Una aproximación al significado biológico del polimorfismo del Complejo Mayor de Histocompatibilidad. El modelo de la asociación HLA y ARJ*

Resumen Objetivos. Llevar a cabo una actualización del estado del arte acerca del significado biológico del polimorfismo del sistema genético Complejo Mayor de Histocompatibilidad (CMH). Revisar la literatura relacionada con la asociación de los antígenos de histocompatibilidad en el humano (HLA ) y la susceptibilidad o resistencia al desarrollo de la artritis reumatoidea juvenil (ARJ). Presentar un modelo hipotético para la comprensión de la susceptibilidad genética a desarrollar ARJ. Fuente de datos. Las referencia bibliográficas que soportan este artículo se obtuvieron a través de búsquedas en las siguientes bases de datos: Pubmed, Ovid, Ebsco. Inicialmente se encontraron 139 artículos, de los cuales se seleccionaron 75. Se incluyó también información del desarrollo de un proyecto de investigación de nuestro grupo, «Polimorfismo molecular de los antígenos HLA en ARJ» (cod. Colciencias 1215-04-280-96). Resultados. L artritis reumatoidea juvenil (ARJ) es la enfermedad más común en la práctica reumatológica pediátrica y la menos estudiada inmunogenéticamente. A diferencia de la artritis reumatoide (AR) del adulto, la ARJ tiene ciertas variantes clínicas, lo que la hace más interesante desde el punto de vista genético (fenotipos). En su etiopatogenia se han identificado varios factores que en su conjunto explicarían el inicio y la perpetuación de la respuesta inflamatoria que afecta las articulaciones y tejidos vecinos, y que de no ser controlados llegan a destruirlos, tal como sucede en otras enfermedades autoinmunes. La patogénesis de la enfermedad puede determinarse por alteraciones a nivel de complejo trimolecular, constituido por un antígeno putativo, el receptor de linfocitos T y el Complejo Mayor de Histocompatibilidad (CMH). Nuestro grupo durante los últimos 4 años ha estado estudiando la asociación entre ARJ y el polimorfismo de los alelos HLA DRB1* y DQB1* en niños mestizos de nuestro país. Los resultados son congruentes con otros hallazgos descritos en la literatura por diferentes grupos de investigadores. En la serie de pacientes estudiados por nosotros se encontró que los alelos HLA DRB1* 1104, HLA*0701 y HLA*1602 están asociados a la susceptibilidad de desarrollar ARJ, además nuestros datos muestran que los alelos HLA DRB1* 1501 y HLA DQB1* 0602 están claramente asociados con protección.Es importante resaltar que todos los alelos asociados a susceptibilidad comparten el aminoácido Asp en la posición 70, y aquellos que se muestran como marcadores de protección contienen Val en la misma posición. Conclusión. La información obtenida de la literatura y los hallazgos encontrados en nuestra serie de pacientes colombianos son relevantes e importantes, dado que desde el punto de vista molecular, a nivel de la presentación antigénica, el aminoácido en la posición 70 en el motivo 67 a la 73, a nivel de la molécula HLA podría activar células TH1 o TH2, las cuales estarían comprometidas en la inmunopatología de esta entidad. Otros factores genéticos y/o ambientales en asocio con estas características moleculares, expresadas a nivel de la molécula HLA, comprometida en la presentación antigénica, podrían interactuar y su resultado estaría influenciando el desarrollo y la expresión de la ARJ. Palabras clave: Complejo Mayor de Histocompatiblilidad (CMH), artritis reumatoide juvenil, HLA y ARJ. Abstract Objectives. To carry out an updating of the state of the art about the biological meaning of genetic system polymorphism Major Histocompatibility Complex (MHC). To review the literature related to the association of histocompatibility antigens in humans (HLA) and the susceptibility or resistance to the development of Juvenile Rheumatoid Arthritis (JRA). To present a hypothetical model to understand the genetic susceptibility to develop JRA. Data source. The bibliographic references supporting this paper were obtained through searching in the following data base: Pubmed, Ovid, Ebsco. Initially, 139 articles were found, from which 75 were selected . Information about the development of a research of our group, «Molecular polymorphism of HLA and JRA antigens» was also included. (Colciencias code No 1215-04-280-96). Results. Juvenile rheumatoid Arthritis (JRA) is the most common disease in pediatric rheumatologic practice as well as the one with less immunogenetic studies. Contrary to the adult rheumatoid arthritis (RA), JRA has certain clinical variants which make it more interesting from the genetic point of view (phenotypes). In its pathogenesis several factors have been identified, which as a whole would explain the onset and the perpetuation of the inflammatory response affecting joints and nearby tissue as well as its imminent destruction given no control of it as is the case in other autoimmune diseases. The disease pathogenesis can be determined by alterations at the trimolecular level formed by a putative antigen: lymphocyte T receptor and the Major Histocampatibility Complex (MHC). During the last four years our group has been studying the link between JRA and the HLA DRB1* and DQB1* alleles in mestizo children of our country. Results are congruent with the findings described in the literature by different investigation groups. In the series of patients studied, we have found that the alleles HLA DRB1* 1104, HLA*0701 and HLA*1602 are linked to the susceptibility of developing JRA. Our data also show that the alleles HLA DRB1* 1501 y HLA DQB1* 0602 are clearly linked to protection. It is important to highlight that all the alleles linked to susceptibility share the Asp amino acid in position 70, and those shown as protection markers have Val in the same position. Conclusion. The information obtained from the literature and the findings in our series of Colombian patients are relevant and important because from the molecular point of view, at an antigenic presentation level, the amino acid in position 70 in the motif 67 to 73, at HLA molecule level, could activate TH1 or TH2 cells, which would be compromised in the immunopathology of this entity. Other genetic or/and environmental factors linked to these molecular characteristics expressed at the level of the HLA molecule and compromised in the antigenic response could interact and its result would be influencing the development and the expression of JRA. Key words: Major Histocompatibility Complex (MHC), juvenile rheumatoid arthritis (JRA)

