Broadly neutralizing antibodies against emerging delta-coronaviruses (preprint)

Porcine deltacoronavirus (PDCoV) spillovers were recently detected in children with acute undifferentiated febrile illness, underscoring recurrent zoonoses of divergent coronaviruses. To date, no vaccines or specific therapeutics are approved for use in humans against PDCoV. To prepare for possible future PDCoV epidemics, we isolated human spike (S)-directed monoclonal antibodies from transgenic mice and found that two of them, designated PD33 and PD41, broadly neutralized a panel of PDCoV variants. Cryo-electron microscopy structures of PD33 and PD41 in complex with the PDCoV receptor-binding domain and S ectodomain trimer provide a blueprint of the epitopes recognized by these mAbs, rationalizing their broad inhibitory activity. We show that both mAbs inhibit PDCoV by competitively interfering with host APN binding to the PDCoV receptor-binding loops, explaining the mechanism of viral neutralization. PD33 and PD41 are candidates for clinical advancement, which could be stockpiled to prepare for possible future PDCoV outbreaks.

Real world use of Tixagevimab/Cilgavimab pre-exposure prophylaxis of COVID-19 in immunocompromised individuals: data from the OCTOPUS study. (preprint)

We report real world use over time in immunocompromised subjects receiving tixagevimab/cilgavimab (T/C) pre-exposure prophylaxis (PrEP). Observational study on participants receiving T/C PrEP stratified: never had COVID-19 (NoC), hybrids (H) and breakthrough infections (BTIs) if COVID-19 before or after PrEP, respectively. Anti-RBD IgG and BA.5 neutralizing antibodies (nAbs), mucosal IgG, T-cell immunity at the administration of T/C (T0), 3 (T1), 6 (T2), and 9 (T3) months after, were measured. Comparison of markers in each group across timepoints, Poisson regression model for BTIs incidence rate ratios were performed. N=231 participants: median age 63 years (IQR 54.0-73.0), 84% hematological disease, median vaccine dose of three. N=72 NoC, 103 H and 56 (24%) BTIs, mostly mild/moderate, IR 4.2 (95%CI 3.2-5.4) BTIs/100 patients-months, no factors associated with. A significant increase of anti-RBD IgG at T1 was observed in all the groups, with a decline at T2. GMTs of anti-BA.5 nAbs were low at T1 for all the groups and around/below the cut off. No changes of IFN-γ. Overall, a mucosal response was observed at T1. An incidence of 24% of mild/moderate BTIs was observed. Anti-RBD IgG levels persistence was ensured, BA.5 nAbs were low/undetectable, cellular T immunity remained stable.

Parents’ Participation in Care during Neonatal Intensive Care Unit Stay in COVID-19 Era: A Quantitative Observational Study (preprint)

Background: During the stay in the neonatal intensive care unit, parents play a crucial role in the care of their infants. Recent studies reported a decrease in parental participation due to Coronavirus Disease (COVID-19) pandemic that determined restricted access policies in hospitals. The aim of this study is to describe the barriers to a good parents’ participation during the stay in the neonatal intensive care unit in the COVID-19 era. Methods: A quantitative observational study was carried out. Results: 270 parents participated in this study. Mothers’ participation in care seems to be higher as compared to fathers (p = 0.017). Parents who lived the birth of their first child reported a better level of participation in care when compared to those who lived the birth of their second born (p = 0.005). Parents of extremely preterm neonates reported a lower interaction with their infant if compared to parents of term newborns (p < 0.001). Conclusions: Some more disadvantaged categories have reported lower scores: cultural and linguistic minorities, parents of multiple children and fathers. COVID-19 pandemic made several Family Centred Care activities not possible with a higher impact on those who benefited the most of these facilities. This study was prospectively registered by the IRB-CRRM of the University “G. d’Annunzio” Chieti-Pescara on the 23/01/2024 with registration number CRRM;2023_12_07_01.

