Treatment with tocilizumab or corticosteroids for COVID-19 patients with hyperinflammatory state: a multicentre cohort study (SAM-COVID-19)

Objectives: The objective of this study was to estimate the association between tocilizumab or corticosteroids and the risk of intubation or death in patients with coronavirus disease 19 (COVID-19) with a hyperinflammatory state according to clinical and laboratory parameters. Methods: A cohort study was performed in 60 Spanish hospitals including 778 patients with COVID-19 and clinical and laboratory data indicative of a hyperinflammatory state. Treatment was mainly with tocilizumab, an intermediate-high dose of corticosteroids (IHDC), a pulse dose of corticosteroids (PDC), combination therapy, or no treatment. Primary outcome was intubation or death; follow-up was 21 days. Propensity score-adjusted estimations using Cox regression (logistic regression if needed) were calculated. Propensity scores were used as confounders, matching variables and for the inverse probability of treatment weights (IPTWs). Results: In all, 88, 117, 78 and 151 patients treated with tocilizumab, IHDC, PDC, and combination therapy, respectively, were compared with 344 untreated patients. The primary endpoint occurred in 10 (11.4%), 27 (23.1%), 12 (15.4%), 40 (25.6%) and 69 (21.1%), respectively. The IPTW-based hazard ratios (odds ratio for combination therapy) for the primary endpoint were 0.32 (95%CI 0.22-0.47; p < 0.001) for tocilizumab, 0.82 (0.71-1.30; p 0.82) for IHDC, 0.61 (0.43-0.86; p 0.006) for PDC, and 1.17 (0.86-1.58; p 0.30) for combination therapy. Other applications of the propensity score provided similar results, but were not significant for PDC. Tocilizumab was also associated with lower hazard of death alone in IPTW analysis (0.07; 0.02-0.17; p < 0.001). Conclusions: Tocilizumab might be useful in COVID-19 patients with a hyperinflammatory state and should be prioritized for randomized trials in this situatio

Psicothema

Resumen tomado de la publicaciónLa esclerosis múltiple (EM) es una enfermedad inflamatoria crónica del sistema nervioso central muy heterogénea en sus manifestaciones. A diferencia de los déficits sensitivos-motores, muy bien estudiados, los aspectos cognitivos están siendo analizados sólo en las últimas décadas. A 28 pacientes con EM recurrente-remitente (EMRR) (tiempo de evolución, mediana 7 años; EDSS, mediana 2) se les realizó una evaluación de atención, función ejecutiva y memoria mediante una batería neuropsicológica específica. Se evaluaron también el grado de depresión (BDI), ansiedad (STAI) y fatiga (EGF). Veinticinco fueron seleccionados para el estudio por presentar alteración en algún aspecto cognitivo. El 24 por ciento mostraba disminución en memoria y el 80 por ciento en atención y funciones ejecutivas relacionadas con regiones prefrontales. No se observaron dificultades globales de memoria, salvo en memoria inmediata visual de elementos complejos (Figura de Rey reproducción inmediata), sin afectarse la prueba de reproducción visual I de la WMS-R. En pacientes con EMRR con un tiempo medio de evolución y bajo nivel de incapacidad, las alteraciones cognitivas afectan fundamentalmente a funciones atribuidas a regiones prefrontales. Las dificultades en memoria inmediata visual de elementos complejos se explicarían también por un fallo de estas áreas al alterarse la organización y uso estratégico del material a codificar.AsturiasColegio Oficial de Psicólogos de Asturias; Calle Ildefonso Sánchez del Río, 4-1 B; 33001 Oviedo; Tel. +34985285778; Fax +34985281374;ES

Biallelic germline mutations in MAD1L1 induce a syndrome of aneuploidy with high tumor susceptibility.

Germline mutations leading to aneuploidy are rare, and their tumor-promoting properties are mostly unknown at the molecular level. We report here novel germline biallelic mutations in MAD1L1, encoding the spindle assembly checkpoint (SAC) protein MAD1, in a 36-year-old female with a dozen of neoplasias. Functional studies demonstrated lack of full-length protein and deficient SAC response, resulting in ~30 to 40% of aneuploid blood cells. Single-cell RNA analysis identified mitochondrial stress accompanied by systemic inflammation with enhanced interferon and NFκB signaling both in aneuploid and euploid cells, suggesting a non-cell autonomous response. MAD1L1 mutations resulted in specific clonal expansions of γδ T cells with chromosome 18 gains and enhanced cytotoxic profile as well as intermediate B cells with chromosome 12 gains and transcriptomic signatures characteristic of leukemia cells. These data point to MAD1L1 mutations as the cause of a new variant of mosaic variegated aneuploidy with systemic inflammation and unprecedented tumor susceptibility.This work is supported by Spanish Ministry of Science, Juan de la Cierva programme (C.V.-B.); Spanish Ministry of Science and Innovation, Agencia Estatal de Investigacion (MCI-AEI), BIO2017-91272-EXP (S.R.-P.); Spanish National Research and Development Plan, ISCIII, and FEDER, PI17/02303, PI20/01837, and DTS19/00111 (S.R.-P.); Spanish National Research and Development Plan, ISCIII, and FEDER, PI21/01641 (R.T.-R.); Fundacion Cientifica de la Asociacion Espanola contra el Cancer, LABAE20049RODR (S.R.-P.); MCI-AEI/FEDER, RTI2018-095582-B-I00, and RED2018-102723-T (M.M.); Comunidad de Madrid iLUNG and scCANCER programmes, B2017/BMD-3884 and Y2020/BIO-6519 (M.M.); and MCI-AEI, Severo Ochoa Center of Excellence, CEX2019-000891-S (S.R.-P., M.M., and M.U.).S