Inflammatory monocytes require type I interferon receptor signaling to activate NK cells via IL-18 during a mucosal viral infection

The requirement of type I interferon (IFN) for natural killer (NK) cell activation in response to viral infection is known, but the underlying mechanism remains unclear. Here, we demonstrate that type I IFN signaling in inflammatory monocytes, but not in dendritic cells (DCs) or NK cells, is essential for NK cell function in response to a mucosal herpes simplex virus type 2 (HSV-2) infection. Mice deficient in type I IFN signaling, Ifnar(-/-) and Irf9(-/-) mice, had significantly lower levels of inflammatory monocytes, were deficient in IL-18 production, and lacked NK cell-derived IFN-gamma. Depletion of inflammatory monocytes, but not DCs or other myeloid cells, resulted in lower levels of IL-18 and a complete abrogation of NK cell function in HSV-2 infection. Moreover, this resulted in higher susceptibility to HSV-2 infection. Although Il18(-/-) mice had normal levels of inflammatory monocytes, their NK cells were unresponsive to HSV-2 challenge. This study highlights the importance of type I IFN signaling in inflammatory monocytes and the induction of the early innate antiviral response

ASPCAT: qui som? què fem?

Visibilitat; Salut pública; ASPCATVisibilidad; Salud pública; ASPCATVisibility; Public health; ASPCATLa salut pública es defineix com el conjunt organitzat d’actuacions dels poders públics i de la societat mitjançant la mobilització de recursos humans i materials per protegir i promoure la salut de les persones, prevenir la malaltia i tenir cura de la vigilància de la salut pública. Aquestes actuacions són, en gran mesura, dutes a terme des de l’Agència de Salut Pública de Catalunya (ASPCAT) amb la col·laboració del sector públic (organismes internacionals, estatals, autonòmics i locals) i privat, així com del conjunt de la ciutadania. Tanmateix, existeix certa confusió en la ciutadania entre sanitat pública i salut pública, quan aquesta darrera acostuma a ser inclosa sota el paraigües de la salut assistencial. Aquest treball pretén dimensionar la nostra visibilitat com a agència i, alhora, ser la base per focalitzar actuacions futures que ajudin a augmentar la nostra presència en la societat. Per a tal fi, s’han treballat quatre àmbits d’actuació: ciutadania, entorn web, xarxes socials i mitjans de comunicació. Per a cadascun d’aquests àmbits s’ha volgut posar de manifest la situació actual a través de diferents estudis com són l’elaboració d’una enquesta, estudis de benchmarking d’altres organismes, estatals i internacionals amb funcions anàlogues, i la cerca de projectes passats de l’Agència de Salut Pública de Catalunya. Com a resultat, es presenten diverses conclusions i propostes d’actuacions que poden ajudar a fer més visible la gran tasca realitzada pels professionals que formen l’ASPCAT.La salud pública se define como el conjunto organizado de actuaciones de los poderes públicos y la sociedad mediante la movilización de recursos humanos y materiales para proteger y promover la salud de las personas, prevenir la enfermedad y velar por la vigilancia de la salud pública. Dichas actuaciones son, en gran medida, llevadas a cabo por la Agencia de Salud Pública de Cataluña (ASPCAT), con la colaboración del sector público (organismos internacionales, estatales, autonómicos y locales) y privado, así como del conjunto de la ciudadanía. No obstante, existe cierta confusión en la ciudadanía entre sanidad pública y salud pública, cuando esta última suele incluirse bajo el paraguas de la salud asistencial. El presente trabajo pretende dimensionar nuestra visibilidad como agencia y, al tiempo, ser la base per centrarse en futuras actuaciones que ayuden a aumentar nuestra presencia en la sociedad. Para dicho fin, se han trabajado cuatro ámbitos de actuación: ciudadanía, entorno web, redes sociales y medios de comunicación. Para cada uno de estos ámbitos se ha deseado poner de manifiesto la actual situación a través de distintos estudios, tales como la elaboración de una encuesta, estudios de benchmarking de otros organismos ─estatales e internacionales─ con funciones análogas, y la búsqueda de pasados proyectos de la ASPCAT. Como resultado, se presentan varias conclusiones y propuestas de actuación que pueden ayudar a dar mayor visibilidad a la gran labor realizada por los profesionales que conforman la ASPCAT. ExecutivePublic health is defined as an organized set of actions by public authorities and society through the mobilisation of human and material resources for protecting and promoting population health, preventing disease, and monitoring public health surveillance. These actions are to a large extent developed by the Public Health Agency of Catalonia (ASPCAT) with the collaboration by the public (international, national, regional and local) and private sectors, as well as the community as a whole. However, there is a certain confusion among population between public health and health services provision. This work aims to increase our visibility as an agency and, at the same time, be the basis for focusing on future actions that help increase our presence in society. To this end, four areas of action have been worked on: target groups, websites, social networks, and the media. For each one of these areas, the intention has been to highlight the current situation through different studies, such as the preparation of a survey, benchmarking studies of other agencies – both national and international – with equivalent functions, and the search of past projects undertaken by the ASPCAT. As a result, several conclusions and proposals for action are presented that can help give greater visibility to the great work done by professionals that make up the ASPCAT

