Remdesivir treatment in hospitalized patients affected by COVID-19 pneumonia: a case-control study

Background: to date the optimal antiviral treatment against severe coronavirus disease 2019 (COVID-19) has not been proven; remdesivir is a promising drug with in vitro activity against several virus, but in COVID-19 the clinical results are currently not definitive. Methods: in this retrospective observational study we analyzed the clinical outcomes (survival analysis, efficacy and safety) in a group of hospitalized patients with COVID-19 treated with remdesivir in comparison with a control group of patients treated with other antiviral or supportive therapies. Results: we included 163 patients treated with remdesivir and 403 subjects in the control group; the baseline characteristics were similar in the two groups; mortality rate was higher in control group (24.8% vs 2.4%, p<0.001), the risk of intensive-care-unit (ICU) admission was higher in control group (17.8% vs 9.8%, p=0.008); hospitalization time was significantly lower in patients treated with remdesivir (9.5 vs 12.5 days, p<0.001). The safety of remdesivir was good and no significant adverse events were reported. In multivariate analysis the remdesivir treatment was independently associated with a 34% lower mortality rate (OR=0.669; p=0.014). Conclusions: in this analysis the treatment with remdesivir was associated with lower mortality, lower rate of ICU admission, shorter time of hospitalization. No adverse events were observed. This promising antiviral treatment should also be confirmed by other studies. This article is protected by copyright. All rights reserved

Methionine Sulfoxides on Prion Protein Helix-3 Switch on the α-Fold Destabilization Required for Conversion

BACKGROUND: The conversion of the cellular prion protein (PrP(C)) into the infectious form (PrP(Sc)) is the key event in prion induced neurodegenerations. This process is believed to involve a multi-step conformational transition from an alpha-helical (PrP(C)) form to a beta-sheet-rich (PrP(Sc)) state. In addition to the conformational difference, PrP(Sc) exhibits as covalent signature the sulfoxidation of M213. To investigate whether such modification may play a role in the misfolding process we have studied the impact of methionine oxidation on the dynamics and energetics of the HuPrP(125-229) alpha-fold. METHODOLOGY/PRINCIPAL FINDINGS: Using molecular dynamics simulation, essential dynamics, correlated motions and signal propagation analysis, we have found that substitution of the sulfur atom of M213 by a sulfoxide group impacts on the stability of the native state increasing the flexibility of regions preceding the site of the modification and perturbing the network of stabilizing interactions. Together, these changes favor the population of alternative states which maybe essential in the productive pathway of the pathogenic conversion. These changes are also observed when the sulfoxidation is placed at M206 and at both, M206 and M213. CONCLUSIONS/SIGNIFICANCE: Our results suggest that the sulfoxidation of Helix-3 methionines might be the switch for triggering the initial alpha-fold destabilization required for the productive pathogenic conversion

Prolonged higher dose methylprednisolone vs. conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS)

Dysregulated systemic inflammation is the primary driver of mortality in severe COVID-19 pneumonia. Current guidelines favor a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg·day-1. A comparative RCT with a higher dose and a longer duration of intervention was lacking

All in the Game. The Wire: un campo di ricerca sociologica

Analyzing with an ethnographic approach The Wire, one of the most important TV series on American ghettos, to understand and question the sociological perspective that emerges from the series, positioning it into the broader scientific debate. This is, in a nutshell, the work presented in the book It's all in the Game, the outcome of a laboratorial research activity carried out in 2020 by students and teachers of the Sociology of Communities and Urban Neighborhoods class, at the University of Bologna. The text is structured into four chapters, resulting from the four topics used to analysis the TV series: forms of social capital, the relationship between structural forces- culture of poverty and individual agency, neighborhood effects mechanism and the relationship between statistics and political action. Four subjects that are the core of many neighborhood- studies related researches and on which the TV series makes a clear stand. We analyzed those topics through a critical perspective, not considering them as a truth about ghettos, but as a very precise way of thinking about life in the American suburbs

