Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

Immunitat adaptativa; Envelliment; Esclerosi múltipleInmunidad adaptativa; Envejecimiento; Esclerosis múltipleAdaptive immunity; Aging; Multiple sclerosisPatients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.This work was supported by grants FIS-PI15/00513, FIS-PI18/00572 and RD16/0015/0001 from the Instituto de Salud Carlos III. Ministerio de Ciencia e Innovación, Spain and FEDER: "Una manera de hacer Europa"

Mannose-binding lectin gene variants and infections in patients receiving autologous stem cell transplantation

BACKGROUND: Serious infections are common in patients undergoing autologous stem cell transplantation (ASCT) mainly because of the effects of immunosuppression. The innate immune system plays an important role in the defense against different infections. Mannose binding lectin (MBL) is a central molecule of the innate immune system. There are several promoter polymorphisms and structural variants of the MBL2 gene that encodes for this protein. These variants produce low levels of MBL and have been associated with an increased risk for infections. METHODS: Prospective cohort study. The incidence, severity of infections and mortality in 72 consecutive patients with hematologic diseases who underwent ASCT between February 2006 and June 2008 in a tertiary referral center were analyzed according to their MBL2 genotype. INNO-LiPA MBL2 was used for MBL2 gene amplification and genotyping. Relative risks (RR) (IC95%) as measure of association were calculated. Multivariate analysis was performed using logistic regression. RESULTS: A statistically significant higher number of fungal infections was found in patients with MBL2 variants causing low MBL levels (21.1%versus1.9%, p=0.016). In this MBL2 variant group infection was more frequently the cause of mortality than in the MBL2 wild-type group (p=0.05). Although not statistically significant, there was a higher incidence of major infections in the MBL2 variant group as well as a higher number of infections caused by gram-positive bacteria. CONCLUSIONS: Low-producer MBL2 genotypes were associated with an increased number of fungal infections in ASCT patients, which would suggest that MBL has a protective role against such infections. ASCT patients with MBL2 variant genotypes are more likely to die as a result of an infection

Identification of the Immunological Changes Appearing in the CSF During the Early Immunosenescence Process Occurring in Multiple Sclerosis

Patients with multiple sclerosis (MS) suffer with age an early immunosenescence process, which influence the treatment response and increase the risk of infections. We explored whether lipid-specific oligoclonal IgM bands (LS-OCMB) associated with highly inflammatory MS modify the immunological profile induced by age in MS. This cross-sectional study included 263 MS patients who were classified according to the presence (M+, n=72) and absence (M-, n=191) of LS-OCMB. CSF cellular subsets and molecules implicated in immunosenescence were explored. In M- patients, aging induced remarkable decreases in absolute CSF counts of CD4+ and CD8+ T lymphocytes, including Th1 and Th17 cells, and of B cells, including those secreting TNF-alpha. It also increased serum anti-CMV IgG antibody titers (indicative of immunosenescence) and CSF CHI3L1 levels (related to astrocyte activation). In contrast, M+ patients showed an age-associated increase of TIM-3 (a biomarker of T cell exhaustion) and increased values of CHI3L1, independently of age. Finally, in both groups, age induced an increase in CSF levels of PD-L1 (an inductor of T cell tolerance) and activin A (part of the senescence-associated secretome and related to inflammaging). These changes were independent of the disease duration. Finally, this resulted in augmented disability. In summary, all MS patients experience with age a modest induction of T-cell tolerance and an activation of the innate immunity, resulting in increased disability. Additionally, M- patients show clear decreases in CSF lymphocyte numbers, which could increase the risk of infections. Thus, age and immunological status are important for tailoring effective therapies in MS.This work was supported by grants FIS-PI15/00513, FIS-PI18/00572 and RD16/0015/0001 from the Instituto de Salud Carlos III. Ministerio de Ciencia e Innovación, Spain and FEDER: "Una manera de hacer Europa"

Quantification of inaccurate diagnosis of COPD in primary care medicine: an analysis of the COACH clinical audit

[Background] Inaccurate diagnosis in COPD is a current problem with relevant consequences in terms of inefficient health care, which has not been thoroughly studied in primary care medicine. The aim of the present study was to evaluate the degree of inaccurate diagnosis in Primary Care in Spain and study the determinants associated with it.[Methods] The Community Assessment of COPD Health Care (COACH) study is a national, observational, randomized, non-interventional, national clinical audit aimed at evaluating clinical practice for patients with COPD in primary care medicine in Spain. For the present analysis, a correct diagnosis was evaluated based on previous exposure and airway obstruction with and without the presence of symptoms. The association of patient-level and center-level variables with inaccurate diagnosis was studied using multivariate multilevel binomial logistic regression models.[Results] During the study 4,307 cases from 63 centers were audited. The rate of inaccurate diagnosis was 82.4% (inter-regional range from 76.8% to 90.2%). Patient-related interventions associated with inaccurate diagnosis were related to active smoking, lung function evaluation, and specific therapeutic interventions. Center-level variables related to the availability of certain complementary tests and different aspects of the resources available were also associated with an inaccurate diagnosis.[Conclusions] The prevalence data for the inaccurate diagnosis of COPD in primary care medicine in Spain establishes a point of reference in the clinical management of COPD. The descriptors of the variables associated with this inaccurate diagnosis can be used to identify cases and centers in which inaccurate diagnosis is occurring considerably, thus allowing for improvement.Peer reviewe