Peanut Allergen Reaction Thresholds during Controlled Food Challenges in 2 Canadian Randomized Studies (Canada-ARM1 and PISCES)

In 2 randomized studies addressing peanut allergy (Canada-Food Allergy Risk Management 1 [NCT01812798] and Peanut Immunotherapy Starting in Canada, Evaluation and DiScovery [NCT0 1601522]), we quantified peanut allergen thresholds to food challenge using Bayesian stacked model averaging to inform policy and clinical practice. About 50% of patients tolerated more than 70 mg (~ ¼ peanut)

Detection of lesions in the optic nerve with magnetic resonance imaging using a 3D convolutional neural network

Deep learning; Multiple sclerosis, Optic nerveAprendizaje profundo; Esclerosis múltiple; Nervio ópticoAprenentatge profund; Esclerosi múltiple; Nervi òpticBackground Optic neuritis (ON) is one of the first manifestations of multiple sclerosis, a disabling disease with rising prevalence. Detecting optic nerve lesions could be a relevant diagnostic marker in patients with multiple sclerosis. Objectives We aim to create an automated, interpretable method for optic nerve lesion detection from MRI scans. Materials and Methods We present a 3D convolutional neural network (CNN) model that learns to detect optic nerve lesions based on T2-weighted fat-saturated MRI scans. We validated our system on two different datasets (N = 107 and 62) and interpreted the behaviour of the model using saliency maps. Results The model showed good performance (68.11% balanced accuracy) that generalizes to unseen data (64.11%). The developed network focuses its attention to the areas that correspond to lesions in the optic nerve. Conclusions The method shows robustness and, when using only a single imaging sequence, its performance is not far from diagnosis by trained radiologists with the same constraint. Given its speed and performance, the developed methodology could serve as a first step to develop methods that could be translated into a clinical setting.This project was developed as a part of Gerard Martí-Juan ECTRIMS Research Fellowship Program 2021–2022. This study was partially supported by the Projects (PI18/00823, PI19/00950), from the Fondo de Investigación Sanitaria (FIS), Instituto de Salud Carlos III

T1/T2-weighted ratio in multiple sclerosis: A longitudinal study with clinical associations

