Sarilumab plus standard of care vs standard of care for the treatment of severe COVID-19: a phase 3, randomized, open-labeled, multi-center study (ESCAPE study)

Background Among interleukin-6 inhibitors suggested for use in COVID-19, there are few robust evidences for the efficacy of sarilumab. Herein, we evaluated the efficacy and safety of sarilumab in severe COVID-19.Methods In this phase 3, open-labeled, randomized clinical trial, conducted at 5 Italian hospitals, adults with severe COVID-19 pneumonia (excluding mechanically ventilated) were randomized 2:1 to receive intravenous sarilumab (400 mg, repeatable after 12 h) plus standard of care (SOC) (arm A) or to continue SOC (arm B). Randomization was web-based. As post-hoc analyses, the participants were stratified according to baseline inflammatory parameters. The primary endpoint was analysed on the modified Intention-To-Treat population, including all the randomized patients who received any study treatment (sarilumab or SOC). It was time to clinical improvement of 2 points on a 7-points ordinal scale, from baseline to day 30. We used Kaplan Meier method and log-rank test to compare the primary outcome between two arms, and Cox regression stratified by clinical center and adjusted for severity of illness, to estimate the hazard ratio (HR). The trial was registered with EudraCT (2020-001390-76).Findings Between May 2020 and May 2021, 191 patients were assessed for eligibility, of whom, excluding nine dropouts, 176 were assigned to arm A (121) and B (55). At day 30, no significant differences in the primary endpoint were found (88% [95% CI 81-94] in arm A vs 85% [74-93], HR 1.07 [0.8-1.5] in arm B; log-rank p = 0.50). After stratifying for inflammatory parameters, arm A showed higher probability of improvement than B without statistical significance in the strata with C reactive protein (CRP) < 7 mg/dL (88% [77-96] vs 79% [63-91], HR 1.55 [0.9-2.6]; log-rank p = 0.049) and in the strata with lymphocytes <870/mmc (90% [79-96]) vs (73% [55-89], HR 1.53 [0.9-2.7]; log-rank p = 0.058). Overall, 39/121 (32%) AEs were reported in arm A and 14/55 (23%) in B (p = 0.195), while serious AEs were 22/121 (18%) and 7/55 (11%), respectively (p = 0.244). There were no treatment-related deaths.Interpretation The efficacy of sarilumab in severe COVID-19 was not demonstrated both in the overall and in the stratified for severity analysis population. Exploratory analyses suggested that subsets of patients with lower CRP values or lower lymphocyte counts might have had benefit with sarilumab treatment, but this finding would require replication in other studies. The relatively low rate of concomitant corticosteroid use, could partially explain our results.Funding This study was supported by INMI "Lazzaro Spallanzani" Ricerca Corrente Linea 1 on emerging and ree-merging infections, funded by Italian Ministry of Health.Copyright (c) 2023 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Synergy between vitamin D and sex hormones in respiratory functionality of patients affected by COVID-19

The outcome of COVID-19 appears to be influenced by vitamin D status of population. Although epidemiological data indicate that COVID-19 produces more severe symptoms and higher mortality in elderly in comparison to young patients and in men in comparison to women to date sex and age differences in vitamin D status in infected patients have not been evaluated yet. In this study we evaluated the levels of circulating 25(OH)D in patients hospitalized for COVID-19 divided accordingly to their sex and age. We also correlated 25(OH)D levels with patient’s respiratory status (i.e., PaO2/FiO2 ratio) and with sex hormones plasma levels to analyze the potential relationship of these parameters. We found no significant differences in plasma levels of 25(OH)D between pre- and post-menopausal female patients and age matched male patients. Interestingly, the 25(OH)D plasma levels positively correlated to PaO2/FiO2 ratio only in young patients, regardless of their sex. We also found a significantly positive correlation between 17β-estradiol and 25(OH)D in elderly women and between testosterone and 25(OH)D in elderly men, supporting the role of sex hormones in maintaining 25(OH)D levels. In conclusion, we suggest that a synergy between vitamin D and sex hormones could contribute to the age-related outcome of COVID-19

Switching Dynamics of Ag-Based Filamentary Volatile Resistive Switching Devices--Part II: Mechanism and Modeling

