Harnessing Higher-Order (Meta-)Logic to Represent and Reason with Complex Ethical Theories

The computer-mechanization of an ambitious explicit ethical theory, Gewirth's Principle of Generic Consistency, is used to showcase an approach for representing and reasoning with ethical theories exhibiting complex logical features like alethic and deontic modalities, indexicals, higher-order quantification, among others. Harnessing the high expressive power of Church's type theory as a meta-logic to semantically embed a combination of quantified non-classical logics, our work pushes existing boundaries in knowledge representation and reasoning. We demonstrate that intuitive encodings of complex ethical theories and their automation on the computer are no longer antipodes.Comment: 14 page

Gene editing of PKLR gene in human hematopoietic progenitors through 5' and 3' UTR modified TALEN mRNA

TheauthorswouldliketothankMiguelA.MartinforthecarefulmaintenanceofNSGmice,andRebecaSa ́nchezandOmairaAlberquillafortheirtechnicalassistanceinflowcytometry.TheauthorsalsothankFundacio ́n Botı ́n forpromotingtranslationalresearchattheHemato-poieticInnovativeTherapiesDivisionoftheCIEMATPyruvate Kinase Deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene, which encodes the erythroid specific Pyruvate Kinase enzyme. Erythrocytes from PKD patients show an energetic imbalance and are susceptible to hemolysis. Gene editing of hematopoietic stem cells (HSCs) would provide a therapeutic benefit and improve safety of gene therapy approaches to treat PKD patients. In previous studies, we established a gene editing protocol that corrected the PKD phenotype of PKD-iPSC lines through a TALEN mediated homologous recombination strategy. With the goal of moving toward more clinically relevant stem cells, we aim at editing the PKLR gene in primary human hematopoietic progenitors and hematopoietic stem cells (HPSCs). After nucleofection of the gene editing tools and selection with puromycin, up to 96% colony forming units showed precise integration. However, a low yield of gene edited HPSCs was associated to the procedure. To reduce toxicity while increasing efficacy, we worked on i) optimizing gene editing tools and ii) defining optimal expansion and selection times. Different versions of specific nucleases (TALEN and CRISPR-Cas9) were compared. TALEN mRNAs with 5' and 3' added motifs to increase RNA stability were the most efficient nucleases to obtain high gene editing frequency and low toxicity. Shortening ex vivo manipulation did not reduce the efficiency of homologous recombination and preserved the hematopoietic progenitor potential of the nucleofected HPSCs. Lastly, a very low level of gene edited HPSCs were detected after engraftment in immunodeficient (NSG) mice. Overall, we showed that gene editing of the PKLR gene in HPSCs is feasible, although further improvements must to be done before the clinical use of the gene editing to correct PKD.S

Community Structure Characterization

This entry discusses the problem of describing some communities identified in a complex network of interest, in a way allowing to interpret them. We suppose the community structure has already been detected through one of the many methods proposed in the literature. The question is then to know how to extract valuable information from this first result, in order to allow human interpretation. This requires subsequent processing, which we describe in the rest of this entry

Knowledge, Awareness and Practice with Antimicrobial Stewardship Programmes among Healthcare Providers in a Ghanaian Tertiary Hospital

Antimicrobial resistance (AMR) is a significant problem in global health today, particularly in low- and middle-income countries (LMICs) where antimicrobial stewardship programmes are yet to be successfully implemented. We established a partnership between AMR pharmacists from a UK NHS hospital and in Ho Teaching Hospital with the aim of enhancing antimicrobial stewardship knowledge and practice among healthcare providers through an educational intervention. We employed a mixed-method approach that included an initial survey on knowledge and awareness before and after training, followed by qualitative interviews with healthcare providers conducted six months after delivery of training. This study was carried out in two phases in Ho Teaching Hospital with healthcare professionals, including pharmacists, medical doctors, nurses and medical laboratory scientists. Ethical approval was obtained prior to data collection. In the first phase, we surveyed 50 healthcare providers, including nurses (33%), pharmacists (29%) and biomedical scientists (23%). Of these, 58% of participants had engaged in continuous professional development on AMR/AMS, and above 95% demonstrated good knowledge on the general use of antibiotics. A total of 18 participants, which included four medical doctors, five pharmacists, four nurses, two midwives and three biomedical scientists, were interviewed in the second phase and demonstrated greater awareness of AMS practices, particularly the role of education for patients, as well as healthcare professionals. We found that knowledge and practice with AMS was markedly improved six months after the training session. There is limited practice of AMS in LMICs; however, through AMR-focused training, we demonstrated improved AMS skills and practice among healthcare providers in Ho Teaching Hospital. There is a need for continuous AMR training sessions for healthcare professionals in resource-limited settings

