Neurological Involvement in Children with COVID-19 and MIS-C: A Retrospective Study Conducted for More than Two Years in a Pediatric Hospital

This study aimed to evaluate the type and severity of neurological involvement in children with SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) and compare these findings between the two groups. Children hospitalized with the diagnosis of COVID-19 or MIS-C at Meyer Children’s Hospital between February 2020 and June 2022 were retrospectively studied. One hundred twenty-two patients were enrolled, 95 in the COVID-19 group and 27 in the MIS-C group. In the COVID-19 group, impairment of consciousness was found in 67.4% of patients, headache in 18.9% and about 16.8% of patients experienced seizures. In this group, three patients were diagnosed with arterial ischemic stroke and one patient was diagnosed with Guillain-Barré syndrome (GBS). In the MIS-C group, about 70% of patients experienced consciousness impairment, about 20% behavioral changes, and another 20% mood deflection. Neurological symptoms and signs were highly heterogeneous and could be differentiated in COVID-19 and MIS-C. Consciousness impairment remained the most frequent manifestation in both groups, potentially underlying an encephalopathy. We also highlight the importance of considering psychiatric symptoms in children with COVID-19 and/or MIS-C. Most neurological manifestations were mild in our series; however, severe complications such as ischemic stroke and GBS are worthy of note

Uso dei codici di calcolo per l’analisi sismica nonlineare di edifici in muratura: confronto dei risultati ottenuti con diversi software su un caso studio reale = Use of computer programs for the nonlinear seismic analysis of masonry buildings: comparison of the results obtained with different software on an actual case study

L’articolo presenta il confronto dei risultati ottenuti su un edificio in muratura da analisi statiche nonlineari utilizzando diversi software, disponibili anche a livello professionale, che operano nell’ambito di vari approcci di modellazione. La struttura esaminata è ispirata ad un edificio reale, la scuola “P. Capuzi” di Visso (MC), gravemente danneggiata a seguito degli eventi sismici che hanno interessato il Centro Italia nel 2016/2017. L’attività descritta si inquadra in un più ampio programma di ricerca svolto in sinergia da varie unità coinvolte nel progetto ReLUIS 2017/2108 – Linea Strutture in Muratura e avente come oggetto l’analisi di strutture benchmark per la valutazione dell’affidabilità di codici di calcolo. Obiettivi più generali dell’attività sono quelli di sensibilizzare i professionisti ad un uso più consapevole dei software e fornire loro strumenti utili ad analizzare criticamente qualità e correttezza delle soluzioni ottenute. I dati di input e alcune scelte di modellazione sono stati condivisi al fine di limitare la potenziale dispersione dei risultati e renderne meno problematico il confronto. Quest’ultima finalità è guidata dalla volontà di ottimizzare la fase di controllo dei risultati, per la quale sono state individuate precise modalità operative. Il confronto delle analisi è stato svolto in relazione a parametri: globali (inerenti le proprietà dinamiche, le curve di capacità globale e le relative curve bilineari equivalenti), sintetici della sicurezza strutturale (quale, ad esempio, l’accelerazione massima compatibile con lo stato limite di salvaguardia della vita) e interpretativi della risposta complessiva (relativi al quadro di danno simulato). I risultati presentati consentono di eseguire delle riflessioni sull’utilizzo dei software, sulla dispersione dei risultati ottenibili e sulle potenziali ricadute in ambito professionale.----The paper presents the comparison of the results of nonlinear static analyses performed on a masonry building by adopting different computer programs (available also for professional use) that work within various modelling approaches. The examined case study is inspired by an existing building, the school “P. Capuzi” of Visso (MC), significantly damaged after the 2016/2017 seismic events which hit the Central Italy. The activity here described is part of a wider research program carried out within the ReLUIS 2017/2018 project – Line Masonry Structures focused on the analysis of benchmark structures for assessing the reliability of software packages. The general activity’s objectives are to support the professional engineers in acquiring a proper awareness in the use of software packages and to provide them proper tools for the critical analysis of the obtained results. The input data and some modelling assumptions have been shared in order to limit the possible scattering of the results and make less problematic their comparison. This latter aim is driven by the will to optimize the further phase of results’ check, for which specific operative procedures have been defined. The comparison of the analyses involves different aspects: the global scale response (in terms of dynamic properties, capacity curves and corresponding equivalent bi-linear curves); concise parameters concerning the structural safety (such as, for example, the maximum acceleration corresponding to the achievement of the “life safety” limit state); parameters aimed to interpret the whole global response (related to the predicted damage pattern). The presented results allow thinking about the use of software, the scattering of the obtained results and the possible consequences on the engineering practice

