A child with resistant Kawasaki disease successfully treated with anakinra: a case report

Background: Kawasaki disease (KD) is an acute self-limited systemic vasculitis of unknown etiology. Intravenous immunoglobulin (IVIG) is an effective treatment and decreases the risk of cardiac complications to less than 5%. In spite of its effectiveness, some children do not respond to this therapy and still develop coronary aneurysms (CAA). The optimal treatment for IVIG non-responsive patients remains controversial although corticoids have been suggested to be an effective treatment in some patients. For those patients still resistant to IVIG and corticoids, interleukin-1 receptor antagonists (IL-1RA) such anakinra could be an alternative. Case presentation: We present a 3 year-old Caucasian patient with KD without cardiac complications but with important resistance to treatment. After becoming resistant to IVIG and corticoids, anakinra proved to be an effective treatment. Conclusions: To our knowledge, this is the first report of the utility of IL-1RA in refractory KD without coronary impairment. The patient fulfilled the classical criteria for KD and, after becoming resistant to first and second line treatments, anakinra proved to be an effective treatment. Further studies are required to determine if this is an effective treatment option for other cases of resistant Kawasaki disease

Evidence-based diagnosis and treatment of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

Background Macrophage activation syndrome (MAS) is a severe and potentially lethal complication of several inflammatory diseases but seems particularly linked to systemic juvenile idiopathic arthritis (sJIA). Standardized diagnostic and treatment guidelines for MAS in sJIA are currently lacking. The aim of this systematic literature review was to evaluate currently available literature on diagnostic criteria for MAS in sJIA and provide an overview of possible biomarkers for diagnosis, disease activity and treatment response and recent advances in treatment. Methods A systematic literature search was performed in MEDLINE, EMBASE and Cochrane. 495 papers were identified. Potentially relevant papers were selected by 3 authors after which full text screening was performed. All selected papers were evaluated by at least two independent experts for validity and level of evidence according to EULAR guidelines. Results 27 papers were included: 7 on diagnosis, 9 on biomarkers and 11 on treatment. Systematic review of the literature confirmed that there are no validated diagnostic criteria for MAS in sJIA. The preliminary Ravelli criteria, with the addition of ferritin, performed well in a large retrospective case-control study. Recently, an international consortium lead by PRINTO proposed a new set of diagnostic criteria able to distinguish MAS from active sJIA and/or infection with superior performance. Other promising diagnostic biomarkers potentially distinguish MAS complicating sJIA from primary and virus-associated hemophagocytic lymphohistiocytosis. The highest level of evidence for treatment comes from case-series. High dose corticosteroids with or without cyclosporine A were frequently reported as first-line therapy. From the newer treatment modalities, promising responses have been reported with anakinra. Conclusion MAS in sJIA seems to be diagnosed best by the recently proposed PRINTO criteria, although prospective validation is needed. Novel promising biomarkers for sJIA related MAS are in need of prospective validation as well, and are not widely available yet. Currently, treatment of MAS in sJIA relies more on experience than evidence based medicine. Taking into account the severity of MAS and the scarcity of evidence, early expert consultation is recommended as soon as MAS is suspected

Advances in interferometric techniques for the analysis of the three-dimensional flow in a lid-driven cylindrical cavity

Abstract: In this work, a qualitative and quantitative characterization of the three-dimensional flow in a lid-driven cylindrical cavity with different optical techniques is presented. Mach–Zehnder interferometry and photographic techniques have been used for a qualitative description of some flow features. However, the real challenge is to obtain quantitative measurements, as the cavity dimensions and geometry prevent the application of 3D digital techniques for measuring the flow velocity in the whole cavity with enough spatial resolution. Digital in-line holography was applied to the measure of the vortex-breakdown bubble that appears near the cavity bottom at Re = 2000. A 22 × 22 × 80 mm3 volume was recorded, its longest dimension parallel to the camera optical axis. This large volume in a liquid fluid combined with a high particle density forces us to develop new analysis strategies. Holograms have been analyzed using a new method, called Adaptive Cross Correlation with Tracking From Beginning, which includes the use of the reconstructed complex amplitude for particle localization. Particle tracking is based on the three-dimensional cross correlation of three-dimensional interrogation windows. The particle set defined in the first hologram is always used to find the particle position in subsequent holograms. This method provides an accurate 3D velocity map and the vortex-breakdown bubble spatial structure. Experimental and numerical data show a very good agreement. A new criterion for determining the accuracy in the particle position along the optical axis is introduced, achieving a spatial resolution of 0.1 mm. This tracking method can be applied not only to laminar flows but also to turbulent flows

Recommendations for the management of autoinflammatory diseases.

