Fiscal data revisions in Europe

Public deficit figures are subject to revisions, as most macroeconomic aggregates are. Nevertheless, in the case of Europe, the latter could be particularly worrisome given the role of fiscal data in the functioning of EU’s multilateral surveillance rules. Adherence to such rules is judged upon initial releases of data, in the framework of the so-called Excessive Deficit Procedure (EDP) Notifications. In addition, the lack of reliability of fiscal data may hinder the credibility of fiscal consolidation plans. In this paper we document the empirical properties of revisions to annual government deficit figures in Europe by exploiting the information contained in a pool of real-time vintages of data pertaining to fifteen EU countries over the period 1995-2008. We build up such real-time dataset from official publications. Our main findings are as follows: (i) preliminary deficit data releases are biased and non-efficient predictors of subsequent releases, with later vintages of data tending to show larger deficits on average; (ii) such systematic bias in deficit revisions is a general feature of the sample, and cannot solely be attributed to the behaviour of a small number of countries, even though the Greek case is clearly an outlier; (iii) Methodological improvements and clarifications stemming from Eurostat’s decisions that may lead to data revisions explain a significant share of the bias, providing some evidence of window dressing on the side of individual countries; (iv) expected real GDP growth, political cycles and the strength of fiscal rules also contribute to explain revision patterns; (v) nevertheless, if the systematic bias is excluded, revisions can be considered rational after two years. JEL Classification: E01, E21, E24, E31, E5, H600data revisions, fiscal statistics, news and noise, Rationality, real-time data

How apoptotic β-cells direct immune response to tolerance or to autoimmune diabetes : a review

Type 1 diabetes (T1D) is a metabolic disease that results from the autoimmune attack against insulin-producing β-cells in the pancreatic islets of Langerhans. Currently, there is no treatment to restore endogenous insulin secretion in patients with autoimmune diabetes. In the last years, the development of new therapies to induce long-term tolerance has been an important medical health challenge. Apoptosis is a physiological mechanism that contributes to the maintenance of immune tolerance. Apoptotic cells are a source of autoantigens that induce tolerance after their removal by antigen presenting cells (APCs) through a process called efferocytosis. Efferocytosis will not cause maturation in dendritic cells, one of the most powerful APCs, and this process could induce tolerance rather than autoimmunity. However, failure of this mechanism due to an increase in the rate of β-cells apoptosis and/or defects in efferocytosis results in activation of APCs, contributing to inflammation and to the loss of tolerance to self. In fact, T1D and other autoimmune diseases are associated to enhanced apoptosis of target cells and defective apoptotic cell clearance. Although further research is needed, the clinical relevance of immunotherapies based on apoptosis could prove to be very important, as it has translational potential in situations that require the reestablishment of immunological tolerance, such as autoimmune diseases. This review summarizes the effects of apoptosis of β-cells towards autoimmunity or tolerance and its application in the field of emerging immunotherapies

Immune System Remodelling by Prenatal Betamethasone : Effects on β-Cells and Type 1 Diabetes

Type 1 diabetes (T1D) is a multifactorial disease of unknown aetiology. Studies focusing on environment-related prenatal changes, which might have an influence on the development of T1D, are still missing. Drugs, such as betamethasone, are used during this critical period without exploring possible effects later in life. Betamethasone can interact with the development and function of the two main players in T1D, the immune system and the pancreatic β-cells. Short-term or persistent changes in any of these two players may influence the initiation of the autoimmune reaction against β-cells. In this review, we focus on the ability of betamethasone to induce alterations in the immune system, impairing the recognition of autoantigens. At the same time, betamethasone affects β-cell gene expression and apoptosis rate, reducing the danger signals that will attract unwanted attention from the immune system. These effects may synergise to hinder the autoimmune attack. In this review, we compile scattered evidence to provide a better understanding of the basic relationship between betamethasone and T1D, laying the foundation for future studies on human cohorts that will help to fully grasp the role of betamethasone in the development of T1D

