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2-Benzylbenzimidazole derivatives or ‘nitazenes’ are increasingly present on the recreational drug market. Here, we report the synthesis and pharmacological characterization of 15 structurally diverse nitazenes that might be predicted to emerge or grow in popularity. This work expands the existing knowledge about 2-benzylbenzimidazole structure-activity relationships (SARs), while also helping stakeholders (e.g., forensic toxicologists, clinicians, policymakers) in their risk assessment and preparedness for the potential next generation of nitazenes. In vitro µ-opioid receptor (MOR) affinity was determined via competition radioligand (3[H]DAMGO) binding assays in rat brain tissue. MOR activation (potency and efficacy) was studied by means of a cell-based β-arrestin 2 recruitment assay. For seven nitazenes, including etonitazene, opioid-like pharmacodynamic effects (antinociception, locomotor activity, body temperature changes) were evaluated after subcutaneous administration in male C57BL/6 J mice. The results showed that all nitazenes bound to MOR with nanomolar affinities, and the functional potency of several of them was comparable to or exceeded that of fentanyl. In vivo, dose-dependent effects were observed for antinociception, locomotor activity, and body temperature changes in mice. SAR insights included the high opioid-like activity of methionitazene, iso-butonitazene, sec-butonitazene, and the etonitazene analogues 1-ethyl-pyrrolidinylmethyl N-desalkyl etonitazene and ethylene etonitazene. The most potent analogue of the panel across all functional assays was α’-methyl etonitazene. Taken together, through critical pharmacological evaluation, this work provides a framework for strengthened preparedness and risk assessments of current and future nitazenes that have the potential to cause harm to users.

Introduction: 2-Benzylbenzimidazole opioids (‘nitazenes’) have become increasingly prevalent on the recreational drug market. We performed pharmacological characterization of various 'prophetic' nitazenes, allowing risk prioritization based on structure-activity relationships. Ethyleneoxynitazene, which we predicted to emerge and which was first found in January 2023, is presented as a case example. Methods: In vitro pharmacological characterization encompassed radioligand binding assays in rat brain tissue and a cell-based µ-opioid receptor activation (MOR-β-arrestin2) assay. Antinociception (hot plate assay), locomotor activity, and thermic effects were evaluated after subcutaneous administration in C57BL/6J mice. Results: Binding assays revealed a Ki of 57.9 nM; only slightly higher than that of etonitazene (38.4 nM). However, ethyleneoxynitazene had a >100-fold lower potency in the MOR-β-arrestin2 assay (EC50, ethyleneoxynitazene=70.0 nM; EC50, etonitazene=0.588 nM). Its efficacy (relative to the reference hydromorphone) was also lower (Emax,ethyleneoxynitazene=187% vs. Emax,etonitazene=254%). The strongly reduced activity was reflected in vivo, with an ED50, antinociception of 11.1 mg/kg and 0.0223 mg/kg for ethyleneoxynitazene and etonitazene, respectively. Hypothermia and locomotor assays revealed the same pattern. Conclusions: The a priori availability of pharmacological data upon the first emergence of ethyleneoxynitazene allowed to rapidly communicate that (compared to other nitazenes) this is likely not the opioid of highest concern. Similarly, pharmacological data for other anticipated nitazenes are readily available.

Summary: Transgender and gender-diverse individuals experience substantial health disparities across the cancer care continuum. Despite well recognized unique healthcare needs, there are barriers in accessing cancer prevention and treatment services, influenced by disadvantages in key social-economic determinants of health which result in worse clinical outcomes, as compared to the general population. The Italian Association of Medical Oncology (AIOM) acknowledges the critical relevance of this issue. The “Assisi Recommendations” here summarize the outcomes of the “AIOM Oncology Ethics Day” dedicated to gender differences in oncology and cancer care of transgender and gender-diverse people. The recommendations generated during a 2-day multidisciplinary discussion address the various aspects of cancer care experience of transgender and gender-diverse people. The promotion of research in this field, through the generation of new evidence and the collection of prospective data, has been identified as a priority action to mitigate these disparities. By acknowledging the challenges of cancer care in transgender and gender-diverse people and recognizing the need for dedicated policy and clinical recommendations, AIOM demonstrates its commitment to improving the health and well-being of all patients with cancer, regardless of their gender identity or any other personal or social circumstances, as part of health-for-all societal vision.