ISG15 Is Upregulated in Respiratory Syncytial Virus Infection and Reduces Virus Growth through Protein ISGylation

UNLABELLED: Human respiratory syncytial virus (RSV), for which neither a vaccine nor an effective therapeutic treatment is currently available, is the leading cause of severe lower respiratory tract infections in children. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like protein that is highly increased during viral infections and has been reported to have an antiviral or a proviral activity, depending on the virus. Previous studies from our laboratory demonstrated strong ISG15 upregulation during RSV infection in vitro. In this study, an in-depth analysis of the role of ISG15 in RSV infection is presented. ISG15 overexpression and small interfering RNA (siRNA)-silencing experiments, along with ISG15 knockout (ISG15(-/-)) cells, revealed an anti-RSV effect of the molecule. Conjugation inhibition assays demonstrated that ISG15 exerts its antiviral activity via protein ISGylation. This antiviral activity requires high levels of ISG15 to be present in the cells before RSV infection. Finally, ISG15 is also upregulated in human respiratory pseudostratified epithelia and in nasopharyngeal washes from infants infected with RSV, pointing to a possible antiviral role of the molecule in vivo. These results advance our understanding of the innate immune response elicited by RSV and open new possibilities to control infections by the virus. IMPORTANCE: At present, no vaccine or effective treatment for human respiratory syncytial virus (RSV) is available. This study shows that interferon-stimulated gene 15 (ISG15) lowers RSV growth through protein ISGylation. In addition, ISG15 accumulation highly correlates with the RSV load in nasopharyngeal washes from children, indicating that ISG15 may also have an antiviral role in vivo. These results improve our understanding of the innate immune response to RSV and identify ISG15 as a potential target for virus control.This work was supported by grant PI11/00590 from Fondo de Investigación Sanitaria to I.M.S