Improving growing substrates by adding the seaweed Cystoseira baccata

We examined the impact of adding the seaweed Cystoseira baccata (Ochrophyta, Sargassaceae) in various forms to two different growing substrates: pine bark and gorse compost. Specifically, we examined the influence of the seaweed on the physical and chemical properties of the substrates, and on their agronomic performance on a lettuce crop. The seaweed was used in a 20% (v/v) proportion and three different forms, namely: fresh (FS), washed fresh (WFS), and washed and dried (WDS). The mixed substrates exhibited no signs of instability. FS and DWS increased the total water retention capacity of pine bark by 20% and 27%, respectively. Adding the seaweed in any of its three forms to this type of substrate, which is poor in nutrients and has a low electrical conductivity (EC), significantly increased its P, K, Mg and Na contents, as well as its EC (from 0.08 dS m–1 in the control substrate to 0.69, 0.12 and 0.27 dS m–1 in those containing FS, WFS and WDS, respectively). On the other hand, only in fresh form (FS) altered the salinity and total K content of a substrate rich in nutrients and salts such gorse compost (from 0.89 to 1.42 dS m−1 in terms of EC and 0.59% to 0.98% in K). All mixtures performed well as substrates for a lettuce crop. Those containing DWS increased aerial mass in gorse compost, while any of the tested formats increased aerial mass in pine barkOpen Access funding provided thanks to the CRUE-CSIC agreement with Springer NatureS

Prenatal Betamethasone Exposure and its Impact on Pediatric Type 1 Diabetes Mellitus : A Preliminary Study in a Spanish Cohort

Betamethasone, a glucocorticoid used to induce lung maturation when there is a risk of preterm delivery, can affect the immune system maturation and type 1 diabetes (T1D) incidence in the progeny. It has been described that prenatal betamethasone protects offspring from experimental T1D development. The main aim of this study was to evaluate the possible association between betamethasone prenatal exposure and T1D in humans. Research Design and Methods. A retrospective case-control study with a total of 945 children, including 471 patients with T1D and 474 healthy siblings, was performed. Participants were volunteers from the Germans Trias i Pujol Hospital and DiabetesCero Foundation. Parents of children enrolled in the study completed a questionnaire that included questions about weeks of gestation, preterm delivery risk, weight at birth, and prenatal betamethasone exposure of their children. Multiple logistic regression was used to detect the association between betamethasone exposure and T1D. We compared T1D prevalence between subjects prenatally exposed or unexposed to betamethasone. The percent of children with T1D in the exposed group was 37.5% (21 of 56), and in the unexposed group was 49.52% (410 of 828) (p = 0.139). The percentage of betamethasone-treated subjects with T1D in the preterm group (18.05%, 13 of 72) was significantly higher than that found in the control group (12.5%, 9 of 72) (p = 0.003). The odds ratio for T1D associated with betamethasone in the univariate logistic regression was 0.59 (95% confidence interval, 0.33; 1.03 [ p = 0.062]) and in the multivariate logistic regression was 0.83 (95% confidence interval, 0.45; 1.52 [ p = 0.389]). The results demonstrate that the prenatal exposure to betamethasone does not increase T1D susceptibility, and may even be associated with a trend towards decreased risk of developing the disease. These preliminary findings require further prospective studies with clinical data to confirm betamethasone exposure effect on T1D risk

Compliance with Good Manufacturing Practice in the Assessment of Immunomodulation Potential of Clinical Grade Multipotent Mesenchymal Stromal Cells Derived from Wharton’s Jelly

Cell culture; Cellular therapy; Good manufacturing practiceCultiu cel·lular; Teràpia cel·lular; Bones pràctiques de manufacturaCultivo celular; Terapia celular; Buenas prácticas de fabricaciónThe selection of assays suitable for testing the potency of clinical grade multipotent mesenchymal stromal cell (MSC)-based products and its interpretation is a challenge for both developers and regulators. Here, we present a bioprocess design for the production of Wharton's jelly (WJ)-derived MSCs and a validated immunopotency assay approved by the competent regulatory authority for batch release together with the study of failure modes in the bioprocess with potential impact on critical quality attributes (CQA) of the final product. Methods: The lymphocyte proliferation assay was used for determining the immunopotency of WJ-MSCs and validated under good manufacturing practices (GMP). Moreover, failure mode effects analysis (FMEA) was used to identify and quantify the potential impact of different unexpected situations on the CQA. Results: A production process based on a two-tiered cell banking strategy resulted in batches with sufficient numbers of cells for clinical use in compliance with approved specifications including MSC identity (expressing CD73, CD90, CD105, but not CD31, CD45, or HLA-DR). Remarkably, all batches showed high capacity to inhibit the proliferation of activated lymphocytes. Moreover, implementation of risk management tools led to an in-depth understanding of the manufacturing process as well as the identification of weak points to be reinforced. Conclusions: The bioprocess design showed here together with detailed risk management and the use of a robust method for immunomodulation potency testing allowed for the robust production of clinical-grade WJ-MSCs under pharmaceutical standards

