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Objective: Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production. Methods: Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes. Results: GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production. Conclusions: Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production.

Item does not contain fulltext, BACKGROUND: The Surprise Question ('Would I be surprised if this patient died within 12 months?') identifies patients in the last year of life. It is unclear if 'surprised' means the same for each clinician, and whether their responses are internally consistent. AIM: To determine the consistency with which the Surprise Question is used. DESIGN: A cross-sectional online study of participants located in Belgium, Germany, Italy, The Netherlands, Switzerland and UK. Participants completed 20 hypothetical patient summaries ('vignettes'). Primary outcome measure: continuous estimate of probability of death within 12 months (0% [certain survival]-100% [certain death]). A threshold (probability estimate above which Surprise Question responses were consistently 'no') and an inconsistency range (range of probability estimates where respondents vacillated between responses) were calculated. Univariable and multivariable linear regression explored differences in consistency. Trial registration: NCT03697213. SETTING/PARTICIPANTS: Registered General Practitioners (GPs). Of the 307 GPs who started the study, 250 completed 15 or more vignettes. RESULTS: Participants had a consistency threshold of 49.8% (SD 22.7) and inconsistency range of 17% (SD 22.4). Italy had a significantly higher threshold than other countries (p = 0.002). There was also a difference in threshold levels depending on age of clinician, for every yearly increase, participants had a higher threshold. There was no difference in inconsistency between countries (p = 0.53). CONCLUSIONS: There is variation between clinicians regarding the use of the Surprise Question. Over half of GPs were not internally consistent in their responses to the Surprise Question. Future research with standardised terms and real patients is warranted.

Item does not contain fulltext, Trained immunity (TI) is a proinflammatory program induced in monocyte/macrophages upon sensing of specific pathogens and is characterized by immunometabolic and epigenetic changes that enhance cytokine production. Maladaptive activation of TI (ie, in the absence of infection) may result in detrimental inflammation and development of disease; however, the exact role and extent of inappropriate activation of TI in the pathogenesis of human diseases is undetermined. In this study, we uncovered the oncogene-induced, maladaptive induction of TI in the pathogenesis of a human inflammatory myeloid neoplasm (Erdheim-Chester disease, [ECD]), characterized by the BRAFV600E oncogenic mutation in monocyte/macrophages and excess cytokine production. Mechanistically, myeloid cells expressing BRAFV600E exhibit all molecular features of TI: activation of the AKT/mammalian target of rapamycin signaling axis; increased glycolysis, glutaminolysis, and cholesterol synthesis; epigenetic changes on promoters of genes encoding cytokines; and enhanced cytokine production leading to hyperinflammatory responses. In patients with ECD, effective therapeutic strategies combat this maladaptive TI phenotype; in addition, pharmacologic inhibition of immunometabolic changes underlying TI (ie, glycolysis) effectively dampens cytokine production by myeloid cells. This study revealed the deleterious potential of inappropriate activation of TI in the pathogenesis of human inflammatory myeloid neoplasms and the opportunity for inhibition of TI in conditions characterized by maladaptive myeloid-driven inflammation.

Chamaedorea glaucifolia H. Wendl is a species of the family Arecaceae, considered endemic to the southeast of Mexico and classified in danger according to the Nom-059-Semarnat-2010, given the ornamental importance of this palm and the lack of studies focused on its germination , storage and morphometry, the present work had as objective to determine the morphometric characteristics of the infructescence, fruit and seed, as well as to study the germinative process and the effect of storage on the viability and germinative capacity. To 100 fruits and seeds taken at random were individually determined weight, length and diameter, for the effect of the storage period (30, 60, 90 and 120 days), viability was assessed by tetrazolium test and germination with seed sowing, in a completely random experimental design with four replicates of 25 seeds each, making a total of 100 seeds per treatment. On average the infructescences contain 1 113.75 fruits (N = 5). The fruit presented 0.85 ± 0.52 cm (N = 100) in length, 0.70 ± 0.35 cm (N = 100) in diameter and 0.25 ± 0.028 g (N = 100) in weight. Each fruit contains a globose seed with a length of 0.62 ± 0.21 cm (N = 100), a diameter of 0.52 ± 0.28 cm (N = 100) and 0.11 ± 0.025 g (N = 100) weight, one kilogram contains on average 8 500 seeds. The seeds presented 100% viability at 30 days of storage, this drops to 65% at 120 days, the germination capacity of the seeds is also affected by the storage period. Germination is hypogeal, the radicle in seeds with 120 days of storage, begins to emerge at 49 days after sowing (das). Studies on morphometry, viability and germination allow obtaining fundamental information for the propagation of endangered species such as C. glaucifolia, which urgently needs conservation and management strategies to reduce the impact on wild populations., RESUMEN Chamaedorea glaucifolia H. Wendl, es una especie de la familia Arecaceae, considerada endémica del sureste de México y catalogada en peligro según la Nom-059-Semarnat-2010, dada la importancia ornamental de esta palma y la carencia de estudios enfocados a su germinación, almacenamiento y morfometría, el presente trabajo tuvo como objetivo evaluar el efecto del almacenamiento sobre la viabilidad y germinación de la semilla; así como determinar características morfométricas de la infrutescencia, fruto y semilla. A 100 frutos y semillas tomados al azar se les determinó peso, longitud y diámetro de manera individual, para el efecto del periodo de almacenamiento (30, 60, 90 y 120 días), se evaluó la viabilidad mediante la prueba de tetrazolio y la germinación con la siembra de semilla, en un diseño experimental completamente aleatorio con cuatro repeticiones de 25 semillas cada una, haciendo un total de 100 semillas por tratamiento. En promedio las infrutescencias contienen 1 113.75 frutos (N = 5). El fruto presenta 0.85 ± 0.52 cm (N = 100) de longitud, 0.70 ± 0.35 cm (N = 100) de diámetro y 0.25±0.028 g (N = 100) de peso. Cada fruto contiene una semilla globosa, con longitud de 0.62 ± 0.21 cm (N = 100), diámetro de 0.52 ± 0.28 cm (N = y 0.11 ± 0.025 g (N = 100) de peso, un kilogramo contiene en promedio 8 500 semillas. Las semillas presentaron 100 % de viabilidad a los 30 días de almacenamiento, esto desciende hasta 65% a los 120 días, la capacidad germinativa de las semillas también es afectada por el periodo de almacenamiento. La germinación es hipogea, la radícula en semillas con 120 días de almacenamiento, empieza a emerger a los 49 días después de la siembra (dds). Los estudios sobre morfometría, viabilidad y germinación permiten obtener información fundamental para la propagación de especies en riesgo como C. glaucifolia.