Critically short telomeres and toxicity of chemotherapy in early breast cancer

Cumulative toxicity from weekly paclitaxel (myalgia, peripheral neuropathy, fatigue) compromises long-term administration. Preclinical data suggest that the burden of critically short telomeres ( 21.9% CSTs) had 2-fold higher number of neuropathy (P = 0.04) or fatigue (P = 0.019) episodes and >3-fold higher number of myalgia episodes (P = 0.005). The average telomere length was unrelated to the incidence of side effects.The percentage of CSTs, but not the average telomere size, is associated with weekly paclitaxel-derived toxicity.This work was supported by the Fondo de Investigación Sanitaria [FIS PI10/00288 and FIS PI13/00430]; AECC Scientific Foundation [Beca de Retorno-2010, to MQF]; Spanish Ministry of Economy and Competitiveness Projects [SAF2013-45111-R]; Madrid Regional Government Projects [S2010/BMD- 2303]; AXA Research Found; Fundación Botin; AVON Spain; and Boehringer-Ingelheim Spain.S

Remdesivir in Very Old Patients (≥80 Years) Hospitalized with COVID-19: Real World Data from the SEMI-COVID-19 Registry

Background: Large cohort studies of patients with COVID-19 treated with remdesivir have reported improved clinical outcomes, but data on older patients are scarce. Objective: This work aims to assess the potential benefit of remdesivir in unvaccinated very old patients hospitalized with COVID-19; (2) Methods: This is a retrospective analysis of patients >= 80 years hospitalized in Spain between 15 July and 31 December 2020 (SEMI-COVID-19 Registry). Differences in 30-day all-cause mortality were adjusted using a multivariable regression analysis. (3) Results: Of the 4331 patients admitted, 1312 (30.3%) were >= 80 years. Very old patients treated with remdesivir (n: 140, 10.7%) had a lower mortality rate than those not treated with remdesivir (OR (95% CI): 0.45 (0.29-0.69)). After multivariable adjustment by age, sex, and variables associated with lower mortality (place of COVID-19 acquisition; degree of dependence; comorbidities; dementia; duration of symptoms; admission qSOFA; chest X-ray; D-dimer; and treatment with corticosteroids, tocilizumab, beta-lactams, macrolides, and high-flow nasal canula oxygen), the use of remdesivir remained associated with a lower 30-day all-cause mortality rate (adjusted OR (95% CI): 0.40 (0.22-0.61) (p < 0.001)). (4) Conclusions: Remdesivir may reduce mortality in very old patients hospitalized with COVID-19

Evolution of Quality of Life and Treatment Adherence after One Year of Intermittent Bladder Catheterisation in Functional Urology Unit Patients

Objective: To determine patient difficulties and concerns when performing IBC (Intermittent Bladder Catheterisation), as well as the evolution of adherence, quality of life, and emotional state of patients one year after starting IBC. Method: A prospective, observational, multicentre study conducted in 20 Spanish hospitals with a one-year follow-up. Data sources were patient records and the King's Health Questionnaire on quality of life, the Mini-Mental State Examination (MMSE), and the Hospital Anxiety and Depression Scale (HADS). Perceived adherence was measured using the ICAS (Intermittent Catheterization Adherence Scale) and perceived difficulties with IBC were assessed using the ICDQ (Intermittent Catheterization Difficulty Questionnaire). For data analysis, descriptive and bivariate statistics were performed for paired data at three points in time (T1: one month, T2: three months, T3: one year). Results: A total of 134 subjects initially participated in the study (T0), becoming 104 subjects at T1, 91 at T2, and 88 at T3, with a mean age of 39 years (standard deviation = 22.16 years). Actual IBC adherence ranged from 84.8% at T1 to 84.1% at T3. After one year of follow-up, a statistically significant improvement in quality of life (p <= 0.05) was observed in all dimensions with the exception of personal relationships. However, there were no changes in the levels of anxiety (p = 0.190) or depression (p = 0.682) at T3 compared to T0. Conclusions: Patients requiring IBC exhibit good treatment adherence, with a significant proportion of them performing self-catheterisation. After one year of IBC, a significant improvement in quality of life was noted, albeit with a significant impact on their daily lives and their personal and social relationships. Patient support programmes could be implemented to improve their ability to cope with difficulties and thus enhance both their quality of life and the maintenance of their adherence

