Accuracy of Xpert Ultra for the diagnosis of paediatric tuberculosis in a low TB burden country: a prospective multicentre study

[Introduction] Childhood pulmonary tuberculosis (TB) remains a diagnostic challenge. This study aimed to evaluate the performance of Xpert Ultra for the diagnosis of pulmonary TB in children in a low TB prevalence setting.[Methods] Prospective, multicentre, diagnostic accuracy study. Children with clinical or radiological suspicion of pulmonary TB were recruited at 11 paediatric units in Spain. Up to three gastric or sputum specimens were taken on 3 consecutive days, and analysed by Xpert MTB/RIF, Xpert Ultra and culture in parallel.[Results] 86 children were included (median age 4.9 years, IQR 2.0–10.0; 51.2% male). The final diagnosis was pulmonary TB in 75 patients (87.2%); 33 (44.0%) were microbiologically confirmed. A total of 219 specimens, comprising gastric aspirates (n=194; 88.6%) and sputum specimens (n=25; 11.4%), were analysed. Using culture as reference standard and comparing individual specimens, the sensitivity was 37.8% (14/37) for Xpert MTB/RIF and 81.1% (30/37) for Xpert Ultra (p<0.001); specificity was 98.4% (179/182) and 93.4% (170/182), respectively (p=0.02). In the per-patient analysis, considering positive results on any specimen, the sensitivity was 42.9% (9/21) for Xpert MTB/RIF and 81.0% for Xpert Ultra (17/21, p=0.01); specificity was 96.9% (63/65) and 87.7% (57/65, p=0.07), respectively.[Conclusions] In children with pulmonary TB in a low burden setting, Xpert Ultra has significantly higher sensitivity than the previous generation of Xpert assay and only marginally lower specificity. Therefore, in children undergoing evaluation for suspected pulmonary TB, Xpert Ultra should be used in preference to Xpert MTB/RIF whenever possible.This study did not receive any project-specific funding. DA-A was supported by the Spanish Ministry of Health – Instituto de Salud Carlos III (ISCIII) and cofunded by the European Union (FEDER) (Contrato Río Hortega CM18/00100). AN-J was supported by 'Subvencions per a la Intensificació de Facultatius Especialistes' (Departament de Salut de la Generalitat de Catalunya, Programa PERIS 2016-2020) (SLT008/18/00193). DBG was supported by the Spanish Ministry of Science and Innovation – Instituto de Salud Carlos III and Fondos FEDER by 'Contratos para la intensificación de la actividad investigadora en el Sistema Nacional de Salud, 2020 (INT20/00086)'. BS-G was supported by the Spanish Ministry of Health – Instituto de Salud Carlos III (ISCIII) and cofunded by the European Union (FEDER) (Contrato Juan Rodés JR16/00036).Peer reviewe

La gestión académica en pandemia : adecuaciones, innovaciones y desafíos de la Universidad Nacional de Cuyo