Clinically isolated syndrome; Magnetic resonance imaging; Multiple sclerosisSíndrome clínicamente aislado; Imágenes por resonancia magnética; Esclerosis múltipleSíndrome clínicament aïllat; Imatges per ressonància magnètica; Esclerosi múltipleBackground T1w/T2-w ratio has been proposed as a clinically feasible MRI biomarker to assess tissue integrity in multiple sclerosis. However, no data is available in the earliest stages of the disease and longitudinal studies analysing clinical associations are scarce. Objective To describe longitudinal changes in T1-w/T2-w in patients with clinically isolated syndrome (CIS) and multiple sclerosis, and to investigate their clinical associations. Methods T1-w/T2-w images were generated and the mean value obtained in the corresponding lesion, normal-appearing grey (NAGM) and white matter (NAWM) masks. By co-registering baseline to follow-up MRI, evolved lesions were assessed; and by placing the mask of new lesions to the baseline study, the pre-lesional tissue integrity was measured. Results We included 171 CIS patients and 22 established multiple sclerosis patients. In CIS, evolved lesions showed significant T1-w/T2-w increases compared to baseline (+7.6%, P < 0.001). T1-w/T2-w values in new lesions were lower than in pre-lesional tissue (-28.2%, P < 0.001), and pre-lesional tissue was already lower than baseline NAWM (-7.8%, P < 0.001). In CIS at baseline, higher NAGM T1-w/T2-w was associated with multiple sclerosis diagnosis, and longitudinal decreases in NAGM and NAWM T1-w/T2-w were associated with disease activity. In established multiple sclerosis, T1-w/T2-w was inversely correlated with clinical disability and disease duration. Conclusion A decrease in T1-w/T2-w ratio precedes lesion formation. In CIS, higher T1-w/T2-w was associated with multiple sclerosis diagnosis. In established multiple sclerosis, lower T1-w/T2-w values were associated with clinical disability. The possible differential impact of chronic inflammation, iron deposition and demyelination should be considered to interpret these findings.This project was developed as a part of Mateus Boaventura ECTRIMS Clinical Training Fellowship Programme 2018–2019. This study was partially supported by the Project PI18/00823, from the Fondo de Investigación Sanitaria (FIS), Instituto de Salud Carlos III

Intestinal Microbiota Modulates Gluten-Induced Immunopathology in Humanized Mice

Celiac disease (CD) is an immune-mediated enteropathy triggered by gluten in genetically susceptible individuals. The recent increase in CD incidence suggests that additional environmental factors, such as intestinal microbiota alterations, are involved in its pathogenesis. However, there is no direct evidence of modulation of gluten-induced immunopathology by the microbiota. We investigated whether specific microbiota compositions influence immune responses to gluten in mice expressing the human DQ8 gene, which confers moderate CD genetic susceptibility. Germ-free mice, clean specific-pathogen-free (SPF) mice colonized with a microbiota devoid of opportunistic pathogens and Proteobacteria, and conventional SPF mice that harbor a complex microbiota that includes opportunistic pathogens were used. Clean SPF mice had attenuated responses to gluten compared to germ-free and conventional SPF mice. Germ-free mice developed increased intraepithelial lymphocytes, markers of intraepithelial lymphocyte cytotoxicity, gliadin-specific antibodies, and a proinflammatory gliadin-specific T-cell response. Antibiotic treatment, leading to Proteobacteria expansion, further enhanced gluten-induced immunopathology in conventional SPF mice. Protection against gluten-induced immunopathology in clean SPF mice was reversed after supplementation with a member of the Proteobacteria phylum, an enteroadherent Escherichia coli isolated from a CD patient. The intestinal microbiota can both positively and negatively modulate gluten-induced immunopathology in mice. In subjects with moderate genetic susceptibility, intestinal microbiota changes may be a factor that increases CD risk.Facultad de Ciencias Exacta

Deciphering multiple sclerosis disability with deep learning attention maps on clinical MRI