Impaired Phagocytosis in Dendritic Cells From Pediatric Patients With Type 1 Diabetes Does Not Hamper Their Tolerogenic Potential

Type 1 diabetes (T1D) is prompted by defective immunological tolerance, an event in which dendritic cells (DCs) are crucial as immune response orchestrators. In fact, they contribute to maintaining tolerance to self-antigens, but they can also prompt an immunogenic response against them, leading to autoimmunity. Countless factors can potentially impact on the proper functionality of the DCs, which range from altered subset distribution, impaired phagocytic function to abnormal gene expression. Moreover, in T1D, metabolic dysregulation could impair DC functions as well. Indeed, since T1D clinical course is likely to be more aggressive in children and adolescents and entails severe dysglycemia, the aim of this study was to analyze circulating DCs subpopulations in pediatric T1D at different stages, as well as to characterize their phagocytosis ability and tolerance induction potential. Thus, pediatric patients newly diagnosed with T1D, with established disease and control subjects were recruited. Firstly, DCs subsets from peripheral blood were found quantitatively altered during the first year of disease, but recovered in the second year of progression. Secondly, to study the tolerogenic functionality of DCs, liposomes with phosphatidylserine (PS) were designed to mimic apoptotic beta cells, which are able to induce tolerance, as previously demonstrated by our group in DCs from adult patients with T1D. In this study, monocyte-derived DCs from pediatric patients with T1D and control subjects were assessed in terms of PS-liposomes capture kinetics, and transcriptional and phenotypic changes. DCs from pediatric patients with T1D were found to phagocyte PS-liposomes more slowly and less efficiently than DCs from control subjects, inversely correlating with disease evolution. Nonetheless, the transcription of PS receptors and immunoregulatory genes, cytokine profile, and membrane expression of immunological markers in DCs was consistent with tolerogenic potential after PS-liposomes phagocytosis. In conclusion, T1D progression in childhood entails altered peripheral blood DCs subsets, as well as impaired DCs phagocytosis, although tolerance induction could still function optimally. Therefore, this study provides useful data for patient follow-up and stratification in immunotherapy clinical trials

Immunoregulatory Biomarkers of the Remission Phase in Type 1 Diabetes : miR-30d-5p Modulates PD-1 Expression and Regulatory T Cell Expansion

The partial remission (PR) phase of type 1 diabetes (T1D) is an underexplored period characterized by endogenous insulin production and downmodulated autoimmunity. To comprehend the mechanisms behind this transitory phase and develop precision medicine strategies, biomarker discovery and patient stratification are unmet needs. MicroRNAs (miRNAs) are small RNA molecules that negatively regulate gene expression and modulate several biological processes, functioning as biomarkers for many diseases. Here, we identify and validate a unique miRNA signature during PR in pediatric patients with T1D by employing small RNA sequencing and RT-qPCR. These miRNAs were mainly related to the immune system, metabolism, stress, and apoptosis pathways. The implication in autoimmunity of the most dysregulated miRNA, miR-30d-5p, was evaluated in vivo in the non-obese diabetic mouse. MiR-30d-5p inhibition resulted in increased regulatory T cell percentages in the pancreatic lymph nodes together with a higher expression of CD200. In the spleen, a decrease in PD-1 + T lymphocytes and reduced PDCD1 expression were observed. Moreover, miR-30d-5p inhibition led to an increased islet leukocytic infiltrate and changes in both effector and memory T lymphocytes. In conclusion, the miRNA signature found during PR shows new putative biomarkers and highlights the immunomodulatory role of miR-30d-5p, elucidating the processes driving this phase