Abstract Background Escalation and de-escalation are a routine part of high-quality care that should be matched with clinical needs. The aim of this study was to describe escalation of care in relation to the occurrence and timing of Pediatric Intensive Care Unit (PICU) admission in a cohort of pediatric inpatients with acute worsening of their clinical condition. Methods A monocentric, observational cohort study was performed from January to December 2018. Eligible patients were children: 1) admitted to one of the inpatient wards other than ICU; 2) under the age of 18 years at the time of admission; 3) with two or more Bedside-Paediatric-Early-Warning-System (BedsidePEWS) scores ≥ 7 recorded at a distance of at least one hour and for a period of 4 h during admission. The main outcome -the 24-h disposition – was defined as admission to PICU within 24-h of enrolment or staying in the inpatient ward. Escalation of care was measured using an eight-point scale—the Escalation Index (EI), developed by the authors. The EI was calculated every 6 h, starting from the moment the patient was considered eligible. Analyses used multivariate quantile and logistic regression models. Results The 228 episodes included 574 EI calculated scores. The 24-h disposition was the ward in 129 (57%) and the PICU in 99 (43%) episodes. Patients who were admitted to PICU within 24-h had higher top EI scores [median (IQR) 6 (5–7) vs 4 (3–5), p

Antibiotic resistance has become more and more widespread over the recent decades, becoming a major global health problem and causing colistin to be increasingly used as an antibiotic of last resort. Acinetobacter baumannii, an opportunistic pathogen that has rapidly evolved into a superbug exhibiting multidrug-resistant phenotypes, is responsible for a large number of hospital infection outbreaks. With the intensive use of colistin, A. baumannii resistance to colistin has been found to increase significantly. In previous work, we identified a deflazacort derivative, PYED-1 (pregnadiene-11-hydroxy-16,17-epoxy-3,20-dione-1), which exhibits either direct-acting or synergistic activity against Gram-positive and Gram-negative species and Candida spp., including A. baumannii. The aim of this study was to evaluate the antibacterial activity of PYED-1 in combination with colistin against both A. baumannii planktonic and sessile cells. Furthermore, the cytotoxicity of PYED-1 with and without colistin was assessed. Our results show that PYED-1 and colistin can act synergistically to produce a strong antimicrobial effect against multidrug-resistant populations of A. baumannii. Interestingly, our data reveal that PYED-1 is able to restore the efficacy of colistin against all colistin-resistant A. baumannii isolates. This drug combination could achieve a much stronger antimicrobial effect than colistin while using a much smaller dosage of the drugs, additionally eliminating the toxicity and resistance issues associated with the use of colistin.

Belantamab-mafodotin is an innovative and selective treatment for multi-refractory/relapsed multiple myeloma (MM) patients; however, available real-life experiences on efficacy and safety are limited. In this real-world multicentric retrospective study, we enrolled 28 MM patients treated in four Hematology units of Campania region, Italy, who received a median of six treatment lines prior to belantamab-mafodotin. The overall response rate (ORR) was 40% (complete remission, CR, 11%; very good partial remission, VGPR, 11%; and partial remission, PR, 18%), with a median progression-free survival (PFS) and overall survival (OS) of 3 and 8 months, respectively. One of the most frequent drug-related adverse events was keratopathy observed in nine (32%) patients, leading to therapy discontinuation in only three (11%) of them. Moreover, 22 out of 28 total patients who were treated with at least two administrations achieved an ORR of 50% (CR, 14%; VGPR, 14%; and PR, 22%) with a median PFS and OS of 5 and 11 months, respectively. In conclusion, our multicentric study confirmed efficacy and safety of belantamab-mafodotin in triple-refractory MM patients even in the real-life setting.

The second half of the nineteenth century saw a proliferation of translations from romance languages into Romanian as a consequence of the economic and cultural development of the Romanian society. In this context, 1893 saw the publication of the first Romanian translation of De Amicis’s Cuore (Heart): An Italian Schoolboy’s Journal, by Clelia Bruzzesi (1836-1903). The twentieth century brought five other versions, two of them signed by women translators: Sofia Nădejde (1856-1946) in 1916 and Mia Frollo (1885-1962) in 1936. Until recently, Cuore was part of the primary school curriculum in Romania, so the text left a mark on the cultural history of the country. This paper aims to raise awareness of the often neglected translation activity of women and to reveal Bruzzesi, Nădejde and Frollo’s place in society as well their motivations and the public reception of their translations.

