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Diabetic retinopathy (DR) affects about 25% of people with diabetes in Canada. Early detection of DR is essential for preventing vision loss. We evaluated the real-world performance of an artificial intelligence (AI) system that analyzes fundus images for DR screening in a Quebec tertiary care center. We prospectively recruited adult patients with diabetes at the Centre hospitalier de l'Université de Montréal (CHUM) in Montreal, Quebec, Canada. Patients underwent dual-pathway screening: first by the Computer Assisted Retinal Analysis (CARA) AI system (index test), then by standard ophthalmological examination (reference standard). We measured the AI system's sensitivity and specificity for detecting referable disease at the patient level, along with its performance for detecting any retinopathy and diabetic macular edema (DME) at the eye level, and potential cost savings. This study included 115 patients. CARA demonstrated a sensitivity of 87.5% (95% CI 71.9-95.0) and specificity of 66.2% (95% CI 54.3-76.3) for detecting referable disease at the patient level. For any retinopathy detection at the eye level, CARA showed 88.2% sensitivity (95% CI 76.6-94.5) and 71.4% specificity (95% CI 63.7-78.1). For DME detection, CARA had 100% sensitivity (95% CI 64.6-100) and 81.9% specificity (95% CI 75.6-86.8). Potential yearly savings from implementing CARA at the CHUM were estimated at CAD $245,635 (US $177,643.23, as of July 26, 2024) considering 5000 patients with diabetes. Our study indicates that integrating a semiautomated AI system for DR screening demonstrates high sensitivity for detecting referable disease in a real-world setting. This system has the potential to improve screening efficiency and reduce costs at the CHUM, but more work is needed to validate it.

This paper pertains to research works aiming at linking ethics and automated reasoning in autonomous machines. It focuses on a formal approach that is intended to be the basis of an artificial agent’s reasoning that could be considered by a human observer as an ethical reasoning. The approach includes some formal tools to describe a situation and models of ethical principles that are designed to automatically compute a judgement on possible decisions that can be made in a given situation and explain why a given decision is ethically acceptable or not. It is illustrated on three ethical frameworks—utilitarian ethics, deontological ethics and the Doctrine of Double effect whose formal models are tested on ethical dilemmas so as to examine how they respond to those dilemmas and to highlight the issues at stake when a formal approach to ethical concepts is considered. The whole approach is instantiated on the drone dilemma, a thought experiment we have designed; this allows the discrepancies that exist between the judgements of the various ethical frameworks to be shown. The final discussion allows us to highlight the different sources of subjectivity of the approach, despite the fact that concepts are expressed in a more rigorous way than in natural language: indeed, the formal approach enables subjectivity to be identified and located more precisely.

Pathogenic Escherichia coli 4787 (O115:KV165) causes septicemia in pigs and expresses the fimbriae F165₁ encoded by the foo operon that belongs to the P fimbrial family. fooI and fooB, encoding specific foo regulators, are divergently transcribed; their intergenic region is responsible for the regulation of foo expression. The role of global and local supercoiling (transcription-induced supercoiling within the intergenic region) on the regulation of foo expression was investigated. Expression of fooB was significantly altered when global negative supercoiling was reduced by a mutation that decreases DNA gyrase activity. Deletion of the topA gene, encoding for topoisomerase I that relaxes local negative supercoiling, further reduced fooB expression. This suggests that both global and local supercoiling can significantly affect fooB expression. Moreover, FooI, a positive regulator of fooB expression, has no effect on fooB expression in the topA null mutant. This study showed that divergent transcription from a strong promoter can significantly enhance fooB expression and compensate for the absence of FooI in a wild-type strain.

Asthma, atopy, and related phenotypes are heterogeneous complex traits, with both genetic and environmental risk factors. Extensive research has been conducted and over hundred genes have been associated with asthma and atopy phenotypes, but many of these findings have failed to replicate in subsequent studies. To separate true associations from false positives, candidate genes need to be examined in large well-characterized samples, using standardized designs (genotyping, phenotyping and analysis). In an attempt to replicate previous associations we amalgamated the power and resources of four studies and genotyped 5,565 individuals to conduct a genetic association study of 93 previously associated candidate genes for asthma and related phenotypes using the same set of 861 single-nucleotide polymorphisms (SNPs), a common genotyping platform, and relatively harmonized phenotypes. We tested for association between SNPs and the dichotomous outcomes of asthma, atopy, atopic asthma, and airway hyperresponsiveness using a general allelic likelihood ratio test. No SNP in any gene reached significance levels that survived correction for all tested SNPs, phenotypes, and genes. Even after relaxing the usual stringent multiple testing corrections by performing a gene-based analysis (one gene at a time as if no other genes were typed) and by stratifying SNPs based on their prior evidence of association, no genes gave strong evidence of replication. There was weak evidence to implicate the following: IL13, IFNGR2, EDN1, and VDR in asthma; IL18, TBXA2R, IFNGR2, and VDR in atopy; TLR9, TBXA2R, VDR, NOD2, and STAT6 in airway hyperresponsiveness; TLR10, IFNGR2, STAT6, VDR, and NPSR1 in atopic asthma. Additionally we found an excess of SNPs with small effect sizes (OR < 1.4). The low rate of replication may be due to small effect size, differences in phenotypic definition, differential environmental effects, and/or genetic heterogeneity. To aid in future replication studies of asthma genes a comprehensive database was compiled and is available to the scientific community at http://genapha.icapture.ubc.ca/.

