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Objective: The primary objective of this study is to assess common sites of injury and the associated imaging findings in penetrating injuries. We pay particular attention to gluteal, anterior abdominal wall and junctional zone injuries. The aim is to highlight areas of diagnostic uncertainty and discrepancy between imaging and surgical findings, to improve review areas in trauma reporting., Methods: A retrospective, observational study reviewing all paediatric admissions to the emergency department of a major trauma Centre with a penetrating injury, from 2015 to 2019., Results: Gluteal penetrating injuries are by far the most commonly sustained injury in the adolescent population, making up over 1/3 of cases. The vast majority of these cases sustained superficial injuries or shallow intramuscular haematomas, however in a small group (15%), serious vascular or rectal injuries were demonstrated on dual phase CT, requiring emergent surgical or endovascular treatment. Penetrating injuries to the anterior abdominal wall and junctional zone are less common but are associated with higher morbidity, with 43% of cases demonstrating solid organ or bowel injury. These cases also lead to an increased degree of diagnostic uncertainty., Conclusion: Gluteal injuries are common and although the overall morbidity of these cases is low, these patients are at risk of serious and life threatening consequences such as vascular and rectal injury and it is imperative that these complications are considered and ruled out via dual phase CT or direct visualization. Anterior abdominal wall and junctional zone injuries are less common, but lead to greater morbidity and also greater diagnostic uncertainty. The use of other salient findings as described in this report can aid diagnostic accuracy and reduce discrepancies., Competing Interests: Declaration of competing interest The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of the article., (Copyright © 2024. Published by Elsevier Ltd.)

Standard information reporting helps to ensure that assay conditions and data are consistently reported and to facilitate inter-laboratory comparisons. Here, we present recommendations on minimum information for reporting on the TEER (trans-epithelial/endothelial electrical resistance) assay (MIRTA). The TEER assay is extensively used to evaluate the health of an epithelial/endothelial cell culture model and as an indicator of the potential toxicity of a test substance. This publication is the result of an international collaboration─called the RespTox (Respiratory Toxicity) Collaborative─through which twelve laboratories shared their protocols for assessing the barrier function of respiratory epithelial cells using the TEER assay following exposure to substances. The protocols from each laboratory were reviewed to identify general steps for performing the TEER assay, interlaboratory differences between steps, the rationale for differences, whether these differences impact results or cross-laboratory comparisons between TEER measurements. While the MIRTA recommendations are focused on respiratory epithelial cell systems, these recommendations can be adapted for other cell systems that form barriers. The use of these recommendations will support data transparency and reproducibility, reduce challenges in data interpretation, enable cross-laboratory comparisons, help assess study quality, and facilitate the incorporation of the TEER assay into national and international testing guidance., Competing Interests: Declarations. Conflict of interest: The authors declare no conflict of interest., (© 2024. The Author(s).)

Pulmonary mucus serves as a crucial protective barrier in the respiratory tract, defending against pathogens and contributing to effective clearance mechanisms. In Muco Obstructive Pulmonary Diseases (MOPD), abnormal rheological properties lead to highly viscous mucus, fostering chronic infections and exacerbations. While prior research has linked mucus viscoelasticity to its mucin content, the variability in MOPD patients implies the involvement of other factors. To isolate these effects, mucus produced by epithelia reconstituted in vitro serves as a powerful versatile model for mucin research. This study characterises the rheology of mucus collected from Air-Liquid Interface (ALI) cultures and compares it to sputum samples from MOPD patients, demonstrating that macrorheology with cone-plate geometries is a reproducible method for analysing small mucus quantities from ALI cultures. While sputum samples exhibit similarities in rigidity with ALI mucus, they also display structural differences and variations in their response to substantial deformations. The study highlights the importance of understanding mucus behaviour under large deformations, emphasising the role of ALI cultures as a controlled environment for conducting detailed studies., Competing Interests: Declarations. Competing interests: L.E.E., V.T.P. and J.P. are full time employees of Rheonova, the company which designs and produces the rheometer used in this study. M.B., H.S. and S.C. are full time employees of Epithelix, the company producing the ALI cultures., (© 2024. The Author(s).)