Autoinflammatory diseases are characterised by fever and systemic inflammation, with potentially serious complications. Owing to the rarity of these diseases, evidence-based guidelines are lacking. In 2012, the European project Single Hub and Access point for paediatric Rheumatology in Europe (SHARE) was launched to optimise and disseminate regimens for the management of children and young adults with rheumatic diseases, facilitating the clinical practice of paediatricians and (paediatric) rheumatologists. One of the aims of SHARE was to provide evidence-based recommendations for the management of the autoinflammatory diseases cryopyrin-associated periodic syndromes (CAPS), tumour necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and mevalonate kinase deficiency (MKD). These recommendations were developed using the European League Against Rheumatism standard operating procedure. An expert committee of paediatric and adult rheumatologists was convened. Recommendations derived from the systematic literature review were evaluated by an online survey and subsequently discussed at a consensus meeting using Nominal Group Technique. Recommendations were accepted if more than 80% agreement was reached. In total, four overarching principles, 20 recommendations on therapy and 14 recommendations on monitoring were accepted with ≥ 80% agreement among the experts. Topics included (but were not limited to) validated disease activity scores, therapy and items to assess in monitoring of a patient. By developing these recommendations, we aim to optimise the management of patients with CAPS, TRAPS and MKD

Mid-Holocene Palaeoenvironment, Plant Resources and Human Interaction in Northeast Iberia: An Archaeobotanical Approach

MDPI accés obert UTPThe role of the adoption of farming economies in the transformation of mid-Holocene landscapes in Northeast Iberia is under discussion given that the Neolithization coincides with the cold climatic phase dated ca. 7500-7000 cal BP. The main aim of this paper is to assess whether human activities or climate were the main driver of vegetation changes during the Middle Holocene through the study of the archaeobotanical data from three case studies: Cova del Sardo, La Draga, and Coves del Fem. The application of diverse archaeobotanical techniques to the different plant remains provides a complete picture of the vegetation composition and plant uses. During the early Neolithic, settlement surroundings were intensively exploited for firewood, wood raw material, timber, and plant fibers. The resources were obtained mainly from deciduous and pine forests, de-pending on the site localization, but also from riparian zones. The diversity of plants exploited was high, not only trees but shrubs and herbs. Evidence of deforestation has been identified in the settlement surroundings in La Draga and Cova del Sardo. The combination of plant exploitation with other agropastoral activities favored the expansion of colonizing species and enhanced biodiversity at a local scale

Kawasaki disease is more prevalent in rural areas of Catalonia (Spain)

INTRODUCTION: Kawasaki disease (KD) is an acute self-limited systemic vasculitis relatively common in childhood. The etiology of KD is still unknown, although clinical, laboratory and epidemiological features suggest an infectious origin or trigger. Differences on incidence between countries have been related to specific genetic factors, ethnicity, country of birth and some other sociocultural and environmental factors. We present a population-based study on incidence of KD in Catalonia (Spain), focusing on differences between patients in rural and non-rural areas of the region. METHODS: Observational population-based study including all Pediatric Units in Catalan hospitals, between 2004 and 2014. A 12-month (March 2013-March 2014) prospective collection of new cases of KD was carried out to determine the incidence of KD. The rest of the data was retrieved retrospectively. RESULTS: Data from 399 patients over the 10-year study period was analyzed. Among the total KD patients, 353 (88.5%) lived in non-rural areas and 46 (11.5%) in rural areas. It was found that there is a significant difference (P<.001) between the percentage of rural population observed in patients with KD (11.5%), and the expected 5% of the Catalan population. CONCLUSION: This is the first population-based study showing significant differences on KD incidence rates between rural and non-rural areas

Mathematical modeling of SARS-CoV-2 variant substitutions in European countries: transmission dynamics and epidemiological insights

