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Background. Pseudomonas aeruginosa is one of the major concerns among bacterial diseases even when it shows a wild-type susceptibility pattern. In 2020, EUCAST reconsidered antibiogram interpretation shifting “I” from “intermediate” to “sensible, increased exposure” with possible significant impact on antibiotic prescription. The aim of this study was to evaluate mortality in patients with P. aeruginosa bloodstream infections treated with antipseudomonal penicillins or cephalosporins vs. carbapenems and ceftazidime/avibactam. Methods. This is a retrospective observational study. All the patients with a bloodstream infection due to P. aeruginosa admitted to our hospital were enrolled. Exclusion criteria were as follows: extremely critical conditions, age p > 0.1). In group A, in-hospital BSI-related mortality was 23.2% (13/56), while it was 14.3% (3/21) in group B (p > 0.1). After multivariate analysis, only the PITT score represented a risk factor for BSI-related mortality (OR 2.917, 95% CI 1.381–6.163). Conclusions. Both all-cause and BSI-related mortality were comparable between the two groups. Treatment with carbapenem or ceftazidime/avibactam did not represent a protective factor for mortality in wild-type P. aeruginosa BSI.

In this article, we present the evaluation of a kindergarten teachers' professional development programme, 'Upgrading the quality of the pre-school environment' conducted by the participating teacher--thee programme is aimed at the improvement of the quality of Early Childhood Education and Care. The evaluation, which followed a mixed-method design, combining quantitative and qualitative approaches, was based on Guskey's (2002) five levels model. ?he Interconnected Model of Teacher Professional Growth (Clarke, D., & Hollingsworth, H., 2002) was used to study participants' professional growth. Fourteen teachers serving in public Kindergartens in Greece participated in this study (n=14). Findings showed that the overall programme, the acquisition of knowledge and competences and the possibility of their application in the teaching practice were assessed as positive. The significance of a supportive context in the application of new knowledge and practices was also outlined. Moreover, the main correlations between domains of the Interconnected Model of Teacher Professional Growth are presented, which depict the sequences through which the changes in the teachers occurred. Therefore the present research provides valuable information regarding the design of future professional development programmes aiming to improve the quality of the preschool environment.

Background: Bictegravir (BIC), a recently introduced integrase inhibitor, is available in a single tablet regimen with tenofovir alafenamide (TAF) and emtricitabine (FTC) (BIC-STR). This study aimed to describe a real-life experience with BIC-STR. Methods: We retrospectively analyzed the data of people living with HIV (PLWH) on antiretroviral therapy (ART) with BIC-STR followed by the Clinic of Infectious Diseases of Perugia (Perugia, Italy) from September 2019 to February 2023. Results: 270 PLWH were enrolled with a median follow-up time on BIC-STR of 2.2 years (IQR 1.2–2.7). In the overall population, in treatment-experienced (N = 242), in treatment-naïve (N = 28), and in population with age > 60 years old (N = 86), we observed that CD4 cell count improved in absolute number, percentage and CD4/CD8 ratio, under BIC-STR. Patients with viremia < 50 cp/mL increased in all groups. In the overall population, previous ART with TAF and nadir CD4 cell count favored immunological recovery. In the ART-experienced group, time in therapy with BIC-STR was associated with HIV-RNA undetectability. In the older group, previous opportunistic infection and advanced age were associated with lower CD4 count. Conclusions: BIC-STR was demonstrated, in real-life, to be a valid option for a switch, such as initial ART.

Sublethal exposure to insecticides can adversely impact various biological and behavioral characteristics of insects. Although α-cypermethrin has been previously tested for its effects on control of Alphitobius diaperinus, there is no knowledge about the effect of this insecticide on its behavioral asymmetries and mating success. Μales at all exposures (control, LC10, and LC30), that first approached their mate, showed right-biased tendency (approached their mate from their right side) in mate recognition. Females, however, showed variation in this behavior between the three exposures. Right-biased tendency of males in all treatment scenarios led to a higher percentage of successful copulations compared to the three other directions. For males that first approached their mate, the insecticide did not affect their lateralization of the first approach but did affect their copulation success. The duration of copulation time was reduced after the exposure to the insecticide, with the longest duration noted in the control females (63.0 s) and the lowest in the α-cypermethrin LC30 females (46.9 s). Moreover, at the α-cypermethrin LC10 exposure, mate recognition time was reduced, as opposed to α-cypermethrin LC30 exposure where mate recognition time was increased. These results can be further utilized to uncover the behavioral impacts of insecticides, enhancing the effectiveness of pest management in warehouses and poultry production facilities.

Aspergillus fumigatus is an environmental fungus recently included in the fungal high-priority pathogens by the World Health Organization. While immunodeficiency and/or pre-existing lung damage represent a well-recognized fertile ground for fungal growth, it is increasingly being recognized that severe viral infections may similarly favor A. fumigatus colonization and infection, as recently experienced in the Coronavirus disease 2019 (COVID-19) pandemic. Herein, in a murine model of COVID-19-associated pulmonary aspergillosis (CAPA), obtained by the concomitant exposure to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein and A. fumigatus conidia, we found that the microbial compound indole-3-aldehyde (3-IAld) was able to ameliorate CAPA by working at multiple levels during viral infection and fungal superinfection, including epithelial barrier protection, promotion of antiviral responses, and limiting viral replication. As a consequence, 3-IAld limited the pathogenic sequelae of fungal superinfection as revealed by the controlled fungal burden and restrained inflammatory pathology. These results point to indole compounds as potential agents to prevent CAPA.

