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The anticoagulant therapy is widely used to prevent and treat thromboembolic events. Until the last decade, vitamin K antagonists were the only available oral anticoagulants; recently, direct oral anticoagulants (DOACs) have been developed. Since 55% to 95% of DOACs are bound to plasma proteins, the in silico docking and ligand‐binding properties of drugs apixaban, betrixaban, dabigatran, edoxaban, and rivaroxaban and of the prodrug dabigatran etexilate to human serum albumin (HSA), the most abundant plasma protein, have been investigated. DOACs bind to the fatty acid (FA) site 1 (FA1) of ligand‐free HSA, whereas they bind to the FA8 and FA9 sites of heme‐Fe(III)‐ and myristic acid‐bound HSA. DOACs binding to the FA1 site of ligand‐free HSA has been validated by competitive inhibition of heme‐Fe(III) recognition. Values of the dissociation equilibrium constant for DOACs binding to the FA1 site (ie, calcKDOAC) derived from in silico docking simulations (ranging between 1.2 × 10−8 M and 1.4 × 10−6 M) agree with those determined experimentally from competitive inhibition of heme‐Fe(III) binding (ie, expKDOAC; ranging between 2.5 × 10−7 M and 2.2 × 10−6 M). In addition, this study highlights the inequivalence of rivaroxaban binding to mammalian serum albumin. Given the HSA concentration in vivo (~7.5 × 10−4 M), values of KDOAC here determined indicate that the formation of the HSA:DOACs complexes in the absence and presence of FAs and heme‐Fe(III) may occur in vivo. Therefore, HSA appears to be an important determinant for DOACs transport. [ABSTRACT FROM AUTHOR]

Neonicotinoids are a widely used class of insecticides that target the acetylcholine recognition site of the nicotinic acetylcholine receptors in the central nervous system of insects. Although neonicotinoids display a high specificity for insects, their use has been recently debated since several studies led to the hypothesis that they may have adverse ecological effects and potential risks to mammals and even humans. Due to their hydrophobic nature, neonicotinoids need specific carriers to allow their distribution in body fluids. Human serum albumin (HSA), the most abundant plasma protein, is a key carrier of endogenous and exogenous compounds. The in silico docking and ligand binding properties of acetamiprid, clothianidin, dinotefuran, imidacloprid, nitenpyram, thiacloprid, and thiamethoxam to HSA are here reported. Neonicotinoids bind to multiple fatty acid (FA) binding sites, preferentially to the FA1 pocket, with high affinity. Values of the dissociation equilibrium constant for neonicotinoid binding FA1 of HSA (i.e., calcKn) derived from in silico docking simulations (ranging between 3.9 × 10−5 and 6.3 × 10−4 M) agree with those determined experimentally from competitive inhibition of heme‐Fe(III) binding (i.e., expKn; ranging between 2.1 × 10−5 and 6.9 × 10−5 M). Accounting for the HSA concentration in vivo (~7.5 10−4 M), values of Kn here determined suggest that the formation of the HSA:neonicotinoid complexes may occur in vivo. Therefore, HSA appears to be an important determinant for neonicotinoid transport and distribution to tissues and organs, particularly to the liver where they are metabolized. [ABSTRACT FROM AUTHOR]

The present study aimed to investigate the pharyngeal and nasal microbiota composition in children with adenotonsillar hypertrophy (AH) and assess longitudinal alterations in both microbiota after a probiotic oral spray treatment. A cohort of 57 AH patients were enrolled and randomly assigned to the probiotic and placebo groups for a 5-month treatment course. Pharyngeal and nasal swabs were collected before and after treatment and analyzed by 16S rRNA-based metataxonomics and axenic cultures for pathobiont identification. 16S rRNA sequences from pharyngeal and nasal swabs of 65 healthy children (HC) were used as microbiota reference profiles. We found that the pharyngeal and nasal microbiota of AH children were similar. When compared to HC, we observed an increase of the genera Rothia , Granulicatella , Streptococcus , Neisseria , and Haemophilus , as well as a reduction of Corynebacterium , Pseudomonas, Acinetobacter, and Moraxella in both microbiota of AH patients. After probiotic treatment, we confirmed the absence of adverse effects and a reduction of upper respiratory tract infections (URTI). Moreover, the composition of pharyngeal microbiota was positively influenced by the reduction of potential pathobionts, like Haemophilus spp., with an increase of beneficial microbial metabolic pathways. Finally, the probiotic reduced the abundance of the pathobionts Streptococcus mitis and Gemella haemolysans in relation to AH severity. In conclusion, our results highlight the alterations of the pharyngeal and nasal microbiota associated with AH. Moreover, probiotic administration conferred protection against URTI and reduced the presence of potential pathobionts in patients with AH., Importance: Adenotonsillar hypertrophy (AH) is considered the main cause of breathing disorders during sleep in children. AH patients, after significant morbidity and often multiple courses of antibiotics, often proceed to tonsillectomy and/or adenoidectomy. Given the potential risks associated with these procedures, there is a growing interest in the use of nonsurgical adjuvant therapies, such as probiotics, that could potentially reduce their need for surgical intervention. In this study, we investigated the pharyngeal and nasal microbiota in patients with AH compared with healthy children. Furthermore, we tested the effects of probiotic spray administration on both disease symptoms and microbiota profiles, to evaluate the possible use of this microbial therapy as an adjuvant for AH patients.