Multicentre, randomised, single-blind, parallel group trial to compare the effectiveness of a Holter for Parkinson's symptoms against other clinical monitoring methods: study protocol

Introduction In recent years, multiple studies have aimed to develop and validate portable technological devices capable of monitoring the motor complications of Parkinson's disease patients (Parkinson's Holter). The effectiveness of these monitoring devices for improving clinical control is not known. Methods and analysis This is a single-blind, cluster-randomised controlled clinical trial. Neurologists from Spanish health centres will be randomly assigned to one of three study arms (1:1:1): (a) therapeutic adjustment using information from a Parkinson?s Holter that will be worn by their patients for 7 days, (b) therapeutic adjustment using information from a diary of motor fluctuations that will be completed by their patients for 7 days and (c) therapeutic adjustment using clinical information collected during consultation. It is expected that 162 consecutive patients will be included over a period of 6 months. The primary outcome is the efficiency of the Parkinson?s Holter compared with traditional clinical practice in terms of Off time reduction with respect to the baseline (recorded through a diary of motor fluctuations, which will be completed by all patients). As secondary outcomes, changes in variables related to other motor complications (dyskinesia and freezing of gait), quality of life, autonomy in activities of daily living, adherence to the monitoring system and number of doctor?patient contacts will be analysed. The noninferiority of the Parkinson's Holter against the diary of motor fluctuations in terms of Off time reduction will be studied as the exploratory objective. Ethics and dissemination approval for this study has been obtained from the Hospital Universitari de Bellvitge Ethics Committee. The results of this study will inform the practical utility of the objective information provided by a Parkinson's Holter and, therefore, the convenience of adopting this technology in clinical practice and in future clinical trials. We expect public dissemination of the results in 2022.Funding This work is supported by AbbVie S.L.U, the Instituto de Salud Carlos III [DTS17/00195] and the European Fund for Regional Development, 'A way to make Europe'

Risk factors associated with adverse fetal outcomes in pregnancies affected by Coronavirus disease 2019 (COVID-19): a secondary analysis of the WAPM study on COVID-19.

Objectives To evaluate the strength of association between maternal and pregnancy characteristics and the risk of adverse perinatal outcomes in pregnancies with laboratory confirmed COVID-19. Methods Secondary analysis of a multinational, cohort study on all consecutive pregnant women with laboratory-confirmed COVID-19 from February 1, 2020 to April 30, 2020 from 73 centers from 22 different countries. A confirmed case of COVID-19 was defined as a positive result on real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay of nasal and pharyngeal swab specimens. The primary outcome was a composite adverse fetal outcome, defined as the presence of either abortion (pregnancy loss before 22 weeks of gestations), stillbirth (intrauterine fetal death after 22 weeks of gestation), neonatal death (death of a live-born infant within the first 28 days of life), and perinatal death (either stillbirth or neonatal death). Logistic regression analysis was performed to evaluate parameters independently associated with the primary outcome. Logistic regression was reported as odds ratio (OR) with 95% confidence interval (CI). Results Mean gestational age at diagnosis was 30.6+/-9.5 weeks, with 8.0% of women being diagnosed in the first, 22.2% in the second and 69.8% in the third trimester of pregnancy. There were six miscarriage (2.3%), six intrauterine device (IUD) (2.3) and 5 (2.0%) neonatal deaths, with an overall rate of perinatal death of 4.2% (11/265), thus resulting into 17 cases experiencing and 226 not experiencing composite adverse fetal outcome. Neither stillbirths nor neonatal deaths had congenital anomalies found at antenatal or postnatal evaluation. Furthermore, none of the cases experiencing IUD had signs of impending demise at arterial or venous Doppler. Neonatal deaths were all considered as prematurity-related adverse events. Of the 250 live-born neonates, one (0.4%) was found positive at RT-PCR pharyngeal swabs performed after delivery. The mother was tested positive during the third trimester of pregnancy. The newborn was asymptomatic and had negative RT-PCR test after 14 days of life. At logistic regression analysis, gestational age at diagnosis (OR: 0.85, 95% CI 0.8-0.9 per week increase; pPeer reviewe