Background: Countries across Europe have faced similar evolutions of SARS-CoV-2 variants of concern, including the Alpha, Delta, and Omicron variants. Materials and methods: We used data from GISAID and applied a robust, automated mathematical substitution model to study the dynamics of COVID-19 variants in Europe over a period of more than 2 years, from late 2020 to early 2023. This model identifies variant substitution patterns and distinguishes between residual and dominant behavior. We used weekly sequencing data from 19 European countries to estimate the increase in transmissibility (Δβ) between consecutive SARS-CoV-2 variants. In addition, we focused on large countries with separate regional outbreaks and complex scenarios of multiple competing variants. Results: Our model accurately reproduced the observed substitution patterns between the Alpha, Delta, and Omicron major variants. We estimated the daily variant prevalence and calculated Δβ between variants, revealing that: (i) Δβ increased progressively from the Alpha to the Omicron variant; (ii) Δβ showed a high degree of variability within Omicron variants; (iii) a higher Δβ was associated with a later emergence of the variant within a country; (iv) a higher degree of immunization of the population against previous variants was associated with a higher Δβ for the Delta variant; (v) larger countries exhibited smaller Δβ, suggesting regionally diverse outbreaks within the same country; and finally (vi) the model reliably captures the dynamics of competing variants, even in complex scenarios. Conclusion: The use of mathematical models allows for precise and reliable estimation of daily cases of each variant. By quantifying Δβ, we have tracked the spread of the different variants across Europe, highlighting a robust increase in transmissibility trend from Alpha to Omicron. Additionally, we have shown that the geographical characteristics of a country, as well as the timing of new variant entrances, can explain some of the observed differences in variant substitution dynamics across countries

Disease phenotype and outcome depending on the age at disease onset in patients carrying the R92Q low-penetrance variant in TNFRSF1A gene

BACKGROUND: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in the TNFRSF1A gene. R92Q, a low-penetrance variant, is usually associated with a milder TRAPS phenotype than structural or pathogenic mutations. No studies differentiating R92Q-related disease in patients with pediatric and adult onset have been performed to date. OBJECTIVE: To analyze clinical features and disease outcomes in patients diagnosed with TRAPS associated with R92Q variant and to investigate differences between patients with pediatric and adult disease onset. METHODS: A retrospective review of patients with R92Q-related disease from four reference centers for autoinflammatory diseases was performed. Clinical and laboratory features, family history of autoinflammatory diseases, treatments received, and outcomes during follow-up were recorded and separately analyzed in pediatric and adult patients. Our results were included in the analysis with other reported pediatric and adult R92Q-related disease series. RESULTS: Our series encompassed 18 patients (9 females and 9 males) with R92Q variant. In 61% of patients, disease onset occurred during infancy and in 39%, during adulthood, with a median diagnostic delay of 5 years and a follow-up of 5.4 years. A positive family history of autoinflammatory disease was detected in 28% of patients. All patients presented with febrile recurrent episodes. Other common symptoms included arthralgia/arthritis (61%), myalgia (39%), asthenia/fatigue (44%), abdominal pain (39%), headache (33%), odynophagia (33%), skin rash (28%), and chest pain (22%). During attacks, 80% of patients increased acute phase reactants levels. No patient had developed amyloidosis during the study period. At the end of follow-up, 28% of patients were asymptomatic and treatment free, 50% were receiving non-steroidal anti-inflammatory drugs or glucocorticoids on demand, and 22% were being treated with biologic agents. When differences between pediatric and adult patients were globally analyzed, adults tended to have longer attacks duration and presented more frequently with chest pain and headache, while abdominal pain, vomiting, cervical adenitis, and pharyngitis predominated in pediatric patients. No differences in outcomes and treatment requirements were observed in both age groups. CONCLUSION: This study has contributed to characterize R92Q-related disease by identifying trends in disease phenotypes depending on the age at disease onset

Testing the deep water source variations in the Atlantic Iberianmargin over the last deglaciation

