte populations exert either immune-permissive and tumor-suppressive functions or vice versa, and the dynamic equilibrium established among them either dictates the tumor immune milieu towards an immune-tolerance state or enables the development of a productive spontaneous tumoricidal response. The immunologically “hot” microenvironment, defining a significant proportion of TETs, makes them a promising candidate for the implementation of immune checkpoint inhibitors (ICIs). A number of phase I and II clinical trials have already demonstrated significant, type-specific clinical efficacy of PD-L1 inhibitors, even though substantial limitations in their utilization derive from their immune-mediated adverse effects. Moreover, the completed clinical studies involved relatively restricted patient samples and an expansion in the enrolled cohorts is required, so that more trustworthy conclusions regarding the benefit from ICIs in TETs can be extracted.