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Martina Spaziante,1 Carolina Venditti,2 Ornella Butera,2 Francesco Messina,2 Antonino Di Caro,2 Gilda Tonziello,1 Simone Lanini,1 Maria Adriana Cataldo,1 Vincenzo Puro1 1Emerging Infection Unit and Regional Service for Surveillance and Control of Infectious Diseases (SeRESMI), National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, Rome, Italy; 2Laboratory of Microbiology, National Institute for Infectious Diseases “Lazzaro Spallanzani” IRCCS, Rome, ItalyCorrespondence: Maria Adriana Cataldo Tel +39 0655170786Email adriana.cataldo@inmi.itIntroduction: New Delhi metallo-β-lactamase producing Klebsiella pneumoniae (NDM-Kpn) strains have been causing healthcare-associated infections worldwide. The aim of this study was to describe the molecular mechanisms of antimicrobial resistance and to analyze the clonality of NDM-Kpn isolates collected between January 2019 and June 2020 from patients admitted to hospitals from the Lazio region, Italy.Methods: We performed a retrospective cohort study. Whole-genome sequencing (WGS) was performed on all NDM-Kpn strains; clonality and genetic relationships were further investigated.Results: During the surveillance period, 17 NDM-Kpn isolates were obtained from 17 patients admitted to seven different hospitals. Eight different sequence types (STs) were detected: ST147 (n = 4), ST383 (n = 4), ST15 (n = 3), ST11 (n = 2), ST17 (n = 1), ST29 (n = 1), ST307 (n = 1) and the newly identified ST4853 (n = 1). Genetic relationships were further investigated by the WGS-based core genome MLST (cgMLST) scheme, and 5 cluster types (CTs) were identified. Whereas a substantial overall heterogeneity among isolates was detected (8 different STs were identified out of 17 isolates), the strains within each cluster showed a very high level of genome similarity.Discussion: Our study highlights the key role of surveillance, which allowed taking a picture of a part of the NDM-Kpn strains circulating in Italy, adding further insight into their molecular features.Keywords: carbapenem-resistant Klebsiella pneumoniae, New Delhi metallo-β-lactamase, surveillance, healthcare-associated infections

A Cannas,1 O Butera,1 G Gualano,2 MP Parracino,3 C Venditti,1 A Mazzarelli,1 F Palmieri,2 E Girardi,3,* A Di Caro1,* 1Microbiology and Bio-Repository Unit, National Institute for Infectious Diseases “L. Spallanzani” IRCCS, Rome, Italy; 2Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases “L. Spallanzani” IRCCS, Rome, Italy; 3Clinical Epidemiology Unit, National Institute for Infectious Diseases “L. Spallanzani” IRCCS, Rome, Italy*These authors contributed equally to this workCorrespondence: A CannasNational Institute for Infectious Diseases “L. Spallanzani” IRCCS, Via Portuense 292, Rome 00149, ItalyTel +39 06 5517 0905Email angela.cannas@inmi.itPurpose: Multidrug-resistant tuberculosis (MDR-TB) is a major burden to public health in low incidence countries in Europe. The aim of this study was to attempt to have a better insight into the trends of MDR-TB in the metropolitan area of Rome, within the Italian and the foreign-born population, based on microbiological and demographic data.Patients and methods: We performed a prospective study, collecting microbiological data based on phenotypic drug-resistant testing (DST) of TB strains consecutively isolated in a referral hospital in Rome, the capital city of a low TB incidence country, over a 6-year period, and correlated them to the geographical origin of patients. This study was carried out in a referral hospital for patients with drug-resistant TB from the whole region.Results: Drug-resistance data from 926 patients with a microbiological diagnosis of TB from 2011 to 2016 show a 5.5% rate of MDR-TB, mostly occurring in patients born in a single East European country, that has a high incidence of MDR-TB. The strains isolated from these patients frequently carry additional resistances, leading to an increased risk of developing extensively drug-resistant (XDR) TB.Conclusion: In the great metropolitan area of Rome, MDR-TB more frequently occurs in patients who were born in a single country from Eastern Europe known to have high rates of MDR-TB and long-time residents in Italy. Recent immigrants from non-European countries do not appear to contribute to the rates of MDR-TB reported in this article. This knowledge of local TB trends could help improve the measures of surveillance and prevention of disease.Keywords: tuberculosis, drug-susceptibility testing, MDR-TB, XDR-TB