Deregulated intracellular pathways define novel molecular targets for HBV-specific CD8 T cell reconstitution in chronic hepatitis B

Background & aims: In chronic HBV infection, elevated reactive oxygen species levels derived from dysfunctional mitochondria can cause increased protein oxidation and DNA damage in exhausted virus-specific CD8 T cells. The aim of this study was to understand how these defects are mechanistically interconnected to further elucidate T cell exhaustion pathogenesis and, doing so, to devise novel T cell-based therapies. Methods: DNA damage and repair mechanisms, including parylation, CD38 expression, and telomere length were studied in HBV-specific CD8 T cells from chronic HBV patients. Correction of intracellular signalling alterations and improvement of antiviral T cell functions by the NAD precursor nicotinamide mononucleotide and by CD38 inhibition was assessed. Results: Elevated DNA damage was associated with defective DNA repair processes, including NAD-dependent parylation, in HBV-specific CD8 cells of chronic HBV patients. NAD depletion was indicated by the overexpression of CD38, the major NAD consumer, and by the significant improvement of DNA repair mechanisms, and mitochondrial and proteostasis functions by NAD supplementation, which could also improve the HBV-specific antiviral CD8 T cell function. Conclusions: Our study delineates a model of CD8 T cell exhaustion whereby multiple interconnected intracellular defects, including telomere shortening, are causally related to NAD depletion suggesting similarities between T cell exhaustion and cell senescence. Correction of these deregulated intracellular functions by NAD supplementation can also restore antiviral CD8 T cell activity and thus represents a promising potential therapeutic strategy for chronic HBV infection. Impact and implications: Correction of HBV-specific CD8 T cell dysfunction is believed to represent a rational strategy to cure chronic HBV infection, which however requires a deep understanding of HBV immune pathogenesis to identify the most important targets for functional T cell reconstitution strategies. This study identifies a central role played by NAD depletion in the intracellular vicious circle that maintains CD8 T cell exhaustion, showing that its replenishment can correct impaired intracellular mechanisms and reconstitute efficient antiviral CD8 T cell function, with implications for the design of novel immune anti-HBV therapies. As these intracellular defects are likely shared with other chronic virus infections where CD8 exhaustion can affect virus clearance, these results can likely also be of pathogenetic relevance for other infection models

Phenotypic CD8 T cell profiling in chronic hepatitis B to predict HBV-specific CD8 T cell susceptibility to functional restoration in vitro

ObjectiveExhausted hepatitis B virus (HBV)-specific CD8 T cells in chronic HBV infection are broadly heterogeneous. Characterisation of their functional impairment may allow to distinguish patients with different capacity to control infection and reconstitute antiviral function. DesignHBV dextramer+CD8 T cells were analysed ex vivo for coexpression of checkpoint/differentiation markers, transcription factors and cytokines in 35 patients with HLA-A2+chronic hepatitis B (CHB) and in 29 control HBsAg negative CHB patients who seroconverted after NUC treatment or spontaneously. Cytokine production was also evaluated in HBV peptide-stimulated T cell cultures, in the presence or absence of antioxidant, polyphenolic, PD-1/PD-L1 inhibitor and TLR-8 agonist compounds and the effect on HBV-specific responses was further validated on additional 24 HLA-A2 negative CHB patients. ResultsSeverely exhausted HBV-specific CD8 T cell subsets with high expression of inhibitory receptors, such as PD-1, TOX and CD39, were detected only in a subgroup of chronic viraemic patients. Conversely, a large predominance of functionally more efficient HBV-specific CD8 T cell subsets with lower expression of coinhibitory molecules and better response to in vitro immune modulation, typically detected after resolution of infection, was also observed in a proportion of chronic viraemic HBV patients. Importantly, the same subset of patients who responded more efficiently to in vitro immune modulation identified by HBV-specific CD8 T cell analysis were also identified by staining total CD8 T cells with PD-1, TOX, CD127 and Bcl-2. ConclusionsThe possibility to distinguish patient cohorts with different capacity to respond to immune modulatory compounds in vitro by a simple analysis of the phenotypic CD8 T cell exhaustion profile deserves evaluation of its clinical applicability