The transporter 2, ATP-binding cassette, subfamily B (TAP2) is involved in the transport of antigenic peptides to HLA molecules. Coding TAP2 polymorphisms shows a strong association with type 1 diabetes, but it is not clear whether this association may be entirely due to linkage disequilibrium with HLA DR and DQ. Functionally, rat Tap2 nonsynonymous single-nucleotide polymorphisms (nsSNPs) confer differential selectivity for antigenic peptides, but this was not shown to be the case for human TAP2 nsSNPs. In the human, differential peptide selectivity is rather conferred by two splicing isoforms with alternative carboxy terminals. Here, we tested the hypothesis that alleles at the coding SNPs favor different splicing isoforms, thus determining peptide selectivity indirectly. This may be the basis for independent contribution to the type 1 diabetes association. In RNA from heterozygous lymphoblastoid lines, we measured the relative abundance of each SNP haplotype in each isoform. In isoform NM_000544, the G (Ala) allele at 665 Thr>Ala (rs241447) is more than twice as abundant as A (Thr) (GA = 2.2 +/- 0.4, P = 1.5 x 10(-4)), while isoform NM_018833 is derived almost exclusively from chromosomes carrying A (AG = 18.1 +/- 5.6, P = 2.04 x 10(-7)). In 889 Canadian children with type 1 diabetes, differential transmission of parental TAP2 alleles persisted (P = 0.011) when analysis was confined to chromosomes carrying only DQ*02 alleles, which mark a conserved DR-DQ haplotype, thus eliminating most of the variation at DR-DQ. Thus, we present evidence of TAP2 association with type 1 diabetes that is independent of HLA DR-DQ and describe a plausible functional mechanism based on allele dependence of splicing into isoforms known to have differential peptide selectivities.

Genetic Control of Alternative Splicing in the TAP2 Gene Possible Implication in the Genetics of Type 1 Diabetes Hui-Qi Qu 1 , Yang Lu 1 , Luc Marchand 1 , François Bacot 1 , Rosalie Fréchette 1 , Marie-Catherine Tessier 1 , Alexandre Montpetit 2 and Constantin Polychronakos 1 3 1 Endocrine Genetics Laboratory, The McGill University Health Center (Montreal Children’s Hospital), Montréal, Quebec, Canada 2 McGill University and Genome Quebec Innovation Centre, Montréal, Quebec, Canada 3 Department of Pediatrics, The McGill University Health Center (Montreal Children’s Hospital), Montréal, Quebec, Canada Address correspondence and reprint requests to Constantin Polychronakos, MD, The McGill University Health Center (Montreal Children’s Hospital), 2300 Tupper, Montréal, QC, Canada, H3H 1P3. E-mail: constantin.polychronakos{at}mcgill.ca Abstract The transporter 2, ATP-binding cassette, subfamily B (TAP2) is involved in the transport of antigenic peptides to HLA molecules. Coding TAP2 polymorphisms shows a strong association with type 1 diabetes, but it is not clear whether this association may be entirely due to linkage disequilibrium with HLA DR and DQ . Functionally, rat Tap2 nonsynonymous single-nucleotide polymorphisms (nsSNPs) confer differential selectivity for antigenic peptides, but this was not shown to be the case for human TAP2 nsSNPs. In the human, differential peptide selectivity is rather conferred by two splicing isoforms with alternative carboxy terminals. Here, we tested the hypothesis that alleles at the coding SNPs favor different splicing isoforms, thus determining peptide selectivity indirectly. This may be the basis for independent contribution to the type 1 diabetes association. In RNA from heterozygous lymphoblastoid lines, we measured the relative abundance of each SNP haplotype in each isoform. In isoform NM_000544, the G (Ala) allele at 665 Thr>Ala (rs241447) is more than twice as abundant as A (Thr) (GA = 2.2 ± 0.4, P = 1.5 × 10 −4 ), while isoform NM_018833 is derived almost exclusively from chromosomes carrying A (AG = 18.1 ± 5.6, P = 2.04 × 10 −7 ). In 889 Canadian children with type 1 diabetes, differential transmission of parental TAP2 alleles persisted ( P = 0.011) when analysis was confined to chromosomes carrying only DQ *02 alleles, which mark a conserved DR-DQ haplotype, thus eliminating most of the variation at DR-DQ . Thus, we present evidence of TAP2 association with type 1 diabetes that is independent of HLA DR-DQ and describe a plausible functional mechanism based on allele dependence of splicing into isoforms known to have differential peptide selectivities. AI, allelic imbalance gDNA, genomic DNA LD, linkage disequilibrium nsSNP, nonsynonymous single-nucleotide polymorphism SNP, single-nucleotide polymorphism Footnotes H.-Q.Q. and Y.L. contributed equally to this work. Additional information for this article can be found in an online appendix at http://diabetes.diabetesjournals.org . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted October 9, 2006. Received June 25, 2006. DIABETES

Conflicts between agents acting in a multi-agent environment arise for different reasons, involve different concepts, and are dealt with in different ways, depending on the kind of agents and on the domain where they are considered. Agents may have conflicting beliefs, conflicting goals, or may have to share limited resources. Consequently, conflicts may be expressed as mere differences, or as contradictions, or even as social conflicts. They may be avoided, solved, kept or even created deliberately. This volume studies conflicts in the context of multi-agent systems, for example, artificial societies modelled on the basis of autonomous, interacting agents. The book addresses questions about types of conflicts, conflict definitions and the use of conflicts as trigger functions for activities in multi-agent systems. The book is also dedicated to questions of conflict management, resolution and avoidance, for example, the question of how agents cope with conflicts and conflicting situations.