Chlorantraniliprole, an anthranilic diamide insecticide, has emerged as a promising solution for controlling agricultural pests because of its low mammalian toxicity and selectivity towards non-target organisms. This study investigated the sublethal effects of chlorantraniliprole on the mobility behavior of two significant stored-product pests, Sitophilus oryzae (L.) and Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae). Contact toxicity assays revealed varying susceptibility levels between the two species, with S. zeamais showing higher sensitivity. Subsequent analysis of mobility behavior, both in the presence and absence of food, indicated significant differences between chlorantraniliprole-exposed and control groups. While S. oryzae exhibited altered locomotion patterns and a decreased number of food approaches at sublethal concentrations, S. zeamais displayed increased walking time and reduced immobility periods. These findings highlight the importance of considering sublethal effects in understanding the overall impact of chlorantraniliprole on stored-product pests. Further research into the long-term consequences of sublethal exposure is warranted to inform more effective pest management strategies in storage.

Non-structural protein 5 (Nsp5) is a cysteine protease that plays a key role in SARS-CoV-2 replication, suppressing host protein synthesis and promoting immune evasion. The investigation of natural products as a potential strategy for Nsp5 inhibition is gaining attention as a means of developing antiviral agents. In this work, we have investigated the physicochemical properties and structure-activity relationships of ellagic acid and its gut metabolites, urolithins A–D, as ligands of Nsp5. Results allow us to identify urolithin D as promising ligand of Nsp5, with a dissociation constant in the nanomolar range of potency. Although urolithin D is able to bind to the catalytic cleft of Nsp5, the appraisal of its viral replication inhibition against SARS-CoV-2 in Vero E6 assay highlights a lack of activity. While these results are discussed in the framework of the available literature reporting conflicting data on polyphenol antiviral activity, they provide new clues for natural products as potential viral protease inhibitors.

Background: this study aims to evaluate the efficacy of tixagevimab/cilgavimab (Evusheld™) against various SARS-CoV-2 variants, including newer Omicron sublineages, in an immunocompromised cohort and in vitro. Study design: Conducted in Italy, this research involves immunocompromised patients who received Evusheld. It evaluates serum neutralization activity against different SARS-CoV-2 strains (20A.EU1, BA.5, BQ.1, XBB.1.5, XBB.1.16, and EG.5) before (T0), after 14 (T1), and after 30 (T2) days from the tixagevimab/cilgavimab injection. Furthermore, the in vitro activity of Evusheld against SARS-CoV-2 VOCs was evaluated. Results: The cohort was composed of 72 immunocompromised patients. The serum neutralizing activity of tixagevimab/cilgavimab-treated patients was notably lower against newer variants such as BQ.1, XBB.1.5, XBB.1.16, and EG.5. Then, the in vitro study detailed specific EC50 values to quantify the activity of tixagevimab/cilgavimab against various SARS-CoV-2 VOCs. Newer variants like BQ.1 and XBB.1.5 exhibited notably lower neutralization, underscoring the challenges in effectively countering the evolving virus. Interestingly, tixagevimab/cilgavimab maintained reduced but still valid activity against EG.5 with an EC50 of 189 ng/mL and Cmax/EC90 of 110.7. Conclusions: Tixagevimab/cilgavimab efficacy wanes against novel subvariants. This underscores the critical need for ongoing adaptation and vigilance in prophylactic strategies to effectively counter the dynamic and unpredictable nature of the COVID-19 pandemic.

The Apiaceae family, known for aromatic plants producing bioactive essential oils (EOs), holds significance across sectors, including agrochemicals. This study evaluated the insecticidal potential of four Apiaceae EOs from Crithmum maritimum L., Trachyspermum ammi (L.) Sprague ex Turrill, Smyrnium olusatrum L., and Elwendia persica (Boiss.) Pimenov and Kljuykov against various significant storage pests (Sitophilus oryzae (L.), Trogoderma granarium Everts, Rhyzopertha dominica (F.), Tribolium castaneum (Herbst), T. confusum Jacquelin du Val, Oryzaephilus surinamensis (L.), Alphitobius diaperinus (Panzer), Acarus siro L., and Tenebrio molitor L.) on wheat. Insect mortality rates were monitored at intervals of 1, 2, 3, 4, 5, 6, and 7 days. Smyrnium olusatrum EO exhibited the highest efficacy, followed by T. ammi, C. maritimum, and E. persica EOs, although efficacy varied by species, developmental stage, and concentration. Notably, complete mortality occurred for several pests at 1000 ppm of S. olusatrum and T. ammi EOs. Gas chromatography–mass spectrometry (GC–MS) analysis revealed key compounds in these EOs, including myrcene, germacrone, and curzerene in S. olusatrum EO, and thymol, γ-terpinene, and p-cymene in T. ammi EO. These findings emphasize their potential as botanical insecticides. Smyrnium olusatrum and T. ammi EOs emerge as promising eco-friendly pest management options due to their efficacy, highlighted compound composition, and availability of biomass from both wild and cultivated sources.