Prediction and Monitoring of Partial Remission in Pediatric Type 1 Diabetes

[EN] The partial remission (PR) phase, a period experienced by most patients with type 1 diabetes (T1D) soon after diagnosis, is characterized by low insulin requirements and improved glycemic control. Given the great potential of this phase as a therapeutic window for immunotherapies because of its association with immunoregulatory mechanisms and beta-cell protection, our objective was to find peripheral immunological biomarkers for its better characterization, monitoring, and prediction. The longitudinal follow-up of 17 pediatric patients with new-onset T1D over one year revealed that, during the PR phase, remitter patients show increased percentages of effector memory (EM) T lymphocytes, terminally differentiated EM T lymphocytes, and neutrophils in comparison to non-remitter patients. On the contrary, remitter patients showed lower percentages of naive T lymphocytes, regulatory T cells (T-REG), and dendritic cells (DCs). After a year of follow-up, these patients also presented increased levels of regulatory B cells and transitional T1 B lymphocytes. On the other hand, although none of the analyzed cytokines (IL-2, IL-6, TGF-beta 1, IL-17A, and IL-10) could distinguish or predict remission, IL-17A was increased at T1D diagnosis in comparison to control subjects, and remitter patients tended to maintain lower levels of this cytokine than non-remitters. Therefore, these potential monitoring immunological biomarkers of PR support that this stage is governed by both metabolic and immunological factors and suggest immunoregulatory attempts during this phase. Furthermore, since the percentage of T-REG, monocytes, and DCs, and the total daily insulin dose at diagnosis were found to be predictors of the PR phase, we next created an index-based predictive model comprising those immune cell percentages that could potentially predict remission at T1D onset. Although our preliminary study needs further validation, these candidate biomarkers could be useful for the immunological characterization of the PR phase, the stratification of patients with better disease prognosis, and a more personalized therapeutic management.Funding for this study was provided by the Spanish Government (FIS PI18/00436) co-financed with the European Regional Development funds (FEDER), and by DiabetesCero Foundation. LGM is supported by the Generalitat de Catalunya (PERIS PIF-Salut Grant No. SLT017/20/000049). This work has been supported by positive discussion through Consolidated Research Group #2017 SGR 103, AGAUR, Generalitat de Catalunya

NK Cell Subsets Changes in Partial Remission and Early Stages of Pediatric Type 1 Diabetes

Type 1 diabetes (T1D) is a chronic metabolic disease characterized by the autoimmune destruction of β-cells in the pancreatic islets. T1D is preceded by islet-specific inflammation led by several immune cells. Among them, natural killer (NK) cells are emerging as important players in T1D development. Human NK cells are characterized by CD56 and CD16 expression, which allows classifying NK cells into four subsets: 1) CD56 dim CD16 + or effector NK cells (NK); 2) CD56 bright CD16 − or regulatory NK cells (NK); 3) intermediate CD56 bright CD16 + NK cells; and 4) CD56 dim CD16 − NK cells, whose function is not well determined. Since many studies have shown that T1D progression is associated with changes in various immune cell types, we hypothesize that the kinetics of NK cell subsets in the blood could correlate with different stages of T1D. To that aim, pediatric patients newly diagnosed with T1D were recruited, and peripheral NK cell subsets were analyzed by flow cytometry at several disease checkpoints: disease onset, partial remission (PR), 8 months (for non-remitters), and 12 months of progression. Our results showed that total NK cells and their four subsets are altered at the early stages of T1D. A decrease in the counts and percentage of total NK cells and NK cells at the different disease stages was found when compared to controls. These results suggest the extravasation of these cells into the islets at disease onset, which is maintained throughout the follow-up. By contrast, NK cells increased during the early stages after T1D onset, and both intermediate NK cells and CD56 dim CD16 - NK cells diminished at the PR stage, which might reflect the immunoregulatory attempts and could be candidate biomarkers for this stage. Also, CD56 dim CD16 - NK cells increased during T1D progression. Finally, changes in CD16 expression were identified in the different T1D stages, highlighting a CD16 expression reduction in total NK cells and NK cells 1 year after diagnosis. That may reflect a state of exhaustion after multiple cell-to-cell interactions. Altogether, our preliminary data provide a longitudinal picture of peripheral NK cell subpopulations during the different T1D stages, which could be potential candidate biomarkers indicators of disease progression