Safety and efficacy of ombitasvir/paritaprevir/ritonavir/dasabuvir plus ribavirin in patients over 65 years with HCV genotype 1 cirrhosis

none191norestrictedAscione, Antonio*; De Luca, Massimo; Melazzini, Mario; Montilla, Simona; Trotta, Maria Paola; Petta, Salvatore; Puoti, Massimo; Sangiovanni, Vincenzo; Messina, Vincenzo; Bruno, Savino; Izzi, Antonio; Villa, Erica; Aghemo, Alessio; Zignego, Anna Linda; Orlandini, Alessandra; Fontanella, Luca; Gasbarrini, Antonio; Marzioni, Marco; Giannini, Edoardo G.; Craxì, Antonio; Abbati, Giuseppe; Alberti, Alfredo; Andreone, Pietro; Andreoni, Massimo; Angeli, Paolo; Angelico, Mario; Angarano, Gioacchino; Angrisani, Debora; Antinori, Andrea; Antonini, Cinzia; Avancini, Ivo; Barone, Michele; Bruno, Raffaele; Benedetti, Antonio; Bernabucci, Veronica; Blanc, Pier; Boarini, Chiara; Boffa, Nicola; Boglione, Lucio; Borghi, Vanni; Borgia, Guglielmo; Brancaccio, Giuseppina; Brunetto, Maurizia; Cacciola, Irene; Calabrese, Paolo; Calvaruso, Vincenza; Campagnolo, Davide; Canovari, Benedetta; Caporaso, Nicola; Capra, Franco; Carolo, Giada; Cassola, Giovanni; Castelli, Francesco; Cauda, Roberto; Silberstein, Francesca Ceccherini; Cecere, Roberto; Chessa, Luchino; Chiodera, Alessandro; Chirianni, Antonio; Ciancio, Alessia; Cima, Serena; Coco, Barbara; Colombo, Massimo; Coppola, Nicola; Corti, Giampaolo; Cosco, Lucio; Corradori, Silvia; Cozzolongo, Raffaele; Cristaudo, Antonio; Danieli, Elena; Monforte, Antonella D’Arminio; Monache, Marco delle; Del Poggio, Paolo; de Luca, Andrea; Dentone, Chiara; Di Biagio, Antonio; Di Leo, Alfredo; Di Perri, Giovanni; Di Stefano, Marco; D’Offizi, Giampiero; Donato, Francesca; Durante, Emanuele; Erne, Elke; Fagiuoli, Stefano; Falasca, Katia; Federico, Alessandro; Felder, Martina; Ferrari, Carlo; Gaeta, Giovanni Battista; Ganga, Roberto; Gatti, Pietro; Giacomet, Vania; Giacometti, Andrea; Gianstefani, Alice; Giordani, Maria; Giorgini, Alessia; Grieco, Antonio; Guerra, Michele; Gulminetti, Roberto; Ieluzzi, Donatella; Imparato, Michele; Iodice, Valentina; La Monica, Silvia; Lazzarin, Adriano; Lenzi, Marco; Levrero, Massimo; Lichtner, Myriam; Lionetti, Raffaella; Guercio, Carmela Lo; Madonna, Salvatore; Magnani, Silvia; Maida, Ivana; Marignani, Massimo; Marrone, Aldo; Marsetti, Fabio; Martini, Silvia; Masarone, Mario; Maserati, Renato; Mastroianni, Claudio Maria; Memoli, Massimo; Menzaghi, Barbara; Merli, Manuela; Miele, Luca; Milella, Michele; Mondelli, Mario; Montalbano, Marzia; Monti, Monica; Morelli, Olivia; Morisco, Filomena; Nardone, Gaetano; Novara, Sergio; Onnelli, Giovanna; Onofrio, Mirella; Paganin, Simona; Pani, Luca; Parisi, Maria Rita; Parruti, Giustino; Pasquazzi, Caterina; Pasulo, Luisa; Perno, Carlo Federico; Persico, Marcello; Piai, Guido; Picciotto, Antonino; Pigozzi, Grazielle Marie; Piovesan, Sara; Piras, Maria Chiara; Pirisi, Massimo; Piscaglia, Anna Maria; Ponti, Laura; Potenza, Domenico; Pravadelli, Cecilia; Quartini, Mariano; Quirino, Tiziana; Raimondo, Giovanni; Rapaccini, Gian Ludovico; Rendina, Maria; Rizzardini, Giuliano; Rizzetto, Mario; Rizzo, Salvatore; Romagnoli, Dante; Romano, Antonietta; Rossi, Cristina; Rumi, Maria Grazia; Russello, Maurizio; Russo, Francesca Paolo; Russo, Maria Luisa; Sansonno, Domenico Ettore; Santantonio, Teresa Antonia; Saracco, Giorgio; Schimizzi, Anna Maria; Serviddio, Gaetano; Simeone, Filomena; Solinas, Attilio; Soria, Alessandro; Tabone, Marco; Taliani, Gloria; Tarantino, Giuseppe; Tarquini, Pierluigi; Tavio, Marcello; Termite, Antonio; Teti, Elisabetta; Toniutto, Pierluigi; Torti, Carlo; Tundi, Paolo; Vecchiet, Giacomo; Verucchi, Gabriella; Gentilucci, Umberto