Este libro remite a un contexto especial e inédito que surge a partir de la pandemia de covid-19. Se trata de un contexto de alcance global signado por efectos intensos y perdurables sobre diferentes aspectos de la realidad social, económica y ambiental. En general, estos efectos provocaron, por un lado, situaciones problemáticas nuevas y, por otro lado, agravaron situaciones problemáticas preexistentes que adquirieron mayor visibilidad. En el caso argentino, las restricciones derivadas de la pandemia agudizaron la brecha socioeducativa existente y, al mismo tiempo, exigieron una gestión ágil, dinámica, resolutiva, propositiva y resiliente, especialmente a las instituciones educativas con el objeto de asegurar el derecho a la educación y su calidad. Lógicamente, la provincia de Mendoza y, por tanto, la Universidad Nacional de Cuyo (UNCUYO) no quedaron exentas de los efectos mencionados. Aunque aún no resulta posible identificar con rigor el impacto concreto que ha tenido la pandemia sobre el funcionamiento del sistema educativo provincial, se pueden entrever algunos indicadores que vale la pena atender. Por ejemplo, el egreso en la oferta de educación superior de la uncuyo registró, en 2020, una caída interanual cercana al -18 % 1. Esta oscilación se torna más relevante si se considera que este indicador se mostraba estable a lo largo de los últimos años.Fil: Castañeda, Linda. Universidad de Murcia.Fil: Viñoles Cosentino, Virginia. Universidad de Murcia.Fil: Falcón, Paulo.Fil: Martínez, Ana María.Fil: Meljin Lombard, Mariela Beatriz. Universidad Nacional de Cuyo. Facultad de Artes y Diseño.Fil: Van Den Bosch, Silvia. Universidad Nacional de Cuyo. Facultad de Ciencias Agrarias.Fil: Castro, María Eugenia. Universidad Nacional de Cuyo. Facultad de Ciencias Aplicadas a la Industria.Fil: Puebla, Patricia. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Sánchez, Esther Lucía. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: González Gaviola, Miguel. Universidad Nacional de Cuyo. Facultad de Ciencias Económicas.Fil: Tarabelli, María Florencia. Universidad Nacional de Cuyo. Facultad de Ciencias Exactas y Naturales.Fil: Rüttler, María Elena. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas.Fil: Nalda, Gonzalo. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas.Fil: Castiglia, Mariana. Universidad Nacional de Cuyo. Facultad de Ciencias Políticas y Sociales.Fil: Mussuto, Matías M.. Universidad Nacional de Cuyo. Facultad de Derecho.Fil: Griffouliere, María Gabriela. Universidad Nacional de Cuyo. Facultad de Educación.Fil: Verstraete, María Ana. Universidad Nacional de Cuyo. Facultad de Filosofía y Letras.Fil: Echagaray, Patricia. Universidad Nacional de Cuyo. Facultad de Odontología.Fil: Mirasso, Aníbal. Universidad Nacional de Cuyo. Facultad de Ingeniería.Fil: Molina, Fabiana. Universidad Nacional de Cuyo. Instituto Tecnológico Universitario.Fil: Corral, Patricia. Universidad Nacional de Cuyo. Instituto Universitario de Seguridad Pública.Fil: Chrabalowski, Marina. Universidad Nacional de Cuyo.Fil: Barrozo, María Ana. Universidad Nacional de Cuyo.Fil: Zabala, Cecilia. Universidad Nacional de Cuyo. Escuela de Comercio Martín Zapata.Fil: Sauer, Marcelo. Universidad Nacional de Cuyo.Fil: Romero Day, Marcela. Universidad Nacional de Cuyo. Liceo Agrícola y Enológico Domingo F. Sarmiento.Fil: Marlia, Nora. Universidad Nacional de Cuyo. Facultad de Filosofía y Letras. Departamento de Aplicación Docente.Fil: Zamorano, Cristina. Universidad Nacional de Cuyo. Colegio Universitario Central.Fil: Yapura, Susana. Universidad Nacional de Cuyo. Escuela del Magisterio.Fil: Navarro, María Fernanda. Universidad Nacional de Cuyo.Fil: Bosio, Iris Viviana. Universidad Nacional de Cuyo. EDIUNC.Fil: Degiorgi, Horacio. Universidad Nacional de Cuyo. Sistema Integrado de Documentación.Fil: Bocco, María Susana. Universidad Nacional de Cuyo.Fil: Guayco, Mariana. Universidad Nacional de Cuyo.Fil: Pizzi, Daniel. Universidad Nacional de Cuyo.Fil: Lettelier, Dolores. Universidad Nacional de Cuyo. Secretaría Académica

Primary and Secondary Immunodeficiency Diseases in Oncohaematology: Warning Signs, Diagnosis, and Management