Simple Summary: This study investigated the behavioral asymmetries and mating success of Alphitobius diaperinus (Panzer) (Coleoptera: Tenebrionidae) under sublethal exposures to α-cypermethrin. Control males exhibited a right-side bias, which increased the likelihood of successful copulation, especially when head butts preceded mounting. A similar pattern was observed for LC10-exposed males, though their success rate slightly declined. In females, the right-side approach also enhanced copulation success. The direction of approach and mounting influenced the time required for key mating behaviors like mate detection and mounting. Males exposed to LC30 of α-cypermethrin needed a longer time for mate detection compared to control and LC10, especially when approaching from the back or front side. Females of the LC30 group were also influenced, with shorter copulation times when approaching from the right. These findings demonstrate that α-cypermethrin affects both mating success and the duration of related behaviors. Sublethal exposure to insecticides can adversely impact various biological and behavioral characteristics of insects. Although α-cypermethrin has been previously tested for its effects on control of Alphitobius diaperinus, there is no knowledge about the effect of this insecticide on its behavioral asymmetries and mating success. Μales at all exposures (control, LC10, and LC30), that first approached their mate, showed right-biased tendency (approached their mate from their right side) in mate recognition. Females, however, showed variation in this behavior between the three exposures. Right-biased tendency of males in all treatment scenarios led to a higher percentage of successful copulations compared to the three other directions. For males that first approached their mate, the insecticide did not affect their lateralization of the first approach but did affect their copulation success. The duration of copulation time was reduced after the exposure to the insecticide, with the longest duration noted in the control females (63.0 s) and the lowest in the α-cypermethrin LC30 females (46.9 s). Moreover, at the α-cypermethrin LC10 exposure, mate recognition time was reduced, as opposed to α-cypermethrin LC30 exposure where mate recognition time was increased. These results can be further utilized to uncover the behavioral impacts of insecticides, enhancing the effectiveness of pest management in warehouses and poultry production facilities. [ABSTRACT FROM AUTHOR]

Background. Pseudomonas aeruginosa is one of the major concerns among bacterial diseases even when it shows a wild-type susceptibility pattern. In 2020, EUCAST reconsidered antibiogram interpretation shifting "I" from "intermediate" to "sensible, increased exposure" with possible significant impact on antibiotic prescription. The aim of this study was to evaluate mortality in patients with P. aeruginosa bloodstream infections treated with antipseudomonal penicillins or cephalosporins vs. carbapenems and ceftazidime/avibactam. Methods. This is a retrospective observational study. All the patients with a bloodstream infection due to P. aeruginosa admitted to our hospital were enrolled. Exclusion criteria were as follows: extremely critical conditions, age <18 years, pregnancy, isolation of a strain non-susceptible to piperacillin/tazobactam and antipseudomonal cephalosporins. Patients were divided into group A (treatment with carbapenems or ceftazidime/tazobactam) and group B (treatment with antipseudomonal penicillin or cephalosporins). Results. We enrolled 77 patients, 56 and 21 in groups A and B, respectively. The two groups were homogeneous for age, sex, and biochemical and clinical characteristics at admission. All-cause in-hospital mortality was 17/56 (30.4%) and 3/21 (14.3%) in groups A and B, respectively (p > 0.1). In group A, in-hospital BSI-related mortality was 23.2% (13/56), while it was 14.3% (3/21) in group B (p > 0.1). After multivariate analysis, only the PITT score represented a risk factor for BSI-related mortality (OR 2.917, 95% CI 1.381–6.163). Conclusions. Both all-cause and BSI-related mortality were comparable between the two groups. Treatment with carbapenem or ceftazidime/avibactam did not represent a protective factor for mortality in wild-type P. aeruginosa BSI. [ABSTRACT FROM AUTHOR]

BACKGROUND: Mortality caused by various pyrethroids, and neonicotinoids has been studied for stored‐product insects in the past, yet limited information exists on the sublethal effects they can induce to Oryzaephilus surinamensis. In the current study, the sublethal effects of deltamethrin, λ‐cyhalothrin, α‐cypermethrin, etofenprox, and the mixture of acetamiprid with d‐tetramethrin and piperonyl butoxide on the mobility of O. surinamensis in the presence or the absence of a food source was investigated. RESULTS: Lethal concentrations (LCs) were lower for deltamethrin, α‐cypermethrin, and λ‐cyhalothrin (LC10 = 0.000233, 0.000211, and 0.000271 mg active ingredient (a.i.) cm−2, LC30 = 0.000413, 0.000398, and 0.000447 mg a.i. cm−2, respectively), followed by etofenprox, and the mixture of acetamiprid with d‐tetramethrin and piperonyl butoxide (LC10 = 0.00228 and 0.003267 mg a.i. cm−2, LC30 = 0.00437 and 0.01188 mg a.i. cm−2, respectively). Deltamethrin and λ‐cyhalothrin negatively impacted adult walking behavior, increasing stop durations compared to controls. Adults exposed to LC10 and LC30 of λ‐cyhalothrin, and LC30 of deltamethrin exhibited prolonged periods on their backs compared to the remaining treatments and the controls. The α‐cypermethrin LC30‐exposed adults exhibited significantly shorter walking and stopping durations than controls but demonstrated prolonged climbing on the arena walls compared to adults exposed to the remaining a.i. and the control. A similar trend was observed for etofenprox. CONCLUSIONS: Under sublethal concentrations, λ‐cyhalothrin and deltamethrin increased stop intervals and reduced the duration of climbing attempts of O. surinamensis versus α‐cypermethrin. These findings advance comprehension of the underexplored sublethal impacts of the tested a.i. on O. surinamensis adults, holding potential for leveraging insecticide‐induced behavioral effects to enhance warehouse pest management. © 2024 The Author(s). Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Background: This study aims to investigate the activity of the remdesivir–nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination. Methods: A Vero E6 cell-based infection assay was used to investigate the in vitro activity of the remdesivir–nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic. Results: Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h, with an HSA score of 52.8 and 28.6, respectively (p < 0.0001). These data were confirmed by performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and dexamethasone, with an excellent clinical–radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir until she tested negative. Conclusions: Remdesivir–nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding.

