The M@dnote project. Giving colour to Grey Literature in General Practice. A collaborative GPs knowledge network.

“M@dNotes Project”. Giving colour to Grey Literature in General Practice. A collaborative GPs knowledge network. Sharing the results of research and scientific production is crucial for the survival of all disciplines. Health information is becoming uncertain and powerful economic interests disrupting medical information has triggered a loss of credibility. M@dNotes project (in Spanish NotasL@cas), is the by-product of non-profit collaborative international knowledge network of general practitioners, family physicians, and healthcare workers. One of the aims of this network is to discuss the validity of the information available on sensitive subjects and build a knowledge exchange network inside a community of practice. The project was born because we realized that more than 95% of the postgraduate and pregraduate research/reports/ scholar works (monographic works) to accomplish or finished one part of the training were finally lost and unpublished. Most of them come from interesting "minds" and are interesting topics to improve the applying of evidence in medical healthcare. From this perspective, M@dNotes is a unique local platform to rescue knowledge and support exchange and collaboration. Perhaps is isolated due to the circumstance of being restricted to few countries or a small group of practice. Nevertheless, we are trying to improve our qualifications in order to link M@dNotes to an open access network. It has been created to share different materials excluded from traditional academic publishing and commercial distribution channels: monographic, commented articles, files with references searches. These materials considered “grey literature” are the product of intense learning process and has been produced to achieve a qualification, be presented in a conference or were collected by users spontaneously through the web searches, with a knowledge purpose. Many of them qualified with an appropriate level because were submitted to a peer review or judged by a scientific committee to get an approval. The project includes an indexing method (Q Codes and ICPC) to manage and retrieve the materials received. Q-Codes are intended for indexing Family medicine related documentation jointly with the International Classification of Primary Care (ICPC). The project provides a particular folder to upload and share the documents. A web blog is the dissemination tool or friendly interface to share and retrieve the documents shared in the network. Through a facility in the cloud, it is possible to access an excel file with all the materials shared, codes assigned and the hyperlink to get a pdf file of each material

Indexing grey multilingual literature in General Practice: Family medicine in the era of semantic web

peer reviewedProblem/Goal: Sharing the results of research with General Practitioners (GPs) is crucial for the survival of the discipline of General Practice / Family Medicine (GP/FM). The production of abstracts in GP/FM probably exceeds 15,000 per year worldwide. Each abstract often represents two years of work for its authors and is expressed in local languages. Only 45% of them are published in indexed medical journals. Usual indexing systems like MeSH are not multilingual nor adapted to the particular field of GP/FM. Consequently, these abstracts are lacking bibliographic control and more than half of the research presented by GPs at congresses is lost. Considering the absence of appropriate domain-specific terminologies or classification systems, we propose a new multilingual indexing system. The existing International Classification of Primary Care (ICPC) is currently used for clinical purposes and has now been expanded with a taxonomy related to contextual aspects (called Q-Codes) such as education, research, practice organization, ethics or policy in GP/FM, currently not captured. The set is proposed under the name Core Content Classification in General Practice (3CGP). The aim is to facilitate indexing of GP/FM specific scientific work and to improve performance in information storage and retrieval for research purposes in this field. Research Method/Procedure: Using qualitative analysis, a corpus of 1,702 abstracts from six GP/FM- related European congresses was analyzed to identify main themes discussed by GPs (e.g., continuity, accessibility or medical ethics), handled in a domain-specific taxonomy called Q-Codes and translated in 8 languages. In addition, a methodology for building a lightweight ontology (in OWL-2) was applied to Q-Codes, adding object and datatype properties to the hierarchical relations, including mapping to the MeSH thesaurus, Babelnet (www.babelnet.org) and Dbpedia. Finally, the Q-Codes in 8 languages have been integrated healthcare terminology service (www.hetop.eu/q) with a companion website (http://3cgp.docpatient.net). Anticipated Results of the Research: The creation and the on-line publication of this multilingual terminological resource, for indexing abstracts and for facilitating Medline searches, could reduce loss of knowledge in the domain. In addition, through better indexing of the grey literature (congress abstracts, master’s and doctoral thesis), we hope to enhance the accessibility of research results of GP/FM domain and promote the emergence of networks of researchers. First result of experimental implementations of the new indexing system will be presented. Indication of costs related to the project: This project has not been funded. 3CGP is placed under Attribution-Non-Commercial-Share-Alike 4.0 International (CC BY-NC-SA 4.0). ICPC is copyrighted by WONCA. © 2018 Oriental Scientific Publishing Company. All rights reserved

Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells

Common variable immunodeficiency disorder (CVID) is the most common symptomatic primary immunodeficiency in adults, characterized by B-cell abnormalities and inadequate antibody response. CVID patients have considerable autoimmune comorbidity and we therefore hypothesized that genetic susceptibility to CVID may overlap with autoimmune disorders. Here, in the largest genetic study performed in CVID to date, we compare 778 CVID cases with 10, 999 controls across 123, 127 single-nucleotide polymorphisms (SNPs) on the Immunochip. We identify the first non-HLA genome-wide significant risk locus at CLEC16A (rs17806056, P = 2.0 x 10(-9)) and confirm the previously reported human leukocyte antigen (HLA) associations on chromosome 6p21 (rs1049225, P = 4.8 x 10(-16)). Clec16a knockdown (KD) mice showed reduced number of B cells and elevated IgM levels compared with controls, suggesting that CLEC16A may be involved in immune regulatory pathways of relevance to CVID. In conclusion, the CLEC16A associations in CVID represent the first robust evidence of non-HLA associations in this immunodeficiency condition

The association between elevated ankle systolic pressures and peripheral occlusive arterial disease in diabetic and nondiabetic subjects

No Abstract

Sequential Assembly of Centromeric Proteins in Male Mouse Meiosis

The assembly of the mitotic centromere has been extensively studied in recent years, revealing the sequence and regulation of protein loading to this chromosome domain. However, few studies have analyzed centromere assembly during mammalian meiosis. This study specifically targets this approach on mouse spermatocytes. We have found that during prophase I, the proteins of the chromosomal passenger complex Borealin, INCENP, and Aurora-B load sequentially to the inner centromere before Shugoshin 2 and MCAK. The last proteins to be assembled are the outer kinetochore proteins BubR1 and CENP-E. All these proteins are not detected at the centromere during anaphase/telophase I and are then reloaded during interkinesis. The loading sequence of the analyzed proteins is similar during prophase I and interkinesis. These findings demonstrate that the interkinesis stage, regularly overlooked, is essential for centromere and kinetochore maturation and reorganization previous to the second meiotic division. We also demonstrate that Shugoshin 2 is necessary for the loading of MCAK at the inner centromere, but is dispensable for the loading of the outer kinetochore proteins BubR1 and CENP-E

Higher COVID-19 pneumonia risk associated with anti-IFN-α than with anti-IFN-ω auto-Abs in children

We found that 19 (10.4%) of 183 unvaccinated children hospitalized for COVID-19 pneumonia had autoantibodies (auto-Abs) neutralizing type I IFNs (IFN-alpha 2 in 10 patients: IFN-alpha 2 only in three, IFN-alpha 2 plus IFN-omega in five, and IFN-alpha 2, IFN-omega plus IFN-beta in two; IFN-omega only in nine patients). Seven children (3.8%) had Abs neutralizing at least 10 ng/ml of one IFN, whereas the other 12 (6.6%) had Abs neutralizing only 100 pg/ml. The auto-Abs neutralized both unglycosylated and glycosylated IFNs. We also detected auto-Abs neutralizing 100 pg/ml IFN-alpha 2 in 4 of 2,267 uninfected children (0.2%) and auto-Abs neutralizing IFN-omega in 45 children (2%). The odds ratios (ORs) for life-threatening COVID-19 pneumonia were, therefore, higher for auto-Abs neutralizing IFN-alpha 2 only (OR [95% CI] = 67.6 [5.7-9,196.6]) than for auto-Abs neutralizing IFN-. only (OR [95% CI] = 2.6 [1.2-5.3]). ORs were also higher for auto-Abs neutralizing high concentrations (OR [95% CI] = 12.9 [4.6-35.9]) than for those neutralizing low concentrations (OR [95% CI] = 5.5 [3.1-9.6]) of IFN-omega and/or IFN-alpha 2