The reservoir age of waters and carbon sequestration increased in the deep Atlantic Ocean during the last glacial period. The glacial northern deep water (GNADW) formation reached shallower depths than during the ensuing interglacial, and the underlying southern-sourced bottom water (GAABW) was filling the basin, generally poorly ventilated. The mechanisms within the deep ocean that facilitate the flip from glacial-to-interglacial modes are as yet to be understood. Here we present analysis performed on foraminifera (benthic ¿13C, abundance of oxygen-tolerant benthic species and 14C age difference between benthic and planktonic species), together with the n-hexacosan-1-ol index (biomarker of the oxygenation of the deep-sea floor) in three deep cores at the Atlantic Iberian margin (ca. -5,000 m depth; 40°N). The locations selected follow the pathway of the Northeast Atlantic Deep Water (NEADW): MD03-2698 (Tagus Iberian margin), D219 (Rincão da Pomba) and MD13-3473 (Tore inner basin). Additionally, results of polar northern and southern sites (U1308 and TN057-21 respectively) are discussed as a reference for evaluating long-distance connections. The hypothesis to be tested is whether the deep waters off Iberia were northern- or southernsourced during the deglaciation within the Tore seamount, a crater-shaped geological structure, 300 km off the Iberian continental shelf. It includes an inner basin down to -5,500 m, isolated from the oceanic basin by a summit rim at -2,200 m. The external connection with the Atlantic is by two narrow NW and NE gateways down to ¿4,300 m. This makes the area a singular spot to decipher the NEADW-end member of the Atlantic deep circulation. We find benthic (Cibicidoides wuellerstorfi) ¿13C values around 0 ¿ in the interior of the Tore before 18 ky, slightly heavier than those known from shallower Iberian sites (ca. -3,500 m). This points to isolation of the Tore basin from the influence of GAABW. This contrasts with the other sites MD03-2698 and D219 which record ¿13C around -0.6 ¿, similarly to TN057-21 values. Inside the Tore, benthic foraminifera species grouped according to their oxygen tolerance are oligotrophic during the glacial (oxygen-rich, more ventilated conditions) and mesotrophic over the Holocene (intermediate ventilation). The carbon residence time measured in MD03-2698 and D219, as estimated from the 14C age difference between benthic and planktonic foraminifera, confirms previous reservoir ages in the deep Iberian margin (MD99-2334K; JC89-SHAK03-6K, JC89-SHAK05-3K). In the inner basin (MD13-3473), the estimation is not valid, probably due to increased bioturbation, lower sedimentation rates and mixing turbiditic flow. The hexacosanol index marks the lowest ventilation pattern culminating around 16 ky (MD03-2698, D219), an apparent inflection point from when the ventilation shifts from southern to northern sourced deep waters, the former not registered in the inner Tore (MD13-3473). This occurs in line with a large reduction in the Atlantic meridional overturning circulation (AMOC) and maximum extent of ice sheets. Taken together, interactions between atmospheric, marine, cryosphere and terrestrial climate elements, as recorded by different proxies during the stadial multi-step structure associated within Heinrich event 1 (H1.1) are giving clues to the processes bringing about deglaciation

Mathematical modeling of SARS-CoV-2 variant substitutions in European countries: transmission dynamics and epidemiological insights

BackgroundCountries across Europe have faced similar evolutions of SARS-CoV-2 variants of concern, including the Alpha, Delta, and Omicron variants.Materials and methodsWe used data from GISAID and applied a robust, automated mathematical substitution model to study the dynamics of COVID-19 variants in Europe over a period of more than 2 years, from late 2020 to early 2023. This model identifies variant substitution patterns and distinguishes between residual and dominant behavior. We used weekly sequencing data from 19 European countries to estimate the increase in transmissibility (Δβ)  between consecutive SARS-CoV-2 variants. In addition, we focused on large countries with separate regional outbreaks and complex scenarios of multiple competing variants.ResultsOur model accurately reproduced the observed substitution patterns between the Alpha, Delta, and Omicron major variants. We estimated the daily variant prevalence and calculated Δβ between variants, revealing that: (i) Δβ increased progressively from the Alpha to the Omicron variant; (ii) Δβ showed a high degree of variability within Omicron variants; (iii) a higher Δβ was associated with a later emergence of the variant within a country; (iv) a higher degree of immunization of the population against previous variants was associated with a higher Δβ for the Delta variant; (v) larger countries exhibited smaller Δβ, suggesting regionally diverse outbreaks within the same country; and finally (vi) the model reliably captures the dynamics of competing variants, even in complex scenarios.ConclusionThe use of mathematical models allows for precise and reliable estimation of daily cases of each variant. By quantifying Δβ, we have tracked the spread of the different variants across Europe, highlighting a robust increase in transmissibility trend from Alpha to Omicron. Additionally, we have shown that the geographical characteristics of a country, as well as the timing of new variant entrances, can explain some of the observed differences in variant substitution dynamics across countries