Choice of the initial antiretroviral treatment for HIV-positive individuals in the era of integrase inhibitors

BACKGROUND: We aimed to describe the most frequently prescribed initial antiretroviral therapy (ART) regimens in recent years in HIV-positive persons in the Cohort of the Spanish HIV/AIDS Research Network (CoRIS) and to investigate factors associated with the choice of each regimen. METHODS: We analyzed initial ART regimens prescribed in adults participating in CoRIS from 2014 to 2017. Only regimens prescribed in >5% of patients were considered. We used multivariable multinomial regression to estimate Relative Risk Ratios (RRRs) for the association between sociodemographic and clinical characteristics and the choice of the initial regimen. RESULTS: Among 2874 participants, abacavir(ABC)/lamivudine(3TC)/dolutegavir(DTG) was the most frequently prescribed regimen (32.1%), followed by tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC)/elvitegravir(EVG)/cobicistat(COBI) (14.9%), TDF/FTC/rilpivirine (RPV) (14.0%), tenofovir alafenamide (TAF)/FTC/EVG/COBI (13.7%), TDF/FTC+DTG (10.0%), TDF/FTC+darunavir/ritonavir or darunavir/cobicistat (bDRV) (9.8%) and TDF/FTC+raltegravir (RAL) (5.6%). Compared with ABC/3TC/DTG, starting TDF/FTC/RPV was less likely in patients with CD4100.000 copies/mL. TDF/FTC+DTG was more frequent in those with CD4100.000 copies/mL. TDF/FTC+RAL and TDF/FTC+bDRV were also more frequent among patients with CD4<200 cells//muL and with transmission categories other than men who have sex with men. Compared with ABC/3TC/DTG, the prescription of other initial ART regimens decreased from 2014-2015 to 2016-2017 with the exception of TDF/FTC+DTG. Differences in the choice of the initial ART regimen were observed by hospitals' location. CONCLUSIONS: The choice of initial ART regimens is consistent with Spanish guidelines' recommendations, but is also clearly influenced by physician's perception based on patient's clinical and sociodemographic variables and by the prescribing hospital location

Bio-inspired computation: where we stand and what's next

In recent years, the research community has witnessed an explosion of literature dealing with the adaptation of behavioral patterns and social phenomena observed in nature towards efficiently solving complex computational tasks. This trend has been especially dramatic in what relates to optimization problems, mainly due to the unprecedented complexity of problem instances, arising from a diverse spectrum of domains such as transportation, logistics, energy, climate, social networks, health and industry 4.0, among many others. Notwithstanding this upsurge of activity, research in this vibrant topic should be steered towards certain areas that, despite their eventual value and impact on the field of bio-inspired computation, still remain insufficiently explored to date. The main purpose of this paper is to outline the state of the art and to identify open challenges concerning the most relevant areas within bio-inspired optimization. An analysis and discussion are also carried out over the general trajectory followed in recent years by the community working in this field, thereby highlighting the need for reaching a consensus and joining forces towards achieving valuable insights into the understanding of this family of optimization techniques

China: Challenges and Prospects from an Industrial and Innovation Powerhouse

China is rapidly becoming a major industrial competitor in high tech and growth sectors. Its economic success and related industrial policies have received a high degree of attention, especially in light of its capacity to challenge the leading position of advanced economies in several fields. China aims, through the 'Made in China 2025' strategy, to become a world leader in key industrial sectors. In these sectors, it strives to strengthen its domestic innovation capacity, to reduce its reliance on foreign technologies while moving up in global value chains. This report analyses China's approach to attain a dominant position in international markets through a combination of industrial, R&I, trade and foreign direct investment policies. It offers an assessment of China's current position compared to the EU and US innovation systems across a range of dimensions. It concludes that China has become a major industrial competitor in several rapidly expanding high tech sectors, which may well result in attaining China's goal of becoming an innovation leader in specific areas. As a response, the EU will need to boost its industrial and R&I performance and develop a trade policy that can ensure a level playing field for EU companies in China and for Chinese companies in the EU.JRC.B.7-Knowledge for Finance, Innovation and Growt