OBEDIS Core Variables Project : European Expert Guidelines on a Minimal Core Set of Variables to Include in Randomized, Controlled Clinical Trials of Obesity Interventions

Heterogeneity of interindividual and intraindividual responses to interventions is often observed in randomized, controlled trials for obesity. To address the global epidemic of obesity and move toward more personalized treatment regimens, the global research community must come together to identify factors that may drive these heterogeneous responses to interventions. This project, called OBEDIS (OBEsity Diverse Interventions Sharing - focusing on dietary and other interventions), provides a set of European guidelines for a minimal set of variables to include in future clinical trials on obesity, regardless of the specific endpoints. Broad adoption of these guidelines will enable researchers to harmonize and merge data from multiple intervention studies, allowing stratification of patients according to precise phenotyping criteria which are measured using standardized methods. In this way, studies across Europe may be pooled for better prediction of individuals' responses to an intervention for obesity - ultimately leading to better patient care and improved obesity outcomes.Peer reviewe

ARIA digital anamorphosis : Digital transformation of health and care in airway diseases from research to practice

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed.Peer reviewe

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

ARIA digital anamorphosis: Digital transformation of health and care in airway diseases from research to practice

Digital anamorphosis is used to define a distorted image of health and care that may be viewed correctly using digital tools and strategies. MASK digital anamorphosis represents the process used by MASK to develop the digital transformation of health and care in rhinitis. It strengthens the ARIA change management strategy in the prevention and management of airway disease. The MASK strategy is based on validated digital tools. Using the MASK digital tool and the CARAT online enhanced clinical framework, solutions for practical steps of digital enhancement of care are proposed

Effects of anti-TNF on MiR expression in monocytes and CD4(+) T-Lymphocytes in spondyloarthritis

International audienceBackground/Purpose: TNFα inhibitors are an effective treatment for many inflammatory diseases. However, their mechanism of action is more complicated than just blocking the targeted cytokine. MicroRNAs are important post-translational regulators of gene expression and their expression has been found deregulated in rheumatic diseases such as rheumatoid arthritis or spondyloarthritis. The general goal of this work is to investigate changes in miR expression in monocytes and CD4+ T-lymphocytes from patients with axial spondyloarthritis during anti-TNF treatment. Methods: Sixty-eight patients with axial spondyloarthritis were enrolled in the study. Among these patients, 63 fulfilled the 2009 ASAS classification criteria (imaging arm) with sacro-iliitis on X-rays (n= 47) or objective signs of inflammation on MRI (n=16) and 72% were HLA-B27 positive. All patients were naïve for biologic treatments at baseline and had an active disease (mean BASDAI score of 49 +/- 19 and mean ASDAS score of 3+/-1) requiring the initiation of a TNFα inhibitor (Etanercept 41, Adalimumab 17, Golimumab 10). Mean CRP at baseline was 12.5 +/-18. At 3 months, the BASDAI response rate was 59%. Blood sample were collected at baseline (M0) and 3 months (M3) after the initiation of the treatment. Monocytes and CD4+ T-lymphocytes were isolated from peripheral blood mononuclear cells and 372 miR were investigated by qPCR. A paired Wilcoxon signed-rank test was used to explore differential expression of miRs between M0 and M3. Results: Pair-wise comparison of miR level before and 3 months after anti-TNF treatment identified 35 differentially expressed (DE) miRs in circulating CD4+ T lymphocytes and 53 DE miRs in monocytes (false discovery rate < 5%). Eighteen miRs were commonly deregulated in both cell types, among which 12 were upregulated and 6 were downregulated after treatment. Strikingly, we found DE miRs before and after treatment in patients with good response to TNF inhibitors while there was little or no DE miRs in non-responders according to BASDAI response criteria. Differentially expressed miRs were not correlated to the CRP levels or to the variation of the CRP between 0 and 3 months. Also, in patients with negative CRP at baseline, we found DE miRs (nominal p-value < 5%) suggesting that the modulation of miRs was not only reflecting a better inflammation control. Conclusion: This work demonstrates that TNF inhibitors might at least partially act by modulating miR expression, especially in patients who respond well to treatment