The application of convolutional neural networks (CNNs) to MRI data has emerged as a promising approach to achieving unprecedented levels of accuracy when predicting the course of neurological conditions, including multiple sclerosis, by means of extracting image features not detectable through conventional methods. Additionally, the study of CNN-derived attention maps, which indicate the most relevant anatomical features for CNN-based decisions, has the potential to uncover key disease mechanisms leading to disability accumulation. From a cohort of patients prospectively followed up after a first demyelinating attack, we selected those with T1-weighted and T2-FLAIR brain MRI sequences available for image analysis and a clinical assessment performed within the following six months (N = 319). Patients were divided into two groups according to expanded disability status scale (EDSS) score: ≥3.0 and < 3.0. A 3D-CNN model predicted the class using whole-brain MRI scans as input. A comparison with a logistic regression (LR) model using volumetric measurements as explanatory variables and a validation of the CNN model on an independent dataset with similar characteristics (N = 440) were also performed. The layer-wise relevance propagation method was used to obtain individual attention maps. The CNN model achieved a mean accuracy of 79% and proved to be superior to the equivalent LR-model (77%). Additionally, the model was successfully validated in the independent external cohort without any re-training (accuracy = 71%). Attention-map analyses revealed the predominant role of frontotemporal cortex and cerebellum for CNN decisions, suggesting that the mechanisms leading to disability accrual exceed the mere presence of brain lesions or atrophy and probably involve how damage is distributed in the central nervous system

TNF Drives Monocyte Dysfunction with Age and Results in Impaired Anti-pneumococcal Immunity

Monocyte phenotype and output changes with age, but why this occurs and how it impacts anti-bacterial immunity are not clear. We found that, in both humans and mice, circulating monocyte phenotype and function was altered with age due to increasing levels of TNF in the circulation that occur as part of the aging process. Ly6C+ monocytes from old (18–22 mo) mice and CD14+CD16+ intermediate/inflammatory monocytes from older adults also contributed to this “age-associated inflammation” as they produced more of the inflammatory cytokines IL6 and TNF in the steady state and when stimulated with bacterial products. Using an aged mouse model of pneumococcal colonization we found that chronic exposure to TNF with age altered the maturity of circulating monocytes, as measured by F4/80 expression, and this decrease in monocyte maturation was directly linked to susceptibility to infection. Ly6C+ monocytes from old mice had higher levels of CCR2 expression, which promoted premature egress from the bone marrow when challenged with Streptococcus pneumoniae. Although Ly6C+ monocyte recruitment and TNF levels in the blood and nasopharnyx were higher in old mice during S. pneumoniae colonization, bacterial clearance was impaired. Counterintuitively, elevated TNF and excessive monocyte recruitment in old mice contributed to impaired anti-pneumococcal immunity since bacterial clearance was improved upon pharmacological reduction of TNF or Ly6C+ monocytes, which were the major producers of TNF. Thus, with age TNF impairs inflammatory monocyte development, function and promotes premature egress, which contribute to systemic inflammation and is ultimately detrimental to anti-pneumococcal immunity

Τι είναι η πατρίδα μας; [What is our fatherland?]

Ποια είναι η πατρίδα κάποιων; Ας δούμε το θέμα λίγο σαν πρόβλημα της φιλοσοφίας της γλώσσας: για ένα κατηγόρημα «Άγγλος» «Γάλλος», «Πορτογάλος», «Βέλγος», «Φλαμανδός», πώς να αποφασίσουμε ποια αντικείμενα (ποιοι άνθρωποι) εμπίπτουν σε ποιο κατηγόρημα; Έχουν τελικά νόημα αυτά τα κατηγορήματα; Η χρήση και κατάχρηση αυτών των κατηγορημάτων έχει αποτελέσει μια από τις κυριότερες πηγές δυστυχίας στη διάρκεια των δύο τελευταίων αιώνων και συνεχίζει να είναι στην ημερήσια διάταξη. Συνήθως εμφανίζεται στα πλαίσια αγώνων για την απόκτηση «ελευθερίας» σε αντιπαράθεση με την «καταπίεση», και σε παγκόσμιο επίπεδο και κοντύτερα μας: στη Μακεδονία, την Καταλονία, την Ιρλανδία, το Κουρδιστάν ... Νομίζω πώς αρκετά από αυτά βασίζονται σε λάθη