Background: Immunodeficiencies (ID), in particular primary immunodeficiencies (PID), are often associated with haematological manifestations, such as peripheral cytopenias or lymphoproliferative syndromes. Early diagnosis and management have significant prognostic implications. Secondary immunodeficiencies (SID) may also be induced by oncohaematological diseases and their treatments. Haematologists and oncologists must therefore be aware of the association between blood disorders and cancer and ID, and be prepared to offer their patients appropriate treatment without delay. Our aim was to define the warning signs of primary and secondary IDs in paediatric and adult patients with oncohaematological manifestations.Methods: A multidisciplinary group of six experts (2 haematologists, 2 immunologists, and 2 paediatricians specializing in ID) conducted a literature review and prepared a document based on agreements reached an in-person meeting. An external group of 44 IDs specialists from all over Spain assessed the document and were consulted regarding their level of agreement.Results: This document identifies the haematological and extra-haematological diseases that should prompt a suspicion of PIDs in adults and children, in both primary care and haematology and oncology departments. Cytopenia and certain lymphoproliferative disorders are key diagnostic pointers. The diagnosis must be based on a detailed clinical history, physical exploration, complete blood count and standard laboratory tests. The immunological and haematological tests included in the diagnostic process will depend on the care level. Patients who are candidates for immunoglobulin replacement therapy must be carefully selected, and treatment should be offered as soon as possible to avoid the development of complications. Finally, this document recommends procedures for monitoring these patients.Conclusions: This document combines scientific evidence with the opinion of a broad panel of experts, and emphasizes the importance of an early diagnosis and treatment to avoid complications. The resulting document is a useful tool for primary care physicians and specialists who see both adult and paediatric patients with oncohaematological diseases

Rol del gen supresor de tumores SMARCB1/INI1 en el desarrollo de neoplasias pediátricas.

Fil: Ramirez, Jésica. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Genética.Fil: Mampel, Alejandra. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Genética.Fil: Echeverría, María. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Genética.Fil: Calderón, Adriana. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Genética.Fil: Arce, Cecilia. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Genética.Fil: Nalda, Gonzalo. Hospital Humberto Notti (Mendoza, Argentina). Servicio de OncologíaFil: Ortiz, Leonor. Hospital Humberto Notti (Mendoza, Argentina). Servicio de OncologíaFil: Oliva, Julio. Hospital Humberto Notti (Mendoza, Argentina). Servicio de OncologíaFil: Marino, Miguel. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Laboratorio de ADNFil: Vargas, Ana. Universidad Nacional de Cuyo. Facultad de Ciencias Médicas. Instituto de Genética

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Inborn errors of type I IFN immunity in patients with life-threatening COVID-19

Clinical outcome upon infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ranges from silent infection to lethal coronavirus disease 2019 (COVID-19). We have found an enrichment in rare variants predicted to be loss-of-function (LOF) at the 13 human loci known to govern Toll-like receptor 3 (TLR3)- and interferon regulatory factor 7 (IRF7)-dependent type I interferon (IFN) immunity to influenza virus in 659 patients with life-threatening COVID-19 pneumonia relative to 534 subjects with asymptomatic or benign infection. By testing these and other rare variants at these 13 loci, we experimentally defined LOF variants underlying autosomal-recessive or autosomal-dominant deficiencies in 23 patients (3.5%) 17 to 77 years of age. We show that human fibroblasts with mutations affecting this circuit are vulnerable to SARS-CoV-2. Inborn errors of TLR3- and IRF7-dependent type I IFN immunity can underlie life-threatening COVID-19 pneumonia in patients with no prior severe infection

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population

The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies

International audienceSignificance There is growing evidence that preexisting autoantibodies neutralizing type I interferons (IFNs) are strong determinants of life-threatening COVID-19 pneumonia. It is important to estimate their quantitative impact on COVID-19 mortality upon SARS-CoV-2 infection, by age and sex, as both the prevalence of these autoantibodies and the risk of COVID-19 death increase with age and are higher in men. Using an unvaccinated sample of 1,261 deceased patients and 34,159 individuals from the general population, we found that autoantibodies against type I IFNs strongly increased the SARS-CoV-2 infection fatality rate at all ages, in both men and women. Autoantibodies against type I IFNs are strong and common predictors of life-threatening COVID-19. Testing for these autoantibodies should be considered in the general population