Autoantibodies against type I IFNs in patients with critical influenza pneumonia

In an international cohort of 279 patients with hypoxemic influenza pneumonia, we identified 13 patients (4.6%) with autoantibodies neutralizing IFN-alpha and/or -omega, which were previously reported to underlie 15% cases of life-threatening COVID-19 pneumonia and one third of severe adverse reactions to live-attenuated yellow fever vaccine. Autoantibodies neutralizing type I interferons (IFNs) can underlie critical COVID-19 pneumonia and yellow fever vaccine disease. We report here on 13 patients harboring autoantibodies neutralizing IFN-alpha 2 alone (five patients) or with IFN-omega (eight patients) from a cohort of 279 patients (4.7%) aged 6-73 yr with critical influenza pneumonia. Nine and four patients had antibodies neutralizing high and low concentrations, respectively, of IFN-alpha 2, and six and two patients had antibodies neutralizing high and low concentrations, respectively, of IFN-omega. The patients' autoantibodies increased influenza A virus replication in both A549 cells and reconstituted human airway epithelia. The prevalence of these antibodies was significantly higher than that in the general population for patients 70 yr of age (3.1 vs. 4.4%, P = 0.68). The risk of critical influenza was highest in patients with antibodies neutralizing high concentrations of both IFN-alpha 2 and IFN-omega (OR = 11.7, P = 1.3 x 10(-5)), especially those <70 yr old (OR = 139.9, P = 3.1 x 10(-10)). We also identified 10 patients in additional influenza patient cohorts. Autoantibodies neutralizing type I IFNs account for similar to 5% of cases of life-threatening influenza pneumonia in patients <70 yr old

Vaccine breakthrough hypoxemic COVID-19 pneumonia in patients with auto-Abs neutralizing type I IFNs

Life-threatening `breakthrough' cases of critical COVID-19 are attributed to poor or waning antibody response to the SARS- CoV-2 vaccine in individuals already at risk. Pre-existing autoantibodies (auto-Abs) neutralizing type I IFNs underlie at least 15% of critical COVID-19 pneumonia cases in unvaccinated individuals; however, their contribution to hypoxemic breakthrough cases in vaccinated people remains unknown. Here, we studied a cohort of 48 individuals ( age 20-86 years) who received 2 doses of an mRNA vaccine and developed a breakthrough infection with hypoxemic COVID-19 pneumonia 2 weeks to 4 months later. Antibody levels to the vaccine, neutralization of the virus, and auto- Abs to type I IFNs were measured in the plasma. Forty-two individuals had no known deficiency of B cell immunity and a normal antibody response to the vaccine. Among them, ten (24%) had auto-Abs neutralizing type I IFNs (aged 43-86 years). Eight of these ten patients had auto-Abs neutralizing both IFN-a2 and IFN-., while two neutralized IFN-omega only. No patient neutralized IFN-ss. Seven neutralized 10 ng/mL of type I IFNs, and three 100 pg/mL only. Seven patients neutralized SARS-CoV-2 D614G and the Delta variant (B.1.617.2) efficiently, while one patient neutralized Delta slightly less efficiently. Two of the three patients neutralizing only 100 pg/mL of type I IFNs neutralized both D61G and Delta less efficiently. Despite two mRNA vaccine inoculations and the presence of circulating antibodies capable of neutralizing SARS-CoV-2, auto-Abs neutralizing type I IFNs may underlie a significant proportion of hypoxemic COVID-19 pneumonia cases, highlighting the importance of this particularly vulnerable population

Meta-analysis of shared genetic architecture across ten pediatric autoimmune diseases

Genome-wide association studies (GWASs) have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases. We performed an inverse χ(2) meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls. We identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico-replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG. The pAID-associated single-nucleotide polymorphisms (SNPs) were functionally enriched for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants. We also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing. Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases

Analysis of definitions of General Practice/Family Medicine and Primary Health Care

Abstract Background There are numerous definitions of General Practice and Family Medicine (GP/FM) and Primary Health Care (PHC), but the distinction between the two concepts is unclear. Aim To conduct a terminological analysis of a set of definitions of GP/FM and of PHC, to clarify what binds and what distinguishes these two concepts. Design The terms of 20 definitions were collected in two bags of words (one for GP/FM and one for PHC terms). A terminological analysis of these two bags of words was performed to prioritize the terms and analyze their world of reference. Methods The two collected bags of words were extracted with Vocabgrabber®, configured in two term butts using Wordle®, and further explored for similarities using Tropes®. The prioritized terms were analyzed using the Aristotelian approach to categorization of things. Results Although continuity of care (with person-centered approach and shared decision making) is the central issue of the two sets, the two sets of definitions differ greatly in content. The prioritized terms specific to GP/FM (community, medicine, responsibility, individual, problem, needs, ...) are different from prioritized terms specific to PHC (home, team, promotion, collaborator, engagement, neighborhood, medical center…). Conclusion Terminological analysis of the definitions for GP/FM and PHC shows two entities which are overlapping but distinct, necessitating a different taxonomic approach and different bibliographic search strategies