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Mutations disrupting the kinase domain of IKKα lead to immunodeficiency and immune dysregulation in humans.
Full text linkpeer reviewedIKKα, encoded by CHUK, is crucial in the non-canonical NF-κB pathway and part of the IKK complex activating the canonical pathway alongside IKKβ. The absence of IKKα causes fetal encasement syndrome in humans, fatal in utero, while an impaired IKKα-NIK interaction was reported in a single patient and causes combined immunodeficiency. Here, we describe compound heterozygous variants in the kinase domain of IKKα in a female patient with hypogammaglobulinemia, recurrent lung infections, and Hay-Wells syndrome-like features. We showed that both variants were loss-of-function. Non-canonical NF-κB activation was profoundly diminished in stromal and immune cells while the canonical pathway was unexpectedly partially impaired. Reintroducing wt CHUK restored non-canonical NF-κB activation. The patient had neutralizing autoantibodies against type I IFN, akin to non-canonical NF-κB pathway deficiencies. Thus, this is the first case of biallelic CHUK mutations disrupting IKKα kinase function, broadening non-canonical NF-κB defect understanding, and suggesting IKKα's role in canonical NF-κB target gene expression in humans
Flow Time vs Work In Progress: Benchmark of Algorithms for the Online-Time Job Shop Scheduling Problem
Full text linkThe online-time Job Shop Scheduling Problem provides a useful model for real- time scheduling in industrial settings. In this problem, jobs with precedence constraints arrive according to a Poisson process, and resolution algorithms must generate a schedule at any given time. Two of the most insightful efficiency cri- teria to evaluate a schedule in an industrial context are flow time and work in progress, respectively the duration from a job’s arrival to its completion and the number of jobs being processed at any time. This paper aims to compare the performance for these two criteria of solution algorithms, notably rescheduling algorithms and priority dispatching rules. In order to enhance rescheduling poli- cies performances, a new objective function, termed the “fee-reward objective function”, is implemented in order to find a balance between both flow time and work in progress. The studied algorithms using the fee-reward objective func- tion show significantly better performances on the work in progress criterion and achieve comparable or even superior results on the flow time criterion rela- tive to the best priority dispatching rules and rescheduling algorithms using the makespan objective function
Patient-Centricity in the Pharmaceutical Industry: A Review and Research Agenda
No full textpeer reviewedThe concept of patient-centricity has gained much attention in the healthcare ecosystem in the past few decades. While most healthcare stakeholders have embraced this model of placing the patient at the center of their focus, pharmaceutical companies have only started to adopt patient-centricity more recently. To date, the literature on patient-centricity in the pharmaceutical industry has focused on isolated initiatives, departments, or processes, leading to a fragmented view of the concept. To address this gap, this article conducts a systematic literature review of 46 peer-reviewed articles from the Scopus database. This study uses the “Theory, Context, and Methodology” and “Antecedents, Decisions, and Outcomes” frameworks to organize and structure the literature review. This article offers a comprehensive framework and definition of the concept of patient-centricity in the pharmaceutical industry and concludes with a research agenda to address the gaps. This study provides a unified understanding of patient-centricity and guides future research to develop it further while providing practitioners from the pharmaceutical industry with a framework of initiatives to shift toward patient-centricity
STRATEGY₿: Une Leçon de Finance à Livres Ouverts
Full text linkAu cours de sa présentation des comptes annuels clôturés le 31 décembre 2024, MicroStrategy annonce un changement de nom : STRATEGY₿. Cette évolution reflète sa mission nouvelle de World’s First Bitcoin Treasury Company. Elle affirme son leadership en tant que société consacrée au développement d’un Écosystème Financier reposant sur le réseau Bitcoin. Cette technologie – Bitcoin Core – garantit l’irréversibilité, l’incorruptibilité et l’inviolabilité de tous types de transactions digitales entre opérateurs réels et/ou virtuels. En publiant en temps réel sur son nouveau site – strategy.com – ses objectifs chiffrés, ses modes de financement et sa performance réelle, STRATEGY₿ offre une base de comparaison, un Benchmark, qui sera difficile à ignorer. Elle offre aussi une nouvelle mesure du Coût d’Opportunité associé aux investissements. Une petite révolution dans l’histoire de la Finance
ReFORM synthesis of the 6th International Consensus Statement on Concussion in Sport.
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Diversité linguistique à Rhegium durant le Principat : Le témoignage des inscriptions funéraires
No full textThis paper aims at examining the contribution of the corpus of funerary inscriptions from Rhegium (Reggio Calabria) to our understanding of linguistic diversity during the end of the last century BCE and the three first centuries CE. The continued presence of Hellenistic traditions under Roman rule is corroborated by epigraphic evidence. It appears that Rhegium has maintained some Greek public magistracies, as Neapolis did, during the 1st century CE. Moreover, as a former polis of Magna Graecia, the city of Rhegium was not entirely Latinised following the Roman conquest, as Greek continued to be used there. However, most of the tituli sepulcrales of Rhegium that have survived are written in Latin. In accordance with Strabo (VI, 1, 6), the city was repopulated by Octavian with veterani classiarii (tōn ek tou stolou tinas) in 36 BCE. It seems reasonable to suggest that this Latin-speaking population partly had an influence on the epigraphic habitus of Rhegium. To illustrate to what extant Roman practices had an impact on our corpus, the Latin formulary translated into Greek (Theois Katakhthoniois) has become embedded in funerary inscriptions from the 2nd century CE onwards. Furthermore, a study of these testimonies reveals a variety of bilingual phenomena, as categorised by James N. Adam’s typology of bilingual texts, revised by Alex Mullen. The presence of Latinised Greek names, Greek Latinised cognomina, and Greek Latinised names, as well as intra-sentential code-switching, demonstrates the intricate cultural dynamics of Rhegium. As the evidence of the tombstones can be read as a representation of how the dead wished to be viewed, this modest corpus (more or less thirty items) of funerary inscriptions sheds light on cultural interactions in an area where the Greek cultural substrate was considered by ancient authors to be enduring