Background and Objective: In patients with mild-to-moderate COVID-19 and at high risk of progression, casirivimab/imdevimab and bamlanivimab/etesivimab were utilized in Umbria from late April to November 2021. This period was characterized by an initial prevalence of alpha (B1.1.1.7) and its progressive substitution with the delta variant (B1.617.2). Many delta infections occurred in patients already recently vaccinated. Our study aimed to observe the clinical outcome of patients treated with mAbs associations in a subgroup in which viral isolation was obtained, the pre and post-infusion neutralizing antibody activity against their viral isolate. Methods: In this retrospective observational study, the clinical outcome before and 30 days after infusion, the baseline neutralizing activity of sera against their viral isolate, and the titers of neutralizing antibodies (NAbTs) one-hour post-infusion relative to the type of mAbs associations were evaluated. Results: Better efficacy of the mAbs combinations relative to monotherapy regarding global hospitalization (p = 0.021) and 30 days symptoms (p

Aspergillus fumigatus is an environmental fungus recently included in the fungal high-priority pathogens by the World Health Organization. While immunodeficiency and/or pre-existing lung damage represent a well-recognized fertile ground for fungal growth, it is increasingly being recognized that severe viral infections may similarly favor A. fumigatus colonization and infection, as recently experienced in the Coronavirus disease 2019 (COVID-19) pandemic. Herein, in a murine model of COVID-19-associated pulmonary aspergillosis (CAPA), obtained by the concomitant exposure to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike protein and A. fumigatus conidia, we found that the microbial compound indole-3-aldehyde (3-IAld) was able to ameliorate CAPA by working at multiple levels during viral infection and fungal superinfection, including epithelial barrier protection, promotion of antiviral responses, and limiting viral replication. As a consequence, 3-IAld limited the pathogenic sequelae of fungal superinfection as revealed by the controlled fungal burden and restrained inflammatory pathology. These results point to indole compounds as potential agents to prevent CAPA. [ABSTRACT FROM AUTHOR]

Simple Summary: This study investigates the sublethal effects of chlorantraniliprole, an insecticide known for its low toxicity to mammals and selectivity towards non-target organisms, on two significant stored-product pests, Sitophilus oryzae (L.) and Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae). Through contact toxicity assays, differences in susceptibility between the two species are observed, with S. zeamais showing higher sensitivity. Subsequent analysis reveals altered mobility behavior in chlorantraniliprole-exposed groups compared with controls, particularly in S. oryzae, which displays reduced number of food approaches and altered locomotion patterns. In contrast, S. zeamais exhibits increased walking time and decreased immobility periods under sublethal concentrations. These findings underscore the importance of considering sublethal effects in understanding the overall impact of chlorantraniliprole on stored-product pest populations. Further exploration into the long-term consequences of sublethal exposure is recommended to enhance pest management strategies. Chlorantraniliprole, an anthranilic diamide insecticide, has emerged as a promising solution for controlling agricultural pests because of its low mammalian toxicity and selectivity towards non-target organisms. This study investigated the sublethal effects of chlorantraniliprole on the mobility behavior of two significant stored-product pests, Sitophilus oryzae (L.) and Sitophilus zeamais Motschulsky (Coleoptera: Curculionidae). Contact toxicity assays revealed varying susceptibility levels between the two species, with S. zeamais showing higher sensitivity. Subsequent analysis of mobility behavior, both in the presence and absence of food, indicated significant differences between chlorantraniliprole-exposed and control groups. While S. oryzae exhibited altered locomotion patterns and a decreased number of food approaches at sublethal concentrations, S. zeamais displayed increased walking time and reduced immobility periods. These findings highlight the importance of considering sublethal effects in understanding the overall impact of chlorantraniliprole on stored-product pests. Further research into the long-term consequences of sublethal exposure is warranted to inform more effective pest management strategies in storage. [ABSTRACT FROM AUTHOR]

After almost three years of the pandemic, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is still spreading around the world, causing notable sanitary and social issues. New antiviral therapies are constantly under investigation. However, few options have been approved for the treatment of COVID-19. Clinical trials are currently ongoing to evaluate the efficacy of nelfinavir on mild–moderate COVID-19. This study aims to investigate the activity of this compound on SARS-CoV-2 “Variants of Concern” (VOCs), comparing its effectiveness with the approved drugs remdesivir and molnupiravir. The experiments were conducted in a biosafety level 3 facility. In this study, we used a Vero-E6-cell-based infection assay to investigate the in vitro activity of nelfinavir, molnupiravir, and remdesivir. Four strains of SARS-CoV-2 were tested: 20A.EU1, B.1.1.7, P.1, and B.1.617.2. All compounds reached micromolar/submicromolar EC50, EC90, and EC99. Furthermore, the Cmax/EC50 and Cmax/EC90 ratios were >1 for all compounds and all variants tested. Our study demonstrated that nelfinavir, as molnupiravir, and remdesivir are effective in vitro on SARS-CoV-2 variants.