In recent decades, epidemics and pandemics have multiplied throughout the world, with viruses generally being the primary responsible agents. Among these, influenza viruses play a key role, as they potentially cause severe respiratory distress, representing a major threat to public health. Our study aims to develop new broad-spectrum antivirals against influenza to improve the response to viral disease outbreaks. We engineered macromolecules (named CD-SA) consisting of a β-cyclodextrin scaffold modified with hydrophobic linkers in the primary face, onto which unitary sialic acid epitopes are covalently grafted to mimic influenza virus-host receptors. We assessed the antiviral efficacy, mechanism of action, and the genetic barrier to resistance of this compound against influenza in vitro, ex vivo, and in vivo. We demonstrated that CD-SA, with a unitary SA, without extensive polysaccharides or specific connectivity, acts as a potent virucidal antiviral against several human influenza A and B viruses. Additionally, CD-SA displayed antiviral activity against SARS-CoV-2, a virus that also relies on sialic acid for attachment. We then assessed the genetic barrier to resistance for CD-SA. While resistance emerged after six passages with CD-SA alone, the virus remained sensitive through eight passages when co-treated with interferon-λ1 (IFN λ1). Finally, we completed the characterization of the antiviral activity by conducting both ex vivo and in vivo studies, demonstrating a potent antiviral effect in human airway epithelia and in a mouse model of infection, higher than that of Oseltamivir, a currently approved anti-influenza antiviral. The findings presented in this study support the potential therapeutic utility of a novel β-cyclodextrin-based nanomaterial for the treatment of influenza infections and potentially other sialic acid-dependent viruses., (© 2024 The Author(s). Journal of Medical Virology published by Wiley Periodicals LLC.)

The use of fixed dose-combinations of antivirals with different mechanisms of action has proven key in the successful treatment of infections with HIV and HCV. For the treatment of infections with SARS-CoV-2 and possible future epi-/pandemic coronaviruses, it will be important to explore the efficacy of combinations of different drugs, in particular to avoid resistance development, such as in patients with immunodeficiencies. This work explores the effect of a combination of 3 broad-spectrum antiviral nucleosides on the replication of coronaviruses. To that end, we made use of primary human airway epithelial cell (HAEC) cultures grown at the air-liquid interface that were infected with the beta coronavirus OC43. We found that the triple combination of GS-441524 (the parent nucleoside of remdesivir), molnupiravir and ribavirin resulted in a more pronounced antiviral efficacy than what could be expected from a purely additive antiviral effect. The potency of this triple combination was next tested in SARS-CoV-2 infected hamsters in a prophylactic setup. To that end, for each of the drugs, intentionally suboptimal or even ineffective doses were selected. Yet, in the lungs of all hamsters that received triple prophylactic therapy (but not in those that received the respective double combinations) no infectious virus was detectable. Our findings indicate that co-administration of approved drugs for the treatment of coronavirus infections should be further explored but also against other families of viruses with epidemic and pandemic potential for which no effective antiviral treatment is available., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Cyclosporin A (CsA), an immunosuppressive drug used in transplant recipients, inhibits graft rejection by binding to cyclophilins and competitively inhibiting calcineurin. While concerns about respiratory infections in immunosuppressed patients exist, contradictory data emerged during the COVID-19 pandemic, prompting investigations into CsA's impact on viral infections. This study explores CsA's antiviral effects on SARS-CoV-2 Omicron BA.1, Delta variants, and human parainfluenza virus 3 (HPIV3) using an ex vivo model of human airway epithelium (HAE). CsA exhibited a dose-dependent antiviral effect against the SARS-CoV-2 Delta variant, reducing viral load over 10 days. However, no significant impact was observed against SARS-CoV-2 Omicron or HPIV3, indicating a virus-specific effect. At high concentrations, CsA was associated with an increase of IL-8 and a decrease of IFNλ expression in infected and noninfected HAE. This study highlights the complexity of CsA's antiviral mechanisms, more likely involving intricate inflammatory pathways and interactions with specific viral proteins. The research provides novel insights into CsA's effects on respiratory viruses, emphasizing the need for understanding drug-virus interactions in optimizing therapeutic approaches for transplant recipients and advancing knowledge on immunosuppressive treatments' implications on respiratory viral infections. Limitations include the model's inability to assess T lymphocyte activation, suggesting the necessity for further comprehensive studies to decipher the intricate dynamics of immunosuppressive treatments on respiratory viral infections., (© 2024 The Author(s). Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Background. The emergence, global spread, and persistence of SARS-CoV-2 resulted in an unprecedented need for effective antiviral drugs. Throughout the pandemic, various drug development and treatment strategies were adopted, including repurposing of antivirals designed for other viruses along with a multitude of other drugs with varying mechanisms of action (MoAs). Furthermore, multidrug treatment against COVID-19 is an ongoing topic and merits further investigation. Method/Objectives. We assessed the efficacy of multidrug treatment against SARS-CoV-2 in reconstituted human nasal epithelia, using combinations of molnupiravir and nirmatrelvir as a baseline, adding suboptimal concentrations of either GS-441524 or ivermectin, attempting to increase overall antiviral activity while lowering the overall therapeutic dose. Results. Nirmatrelvir combined with molnupiravir, GS-441524, or ivermectin at suboptimal concentrations show increased antiviral activity compared to single treatment. No triple combinations showed improved inhibition of SARS-CoV-2 replication beyond what was observed for double treatments. Conclusions. In general, we observed that the addition of a third compound is not beneficial for antiviral activity, while various double combinations exhibit increased antiviral activity over single treatment.