Unique epigenetic signature in T cell compartment after epicutaneous immunotherapy in peanut sensitized mice

International audienceRationale Epicutaneous immunotherapy (EPIT) induces naïve Tregs, which play a crucial role in the bystander effect identified in a model of food allergic mice. Previously, EPIT was shown to alter epigenetic modifications and expression of Th2 and Tregs without influencing the expression of Th1 in peanut-sensitized mice. This study investigates methylation modifications occurring in specific T cell compartments. Methods Mice were orally sensitized to peanut and then treated with EPIT or non-treated. Mice were sacrificed at the end of treatment or 8 weeks after the end of immunotherapy. Regulatory T cells (CD62L+Foxp3+ and CD62L-Foxp3+) were sorted directly from the spleen and Th2 and Th1 cells were purified after a short in vitro reactivation of splenocytes. DNA methylation at Gata3 promoter and Foxp3 CNS2 was analysed in all sorted cells by pyrosequencing. Results Epicutaneous immunotherapy did not modify proportions of Th1 and Th2 cells in the spleen. The hypermethylation of CpG islands of Gata3 only occurred in Th2 cells for EPIT-treated mice at the end of immunotherapy and was sustained 8 weeks later (p<0.05 vs Sham). In parallel, significant hypomethylation was observed in the Foxp3 CpG islands of naïve Tregs only (p<0.05), not effector Tregs, at the end of EPIT, and persisted for 8 weeks following the end of treatment (p<0.001). Conclusions The unique epigenetic signature of EPIT is confirmed at cellular level for Gata3 (Th2) and Foxp3 (naïve Tregs), suggesting the induction of tolerance and prevention of further sensitization. Foxp3 hypomethylation occurring only on naïve Tregs underlines the crucial role of EPIT-induced naïve Tregs

MicroRNA-sequencing in a mouse model of peanut sensitized mice treated by EPIT identifies early changes in microRNA expression influencing T-cell plasticity and Th2 cytokine production

International audienceIntroduction:Epicutaneous immunotherapy (EPIT) is a safe treat-ment for food allergy. In animal models, EPIT protection seems toconfer sustained unresponsiveness and prevents further sensitiza-tion. We have previously shown DNA methylation changes in keytranscription factors to be associated with EPIT and sustained unre-sponsiveness.Objectives:This study investigates the kinetics of miRNA expres-sion patterns underlying the therapeutic effect of EPIT and its per-sistence. BALB/c mice were orally sensitized to peanut and thentreated with EPIT or not treated (sham). Mice (n=112) were sacri-ficed during treatment at 1, 2, 4, 6 and 8 weeks; and 8 weeks afterthe end of treatment. MiRNAs were analysed in sorted CD4+cellsfrom spleen using high-throughput sequencing on a HiSeq4000 to adepth of 200M bases / sample and validated by qPCR.Results:Global miRNA profiles consisting of 800-1000 miRNAsreproducibly detected in the CD4 samples distinguished EPIT-treatedmice from controls as early as one week following initiation of treat-ment. Intra-group variability of miRNA expression profiles was muchreduced in the EPIT group at all time points. Between 23 and 190MiRNAs were found to be differentially expressed at padj<.05 with alarge overlap of miRNAs between adjacent time points. Differentiallyexpressed miRNAs include miRNAs controlling T cell stability andplasticity (eg,Tregs, miR-10a) and Th2 cytokine production (eg, miR-92a-3p and miR-423-5p). 34 miRNAs were differentially expressedeight weeks after the end of the treatment, of which 24 (70%)showed similar expression changes at the end of treatment.Conclusions:EPIT leads to homogeneous changes in miRNAexpression profiles shortly after the initiation of treatment differenti-ating EPIT-treated mice from sham-treated control mice and expres-sion changes are maintained following the termination of treatment.Differentially expressed miRNAs include miRNAs in T cell plasticityand postulated targets include genes previously associated withallergy and asthma. Our study provides further evidence for themolecular alterations underlying sustained unresponsiveness in EPIT