Biological modifications of the immune response to COVID-19 vaccine in patients treated with anti-CD20 agents and immune-checkpoint inhibitors (preprint)

Investigating the impact of immune-modulating therapies on mRNA vaccine efficacy remains vital, transcending the immediate context of the COVID-19 pandemic. This study focuses on the differential immune responses to COVID-19 mRNA booster vaccines among healthy subjects, cancer patients undergoing treatment with immune-checkpoint inhibitors (ICIs), and those treated with B-cell depleting agents such as rituximab. Utilizing RNA sequencing, serology, and interferon gamma release assays, we charted the temporal dynamics of the immune response. Our findings indicate that ICIs maintain an immune profile similar to that of healthy individuals, whereas treatments like rituximab lead to a significant reduction in immune competence, affecting both humoral and cellular immunity. This research may not only help tailoring of vaccination strategies for those under immune-modulating treatments, but also deepens our understanding of the sophisticated interplay within the immune system in health and disease states, potentially informing therapeutic strategies across a spectrum of immunological conditions.

Transistors platform for rapid and parallel detection of multiple pathogens by nanoscale-localized multiplexed biological activation (preprint)

The rise in antibiotic-resistant pathogens, highly infectious viruses, and chronic diseases has prompted the search for rapid and versatile medical tests that can be performed by the patient. An electronic biosensing platform based on field-effect transistors (FETs) is particularly attractive due to sensitivity, fast turn-around, and compatibility with semiconductor manufacturing. However, the lack of methods for pathogen-specific functionalization of individual FETs prevents parallel detection of multiple pathogens. Indeed, so far functionalization of FET based biosensors is achieved by drop casting without any spatial selectivity. Here, we propose a paradigm shift in FET’s biofunctionalization. Specifically, we use thermal scanning probe lithography (tSPL) with a thermochemically sensitive polymer that can be spin-coated on any FET material. We demonstrate that this scalable, CMOS compatible methodology can be used to functionalize individual FETs with different bioreceptors on the same chip, at sub-20 nm resolution, paving the way for massively parallel FET detection of multiple pathogens. Antibody- and aptamer-modified FET sensors are then realized, achieving an ultra-sensitive detection of 5 aM of SARS-CoV-2 spike proteins and 10 human SARS-CoV-2 infectious live virus particles/ml, and selectivity against human influenza A (H1N1) live virus.

A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines (preprint)

Continuous evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and monoclonal antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S2 subunit, which folds as a spring-loaded fusion machinery. Here, we describe a protein design strategy enabling prefusion-stabilization of the SARS-CoV-2 S2 subunit and high yield recombinant expression of trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to all sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S2 fusion machineries. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S2 trimer vaccine elicits broadly reactive sarbecovirus antibody responses and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with SARS-CoV-2 XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines motivating future development.

Integrated environmental and clinical surveillance for the prevention of acute respiratory infections (ARIs) in indoor environments and vulnerable communities (Stell-ARI) (preprint)

Background The epidemiological relevance of viral acute respiratory infections (ARIs) has been dramatically highlighted by COVID-19. However, other viruses cannot be neglected, such as the influenza virus, respiratory syncytial virus, human adenovirus. These viruses thrive in closed spaces, influenced by human and environmental factors. High-risk closed communities are the most vulnerable settings, where the real extent of viral ARIs is often difficult to evaluate, due to the natural disease progression and case identification complexities. During the COVID-19 pandemic, wastewater-based epidemiology has demonstrated its great potential for monitoring the circulation and evolution of the virus in the environment. The “Prevention of ARIs in indoor environments and vulnerable communities” study (Stell-ARI) addresses the urgent need for integrated surveillance and early detection of ARIs within enclosed and vulnerable communities such as Long-Term Care Facilities (LTCFs), prisons and primary schools. The rapid transmission of ARIs in such environments underscores the importance of comprehensive surveillance strategies to minimise the risk of outbreaks and safeguard community health, enabling proactive prevention and control strategies to protect the health of vulnerable populations.Methods The Stell-ARI study consists of designing and validating tools for integrated clinical and environmental-based surveillance for each setting, coupled with analytical methods for environmental matrices. The study design encompasses the development of specialised clinical surveillance involving pseudonymized questionnaires and nasopharyngeal swabs for virus identification, while the environmental surveillance includes air and surface microbiological and chemical monitoring, and virological analysis of wastewater. Integrating this information and the collection of behavioural and environmental risk factors into predictive and risk assessment models will provide a useful tool for early warning, risk assessment and informed decision-making.Discussion This study seeks to integrate clinical, behavioural, and environmental data to establish and validate a predictive model and risk assessment tool for the early warning and risk management of viral ARIs in closed and vulnerable communities prior to the onset of an outbreak.