Predictors of Response to Exclusive Enteral Nutrition in Newly Diagnosed Crohn´s Disease in Children: PRESENCE Study from SEGHNP

Exclusive enteral nutrition (EEN) has been shown to be more effective than corticosteroids in achieving mucosal healing in children with Crohn´s disease (CD) without the adverse effects of these drugs. The aims of this study were to determine the efficacy of EEN in terms of inducing clinical remission in children newly diagnosed with CD, to describe the predictive factors of response to EEN and the need for treatment with biological agents during the first 12 months of the disease. We conducted an observational retrospective multicentre study that included paediatric patients newly diagnosed with CD between 2014–2016 who underwent EEN. Two hundred and twenty-two patients (140 males) from 35 paediatric centres were included, with a mean age at diagnosis of 11.6 ± 2.5 years. The median EEN duration was 8 weeks (IQR 6.6–8.5), and 184 of the patients (83%) achieved clinical remission (weighted paediatric Crohn’s Disease activity index [wPCDAI] 15 mg/L and ileal involvement tended to respond better to EEN. EEN administered for 6–8 weeks is effective for inducing clinical remission. Due to the high response rate in our series, EEN should be used as the first-line therapy in luminal paediatric Crohn’s disease regardless of the location of disease and disease activityS

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

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Calidad de los servicios de anticoncepción en El Alto, Bolivia The quality of contraception services in El Alto, Bolivia

El presente estudio tuvo por objetivo evaluar la calidad de los servicios de anticoncepción en la ciudad de El Alto, Bolivia. En su diseño se han contemplado cuatro elementos: 1) las relaciones entre los proveedores de servicios y sus clientes, 2) la disponibilidad de métodos anticonceptivos, 3) las condiciones de los servicios, y 4) la satisfacción de las usuarias. También se han tenido en cuenta las opiniones de los proveedores y de las usuarias y no usuarias de estos servicios, quienes se clasificaron como gubernamentales o no gubernamentales, de acuerdo con la administración de la institución a la que pertenecían. Los datos provinieron de un análisis de la situación de dichos servicios y de testimonios obtenidos de las participantes durante 1995. En cuanto a las relaciones interpersonales, se encontró que los proveedores percibían el trato del médico más favorablemente que las clientas, en tanto que las no usuarias lo percibían desfavorablemente. La percepción de un trato igualitario se correlacionó positivamente con la vestimenta que usaban las clientas. En cuanto a la disponibilidad de los métodos anticonceptivos, 15 de las 36 instituciones encuestadas no disponían de métodos modernos, a pesar de la existencia de una política nacional para proveerlos a la población. La oferta de estos servicios a parejas y a adolescentes es escasa, principalmente en las instituciones gubernamentales. El análisis de las condiciones de los servicios demostró que en algunas instituciones había problemas graves en la provisión de una atención de mínima calidad. Finalmente, este trabajo describe cómo la mayoría de estas limitaciones en la prestación de servicios de anticoncepción en El Alto pueden subsanarse mediante estrategias de costo moderado.<br>The objective of this study was to evaluate the quality of contraception services in the city of El Alto, Bolivia. In the study design, four components were considered: 1) interpersonal relations between service providers and users, 2) the availability of various contraceptive methods, 3) conditions in the service centers, and 4) user satisfaction. The opinions of three groups were taken into account: service providers, service users, and nonusers. The service centers were classified as either governmental or nongovernmental, depending on the management of the institution to which the service center belonged. The study data came from a situation analysis of the services and from comments gathered from study participants in 1995. The study found that providers held a more favorable view than did service users of the interpersonal relations and personal treatment that physicians provided. Nonusers had an unfavorable perception of physicians&#146; treatment of users. Users&#146; perceptions of receiving egalitarian treatment correlated with their style of dress. With regard to the availability of contraceptive methods, 15 of the 36 centers surveyed did not have modern methods, despite there being a national policy to provide them to the public. The supply of contraception services for couples and for adolescents is limited, especially in the governmental institutions. The analysis of the conditions in the service centers demonstrated that some institutions had serious difficulties providing services of at least a minimum quality. Finally, the study describes how most of the service limitations in El Alto can be corrected through moderate-cost strategies