The positioning system of the ANTARES Neutrino Telescope

The ANTARES neutrino telescope, located 40km off the coast of Toulon in the Mediterranean Sea at a mooring depth of about 2475m, consists of twelve detection lines equipped typically with 25 storeys. Every storey carries three optical modules that detect Cherenkov light induced by charged secondary particles (typically muons) coming from neutrino interactions. As these lines are flexible structures fixed to the sea bed and held taut by a buoy, sea currents cause the lines to move and the storeys to rotate. The knowledge of the position of the optical modules with a precision better than 10cm is essential for a good reconstruction of particle tracks. In this paper the ANTARES positioning system is described. It consists of an acoustic positioning system, for distance triangulation, and a compass-tiltmeter system, for the measurement of the orientation and inclination of the storeys. Necessary corrections are discussed and the results of the detector alignment procedure are described

Acute Delta Hepatitis in Italy spanning three decades (1991–2019): Evidence for the effectiveness of the hepatitis B vaccination campaign

Updated incidence data of acute Delta virus hepatitis (HDV) are lacking worldwide. Our aim was to evaluate incidence of and risk factors for acute HDV in Italy after the introduction of the compulsory vaccination against hepatitis B virus (HBV) in 1991. Data were obtained from the National Surveillance System of acute viral hepatitis (SEIEVA). Independent predictors of HDV were assessed by logistic-regression analysis. The incidence of acute HDV per 1-million population declined from 3.2 cases in 1987 to 0.04 in 2019, parallel to that of acute HBV per 100,000 from 10.0 to 0.39 cases during the same period. The median age of cases increased from 27 years in the decade 1991-1999 to 44 years in the decade 2010-2019 (p &lt; .001). Over the same period, the male/female ratio decreased from 3.8 to 2.1, the proportion of coinfections increased from 55% to 75% (p = .003) and that of HBsAg positive acute hepatitis tested for by IgM anti-HDV linearly decreased from 50.1% to 34.1% (p &lt; .001). People born abroad accounted for 24.6% of cases in 2004-2010 and 32.1% in 2011-2019. In the period 2010-2019, risky sexual behaviour (O.R. 4.2; 95%CI: 1.4-12.8) was the sole independent predictor of acute HDV; conversely intravenous drug use was no longer associated (O.R. 1.25; 95%CI: 0.15-10.22) with this. In conclusion, HBV vaccination was an effective measure to control acute HDV. Intravenous drug use is no longer an efficient mode of HDV spread. Testing for IgM-anti HDV is a grey area requiring alert. Acute HDV in foreigners should be monitored in the years to come

Analisi dei marcatori molecolari su acidi nucleici liberi circolanti di pazienti affetti da carcinoma polmonare