Monica Basso,1,* Carolina Venditti,2,* Giammarco Raponi,3 Anna Sara Navazio,3 Francesco Alessandri,4 Emanuela Giombini,2 Carla Nisii,2 Antonino Di Caro,2 Mario Venditti31Department of Molecular Medicine, University of Padova, Padova, Italy; 2Laboratory of Microbiology, L. Spallanzani National Institute for Infectious Diseases, Rome, Italy; 3Department of Public Health and Infectious Diseases, Sapienza University of Rome, Rome Italy; 4Department of Anesthesia and Intensive Care Medicine, Sapienza University of Rome, Rome, Italy*These authors contributed equally to this workAbstract: The Ralstonia spp. genus is a group of non-fermentative, Gram-negative bacteria often resistant to many antibiotics, which are emerging as opportunistic pathogens frequently associated with infections in hospital settings. We present herein a case of combined R. pickettii and R. mannitolilytica persisting and relapsing bacteraemia, possibly caused by a septic arterial thrombosis secondary to the rupture of an internal carotid artery aneurysm. Microbiology studies showed that both Ralstonia isolates produced biofilm and carried class D oxacillinase genes. When confronted with infections caused by members of the Ralstonia genus, identification to the species level is crucial for correct clinical management, as the two species show different antibiotic susceptibility patterns.Keywords: Ralstonia pickettii, Ralstonia mannitolilytica, bacteraemia, endovascular infection

Carolina Venditti,1 Carla Nisii,1 Silvia D’Arezzo,1 Antonella Vulcano,1 Alessandro Capone,2 Mario Antonini,2 Giuseppe Ippolito,3 Antonino Di Caro11Laboratory of Microbiology, National Institute for Infectious Diseases "L. Spallanzani", Rome, Italy; 2Clinical Department, National Institute for Infectious Diseases "L.Spallanzani", Rome, Italy; 3Scientific Direction, National Institute for Infectious Diseases "L.Spallanzani", Rome, ItalyBackground: For years, Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae have represented a serious health problem in hospitals worldwide. Since its approval in 2015, ceftazidime-avibactam (CAZ-AVI) had been successfully used for treating complicated KPC-K. pneumoniae infections, until increasing reports of resistance began to emerge.Methods: Phenotypic tests and molecular analysis were performed in four multidrug-resistant K. pneumoniae isolates, collected from two patients following treatment with CAZ-AVI.Results: In this study, we report two cases of emergence of CAZ-AVI resistance in KPC-3-producing K. pneumoniae isolates, collected from two patients following treatment with CAZ-AVI. Molecular analysis highlighted the D179Y mutation in the blaKPC-3 gene, whose role in the loss of hydrolytic activity (resulting in decreased carpabenem minimum inhibitory concentrations and negative phenotypic tests) of the enzyme has already been shown.Conclusion: Most surveillance schemes aimed at detecting carbapenem-resistant Enterobacteriaceae (CRE) rely on confirmatory phenotypic tests for detecting carbapenemase production. As reports of these treatment-induced, altered CRE phenotypes are increasing, the initial susceptibility testing should be followed by a combination of phenotypic and molecular methods, to make sure that no potential carbapenemase-producing bacteria are missed.Keywords: Klebsiella pneumoniae, carbapenem-resistance, ceftazidime-avibactam

This paper deals with proton exchange membrane (PEM) electrolyzers directly coupled with a photovoltaic source. It proposes a method to increase the energy delivered to the electrolyzer by reconfiguring the electrical connection of the arrays according to solar radiation. Unlike the design criterion proposed by the literature, the suggested approach considers a source obtained by connecting arrays in parallel depending on solar radiation based on a fixed photovoltaic configuration. This method allows for the optimization of the operating point at medium or low solar radiation, where the fixed configuration gives poor results. The analysis is performed on a low-power plant (400 W). It is based on a commercial photovoltaic cell whose equivalent model is retrieved from data provided by the manufacturer. An equivalent model of the PEM electrolyzer is also derived. Two comparisons are proposed: the former considers a photovoltaic source designed according to the traditional approach, i.e., a fixed configuration; in the latter, a DC/DC converter as interface is adopted. The role of the converter is discussed to highlight the pros and cons. The optimal set point of the converter is calculated using an analytical equation that takes into account the electrolyzer model. In the proposed study, an increase of 17%, 62%, and 93% of the delivered energy has been obtained in three characteristic days, summer, spring/autumn, and winter, respectively, compared to the fixed PV configuration. These results are also better than those achieved using the converter. Results show that the proposed direct coupling technique applied to PEM electrolyzers in low-power plants is a good trade-off between a fixed photovoltaic source configuration and the use of a DC/DC converter.

In this paper we focus on an aspect of the change in the syntax of the Gallo-Italic variety of Nicosia (Enna), which is presumably fostered by prolonged contact with Sicilian: the use of the Aviri a + Infinitive Construction (AICo). This periphrasis can cover different functions (deontic, epistemic, futural, and optative) and, in Nicosiano, can surface in different configurations (usually featuring a [d] element). We considered a written corpus containing works (poetry, short stories, novels, theatre plays) by the two major authors in Nicosiano: La Giglia (1862-1922) and Castrogiovanni (1933-2007). We compared the occurrences of the AICo in the corpus with those of modal dövë̀ ‘must’ and synthetic future forms. The functions of the latter two, which are not productive in Sicilian anymore, generally overlap with those of the AICo. The data collected confirm the effects of Sicilian on Nicosiano: the AICo has almost completely taken over dövë̀ and synthetic forms for all the functions considered, the latter constructions generally occurring in crystallised expressions in the corpus.