Coevolution of Neural Architectures and Features for Stock Market Forecasting: A Multi-objective Decision Perspective (preprint)

In a multi objective setting, a portfolio manager's highly consequential decisions can benefit from assessing alternative forecasting models of stock index movement. The present investigation proposes a new approach to identify a set of nondominated neural network models for further selection by the decision maker. A new coevolution approach is proposed to simultaneously select the features and topology of neural networks (collectively referred to as neural architecture), where the features are viewed from a topological perspective as input neurons. Further, the coevolution is posed as a multicriteria problem to evolve sparse and efficacious neural architectures. The well known dominance and decomposition based multiobjective evolutionary algorithms are augmented with a nongeometric crossover operator to diversify and balance the search for neural architectures across conflicting criteria. Moreover, the coevolution is augmented to accommodate the data based implications of distinct market behaviors prior to and during the ongoing COVID 19 pandemic. A detailed comparative evaluation is carried out with the conventional sequential approach of feature selection followed by neural topology design, as well as a scalarized coevolution approach. The results on the NASDAQ index in pre and peri COVID time windows convincingly demonstrate that the proposed coevolution approach can evolve a set of nondominated neural forecasting models with better generalization capabilities.

A comparison of four self-controlled study designs in an analysis of COVID-19 vaccines and myocarditis using five European databases (preprint)

IntroductionThe aim of this study was to assess the possible extent of bias due to violation of a core assumption (event-dependent exposures) when using self-controlled designs to analyse the association between COVID-19 vaccines and myocarditis. MethodsWe used data from five European databases (Spain: BIFAP, FISABIO VID, and SIDIAP; Italy: ARS-Tuscany; England: CPRD Aurum) converted to the ConcePTION Common Data Model. Individuals who experienced both myocarditis and were vaccinated against COVID-19 between 1 September 2020 and the end of data availability in each country were included. We compared a self-controlled risk interval study (SCRI) using a pre-vaccination control window, an SCRI using a post-vaccination control window, a standard SCCS and an extension of the SCCS designed to handle violations of the assumption of event-dependent exposures. ResultsWe included 1,757 cases of myocarditis. In unadjusted analyses, agreement between study designs varied by vaccine brand. There was good agreement between all designs for AstraZeneca and Pfizer, but for Moderna we found harmful incidence rate ratios (IRR) using the standard and extended SCCS (standard SCCS: IRR = 3.12, 95%CI = 1.53 - 6.40; extended SCCS: IRR = 2.43, 95%CI = 1.11 - 5.33) compared with no association with the SCRIs (SCRI-pre: IRR = 0.60, 95%CI = 0.27 - 1.33; SCRI-post: IRR = 0.86, 95%CI = 0.34 - 2.19), although confidence intervals were wide. There was very good agreement between all designs for the unadjusted second dose analyses, confirming the known harmful association between the second dose of Moderna and Pfizer vaccines and myocarditis. ConclusionsIn the context of the known association between COVID-19 vaccines and myocarditis, we have demonstrated that two forms of SCRI and two forms of SCCS led to largely comparable results, possibly because of limited violation of the assumption of event-dependent exposures.

