The CARMA study – children on early suppressive therapy: total HIV-1 DNA quantitation 12 years post ART initiation

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The CARMA Study: Early Infant Antiretroviral Therapy - Timing Impacts on Total HIV-1 DNA Quantitation 12 Years Later

Background. Strategies aimed at antiretroviral therapy (ART)-free remission will target individuals with a limited viral reservoir. We investigated factors associated with low reservoir measured as total human immunodeficiency virus type 1 (HIV-1) DNA in peripheral blood mononuclear cells (PBMCs) in perinatal infection (PaHIV).Methods. Children from 7 European centers in the Early Treated Perinatally HIV Infected Individuals: Improving Children's Actual Life (EPIICAL) consortium who commenced ART aged <2 years, and remained suppressed (viral load [VL] <50 copies/mL) for >5 years were included. Total HIV-1 DNA was measured by quantitative polymerase chain reaction per million PBMCs. Factors associated with total HIV-1 DNA were analyzed using generalized additive models. Age, VL at ART initiation, and baseline CD4% effects were tested including smoothing splines to test nonlinear association.Results. Forty PaHIV, 27 (67.5%) female 21 (52.5%) Black/Black African, had total HIV-1 DNA measured; median 12 (IQR, 7.3-15.4) years after ART initiation. Eleven had total HIV-1 DNA <10 copies/10(6) PBMCs. HIV-1 DNA levels were positively associated with age and VL at ART initiation, baseline CD4%, and Western blot antibody score. Age at ART initiation presented a linear association (coefficient = 0.10 +/- 0.001, P <= .001), the effect of VL (coefficient = 0.35 +/- 0.1, P <= .001) noticeable >6 logs. The effect of CD4% (coefficient = 0.03 +/- 0.01, P <= .049) was not maintained >40%.Conclusions. In this PaHIV cohort, reduced total HIV-1 DNA levels were associated with younger age and lower VL at ART initiation. The impact of early-infant treatment on reservoir size persists after a decade of suppressive therapy

Performance of QuantiFERON-TB Gold Plus assays in children and adolescents at risk of tuberculosis: a cross-sectional multicentre study

Introduction: The QuantiFERON-TB Gold Plus (QFT-Plus) assay, which features two antigen-stimulated tubes (TB1 and TB2) instead of a single tube used in previous-generation interferon-gamma release assays (IGRAs), was launched in 2016. Despite this, data regarding the assay’s performance in the paediatric setting remain scarce. This study aimed to determine the performance of QFT-Plus in a large cohort of children and adolescents at risk of tuberculosis (TB) in a low-burden setting. Methods: Cross-sectional, multicentre study at healthcare institutions participating in the Spanish Paediatric TB Research Network, including patients <18 years who had a QFT-Plus performed between September 2016 and June 2020. Results: Of 1726 patients (52.8% male, median age: 8.4 years), 260 (15.1%) underwent testing during contact tracing, 288 (16.7%) on clinical/radiological suspicion of tuberculosis disease (TBD), 649 (37.6%) during new-entrant migrant screening and 529 (30.6%) prior to initiation of immunosuppressive treatment. Overall, the sensitivity of QFT-Plus for TBD (n=189) and for latent tuberculosis infection (LTBI, n=195) was 83.6% and 68.2%, respectively. The agreement between QFT-Plus TB1 and TB2 antigen tubes was excellent (98.9%, κ=0.961). Only five (2.5%) patients with TBD had discordance between TB1 and TB2 results (TB1+/TB2−, n=2; TB1−/TB2+, n=3). Indeterminate assay results (n=54, 3.1%) were associated with young age, lymphopenia and elevated C reactive protein concentrations. Conclusions: Our non-comparative study indicates that QFT-Plus does not have greater sensitivity than previous-generation IGRAs in children in both TBD and LTBI. In TBD, the addition of the second antigen tube, TB2, does not enhance the assay’s performance substantially

Gramine derivatives targeting Ca2+ channels and Ser/Thr phosphatases: A new dual strategy for the treatment of neurodegenerative diseases