Il tumore del polmone è la prima causa di morte per neoplasia nei paesi industrializzati. La caratterizzazione delle alterazioni molecolari del tumore è essenziale per identificare i pazienti che possono beneficiare di una specifica terapia a bersaglio molecolare. In particolare i soggetti con adenocarcinoma polmonare e con mutazioni attivanti a carico del gene EGFR o con riarrangiamenti del gene ALK possono essere trattati con specifici inibitori delle tirosin chinasi. Il tessuto tumorale (biopsia solida) è considerato il materiale d’elezione per l’analisi molecolare, tuttavia per circa il 20% dei pazienti affetti da adenocarcinoma questo tipo di materiale non è disponibile. A tal proposito diversi studi hanno confermato l’utilità degli acidi nucleici liberi circolanti (cfDNA e cfRNA) per l’analisi dei marcatori predittivi e recentemente l’EMA (Agenzia Europea del Farmaco) ha approvato l’utilizzo del cfDNA per la genotipizzazione di EGFR quando non è possibile effettuare prelievi di tessuti o cellule tumorali. Il mio progetto di tesi fa parte di un ampio studio prospettico volto a verificare la possibilità di analizzare su cfDNA e cfRNA i marcatori predittivi di risposta clinicamente rilevanti per il tumore al polmone, come EGFR, KRAS ed ALK. In questo studio sono stati arruolati 109 pazienti con sospetto clinico di tumore al polmone, per i quali sono stati raccolti 7 ml di plasma (biopsia liquida). Nei 35 pazienti con diagnosi cito-istologica positiva per adenocarcinoma polmonare è stata effettuata su cfDNA l’analisi molecolare di EGFR e KRAS, sia con saggi di Real Time PCR che mediante un pannello multi-target basato sulla tecnica Sequenom (MALDI-TOF). Per 12 dei 35 pazienti è stata valutata l’espressione aberrante di ALK su cfRNA usando uno specifico kit di Real-Time PCR. Per 23 dei 35 pazienti è stato possibile confrontare il risultato dell’analisi su biopsia liquida con quello su biopsia solida. L’analisi su cfDNA ha rilevato la presenza di mutazioni di EGFR in 3 pazienti e di mutazioni di KRAS in 4 pazienti, l’analisi su biopsia solida rispettivamente in 7 e 8 pazienti. I risultati ottenuti su biopsia liquida con Real-Time PCR e con Sequenom sono stati sempre concordanti ad eccezione di 2 casi in cui la scelta della metodica più sensibile (Real-Time PCR) è stata essenziale per una corretta genotipizzazione. Un risultato interessante riguarda un paziente per il quale la biopsia liquida costituiva l’unico materiale disponibile per la caratterizzazione molecolare: l’individuazione di una mutazione attivante a carico di EGFR su cfDNA ha reso possibile il trattamento con lo specifico farmaco a bersaglio molecolare. L’espressione aberrante di ALK è stata rilevata in due casi, per i quali l’analisi FISH su tessuto tumorale ha evidenziato la presenza del riarrangiamento genico. Con questo studio abbiamo delineato un protocollo d’analisi dei marcatori predittivi su cfDNA applicabile a tutti i casi in cui la biopsia solida non è disponibile, dimostrando la possibilità di estendere l’analisi anche all’espressione di ALK su cfRNA. La Real-Time PCR, grazie alla sua elevata sensibilità, è la tecnica migliore per l’analisi su cfDNA, tuttavia per la maggior parte dei casi si è rivelata idonea anche la metodica Sequenom, che consente l’analisi contemporanea di più marcatori, oltre EGFR e KRAS, a partire da quantità ridotte di DNA. Nonostante il tessuto tumorale resti quello d’elezione per la caratterizzazione molecolare dei tumori, i dati ottenuti supportano l’utilità clinica della biopsia liquida sia a scopo predittivo che di monitoraggio di malattia. L’analisi di un maggior numero di casi sarà indispensabile per valutare meglio la concordanza dei risultati da tessuto tumorale e da biopsia liquida e per determinare sensibilità e specificità delle tecniche utilizzate

How the ligand-induced reorganization of protein internal energies is coupled to conformational events

Here, we introduce a novel computational method to identify the protein substructures most likely to support the functionally-oriented structural deformations that occur upon ligand-binding. To this aim, we study of the modulation of protein energetics along the trajectory of a Molecular Dynamics simulation of different proteins in the presence and in the absence of their respective ligands, namely human FGF, human second PDZ from human PTP1E/PTPL1, and the N terminal domain of human Hsp90. The method is based on the idea that a subset of protein residues (hotspots) may initiate the global response via the disassembly and reassembly of interactions, which is reflected in the modulation of the overall protein energetics. To identify structural hotspots and dynamic states linked to the onset of functionally-relevant conformational transitions, we define an energy profile to monitor the protein energetics, based on a previously introduced approach that highlights the essential non-bonded couplings among all residues. The energy profiles are calculated along the trajectory to yield a time dependent evolution and their relative population in the presence and absence of the ligand is evaluated by means of a clustering procedure. It is found that inter-conversion between clusters, as well as their population and the density of specific energy profiles in the vicinity of structural transitions, provides specific information on the impact of the ligand in driving the protein conformational response. This analysis also highlights the hotspot residues that are most responsive to the presence of the ligand. Importantly, identified hotspots are are in agreement with experimental evidence in the three considered systems. We propose that this approach can be generally used in the prediction of 'allosteric hotspots' and ligand induced conformational response, as well as to select conformations more likely to support functional transitions, e.g. in the framework of adaptive sampling approaches