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Seasonal influenza A and B viruses represent a global concern. Antiviral drugs are crucial to treat severe influenza in high-risk patients and prevent virus spread in case of a pandemic. The emergence of viruses showing drug resistance, in particular for the recently licensed polymerase inhibitor baloxavir marboxil, drives the need for developing alternative antivirals. The endonuclease activity residing in the N-terminal domain of the polymerase acidic protein (PAN) is crucial for viral RNA synthesis and a validated target for drug design. Its function can be impaired by molecules bearing a metal-binding pharmacophore (MBP) able to coordinate the two divalent metal ions in the active site. In the present work, the 2,3-dihydro-6,7-dihydroxy-1H-isoindol-1-one scaffold is explored for the inhibition of influenza virus PA endonuclease. The structure-activity relationship was analysed by modifying the substituents on the lipophilic moiety linked to the MBP. The new compounds exhibited nanomolar inhibitory activity in a FRET-based enzymatic assay, and a few compounds (15-17, 21) offered inhibition in the micromolar range, in a cell-based influenza virus polymerase assay. When investigated against a panel of PA-mutant forms, compound 17 was shown to retain full activity against the baloxavir-resistant I38T mutant. This was corroborated by docking studies providing insight into the binding mode of this novel class of PA inhibitors.

Background: This study aimed to evaluate the safety and efficacy of povidone-iodine 0.6% (PVI) irrigation for preventing recurrence of stenosis after punctoplasty in patients with punctal and proximal canalicular stenosis treated using a venous catheter as a stent. Methods: Twenty patients were enrolled and divided into two groups. Group 1 received irrigation of 1 mL 0.6% PVI, while Group 2 received 1 mL of balanced salt solution (BSS). The patients underwent baseline, 15-, 30-, and 90-day assessments using the Ocular Surface Disease Index (OSDI) questionnaire, Symptoms Assessment in Dry Eye (SANDE), Schirmer I test, tear meniscus height (TMH), bulbar redness, meibography, and non-invasive breakup time (NIKBUT) through Keratograph 5M (Oculus, Germany). Results: At three months, both groups demonstrated statistically significant improvements in symptoms and ocular surface parameters. However, Group 1 showed statistically significant improvements in OSDI, SANDE scores, bulbar redness, and NIKBUT compared to Group 2. Additionally, no patients in Group 1 presented a recurrence of stenosis, while three patients in Group 2 demonstrated stenosis relapse at the end of the follow-up period. Conclusions: The application of a venous catheter and PVI 0.6% irrigations proved to be effective in treating proximal lacrimal duct stenosis, reducing the risk of recurrence and improving tear film stability, ocular discomfort symptoms, and ocular surface parameters. [ABSTRACT FROM AUTHOR]

Objective: To determine the learning curve of fetal postmortem ultrasound (PMUS) and evaluate the evolution of its diagnostic performance over the past 8 years. Methods: PMUS was performed by two fetal medicine specialists and two experts on 100 unselected fetuses of 12–38 weeks of gestation in a prospective, double‐blind manner. 21 pre‐defined internal structures were analyzed consecutively by the trainee alone and the expert, with a comparison of diagnosis and immediate feedback. The learning curves for examination duration, non‐recognition of structures and final diagnoses were computed using cumulative summation analysis. Secondly, the expert PMUS diagnostic accuracy using autopsy as the gold standard was compared to the previously published data. Results: The trainees reached expert level of PMUS at 28–36 cases for examination duration (12.1 ± 5.2 min), non‐diagnostic rate (6.5%, 137/2100), and abnormality diagnosis. In a group of 33 fetuses ≥20 weeks who had an autopsy, the experts PMUS performance was improved after 8 years with a reduction of all organs non‐diagnostic rate (6.5 %VS 11.4%, p < 0.01) and higher sensitivity for the heart (100% VS 40.9%, p < 0.01) and the abdomen (100%VS 56.5%, p < 0.05). Conclusion: PMUS offers a short learning curve for fetal medicine specialists and on‐going improvement of diagnostic accuracy over time. Key points: What's already known about this topic? Fetal postmortem imaging has emerged to propose less invasive alternatives to invasive autopsy because of the decline of parental consent.Fetal postmortem ultrasound (PMUS) is a fetal postmortem imaging technique with sensitivity of 74.7% and a specificity of 83.3% for the examination of all gestational age (GA) fetuses.PMUS is less expensive and more easily accessible compared with other fetal postmortem imaging techniques such as Postmortem magnetic resonance imaging (PMMRI). What does this study add? Less than 40 cases were needed by fetal medicine specialists to reach expert‐level PMUS performance for the examination duration, recognition of structures and abnormality diagnosis.The expert PMUS diagnostic accuracy is improved overtime with lower non‐diagnostic image rate and higher sensitivity for cardiac and abdominal examinations. [ABSTRACT FROM AUTHOR]