This document is the unedited author's version of a Submitted Work that was subsequently accepted for publication in Journal of Medicinal Chemistry , copyright © American Chemical Society after peer review. To access the final edited and published work, see http://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b00478We describe the synthesis of gramine derivatives and their pharmacological evaluation as multipotent drugs for the treatment of Alzheimer’s disease. An innovative multitarget approach is presented, targeting both voltage-gated Ca2+ channels, classically studied for neurodegenerative diseases, and Ser/Thr phosphatases, which have been marginally aimed, even despite their key role in protein τ dephosphorylation. Twenty-five compounds were synthesized, and mostly their neuroprotective profile exceeded that offered by the head compound gramine. In general, these compounds reduced the entry of Ca2+ through VGCC, as measured by Fluo-4/AM and patch clamp techniques, and protected in Ca2+ overload-induced models of neurotoxicity, like glutamate or veratridine exposures. Furthermore, we hypothesize that these compounds decrease τ hyperphosphorylation based on the maintenance of the Ser/Thr phosphatase activity and their neuroprotection against the damage caused by okadaic acid. Hence, we propose this multitarget approach as a new and promising strategy for the treatment of neurodegenerative diseasesThis work was supported by the following grant: Proyectos de Investigación en Salud (PI13/00789, IS Carlos III). R.L.C is granted by Universidad Autónoma de Madri

Reflux patterns and risk factors of primary varicose veins clinical severity

Producción CientíficaAbstract Objectives: Primarily, to determine the association between the clinical severity of primary varicose veins and different reflux patterns in an anatomic and haemodynamic clinical study using duplex ultrasonography (DU). Secondly, to analyse the association of clinical severity with other aspects, such as risk factors for chronic venous insufficiency (CVI) and other concurrent diseases. Method: A total of 2036 limbs were evaluated using DU. Clinical status was characterized by the CEAP (clinical, aetiological, anatomical and pathological elements) classification. The degree of clinical severity was grouped into two categories, mild to moderate CVI (C1–C3) and severe CVI, characterized by the presence of skin changes (C4–C6). We analysed the association of the different reflux patterns with CEAP status. Results: Saphenofemoral junction (SFJ) reflux of the great saphenous vein (GSV) was associated with the most severe form of the disease (odds ratio [OR] ¼ 2.96; confidence interval [CI] 95%: 2.2–3.8), whereas competent SFJ of the GSV with reflux from proximal veins (OR ¼ 2; CI 95%: 1.4–2.7) and the pure non-saphenous reflux (OR ¼ 4.1; CI 95%: 1.8–9.0) were associated with mild to moderate CVI. Obesity increased the frequency of severe CVI 2.7 times (OR ¼ 2.7; CI 95%: 1.6–4.6); being a woman also increased the frequency of more severe disease 1.3 times (OR ¼ 1.3; CI 95%: 1.0–1.7). Conclusion: Anatomical and haemodynamic studies by DU are postulated as a useful diagnostic tool that allow, by identifying the pattern of venous reflux of varicose pathology, characterization of the probable association to CVI clinical severity

Recovering and harmonizing research cruises information

The IEO has maintained since late 60s, a local database with basic information on oceanographic campaigns, formerly known as ROSCOF reports, which were established in the framework of IODE initiatives, as a low-level inventory for future access to data. Technological advances in recent decades and different coordination activities between NODCs have favored the implementation of these reports in standardized digital formats (Cruise Summary Reports, CSR) that allow their integration in international repositories as SeaDataNet or POGO. However, this inventory and cataloging activity has suffered ups and downs over 40 years of activity, changes in storage criteria and periods of less activity. In the search for a unique criterion that can last over time and that unifies this information as much as possible with the data generated in these campaigns, an exhaustive review of the existing information has been carried out. The result has been the retrieval of information from short-term campaigns carried out on smaller vessels with great coastal activity, as well as updating information regarding old campaigns performed on the first half of the 20th century onboard of decommissioned vessels. All this is completed with the systematic campaigns carried out by INTECMAR in the Galician rias, research vessels operated by the national Fisheries Administration, and information on research surveys carried out by foreign ships in national waters, forming a catalog of more than 4000 entries. This approach is also followed by the UTM-CSIC, on its own-managed vessels and campaigns carried out since 1991. The common approach allows a unified response to the governmental needs for the planning of future campaigns, and in successive improvements in data recovering, archiving and accessing at NODC/CEDO