This is the first study on gut microbiota (GM) in children affected by coronavirus disease 2019 (COVID-19). Stool samples from 88 patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and 95 healthy subjects were collected (admission: 3-7 days, discharge) to study GM profile by 16S rRNA gene sequencing and relationship to disease severity. The study group was divided in COVID-19 (68), Non-COVID-19 (16), and MIS-C (multisystem inflammatory syndrome in children) (4). Correlations among GM ecology, predicted functions, multiple machine learning (ML) models, and inflammatory response were provided for COVID-19 and Non-COVID-19 cohorts. The GM of COVID-19 cohort resulted as dysbiotic, with the lowest α-diversity compared with Non-COVID-19 and CTRLs and by a specific β-diversity. Its profile appeared enriched in Faecalibacterium , Fusobacterium , and Neisseria and reduced in Bifidobacterium , Blautia , Ruminococcus , Collinsella , Coprococcus , Eggerthella , and Akkermansia , compared with CTRLs ( p < 0.05). All GM paired-comparisons disclosed comparable results through all time points. The comparison between COVID-19 and Non-COVID-19 cohorts highlighted a reduction of Abiotrophia in the COVID-19 cohort ( p < 0.05). The GM of MIS-C cohort was characterized by an increase of Veillonella , Clostridium , Dialister , Ruminococcus , and Streptococcus and a decrease of Bifidobacterium , Blautia , Granulicatella , and Prevotella , compared with CTRLs. Stratifying for disease severity, the GM associated to "moderate" COVID-19 was characterized by lower α-diversity compared with "mild" and "asymptomatic" and by a GM profile deprived in Neisseria , Lachnospira , Streptococcus , and Prevotella and enriched in Dialister , Acidaminococcus , Oscillospora , Ruminococcus , Clostridium , Alistipes , and Bacteroides. The ML models identified Staphylococcus , Anaerostipes , Faecalibacterium , Dorea , Dialister , Streptococcus , Roseburia , Haemophilus , Granulicatella , Gemmiger , Lachnospira , Corynebacterium , Prevotella , Bilophila , Phascolarctobacterium , Oscillospira , and Veillonella as microbial markers of COVID-19. The KEGG ortholog (KO)-based prediction of GM functional profile highlighted 28 and 39 KO-associated pathways to COVID-19 and CTRLs, respectively. Finally, Bacteroides and Sutterella correlated with proinflammatory cytokines regardless disease severity. Unlike adult GM profiles, Faecalibacterium was a specific marker of pediatric COVID-19 GM. The durable modification of patients' GM profile suggested a prompt GM quenching response to SARS-CoV-2 infection since the first symptoms. Faecalibacterium and reduced fatty acid and amino acid degradation were proposed as specific COVID-19 disease traits, possibly associated to restrained severity of SARS-CoV-2-infected children. Altogether, this evidence provides a characterization of the pediatric COVID-19-related GM., Competing Interests: Author GM, VG, and SG are employed by GenomeUp SRL, Viale Pasteur, 6, 00144, Rome, Italy. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Romani, Del Chierico, Macari, Pane, Ristori, Guarrasi, Gardini, Pascucci, Cotugno, Perno, Rossi, Villani, Bernardi, Campana, Palma, Putignani and the CACTUS Study Team.)