COVID-19 remains a severe condition for many including immunocompromised individuals. There remains a need for effective measures against this and other respiratory infections, which transmit via virus-laden droplets that reach the nasal or oral mucosae. Nasal sprays offer potential protection against viruses. Such formulations should preserve normal nasal mucociliary function. The antiviral barrier efficacy and effects on mucociliary function of astodrimer sodium nasal spray (AS-NS) were evaluated and compared with other available nasal sprays-low pH hydroxypropyl methylcellulose (HPMC-NS), iota-carrageenan (Carr-NS), nitric oxide (NO-NS), and povidone iodine (PI-NS). Assays simulated clinical conditions. Antiviral barrier function and cell viability were assessed in airway cell monolayers, while a model of fully differentiated human nasal epithelium (MucilAir™) was utilized to evaluate tissue integrity, cytotoxicity, cilia beating frequency, and mucociliary clearance. AS-NS reduced infectious virus in cell monolayers and demonstrated a benign cytotoxicity profile. In human nasal epithelium ex vivo, AS-NS had no impact on mucociliary function (cilia beating nor mucociliary clearance). Carr-NS, HPMC-NS, NO-NS and PI-NS demonstrated limited antiviral effects, while HPMC-NS caused inhibition of mucociliary function. Astodrimer sodium nasal spray demonstrates an acceptable nonclinical efficacy and safety profile as a barrier nasal spray against respiratory viral infection in the nasal cavity., (© 2024. The Author(s).)

Background: Fexofenadine (FEX) is an antihistamine that acts as an inverse agonist against histamine (HIS) receptor 1 (H1R), which mediates the allergic reaction. Inverse agonists may be more potent than neutral antagonists, as they bind the same receptor as the agonist (HIS) but stabilize the inactive form and induce an opposite pharmacological response, suppressing the basal activity of H1R and preventing HIS from binding. This study aims to establish and validate a model of HIS-induced inflammation based on fully reconstituted human nasal epithelial tissue to assess the activity of FEX as an inverse agonist in this model and explore its link to clinical benefit., Methods: The model was developed using nasal MucilAir™ (Epithelix) in vitro epithelium challenged by HIS. Two conditions were assessed in a side-by-side comparison: tissue was exposed to HIS + FEX with or without FEX pre-treatment (one-hour prior to HIS challenge). Tissue functionality, cytotoxicity, H1R gene expression, and inflammatory cytokines were assessed., Results: HIS at 100 µM induced significant 3.1-fold and 2.2-fold increases for inflammatory biomarkers interleukin (IL)-8 and IL-6, respectively ( p < 0.0001), as well as rapid upregulation of H1R mRNA. Inflammatory biomarkers were inhibited by FEX and H1R expression was significantly reduced ( p < 0.0001). FEX alone decreased H1R expression at all doses tested. With one-hour FEX pre-treatment, there was significantly higher downregulation of IL-8 ( p < 0.05) and further downregulation of H1R expression and IL-6 versus without FEX pre-treatment; the effects of FEX were improved from 22% to 40%., Conclusion: A model of HIS-induced airway inflammation was established based on IL-8, IL-6 and H1R gene expression and was validated with FEX. FEX works as an inverse agonist, with a higher effect when used before+during versus only during the HIS challenge. Taking FEX before+during allergen exposure, or when symptoms first occur, may reduce basal activity and H1R gene expression, providing stronger protection against the worsening of symptoms upon allergen exposure., Competing Interests: Authors AB, ML-B, MM-A, and ML were employed by Sanofi. Authors JV, SH, SC, and BB were employed by Epithelix., (Copyright © 2024 Barbot, Lheritier-Barrand, Murrieta-Aguttes, Leonetti, Vernaz, Huang, Constant and Boda.)