Comparative Organ Disease Burden and Sequelae of Influenza and SARS-CoV-2 Infection: An Observational Study Using Real-World Data (preprint)

Infections with SARS-CoV-2 and influenza are associated with acute and post-acute complications and sequelae of many organ systems (i.e., disease burden). It is important to understand the global disease burden that associates with and follows acute infection in order to establish preventive and therapeutic strategies and to reduce the use of health resources and improve patient health outcomes. To address these questions, we utilized the National Covid Cohort Collaborative, which is an integrated and harmonized data repository of electronic health record data in the USA. From this database, we included in analysis 346,648 eligible SARS-CoV-2-infected patients, 78,086 eligible influenza infected patients, and 146,635 uninfected controls. We describe the disease burden that extends over 2-3 months following infection, and we quantify the reduction of disease burden by treatment. We identify a burden of disease following medically attended influenza that is comparable to that of medically attended SARS-CoV-2 infection. However, in contrast to SARS-CoV-2, influenza acute infection and disease burden are not responsive to antiviral treatment and thus remain as an unmet medical need. Focusing therapeutic strategies solely on the short-term management of acute infection may also underestimate the extended health benefits of antiviral treatment.

A comprehensive study of SARS-CoV-2 main protease (Mpro) inhibitor-resistant mutants selected in a VSV-based system (preprint)

Nirmatrelvir was the first protease inhibitor (PI) specifically developed against the SARS-CoV-2 main protease (3CLpro/Mpro) and licensed for clinical use. As SARS-CoV-2 continues to spread, variants resistant to nirmatrelvir and other currently available treatments are likely to arise. This study aimed to identify and characterize mutations that confer resistance to nirmatrelvir. To safely generate Mpro resistance mutations, we passaged a previously developed chimeric vesicular stomatitis virus (VSV-Mpro) with increasing, yet suboptimal concentrations of nirmatrelvir, using Wuhan-1 and Omicron Mpro variants, and selected a large set of mutants. Some mutations are frequently present in GISAID, suggesting their relevance in SARS-CoV-2. The resistance phenotype of a subset of mutations was characterized against clinically available PIs (nirmatrelvir and ensitrelvir) with cell-based and biochemical assays. Moreover, we showed the putative molecular mechanism of resistance based on in silico molecular modelling. These findings will help to understand SARS-CoV-2 protease-inhibitor-resistance mechanisms, the relevance of specific in the clinic and thereby inform treatment decisions.

Broad receptor tropism and immunogenicity of a clade 3 sarbecovirus (preprint)

Although Rhinolophus bats harbor diverse clade 3 sarbecoviruses, the structural determinants of receptor tropism along with the antigenicity of their spike (S) glycoproteins remain uncharacterized. Here, we show that the African Rinolophus bat clade 3 sarbecovirus PRD-0038 S has a broad ACE2 usage and that RBD mutations further expand receptor promiscuity and enable human ACE2 utilization. We determined a cryoEM structure of the PRD-0038 RBD bound to R. alcyone ACE2, explaining receptor tropism and highlighting differences with SARS-CoV-1 and SARS-CoV-2. Characterization of PRD-0038 S using cryoEM and monoclonal antibody reactivity revealed its distinct antigenicity relative to SARS-CoV-2 and identified PRD-0038 cross-neutralizing antibodies for pandemic preparedness. PRD-0038 S vaccination elicited greater titers of antibodies cross-reacting with vaccine-mismatched clade 2 and clade 1a sarbecoviruses compared to SARS-CoV-2 S due to broader antigenic targeting, motivating the inclusion of clade 3 antigens in next-generation vaccines for enhanced resilience to viral evolution.