Vespasiani; Vinci, Maria; Vullo, Vincenzo; Zolfino, Teresa; Zuin, MassimoAscione, Antonio; De Luca, Massimo; Melazzini, Mario; Montilla, Simona; Trotta, Maria Paola; Petta, Salvatore; Puoti, Massimo; Sangiovanni, Vincenzo; Messina, Vincenzo; Bruno, Savino; Izzi, Antonio; Villa, Erica; Aghemo, Alessio; Zignego, Anna Linda; Orlandini, Alessandra; Fontanella, Luca; Gasbarrini, Antonio; Marzioni, Marco; Giannini, Edoardo G.; Craxì, Antonio; Abbati, Giuseppe; Alberti, Alfredo; Andreone, Pietro; Andreoni, Massimo; Angeli, Paolo; Angelico, Mario; Angarano, Gioacchino; Angrisani, Debora; Antinori, Andrea; Antonini, Cinzia; Avancini, Ivo; Barone, Michele; Bruno, Raffaele; Benedetti, Antonio; Bernabucci, Veronica; Blanc, Pier; Boarini, Chiara; Boffa, Nicola; Boglione, Lucio; Borghi, Vanni; Borgia, Guglielmo; Brancaccio, Giuseppina; Brunetto, Maurizia; Cacciola, Irene; Calabrese, Paolo; Calvaruso, Vincenza; Campagnolo, Davide; Canovari, Benedetta; Caporaso, Nicola; Capra, Franco; Carolo, Giada; Cassola, Giovanni; Castelli, Francesco; Cauda, Roberto; Silberstein, Francesca Ceccherini; Cecere, Roberto; Chessa, Luchino; Chiodera, Alessandro; Chirianni, Antonio; Ciancio, Alessia; Cima, Serena; Coco, Barbara; Colombo, Massimo; Coppola, Nicola; Corti, Giampaolo; Cosco, Lucio; Corradori, Silvia; Cozzolongo, Raffaele; Cristaudo, Antonio; Danieli, Elena; Monforte, Antonella D’Arminio; Monache, Marco delle; Del Poggio, Paolo; de Luca, Andrea; Dentone, Chiara; Di Biagio, Antonio; Di Leo, Alfredo; Di Perri, Giovanni; DI STEFANO, Marco; D’Offizi, Giampiero; Donato, Francesca; Durante, Emanuele; Erne, Elke; Fagiuoli, Stefano; Falasca, Katia; Federico, Alessandro; Felder, Martina; Ferrari, Carlo; Gaeta, Giovanni Battista; Ganga, Roberto; Gatti, Pietro; Giacomet, Vania; Giacometti, Andrea; Gianstefani, Alice; Giordani, Maria; Giorgini, Alessia; Grieco, Antonio; Guerra, Michele; Gulminetti, Roberto; Ieluzzi, Donatella; Imparato, Michele; Iodice, Valentina; La Monica, Silvia; Lazzarin, Adriano; Lenzi, Marco; Levrero, Massimo; Lichtner, Myriam; Lionetti, Raffaella; Guercio, Carmela Lo; Madonna, Salvatore; Magnani, Silvia; Maida, Ivana; Marignani, Massimo; Marrone, Aldo; Marsetti, Fabio; Martini, Silvia; Masarone, Mario; Maserati, Renato; Mastroianni, Claudio Maria; Memoli, Massimo; Menzaghi, Barbara; Merli, Manuela; Miele, Luca; Milella, Michele; Mondelli, Mario; Montalbano, Marzia; Monti, Monica; Morelli, Olivia; Morisco, Filomena; Nardone, Gaetano; Novara, Sergio; Onnelli, Giovanna; Onofrio, Mirella; Paganin, Simona; Pani, Luca; Parisi, Maria Rita; Parruti, Giustino; Pasquazzi, Caterina; Pasulo, Luisa; Perno, Carlo Federico; Persico, Marcello; Piai, Guido; Picciotto, Antonino; Pigozzi, Grazielle Marie; Piovesan, Sara; Piras, Maria Chiara; Pirisi, Massimo; Piscaglia, Anna Maria; Ponti, Laura; Potenza, Domenico; Pravadelli, Cecilia; Quartini, Mariano; Quirino, Tiziana; Raimondo, Giovanni; Rapaccini, Gian Ludovico; Rendina, Maria; Rizzardini, Giuliano; Rizzetto, Mario; Rizzo, Salvatore; Romagnoli, Dante; Romano, Antonietta; Rossi, Cristina; Rumi, Maria Grazia; Russello, Maurizio; Russo, Francesca Paolo; Russo, Maria Luisa; Sansonno, Domenico Ettore; Santantonio, Teresa Antonia; Saracco, Giorgio; Schimizzi, Anna Maria; Serviddio, Gaetano; Simeone, Filomena; Solinas, Attilio; Soria, Alessandro; Tabone, Marco; Taliani, Gloria; Tarantino, Giuseppe; Tarquini, Pierluigi; Tavio, Marcello; Termite, Antonio; Teti, Elisabetta; Toniutto, Pierluigi; Torti, Carlo; Tundi, Paolo; Vecchiet, Giacomo; Verucchi, Gabriella; Gentilucci, Umberto Vespasiani; Vinci, Maria; Vullo, Vincenzo; Zolfino, Teresa; Zuin, Massim

Ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin for patients with hepatitis C virus genotype 1 or 4 infection with cirrhosis (ABACUS): a prospective observational study

Background We ran a compassionate use nationwide programme (ABACUS) to provide access to ombitasvir, paritaprevir, and ritonavir, with dasabuvir, plus ribavirin for hepatitis C virus (HCV) genotype 1 infection and ombitasvir, paritaprevir, and ritonavir, plus ribavirin for HCV genotype 4 infection in patients with cirrhosis at high risk of decompensation while approval of these regimens was pending in Italy. Methods In this prospective observational study, we collected data from a compassionate use nationwide programme from March 17, 2014, to May 28, 2015. Patients with HCV genotype 1 infection and cirrhosis at high risk of decompensation were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once daily and dasabuvir (250 mg) twice daily for 12 weeks (patients with HCV genotype 1b infection) or 24 weeks (patients with HCV genotype 1a infection). Patients with HCV genotype 4 infection were given coformulated ombitasvir (25 mg), paritaprevir (150 mg), and ritonavir (100 mg) once per day for 24 weeks. All patients were given weight-based ribavirin. The primary efficacy endpoint was sustained virological response at week 12 after the end of treatment (SVR12), analysed by intention-to-treat. Univariate and multivariate logistic regression analyses were used to identify baseline characteristics associated with SVR12. Adverse events were recorded throughout the study. Findings 728 (96%) of 762 patients with cirrhosis who were given ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin therapy for 12 or 24 weeks achieved SVR12. Logistic regression analyses identified that bilirubin concentrations of less than 2 mg/dL were associated with SVR12 (odds ratio [OR] 4·76 [95% CI 1·83–12·3]; p=0·001). 166 (23%) of 734 patients included in safety analyses had an adverse event. 25 (3%) patients discontinued treatment because of adverse events. Asthenia was the most commonly reported adverse event, occurring in 36 (5%) patients. Interpretation Our findings suggest that the safety and effectiveness of ombitasvir, paritaprevir, and ritonavir, with or without dasabuvir, plus ribavirin in patients with HCV genotype 1 or 4 infection and cirrhosis at high risk of decompensation in a real-life setting are similar to those reported in clinical trials. The concordance with clinical trials provides reassurance that the reported efficacy of this treatment in clinical trials will translate to its use in routine clinical practice. Funding Dipartimento Biomedico di Medicina Interna e Specialistica dell'Universita di Palermo