Viral infections sustain their replication cycle promoting a pro-oxidant environment in the host cell. In this context, specific alterations of the levels and homeostatic function of the tripeptide glutathione have been reported to play a causal role in the pro-oxidant and cytopathic effects (CPE) of the virus. In this study, these aspects were investigated for the first time in SARS-CoV2-infected Vero E6 cells, a reliable and well-characterized in vitro model of this infection. SARS-CoV2 markedly decreased the levels of cellular thiols, essentially lowering the reduced form of glutathione (GSH). Such an important defect occurred early in the CPE process (in the first 24 hpi). Thiol analysis in N-acetyl-Cys (NAC)-treated cells and membrane transporter expression data demonstrated that both a lowered uptake of the GSH biosynthesis precursor Cys and an increased efflux of cellular thiols, could play a role in this context. Increased levels of oxidized glutathione (GSSG) and protein glutathionylation were also observed along with upregulation of the ER stress marker PERK. The antiviral drugs Remdesivir (Rem) and Nelfinavir (Nel) influenced these changes at different levels, essentially confirming the importance or blocking viral replication to prevent GSH depletion in the host cell. Accordingly, Nel, the most potent antiviral in our in vitro study, produced a timely activation of Nrf2 transcription factor and a GSH enhancing response that synergized with NAC to restore GSH levels in the infected cells. Despite poor in vitro antiviral potency and GSH enhancing function, Rem treatment was found to prevent the SARS-CoV2-induced glutathionylation of cellular proteins. In conclusion, SARS-CoV2 infection impairs the metabolism of cellular glutathione. NAC and the antiviral Nel can prevent such defect in vitro.

Background: this study aims to evaluate the efficacy of tixagevimab/cilgavimab (Evusheld™) against various SARS-CoV-2 variants, including newer Omicron sublineages, in an immunocompromised cohort and in vitro. Study design: Conducted in Italy, this research involves immunocompromised patients who received Evusheld. It evaluates serum neutralization activity against different SARS-CoV-2 strains (20A.EU1, BA.5, BQ.1, XBB.1.5, XBB.1.16, and EG.5) before (T0), after 14 (T1), and after 30 (T2) days from the tixagevimab/cilgavimab injection. Furthermore, the in vitro activity of Evusheld against SARS-CoV-2 VOCs was evaluated. Results: The cohort was composed of 72 immunocompromised patients. The serum neutralizing activity of tixagevimab/cilgavimab-treated patients was notably lower against newer variants such as BQ.1, XBB.1.5, XBB.1.16, and EG.5. Then, the in vitro study detailed specific EC50 values to quantify the activity of tixagevimab/cilgavimab against various SARS-CoV-2 VOCs. Newer variants like BQ.1 and XBB.1.5 exhibited notably lower neutralization, underscoring the challenges in effectively countering the evolving virus. Interestingly, tixagevimab/cilgavimab maintained reduced but still valid activity against EG.5 with an EC50 of 189 ng/mL and Cmax/EC90 of 110.7. Conclusions: Tixagevimab/cilgavimab efficacy wanes against novel subvariants. This underscores the critical need for ongoing adaptation and vigilance in prophylactic strategies to effectively counter the dynamic and unpredictable nature of the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Introduction: The development of effective vaccines has partially mitigated the trend of the SARS-CoV-2 pandemic; however, the need for orally administered antiviral drugs persists. This study aims to investigate the activity of molnupiravir in combination with nirmatrelvir or GC376 on SARS-CoV-2 to verify the synergistic effect. Methods: The SARS-CoV-2 strains 20A.EU, BA.1 and BA.2 were used to infect Vero E6 in presence of antiviral compounds alone or in combinations using five two-fold serial dilution of compound concentrations ≤EC90. After 48 and 72 h post-infection, viability was performed using MTT reduction assay. Supernatants were collected for plaque-assay titration. All experiments were performed in triplicate, each being repeated at least three times. The synergistic score was calculated using Synergy Finder version 2. Results: All compounds reached micromolar EC90. Molnupiravir and GC376 showed a synergistic activity at 48 h with an HSA score of 19.33 (p < 0.0001) and an additive activity at 72 h with an HSA score of 8.61 (p < 0.0001). Molnupiravir and nirmatrelvir showed a synergistic activity both at 48 h and 72 h with an HSA score of 14.2 (p = 0.01) and 13.08 (p < 0.0001), respectively. Conclusion: Molnupiravir associated with one of the two protease-inhibitors nirmatrelvir and GC376 showed good additive-synergic activity in vitro.