PG-Triggers: Triggers for Property Graphs (preprint)

Graph databases are emerging as the leading data management technology for storing large knowledge graphs; significant efforts are ongoing to produce new standards (such as the Graph Query Language, GQL), as well as enrich them with properties, types, schemas, and keys. In this article, we introduce PG-Triggers, a complete proposal for adding triggers to Property Graphs, along the direction marked by the SQL3 Standard. We define the syntax and semantics of PG-Triggers and then illustrate how they can be implemented on top of Neo4j, one of the most popular graph databases. In particular, we introduce a syntax-directed translation from PG-Triggers into Neo4j, which makes use of the so-called {\it APOC triggers}; APOC is a community-contributed library for augmenting the Cypher query language supported by Neo4j. We also cover Memgraph, and show that our approach applies to this system in a similar way. We illustrate the use of PG-Triggers through a life science application inspired by the COVID-19 pandemic. The main objective of this article is to introduce an active database standard for graph databases as a first-class citizen at a time when reactive graph management is in its infancy, so as to minimize the conversion efforts towards a full-fledged standard proposal.

Age differentially affects the maintenance of adaptive immune responses induced by adenoviral versus mRNA vaccines against COVID-19 (preprint)

Adenoviral and mRNA vaccines encoding the viral spike protein have been deployed globally to contain SARS-CoV-2. Elderly individuals are particularly vulnerable to severe infection, likely reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It has nonetheless remained unclear to what extent different vaccine platforms are impacted by immunosenescence. Here, we evaluated spike-specific immune responses elicited by vaccination with two doses of BNT162b2 or ChAdOx1-S and subsequently boosted with a single dose of BNT162b2 or mRNA-1273, comparing age-stratified participants with no evidence of prior infection with SARS-CoV-2. We found that ageing profoundly affected the durability of humoral responses and further limited spike-specific CD4+ T cell immunity as a function of progressive erosion of the naive lymphocyte pool in individuals vaccinated initially with BNT162b2, such that protective immunological memory was best maintained in the elderly after primary vaccination with ChAdOx1-S and subsequent boosting with BNT162b2 or mRNA-1273.

Infectious diseases and social distancing under state-dependent probabilities.

We analyze the implications of infectious diseases and social distancing in an extended SIS framework to allow for the presence of stochastic shocks with state dependent probabilities. Random shocks give rise to the diffusion of a new strain of the disease which affects both the number of infectives and the average biological characteristics of the pathogen causing the disease. The probability of such shock realizations changes with the level of disease prevalence and we analyze how the properties of the state-dependent probability function affect the long run epidemiological outcome which is characterized by an invariant probability distribution supported on a range of positive prevalence levels. We show that social distancing reduces the size of the support of the steady state distribution decreasing thus the variability of disease prevalence, but in so doing it also shifts the support rightward allowing eventually for more infectives than in an uncontrolled framework. Nevertheless, social distancing is an effective control measure since it concentrates most of the mass of the distribution toward the lower extreme of its support.

University and COVID-19: The Experience of the Academic Community of the Single-Cycle Master's Degree in Law of the University of Genoa

The article focuses on challenges and disruption in the higher education sector in Italy due to COVID-19 pandemic. The study explores the experience of the Single-Cycle Master's Degree in Law of the University of Genoa, especially taking into account students' perspective.

What is hidden in the luggage? First assessments of illegal seashells gathering in Sardinia (Italy)

Natural souvenirs collection has been identified as a driving force in biodiversity and habitat degradation of tropical marine ecosystems. This work considers this phenomenon in the Mediterranean region taking Sardinia (Italy), one of the most renowned tourism destinations, as a case study. The biological material seized at Cagliari-Elmas Airport (years 2019–2020: 138 kg) was analyzed: 199 taxa were identified, gastropods (112 species, 7866 pieces) and bivalves (63 species, 34,218 pieces) resulted the most represented classes. Twenty-two protected species were found in the tourists' luggage including Patella ferruginea and Pinna nobilis, the invertebrates most threatened with extinction in the Mediterranean Sea. This study demonstrates that the illegal collection of natural mementos is common in Sardinia, thus its relevance is not limited to tropical regions. Regulation, enforcement and compliance shortcomings emerged, highlighting the importance of strengthening stakeholders' collaboration for a deeper insight on this phenomenon and implementing effective conservation strategies.

