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Objective: To describe the implementation of a multi-step antimicrobial stewardship program in a haemato-oncology and stem cell transplantation program unit. Methods: Pre-post quasi-experimental study with two interrupted time-series analyses, conducted between 01/01/2019 and 31/12/2022 in the Paediatric Haemato-Oncology Unit of the Padua Paediatric Hospital. The interventions were: (1) 02/2020: dissemination of febrile neutropenia clinical pathways, (2) April 2021: provision of the clinical pathways via a customized App (Firstline.org) and implementation of a twice-a-week prospective audit and feedback. The main outcome was antibiotic consumption measured by days of administered therapy (DOTs)/1000 patients' days for all antibiotics and most used molecules., Results: The first intervention (clinical pathways) resulted in a decrease in the overall antibiotic use by the haemato-oncology unit, with an abrupt reduction of 3-gen cephalosporins in favor of piperacillin-tazobactam, as indicated by the clinical pathways. Meropenem and glycopeptide use did not vary. The second intervention (antimicrobial stewardship) further decreased total antibiotic consumption, and a significant decline in meropenem, amikacin, and glycopeptides was achieved., Conclusions: Multi-step stewardship based on guidelines dissemination, multidisciplinary team intervention and collaboration ("handshake" stewardship) was highly effective in optimizing guidelines adherence and reducing overprescriptions in a fragile patient cohort., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical considerations: This study was conducted in accordance with the tenets of the Declaration of Helsinki. The study was granted approval by the ethical committee for clinical trials of the province of Padova on April 7th, 2022 (N. AOP2612). Informed consent: Patient informed consent was waived due to the retrospective nature of the study by the ethical committee for clinical trials of the province of Padova, and the use of wards aggregated data provided by thehospital pharmacy, in accordance with the ethical committee for clinical trials of the province of Padova, (© 2024. The Author(s).)

Transient receptor potential melastatin 8 (TRPM8), a nonselective cation channel, is the predominant mammalian cold temperature thermosensor and it is activated by cold temperatures and cooling compounds, such as menthol and icilin. Because of its role in cold allodynia, cold hyperalgesia and painful syndromes TRPM8 antagonists are currently being pursued as potential therapeutic agents for the treatment of pain hypersensitivity. Recently TRPM8 has been found in subsets of bladder sensory nerve fibres, providing an opportunity to understand and treat chronic hypersensitivity. However, most of the known TRPM8 inhibitors lack selectivity, and only three selective compounds have reached clinical trials to date. Here, we applied two virtual screening strategies to find new, clinics suitable, TRPM8 inhibitors. This strategy enabled us to identify naphthyl derivatives as a novel class of potent and selective TRPM8 inhibitors. Further characterization of the pharmacologic properties of the most potent compound identified, compound 1, confirmed that it is a selective, competitive antagonist inhibitor of TRPM8. Compound 1 also proved itself active in a overreactive bladder model in vivo. Thus, the novel naphthyl derivative compound identified here could be optimized for clinical treatment of pain hypersensitivity in bladder disorders but also in different other pathologies.