Newly emerging SARS-CoV-2 variants may escape monoclonal antibodies (mAbs) and antiviral drugs. By using live virus assays, we assessed the ex vivo inhibition of the B.1 wild-type (WT), delta and omicron BA.1 and BA.2 lineages by post-infusion sera from 40 individuals treated with bamlanivimab/etesevimab (BAM/ETE), casirivimab/imdevimab (CAS/IMD), and sotrovimab (SOT) as well as the activity of remdesivir, nirmatrelvir and molnupiravir. mAbs and drug activity were defined as the serum dilution (ID50) and drug concentration (IC50), respectively, showing 50% protection of virus-induced cytopathic effect. All pre-infusion sera were negative for SARS-CoV-2 neutralizing activity. BAM/ETE, CAS/IMD, and SOT showed activity against the WT (ID50 6295 (4355–8075) for BAM/ETE; 18,214 (16,248–21,365) for CAS/IMD; and 456 (265–592) for SOT) and the delta (14,780 (ID50 10,905–21,020) for BAM/ETE; 63,937 (47,211–79,971) for CAS/IMD; and 1103 (843–1334) for SOT). Notably, only SOT was active against BA.1 (ID50 200 (37–233)), whereas BA.2 was neutralized by CAS/IMD (ID50 174 (134–209) ID50) and SOT (ID50 20 (9–31) ID50), but not by BAM/ETE. No significant inter-variant IC50 differences were observed for molnupiravir (1.5 ± 0.1/1.5 ± 0.7/1.0 ± 0.5/0.8 ± 0.01 μM for WT/delta/BA.1/BA.2, respectively), nirmatrelvir (0.05 ± 0.02/0.06 ± 0.01/0.04 ± 0.02/0.04 ± 0.01 μM) or remdesivir (0.08 ± 0.04/0.11 ± 0.08/0.05 ± 0.04/0.08 ± 0.01 μM). Continued evolution of SARS-CoV-2 requires updating the mAbs arsenal, although antivirals have so far remained unaffected.

Staphylococcus aureus infections associated with implanted medical devices are difficult to treat and require long-lasting antibiotic therapies, especially when device removal is not possible or easy such as in the case of joint prostheses. Biofilm formation is a major cause of treatment failure and infection recurrence. This study aimed to test, for the first time, the in vitro combination of tedizolid plus rifampicin on methicillin-sensitive (MSSA ATCC 6538) and methicillin-resistant (MRSA ATCC 43300) S. aureus mature biofilm. Here, we demonstrated that the combination of tedizolid with rifampicin significantly disaggregated pre-formed biofilm of both strains, reduced their metabolic activity and exerted bactericidal activity at clinically meaningful concentrations. Notably, tedizolid was able to completely prevent the emergence of resistance to rifampicin. Moreover these effects were similar to those obtained with daptomycin plus rifampicin, a well-known and widely used combination. Preliminary results on some MRSA clinical isolates confirmed the efficacy of this combination in reducing biofilm biomass and preventing rifampicin resistance onset. Further in vivo studies are needed to confirm the validity of this promising therapeutic option that can be useful against biofilm-associated S. aureus infections.

The Apiaceae family, known for aromatic plants producing bioactive essential oils (EOs), holds significance across sectors, including agrochemicals. This study evaluated the insecticidal potential of four Apiaceae EOs from Crithmum maritimum L., Trachyspermum ammi (L.) Sprague ex Turrill, Smyrnium olusatrum L., and Elwendia persica (Boiss.) Pimenov and Kljuykov against various significant storage pests (Sitophilus oryzae (L.), Trogoderma granarium Everts, Rhyzopertha dominica (F.), Tribolium castaneum (Herbst), T. confusum Jacquelin du Val, Oryzaephilus surinamensis (L.), Alphitobius diaperinus (Panzer), Acarus siro L., and Tenebrio molitor L.) on wheat. Insect mortality rates were monitored at intervals of 1, 2, 3, 4, 5, 6, and 7 days. Smyrnium olusatrum EO exhibited the highest efficacy, followed by T. ammi, C. maritimum, and E. persica EOs, although efficacy varied by species, developmental stage, and concentration. Notably, complete mortality occurred for several pests at 1000 ppm of S. olusatrum and T. ammi EOs. Gas chromatography–mass spectrometry (GC–MS) analysis revealed key compounds in these EOs, including myrcene, germacrone, and curzerene in S. olusatrum EO, and thymol, γ-terpinene, and p-cymene in T. ammi EO. These findings emphasize their potential as botanical insecticides. Smyrnium olusatrum and T. ammi EOs emerge as promising eco-friendly pest management options due to their efficacy, highlighted compound composition, and availability of biomass from both wild and cultivated sources. [ABSTRACT FROM AUTHOR]

Background: The aim of the study is to evaluate the effectiveness, safety, and tolerability of a two-drug regimen (2-DR) dolutegravir/lamivudine (DTG/3TC) versus a three-drug regimen (3-DR) tenofovir alafenamide/emtricitabine/bictegravir (TAF/FTC/BIC) in a real-life cohort of HIV-1 virologically suppressed treatment-experienced (TE) people living with HIV (PLWH). Methods: This was a single-center, retrospective, observational study analyzing adult TE PLWH who started the 2-DR or 3-DR between January 2018 and January 2023. All PLWH with a viral load (VL) <50 copies/mL at the time of switching, and a follow-up of more than 6 months or interruption of treatment at any time, were included. Results: A total of 324 PLWH were included; of these, 110 (34%) were on the 2-DR and 214 (66%) were on the 3-DR. Most patients remained on therapy in both groups (93.6% 2-DR versus 90.2% 3-DR) and, at the last control, 99.1% achieved VL < 50 copies/mL with the 2-DR versus 97.2% with the 3-DR (p = 0.260). No virological failures occurred in either group. Adverse events occurred in a few cases: four (3.6%) in the 2-DR group and five (2.3%) in the 3-DR group (p = 0.500). The median follow-up-time was 19.6 months for the 2-DR and 27.5 months for the 3-DR. Conclusion: Our study shows a similar effectiveness and safety profile in virologically suppressed PLWH switching to DTG/3TC or TAF/FTC/BIC. [ABSTRACT FROM AUTHOR]