CT1812 is a novel, brain penetrant small molecule modulator of the sigma-2 receptor (S2R) that is currently in clinical development for the treatment of Alzheimer's disease (AD). Preclinical and early clinical data show that, through S2R, CT1812 selectively prevents and displaces binding of amyloid beta (Aβ) oligomers from neuronal synapses and improves cognitive function in animal models of AD. SHINE is an ongoing phase 2 randomized, double-blind, placebo-controlled clinical trial (COG0201) in participants with mild to moderate AD, designed to assess the safety and efficacy of 6 months of CT1812 treatment. To elucidate the mechanism of action in AD patients and pharmacodynamic biomarkers of CT1812, the present study reports exploratory cerebrospinal fluid (CSF) biomarker data from 18 participants in an interim analysis of the first set of patients in SHINE (part A). Untargeted mass spectrometry-based discovery proteomics detects >2000 proteins in patient CSF and has documented utility in accelerating the identification of novel AD biomarkers reflective of diverse pathophysiologies beyond amyloid and tau, and enabling identification of pharmacodynamic biomarkers in longitudinal interventional trials. We leveraged this technique to analyze CSF samples taken at baseline and after 6 months of CT1812 treatment. Proteome-wide protein levels were detected using tandem mass tag-mass spectrometry (TMT-MS), change from baseline was calculated for each participant, and differential abundance analysis by treatment group was performed. This analysis revealed a set of proteins significantly impacted by CT1812, including pathway engagement biomarkers (i.e., biomarkers tied to S2R biology) and disease modification biomarkers (i.e., biomarkers with altered levels in AD vs. healthy control CSF but normalized by CT1812, and biomarkers correlated with favorable trends in ADAS-Cog11 scores). Brain network mapping, Gene Ontology, and pathway analyses revealed an impact of CT1812 on synapses, lipoprotein and amyloid beta biology, and neuroinflammation. Collectively, the findings highlight the utility of this method in pharmacodynamic biomarker identification and providing mechanistic insights for CT1812, which may facilitate the clinical development of CT1812 and enable appropriate pre-specification of biomarkers in upcoming clinical trials of CT1812.

Tuberculosis (TB) remains one of the leading causes of death among infectious diseases, with 10.6 million new cases and 1.3 million deaths reported in 2022, according to the most recent WHO report. Early studies have shown an expansion of γδ T cells following TB infection in both experimental models and humans, indicating their abundance among lung lymphocytes and suggesting a role in protective immune responses against Mycobacterium tuberculosis (M. tuberculosis) infection. In this study, we hypothesized that distinct subsets of γδ T cells are associated with either protection against or disease progression in TB. To explore this, we applied large-scale scRNA-seq and bulk RNA-seq data integration to define the phenotypic and molecular characteristics of peripheral blood γδ T cells. Our analysis identified five unique γδ T subclusters, each with distinct functional profiles. Notably, we identified a unique cluster significantly enriched in the TCR signaling pathway, with high CD81 expression as a conserved marker. This distinct molecular signature suggests a specialized role for this cluster in immune signaling and regulation of immune response against M. tuberculosis. Flow cytometry confirmed our in silico results, showing that the mean fluorescence intensity (MFI) values of CD81 expression on γδ T cells were significantly increased in individuals with latent TB infection (TBI) compared to those with active TB (ATB). This finding underscores the importance of CD81 and its associated signaling mechanisms in modulating the activity and function of γδ T cells under TBI conditions, providing insights into potential therapeutic targets for TB management.

This paper investigates the properties of GO and TAKE used as functional verbs to express the beginning of an action or a state (inchoativity) or a sense of surprise, wonder, astonishment, or regret (mirativity) as found in a group of multiple verb constructions, in a macro-comparative perspective. Multiple Agreement Constructions (V1+mi/mu/da/če+V2[+finite]) and Pseudo-Coordination (V1+‘and’+V2[+finite]) are considered in Italo-Romance (Italian and Sicilian) and Balkan Slavic (Bulgarian), together with the Italo-Romance Infinitival Construction (V1+a+V2[-finite]), drawing from novel fieldwork data and online corpus data. GO and TAKE generally proved to be highly productive as both inchoative and mirative markers in all the languages considered. In particular, an analysis of cases in which these two functional verbs convey (to different degrees) both functions at once is provided, relying on the cognitive basis underlying the process of their grammaticalisation.