Understanding the switching mechanism of the volatile resistive switching random access memory (RRAM) device is important to harness its characteristics and further enhance its performance. Accurate modeling of its dynamic behavior is also of deep value for its applications both as selector and as short-term memory synapse for future neuromorphic applications operating in temporal domain. In this work, we investigate the switching and retention (relaxation) processes of the Ag-based metallic filamentary volatile resistive switching devices. We find that the switching process can be modeled by the ionic drift under electric field, while the retention process can be modeled by the ionic diffusion along the filament surface driven by the gradient of surface atomic concentration. Through further theoretical analysis, we also find that the ionic drift and ionic diffusion can be unified within the general Einstein relation. To confirm this relation, we collect ionic mobility and diffusivity data from the literature using the switching and retention model. Finally, we show that the read voltage dependent retention time can be explained by the competition between the ionic drift and diffusion flux

Raphael Painter and Architect in Rome

In occasione del cinquecentenario della morte di Raffaello Sanzio (1483-1520) si propone un testo agile e informato per scoprire dipinti e architetture eseguiti a Roma dall\u2019arrivo nell\u2019Urbe nel 1508 alla morte nel 1520. Aggiornate e complete dei dati essenziali, le schede esplicative illustrano l\u2019ampio ventaglio della produzione matura del Raffaello pittore, dagli affreschi alle pale d\u2019altare ai ritratti eseguiti per Roma o oggi l\uec conservati, e permettono di individuare e di comprendere le tracce dell\u2019attivit\ue0 del Raffaello architetto. Si svolge attraverso le opere il racconto dell\u2019appassionante stagione romana dell\u2019artista, impegnato nel continuo rinnovamento del proprio linguaggio di pittore nel dialogo travolgente con Michelangelo, nella gara con Sebastiano del Piombo, nella spinta possente delle sollecitazioni fornite dal repertorio antico della scultura, nel nuovo impegno come caposcuola, alla guida di una bottega che far\ue0 da modello per tutto il secolo e oltre, e si segue il definirsi proprio a Roma dei suoi interessi di architetto e degli obiettivi che egli matura sul fronte dell\u2019architettura moderna su sollecitazione di Bramante e poi di altri, nella sfida costituita dal confronto con i resti degli edifici antichi, in uno scambio costante con gli umanisti, come Pietro Bembo e Fra Giocondo, suoi ferventi interlocutori, committenti, sostenitori. Il testo non trascura di segnalare le opere non accessibili legate all\u2019operato del Sanzio, quali, in Vaticano, le Logge o l\u2019Appartamento del cardinal Bibbiena, o quelle che da architetto egli non pot\ue9 realizzare ma di cui ci restano suoi progetti, o che vennero distrutte (Palazzo Branconio dell\u2019Aquila), e dedica un\u2019attenzione speciale, per la forza del suo rapporto con il presente, alla lettera a Leone X scritta da Raffaello e da Baldassarre Castiglione, riconosciuta come primo documento di una consapevole riflessione sull\u2019urgenza della conservazione dell\u2019architettura e dell\u2019arte del passato alla quale oggi pi\uf9 di allora siamo chiamati a rispondere

Raffaello pittore e architetto a Roma

In occasione del cinquecentenario della morte di Raffaello Sanzio (1483-1520) si propone un testo agile e informato per scoprire dipinti e architetture eseguiti a Roma dall’arrivo nell’Urbe nel 1508 alla morte nel 1520. Aggiornate e complete dei dati essenziali, le schede esplicative illustrano l’ampio ventaglio della produzione matura del Raffaello pittore, dagli affreschi alle pale d’altare ai ritratti eseguiti per Roma o oggi lì conservati, e permettono di individuare e di comprendere le tracce dell’attività del Raffaello architetto. Si svolge attraverso le opere il racconto dell’appassionante stagione romana dell’artista, impegnato nel continuo rinnovamento del proprio linguaggio di pittore nel dialogo travolgente con Michelangelo, nella gara con Sebastiano del Piombo, nella spinta possente delle sollecitazioni fornite dal repertorio antico della scultura, nel nuovo impegno come caposcuola, alla guida di una bottega che farà da modello per tutto il secolo e oltre, e si segue il definirsi proprio a Roma dei suoi interessi di architetto e degli obiettivi che egli matura sul fronte dell’architettura moderna su sollecitazione di Bramante e poi di altri, nella sfida costituita dal confronto con i resti degli edifici antichi, in uno scambio costante con gli umanisti, come Pietro Bembo e Fra Giocondo, suoi ferventi interlocutori, committenti, sostenitori. Il testo non trascura di segnalare le opere non accessibili legate all’operato del Sanzio, quali, in Vaticano, le Logge o l’Appartamento del cardinal Bibbiena, o quelle che da architetto egli non poté realizzare ma di cui ci restano suoi progetti, o che vennero distrutte (Palazzo Branconio dell’Aquila), e dedica un’attenzione speciale, per la forza del suo rapporto con il presente, alla lettera a Leone X scritta da Raffaello e da Baldassarre Castiglione, riconosciuta come primo documento di una consapevole riflessione sull’urgenza della conservazione dell’architettura e dell’arte del passato alla quale oggi più di allora siamo chiamati a rispondere