Non-structural protein 5 (Nsp5) is a cysteine protease that plays a key role in SARS-CoV-2 replication, suppressing host protein synthesis and promoting immune evasion. The investigation of natural products as a potential strategy for Nsp5 inhibition is gaining attention as a means of developing antiviral agents. In this work, we have investigated the physicochemical properties and structure-activity relationships of ellagic acid and its gut metabolites, urolithins A–D, as ligands of Nsp5. Results allow us to identify urolithin D as promising ligand of Nsp5, with a dissociation constant in the nanomolar range of potency. Although urolithin D is able to bind to the catalytic cleft of Nsp5, the appraisal of its viral replication inhibition against SARS-CoV-2 in Vero E6 assay highlights a lack of activity. While these results are discussed in the framework of the available literature reporting conflicting data on polyphenol antiviral activity, they provide new clues for natural products as potential viral protease inhibitors. [ABSTRACT FROM AUTHOR]

Background: Bictegravir (BIC), a recently introduced integrase inhibitor, is available in a single tablet regimen with tenofovir alafenamide (TAF) and emtricitabine (FTC) (BIC-STR). This study aimed to describe a real-life experience with BIC-STR. Methods: We retrospectively analyzed the data of people living with HIV (PLWH) on antiretroviral therapy (ART) with BIC-STR followed by the Clinic of Infectious Diseases of Perugia (Perugia, Italy) from September 2019 to February 2023. Results: 270 PLWH were enrolled with a median follow-up time on BIC-STR of 2.2 years (IQR 1.2–2.7). In the overall population, in treatment-experienced (N = 242), in treatment-naïve (N = 28), and in population with age > 60 years old (N = 86), we observed that CD4 cell count improved in absolute number, percentage and CD4/CD8 ratio, under BIC-STR. Patients with viremia < 50 cp/mL increased in all groups. In the overall population, previous ART with TAF and nadir CD4 cell count favored immunological recovery. In the ART-experienced group, time in therapy with BIC-STR was associated with HIV-RNA undetectability. In the older group, previous opportunistic infection and advanced age were associated with lower CD4 count. Conclusions: BIC-STR was demonstrated, in real-life, to be a valid option for a switch, such as initial ART. [ABSTRACT FROM AUTHOR]

The aim of this study was to establish the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on inanimate surfaces such as plastic, stainless steel, and glass during UV-C irradiation which is a physical means commonly utilized in sanitization procedures. The viral inactivation rate, virus half-life, and percentage of titer reduction after UV-C irradiation were assessed. Infectivity was maintained on plastic and glass until 120 h and on stainless steel until 72 h. The virus half-life was 5.3, 4.4, and 4.2 h on plastic, stainless steel, and glass, respectively. In all cases, titer decay was >99% after drop drying. UV-C irradiation efficiently reduced virus titer (99.99%), with doses ranging from 10.25 to 23.71 mJ/cm2. Plastic and stainless steel needed higher doses to achieve target reduction. The total inactivation of SARS-CoV-2 on glass was obtained with the lower dose applied. SARS-CoV-2 survival can be long lasting on inanimate surfaces. It is worth recommending efficient disinfection protocols as a measure of prevention of viral spread. UV-C can provide rapid, efficient and sustainable sanitization procedures of different materials and surfaces. The dosages and mode of irradiation are important parameters to consider in their implementation as an important means to fight the SARS-CoV-2 pandemic.

Background: This study aims to investigate the activity of the remdesivir–nirmatrelvir combination against Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) and to report a case of Coronavirus Disease 2019 (COVID-19) cured with this combination. Methods: A Vero E6 cell-based infection assay was used to investigate the in vitro activity of the remdesivir–nirmatrelvir combination. The SARS-CoV-2 strains tested were 20A.EU1, BA.1 and BA.5. After incubation, a viability assay was performed. The supernatants were collected and used for viral titration. The Highest Single Agent (HSA) reference model was calculated. An HSA score >10 is considered synergic. Results: Remdesivir and nirmatrelvir showed synergistic activity at 48 and 72 h, with an HSA score of 52.8 and 28.6, respectively (p < 0.0001). These data were confirmed by performing supernatant titration and against the omicron variants: the combination reduced the viral titer better than the more active compound alone. An immunocompromised patient with prolonged and critical COVID-19 was successfully treated with remdesivir, nirmatrelvir/ritonavir, tixagevimab/cilgavimab and dexamethasone, with an excellent clinical–radiological response. However, she required further off-label prolonged therapy with nirmatrelvir/ritonavir until she tested negative. Conclusions: Remdesivir–nirmatrelvir combination has synergic activity in vitro. This combination may have a role in immunosuppressed patients with severe COVID-19 and prolonged viral shedding. [ABSTRACT FROM AUTHOR]

The main protease (Mpro or 3CLpro) is an enzyme that is evolutionarily conserved among different genera of coronaviruses. As it is essential for processing and maturing viral polyproteins, Mpro has been identified as a promising target for the development of broad-spectrum drugs against coronaviruses. Like SARS-CoV and MERS-CoV, the mature and active form of SARS-CoV-2 Mpro is a dimer composed of identical subunits, each with a single active site. Individual monomers, however, have very low or no catalytic activity. As such, inhibition of Mpro can be achieved by molecules that target the substrate binding pocket to block catalytic activity or target the dimerization process. In this study, we investigated GC376, a transition-state analog inhibitor of the main protease of feline infectious peritonitis coronavirus, and Nirmatrelvir (NMV), an oral, bioavailable SARS-CoV-2 Mpro inhibitor with pan-human coronavirus antiviral activity. Our results show that both GC376 and NMV are capable of strongly binding to SARS-CoV-2 Mpro and altering the monomer-dimer equilibrium by stabilizing the dimeric state. This behavior is proposed to be related to a structured hydrogen-bond network established at the Mpro active site, where hydrogen bonds between Ser1' and Glu166/Phe140 are formed in addition to those achieved by the latter residues with GC376 or NMV. [ABSTRACT FROM AUTHOR]