This paper discusses the preliminary results of an exploratory study based on acceptability judgments about Pseudo-Coordination (PseCo) as found in the province of Catania (Sicily). PseCo is a monoclausal verbal periphrasis where an inflected verb (V1), usually of motion, is followed by another inflected verb (V2) with an optional connecting element between them (cf. Giusti, Di Caro and Ross 2022). In western Sicilian varieties, the V1 GO can occur as an invariable form (i.e., va-, vo-, uo-, o- as in Oppigghju u pani ‘I go and fetch the bread’) prefixed to the V2. An online anonymous questionnaire was administered to 295 participants (180 female, 115 male; Age M: 20,95 years, Age SD: 2,73 years) to assess whether (i) PseCo with V1 GO in the present indicative is productive among younger speakers; (ii) different forms of invariable V1 GO can cooccur in one and the same variety. The results show that PseCo in the province of Catania is still vital among younger generation of speakers and that invariable V1 GO generally occurs in at least two different forms but with no particular semantic specialization.

In order to be concretely effective, many Natural Language Processing (NLP) applications require the availability of lexical resources providing varied, broadly shared, and language-unbounded (i.e., not limited to any specific language or linguistic system) lexical information. However, state-of-the-art knowledge models typically focus on specific levels of semantic analysis rather than adopting such a comprehensive and cross-lingual approach to lexical knowledge. This is often due to the theoretical paradigms on which such resources are based, each addressing the semantic phenomenon from a (de)finite perspective. In this paper, we first suggest a maximalist approach to lexical semantics to pursue through the idea of semantic prototype and linguistic representativeness as easily applicable to textual corpora. Starting from this conceptual framework, we thus propose a novel corpus-based automatable methodology for knowledge modeling based on a multilingual word alignment mechanism. This model enables the retrieval and encoding of prototypical, language-unbounded, and naturally disambiguated lexical knowledge in the form of diversified conceptual links between words and their senses. Results from a simple implementation of the proposal show relevant outcomes that are not found in other resources. Finally, different application opportunities of the proposed model will be presented.

Abstract Introduction Staphylococcus aureus has emerged as a major nosocomial pathogen in the last decades and also represents the second most common pathogen isolated from patients in outpatient settings. Although methicillin-resistant S.aureus infections were traditionally limited to hospitals, community-associated cases of methicillin-resistant S.aureus infections have been reported. In our case, we observed an unexpected event during treatment. Case presentation A 60-year-old Caucasian man developed fever and multiple muscle and brain abscesses caused by Panton-Valentine leukocidin-negative community-associated methicillin-resistant S. aureus. Conclusion Although our patient was given antimicrobials active against the isolated methicillin-resistant S. aureus strain, it was only after the introduction of daptomycin that his skin, soft tissue and muscle lesions and also brain manifestations improved.

Abstract The management of viral hemorrhagic fevers (VHFs) has mainly focused on strict infection control measures, while standard clinical interventions that are provided to patients with other life-threatening conditions are rarely offered to patients with VHFs. Despite its complexity, a proper clinical case management of VHFs is neither futile nor is it lacking in scientific rationale. Given that patient outcomes improve when treatment is started as soon as possible, development and implementation of protocols to promptly identify and treat patients in the earliest phases of diseases are urgently needed. Different pharmacological options have been proposed to manage patients and, as for other life-threatening conditions, advanced life support has been proved effective to address multiorgan failure. In addition, high throughput screening of small molecular libraries has emerged as a novel promising way to find new candidates drugs for VHFs therapy and a relevant number of new molecules are currently under investigation. Here we discuss the current knowledge about VHF clinical management to propose a way to step up the approach to VHFs beyond the mere application of infection control measures.

Benign hepatosteatosis, affected by lipid uptake, de novo lipogenesis and fatty acid (FA) oxidation, progresses to non-alcoholic steatohepatitis (NASH) on stress and inflammation. A key macronutrient proposed to increase hepatosteatosis and NASH risk is fructose. Excessive intake of fructose causes intestinal-barrier deterioration and endotoxaemia. However, how fructose triggers these alterations and their roles in hepatosteatosis and NASH pathogenesis remain unknown. Here we show, using mice, that microbiota-derived Toll-like receptor (TLR) agonists promote hepatosteatosis without affecting fructose-1-phosphate (F1P) and cytosolic acetyl-CoA. Activation of mucosal-regenerative gp130 signalling, administration of the YAP-induced matricellular protein CCN1 or expression of the antimicrobial peptide Reg3b (beta) peptide counteract fructose-induced barrier deterioration, which depends on endoplasmic-reticulum stress and subsequent endotoxaemia. Endotoxin engages TLR4 to trigger TNF production by liver macrophages, thereby inducing lipogenic enzymes that convert F1P and acetyl-CoA to FA in both mouse and human hepatocytes.