Anemia as a risk factor for disease progression in patients admitted for COVID-19: data from a large, multicenter cohort study.

In respiratory infections, anemia is both a consequence of acute inflammation and a predictor of poor clinical outcomes. There are few studies investigating the role of anemia in COVID-19, suggesting a potential role in predicting disease severity. In this study, we aimed to assess the association between the presence of anemia at admission and incidence of severe disease and death in patients hospitalized for COVID-19. Data from all adult patients admitted for COVID-19 in University Hospital "P. Giaccone" Palermo, and University Hospital of Bari, Italy, were retrospectively collected from 1st of September 2020 to 31 August 2022. The association between anemia (defined as Hb < 13 g/dl and < 12 g/dl in males and females, respectively), in-hospital mortality and severe COVID-19 was tested using a Cox's regression analysis. Severe COVID-19 forms were defined as admission to intensive or sub-intensive care unit or a qSOFAscore ≥ 2 or CURB65scores ≥ 3. p values were calculated using the Student's t test for continuous variables and the Mantel-Haenszel Chi-square test for categorical ones. The association between anemia and the mortality was made using a Cox's regression analysis, adjusted, in two models, for the potential confounders and using a propensity score. Among the 1562 patients included in the analysis, prevalence of anemia was 45.1% (95% CI 43-48%). Patients with anemia were significantly older (p < 0.0001), reported more co-morbidities, and presented higher baseline levels of procalcitonin, CRP, ferritin and IL-6. Overall, the crude incidence of mortality was about four times higher in patients with anemia compared to those without. After adjusting for 17 potential confounders, the presence of anemia significantly increased the risk of death (HR = 2.68; 95% CI: 1.59-4.52) and of risk of severe COVID-19 (OR = 2.31; 95% CI: 1.65-3.24). The propensity score analysis substantially confirmed these analyses. Our study provides evidence that, in patients hospitalized for COVID-19, anemia is both associated with a more pronounced baseline pro-inflammatory profile and higher incidence of in-hospital mortality and severe disease.

Can COVID-19 pandemic surveillance reduce nosocomial urinary infections in urologic surgery?

INTRODUCTION: Since COVID-19 pandemic spread, strict preventive measures were adopted to reduce the risk of transmission. Antiseptic dispensers for hand hygiene were diffusely available for patients and hospital staff. To investigate the prophylactic role played by the strict antiseptic rules adopted during pandemic, the rates of nosocomial urinary infections in 2019 and 2020 were compared. MATERIALS AND METHODS: Patients' clinical pre-operative characteristics, symptoms, fever, and laboratory data were recorded pre- and post-operatively. Urological surgery was classified in five categories: 1. major surgery 2. upper urinary tract endoscopy, 3. lower urinary tract endoscopy, 4. minor surgery, and 5. Nephrostomy and ureteral stenting. Clavien-Dindo complication score was used. Statistical analysis was performed with R 3.4.2 software. RESULTS: Out of 495 patients, 383 (57.1%) underwent surgical intervention in pre-pandemic March-May 2019 period and 212 (42.9%) in the same pandemic 2020 interval. Preoperatively, 40 (14.1%) and 11 (5.2%) and 77 (27.3%) and 37 (17.5%) patients had fever (p < 0.003) and leukocytosis (p < 0.02), in 2019 and 2020 respectively. Urine culture was positive in 29 (10.2%) and 13 (6.2%) patients respectively (p = 0.22). Post-operatively, 54 (19.1%) and 22 (10.4%) patients and 17 (6.1%) and 2 (0.6%) patients showed fever (p < 0.003) and positive urineculture (p < 0.03), in 2019 and 2020 respectively. DISCUSSION AND CONCLUSION: Preoperative and post-operative clinical and laboratory signs of nosocomial urinary infection showed a statistically significant lower incidence during the pandemic period in 2020. This observation could be ascribed to the strong preventive measures, to the medical staff high adherence to hygiene and the diffuse availability of hand sanitizers.