Ionic-electronic halide perovskite memdiodes enabling neuromorphic computing with a second-order complexity

With increasing computing demands, serial processing in von Neumann architectures built with zeroth-order complexity digital circuits is saturating in computational capacity and power, entailing research into alternative paradigms. Brain-inspired systems built with memristors are attractive owing to their large parallelism, low energy consumption, and high error tolerance. However, most demonstrations have thus far only mimicked primitive lower-order biological complexities using devices with first-order dynamics. Memristors with higher-order complexities are predicted to solve problems that would otherwise require increasingly elaborate circuits, but no generic design rules exist. Here, we present second-order dynamics in halide perovskite memristive diodes (memdiodes) that enable Bienenstock-Cooper-Munro learning rules capturing both timing- and rate-based plasticity. A triplet spike timing-dependent plasticity scheme exploiting ion migration, back diffusion, and modulable Schottky barriers establishes general design rules for realizing higher-order memristors. This higher order enables complex binocular orientation selectivity in neural networks exploiting the intrinsic physics of the devices, without the need for complicated circuitry.ISSN:2375-254

The role of education in adherence to Highly Active Antiretroviral Therapy (HAART): a systematic review

Background Suboptimal adherence to Highly Active Antiretroviral Therapy (HAART) is an emerging public health priority. There is contrasting evidence about the association between socio- demographic predictors and HAART adherence. The aim of this study was to perform a systematic review of the literature assessing the impact of educational level on adherence to treatment in HIV infected patients from 1999 to 2011. Methods A systematic search was performed using Pubmed and Scopus database. Key search terms used included \u2018\u2018HAART\u2019\u2019, \u2018\u2018adherence\u2019\u2019, \u2018\u2018compliance\u2019\u2019 and \u2018\u2018educational level\u2019\u2019. The inclusion criteria used for each study were: (a) the age of HIV-infected patients was eighteen or older (b) the patient residence was in developed countries. Studies focused on specific behavioral or psychosocial characteristics or HAART na \u308\u131vepatientswereexcluded. Results Among 210 potentially relevant articles, 18 comparative observational studies, concerning an overall population of 7288, were included in the review. Around 60% of research designs were longitudinal. Papers differed by methodological adherence measurement: 10 studies used self-reported ques- tionnaire, 5 individual interview and 3 other tools as pills count. Eight out of 18 papers (39%-including 3692 indivi- duals) showed that subjects with low educational level were less likely to be adherent to HAART than subjects with higher level. Conclusions Educational level seems to be a noticeable factor to consider in policy and practice, in order to improve the HIV treatment adherence

A systematic review of consistency between health literacy and adherence to Highly Active Antiretroviral Therapy (HAART)

Background Health literacy is considered as the degree to which individuals have the capacity to obtain, process and understand basic information and services needed to make appropriate decision regarding their health. Although many studies have examined the association between health literacy and medication adherence in chronic disease context, findings have been contrasting. Medication adherence among people living with HIV remains an important public health challenge, despite recent simplified drug regimens. The main purpose of this study was to review the association between health literacy and adherence to Highly Active Antiretroviral Therapy (HAART). Additionally, this review aimed to clarify whether different adherence measures could influence that relationship. Methods Literature search was performed in PubMed and Scopus for studies regarding health literacy and HAART adherence among individuals HIV infected adult published between 1999 and 2013. Papers focused on drug users, pregnant women and naive patients were excluded. Furthermore, only studies with a measurement of health literacy with validated tools were included. Reporting was conducted in the form recommended in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and checklist. Results There were 57 potentially relevant articles from which a total of 7 studies concerning an overall population of 1274 were included in the systematic review. Adherence was assessed using objective measures (pharmacy refill records, electronic event monitors and unannounced telephone-based pill counts) in three articles; others papers used self-report tools or interview. Two different validated instruments for measuring literacy were reported. In three studies participants with lower health literacy demonstrated poorer adherence compared to individuals with higher literacy (33% of all population, including 416 individuals). The association between health literacy and adherence was not related to different HAART adherence measurement. Conclusions Additional research was needed to pursue a better understanding of the mechanism by which health literacy affects medication adherence. Key message A better understanding of the impact of health literacy on medication adherence is a public health priority in order to safeguard vulnerable communities such as persons living with HIV