Development of a local antibiogram for a teaching hospital in Ghana

Background: Antimicrobial resistance threatens adequate healthcare provision against infectious diseases. Antibiograms, combined with patient clinical history, enable clinicians and pharmacists to select the best empirical treatments prior to culture results. Objectives: To develop a local antibiogram for the Ho Teaching Hospital. Methods: This was a retrospective cross-sectional study, using data collected on bacterial isolates from January-December 2021. Samples from urine, stool, sputum, blood, and cerebrospinal fluid (CSF) were considered as well as, aspirates and swabs from wound, ears and vagina of patients. Bacteria were cultured on both enrichment and selective media including blood agar supplemented with 5% sheep blood and MacConkey agar, and identified by both the VITEK 2 system and routine biochemical tests. Data on routine culture and sensitivity tests performed on bacterial isolates from patient samples were retrieved from the hospital's health information system. Data were then entered into and analysed using WHONET. Results: In all, 891 pathogenic microorganisms were isolated from 835 patients who had positive culture tests. Gram-negative isolates accounted for about 77% of the total bacterial species. Escherichia coli (246), Pseudomonas spp. (180), Klebsiella spp. (168), Citrobacter spp. (101) and Staphylococcus spp. (78) were the five most isolated pathogens. Most of the bacterial isolates showed high resistance (>70%) to ampicillin, piperacillin, ceftazidime, ceftriaxone, cefotaxime, penicillin G, amoxicillin, amoxicillin/clavulanic acid, ticarcillin/clavulanic acid and trimethoprim/sulfamethoxazole. Conclusions: The isolates from the various samples were not susceptible to most of the antibiotics used in the study. The study reveals the resistance patterns of E. coli and Klebsiella spp.To some antibiotics on the WHO 'Watch' and 'Reserve' lists. Using antibiograms as part of antimicrobial stewardship programmes would optimize antibiotic use and preserve their efficacy

Qualitative Comparison of Community Detection Algorithms

Community detection is a very active field in complex networks analysis, consisting in identifying groups of nodes more densely interconnected relatively to the rest of the network. The existing algorithms are usually tested and compared on real-world and artificial networks, their performance being assessed through some partition similarity measure. However, artificial networks realism can be questioned, and the appropriateness of those measures is not obvious. In this study, we take advantage of recent advances concerning the characterization of community structures to tackle these questions. We first generate networks thanks to the most realistic model available to date. Their analysis reveals they display only some of the properties observed in real-world community structures. We then apply five community detection algorithms on these networks and find out the performance assessed quantitatively does not necessarily agree with a qualitative analysis of the identified communities. It therefore seems both approaches should be applied to perform a relevant comparison of the algorithms.Comment: DICTAP 2011, The International Conference on Digital Information and Communication Technology and its Applications, Dijon : France (2011

Generation of a High Number of Healthy Erythroid Cells from Gene-Edited Pyruvate Kinase Deficiency Patient-Specific Induced Pluripotent Stem Cells

Pyruvate kinase deficiency (PKD) is a rare erythroid metabolic disease caused by mutations in the PKLR gene. Erythrocytes from PKD patients show an energetic imbalance causing chronic non-spherocytic hemolytic anemia, as pyruvate kinase defects impair ATP production in erythrocytes. We generated PKD induced pluripotent stem cells (PKDiPSCs) from peripheral blood mononuclear cells (PB-MNCs) of PKD patients by non-integrative Sendai viral vectors. PKDiPSCs were gene edited to integrate a partial codon-optimized R-type pyruvate kinase cDNA in the second intron of the PKLR gene by TALEN-mediated homologous recombination (HR). Notably, we found allele specificity of HR led by the presence of a single-nucleotide polymorphism. High numbers of erythroid cells derived from gene-edited PKDiPSCs showed correction of the energetic imbalance, providing an approach to correct metabolic erythroid diseases and demonstrating the practicality of this approach to generate the large cell numbers required for comprehensive biochemical and metabolic erythroid analyses.info:eu-repo/semantics/publishedVersio

Sex differences in money pathology in the general population

This study examined sex differences in money beliefs and behaviours. Over 100,000 British participants completed two measures online, one of which assessed “money pathology” (Forman in Mind over money, Doubleday, Toronto, 1987), and the other four “money types”, based on the emotional associations of money (Furnham et al. in Personal Individ Differ, 52:707–711, 2012). Nearly all measures showed significant sex differences with medium to large effect sizes, and with females exhibiting more “money pathology” than males. The biggest difference on the money types was on money being associated with generosity (money representing love) where men scored much lower than females, and autonomy (money representing freedom) where men scored higher than women. For men, more than women, money represented Power and Security. Men were more likely to be Hoarders while women did more emotional regulatory purchasing. Implications and limitations of this study are discussed

HIV Protease Inhibitors Act as Competitive Inhibitors of the Cytoplasmic Glucose Binding Site of GLUTs with Differing Affinities for GLUT1 and GLUT4

The clinical use of several first generation HIV protease inhibitors (PIs) is associated with the development of insulin resistance. Indinavir has been shown to act as a potent reversible noncompetitive inhibitor of zero-trans glucose influx via direct interaction with the insulin responsive facilitative glucose transporter GLUT4. Newer drugs within this class have differing effects on insulin sensitivity in treated patients. GLUTs are known to contain two distinct glucose-binding sites that are located on opposite sides of the lipid bilayer. To determine whether interference with the cytoplasmic glucose binding site is responsible for differential effects of PIs on glucose transport, intact intracellular membrane vesicles containing GLUT1 and GLUT4, which have an inverted transporter orientation relative to the plasma membrane, were isolated from 3T3-L1 adipocytes. The binding of biotinylated ATB-BMPA, a membrane impermeable bis-mannose containing photolabel, was determined in the presence of indinavir, ritonavir, atazanavir, tipranavir, and cytochalasin b. Zero-trans 2-deoxyglucose transport was measured in both 3T3-L1 fibroblasts and primary rat adipocytes acutely exposed to these compounds. PI inhibition of glucose transport correlated strongly with the PI inhibition of ATB-BMPA/transporter binding. At therapeutically relevant concentrations, ritonavir was not selective for GLUT4 over GLUT1. Indinavir was found to act as a competitive inhibitor of the cytoplasmic glucose binding site of GLUT4 with a KI of 8.2 µM. These data establish biotinylated ATB-BMPA as an effective probe to quantify accessibility of the endofacial glucose-binding site in GLUTs and reveal that the ability of PIs to block this site differs among drugs within this class. This provides mechanistic insight into the basis for the clinical variation in drug-related metabolic toxicity