Herein, sexual interactions and left-right asymmetries in brain and behavior (lateralization) of Czech and Turkish strains of Trogoderma granarium Everts (Coleoptera: Dermestidae) were investigated, assessing courtship and mating dynamics within each strain and in all possible cross mating combinations. Trogoderma granarium species identity was confirmed by DNA sequencing, using three mitochondrial DNA genes, Cytochrome Oxidase I (COI), large subunit ribosomal RNA (16S), and Cytochrome b (CYTb). The selected genetic markers were also used to examine any intraspecific variations between the two strains analyzed. The aligned COI and 16S DNA sequences obtained revealed several polymorphisms, when both inter- and intra-strains analyzed. In behavioral experiments, more males of the Czech strain performed left-biased approaches (53%) than right-biased approaches (42%), with 20% of left-biased males and 13% of right-biased males using the right foreleg to explore females, achieving 18% and 10% successful copulations, respectively. Males of the Turkish strain exhibited right- (50%) or left-biased approaches (45%), with 17% of right-biased males and 21% of leftbiased males exploring females with the left foreleg, resulting in 15% and 20% mating success, respectively. During crossmating of strains, all possible combinations exhibited a population-level left-biased approach to the potential mates and a right-biased exploration of females with foreleg, leading to high successful copulations. Significant differences were noted in the duration of copulation of Turkish males interacting with females of the same strain (backside males 122.3 s, leftbiased males 72.0 s, and right-biased males 68.6 s). Overall, this research firstly sheds light on how cross-mating among strains can affect courtship, mating success and laterality in a key beetle pest. [ABSTRACT FROM AUTHOR]

After almost three years of the pandemic, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is still spreading around the world, causing notable sanitary and social issues. New antiviral therapies are constantly under investigation. However, few options have been approved for the treatment of COVID-19. Clinical trials are currently ongoing to evaluate the efficacy of nelfinavir on mild–moderate COVID-19. This study aims to investigate the activity of this compound on SARS-CoV-2 "Variants of Concern" (VOCs), comparing its effectiveness with the approved drugs remdesivir and molnupiravir. The experiments were conducted in a biosafety level 3 facility. In this study, we used a Vero-E6-cell-based infection assay to investigate the in vitro activity of nelfinavir, molnupiravir, and remdesivir. Four strains of SARS-CoV-2 were tested: 20A.EU1, B.1.1.7, P.1, and B.1.617.2. All compounds reached micromolar/submicromolar EC50, EC90, and EC99. Furthermore, the Cmax/EC50 and Cmax/EC90 ratios were >1 for all compounds and all variants tested. Our study demonstrated that nelfinavir, as molnupiravir, and remdesivir are effective in vitro on SARS-CoV-2 variants. [ABSTRACT FROM AUTHOR]

Newly emerging SARS-CoV-2 variants may escape monoclonal antibodies (mAbs) and antiviral drugs. By using live virus assays, we assessed the ex vivo inhibition of the B.1 wild-type (WT), delta and omicron BA.1 and BA.2 lineages by post-infusion sera from 40 individuals treated with bamlanivimab/etesevimab (BAM/ETE), casirivimab/imdevimab (CAS/IMD), and sotrovimab (SOT) as well as the activity of remdesivir, nirmatrelvir and molnupiravir. mAbs and drug activity were defined as the serum dilution (ID50) and drug concentration (IC50), respectively, showing 50% protection of virus-induced cytopathic effect. All pre-infusion sera were negative for SARS-CoV-2 neutralizing activity. BAM/ETE, CAS/IMD, and SOT showed activity against the WT (ID50 6295 (4355–8075) for BAM/ETE; 18,214 (16,248–21,365) for CAS/IMD; and 456 (265–592) for SOT) and the delta (14,780 (ID50 10,905–21,020) for BAM/ETE; 63,937 (47,211–79,971) for CAS/IMD; and 1103 (843–1334) for SOT). Notably, only SOT was active against BA.1 (ID50 200 (37–233)), whereas BA.2 was neutralized by CAS/IMD (ID50 174 (134–209) ID50) and SOT (ID50 20 (9–31) ID50), but not by BAM/ETE. No significant inter-variant IC50 differences were observed for molnupiravir (1.5 ± 0.1/1.5 ± 0.7/1.0 ± 0.5/0.8 ± 0.01 μM for WT/delta/BA.1/BA.2, respectively), nirmatrelvir (0.05 ± 0.02/0.06 ± 0.01/0.04 ± 0.02/0.04 ± 0.01 μM) or remdesivir (0.08 ± 0.04/0.11 ± 0.08/0.05 ± 0.04/0.08 ± 0.01 μM). Continued evolution of SARS-CoV-2 requires updating the mAbs arsenal, although antivirals have so far remained unaffected. [ABSTRACT FROM AUTHOR]