Evaluation of Natural Language Processing for the Identification of Crohn Disease-Related Variables in Spanish Electronic Health Records:A Validation Study for the PREMONITION-CD Project

Background: The exploration of clinically relevant information in the free text of electronic health records (EHRs) holds the potential to positively impact clinical practice as well as knowledge regarding Crohn disease (CD), an inflammatory bowel disease that may affect any segment of the gastrointestinal tract. The EHRead technology, a clinical natural language processing (cNLP) system, was designed to detect and extract clinical information from narratives in the clinical notes contained in EHRs. Objective: The aim of this study is to validate the performance of the EHRead technology in identifying information of patients with CD. Methods: We used the EHRead technology to explore and extract CD-related clinical information from EHRs. To validate this tool, we compared the output of the EHRead technology with a manually curated gold standard to assess the quality of our cNLP system in detecting records containing any reference to CD and its related variables. Results: The validation metrics for the main variable (CD) were a precision of 0.88, a recall of 0.98, and an F1 score of 0.93. Regarding the secondary variables, we obtained a precision of 0.91, a recall of 0.71, and an F1 score of 0.80 for CD flare, while for the variable vedolizumab (treatment), a precision, recall, and F1 score of 0.86, 0.94, and 0.90 were obtained, respectively. Conclusions: This evaluation demonstrates the ability of the EHRead technology to identify patients with CD and their related variables from the free text of EHRs. To the best of our knowledge, this study is the first to use a cNLP system for the identification of CD in EHRs written in Spanish. © 2022 JMIR Medical Informatics. All rights reserved

Low unspliced cell-associated HIV RNA in early treated adolescents living with HIV on long suppressive ART

Introduction Initiation of antiretroviral treatment (ART) in patients early after HIV-infection and long-term suppression leads to low or undetectable levels of HIV RNA and cell-associated (CA) HIV DNA and RNA. Both CA-DNA and CA-RNA, overestimate the size of the HIV reservoir but CA-RNA as well as p24/cell-free viral RNA can be indicators of residual viral replication. This study describes HIV RNA amounts and levels of cytokines/soluble markers in 40 well-suppressed adolescents who initiated ART early in life and investigated which viral markers may be informative as endpoints in cure clinical trials within this population. Methods Forty adolescents perinatally infected with HIV on suppressive ART for &gt;5 years were enrolled in the CARMA study. HIV DNA and total or unspliced CA-RNA in PBMCs were analyzed by qPCR/RT-qPCR and dPCR/RT-dPCR. Cell-free HIV was determined using an ultrasensitive viral load (US-VL) assay. Plasma markers and p24 were analyzed by digital ELISA and correlations between total and unspliced HIV RNA and clinical markers, including age at ART, Western Blot score, levels of cytokines/inflammation markers or HIV CA-DNA, were tested. Results CA-RNA was detected in two thirds of the participants and was comparable in RT-qPCR and RT-dPCR. Adolescents with undetectable CA-RNA showed significantly lower HIV DNA compared to individuals with detectable CA-RNA. Undetectable unspliced CA-RNA was positively associated with age at ART initiation and Western Blot score. We found that a higher concentration of TNF-alpha was predictive of higher CA-DNA and CA-RNA. Other clinical characteristics like US-VL, time to suppression, or percent CD4+ T-lymphocytes were not predictive of the CA-RNA in this cross-sectional study. Conclusions Low CA-DNA after long-term suppressive ART is associated with lower CA-RNA, in concordance with other reports. Patients with low CA-RNA levels in combination with low CA-DNA and low Western Blot scores should be further investigated to characterize candidates for treatment interruption trials. Unspliced CA-RNA warrants further investigation as a marker that can be prioritized in paediatric clinical trials where the sample volume can be a significant limitation

Reflux or not reflux? Reflexiones sobre la publicación anglosajona del término en las varices primarias de los miembros inferiores en relación con nuestro entorno

Producción CientíficaEl significado práctico del término “reflux” en el estudio hemodinámico de las varices primarias publicado en la literatura varía en función del marco conceptual que se tenga de las distintas alteraciones hemodinámicas del sistema venoso. En este trabajo se exponen los fundamentos hemodinámicos y las discrepancias más interesantes entre la literatura anglosajona y “nuestro entorno”