Multimodal biometric systems are often used in a wide variety of applications where high security is required. Such systems show several merits in terms of universality and recognition rate compared to unimodal systems. Among several acquisition technologies, ultrasound bears great potential in high secure access applications because it allows the acquisition of 3D information about the human body and is able to verify liveness of the sample. In this work, recognition performances of a multimodal system obtained by fusing palmprint and hand-geometry 3D features, which are extracted from the same collected volumetric image, are extensively evaluated. Several fusion techniques based on the weighted score sum rule and on a wide variety of possible combinations of palmprint and hand geometry scores are experimented with. Recognition performances of the various methods are evaluated and compared through verification and identification experiments carried out on a homemade database employed in previous works. Verification results demonstrated that the fusion, in most cases, produces a noticeable improvement compared to unimodal systems: an EER value of 0.06% is achieved in at least five cases against values of 1.18% and 0.63% obtained in the best case for unimodal palmprint and hand geometry, respectively. The analysis also revealed that the best fusion results do not include any combination between the best scores of unimodal characteristics. Identification experiments, carried out for the methods that provided the best verification results, consistently demonstrated an identification rate of 100%, against 98% and 91% obtained in the best case for unimodal palmprint and hand geometry, respectively.

This paper comprises results concluding the research activity done so far regarding enhanced web services and system integration. The objective of the paper is to define the software architecture for a coherent framework and methodology for enhancing existing web services into an integrated system. This document presents the research work that has been done so far in this aspect by applying the proposed architecture for system integration in the academic field. The basics concepts used are Enterprise Application Integration (EAI) and Service Oriented Architecture (SOA), as the most commonly used approaches to information systems integration lately. SOA is an Information Technology (IT) architectural style that supports the transformation of businesses into a set of linked services, or repeatable business tasks that can be accessed when needed over a network. This may be a local network, it may be the Internet, or it may be geographically and technologically diverse, combining services in New York, Paris, and Beijing as though they were all installed on a local desktop. These services can coalesce to accomplish a specific business task, enabling businesses to adapt quickly to changing conditions and requirements. (Contains 6 figures.)

Recognition systems based on palm veins are gaining increasing attention as they are highly distinctive and very hard to counterfeit. Most popular systems are based on infrared radiation; they have the merit to be contactless but can provide only 2D patterns. Conversely, 3D patterns can be achieved with Doppler or photoacoustic methods, but these approaches require too long of an acquisition time. In this work, a method for extracting 3D vascular patterns from conventional grayscale volumetric images of the human hand, which can be collected in a short time, is proposed for the first time. It is based on the detection of low-brightness areas in B-mode images. Centroids of these areas in successive B-mode images are then linked through a minimum distance criterion. Preliminary verification and identification results, carried out on a database previously established for extracting 3D palmprint features, demonstrated good recognition performances: EER = 2%, ROC AUC = 99.92%, and an identification rate of 100%. As further merit, 3D vein pattern features can be fused to 3D palmprint features to implement a costless multimodal recognition system.

Background and aims. Scedosporium species and Lomentospora prolificans are the filamentous fungi isolated more frequently from the cystic fibrosis (CF) lower airways, after Aspergillus fumigatus. Previous studies showed that, in CF patients, Scedosporium species and Lomentospora prolificans are responsible for airways colonization/ infection, enhancing pulmonary deterioration, and for severe invasive infections in CF patients undergoing lung transplantation. Aims of our project were to evaluate the prevalence of Scedosporium and Lomentospora species in Italian patients with CF, and to evaluate the interest of the Scedosporium-selective colture medium SceSel compared to routinely used agar-based culture media, in order to improve laboratory diagnostic performances. Materials and methods. A total of 1977 sputum samples from 1154 CF patients were collected and processed according to CF Italian recommendations in the year 2017 (January 1st to December 31st). The SceSel agar was used in addition to the routine culture procedures to burst growth and isolation of Scedosporium/ Lomentospora species. The fungal isolates were identified by classical mycological methods and polymerase chain reaction-based DNA sequencing of ITS1 and ITS4 regions. Susceptibility of the isolates to antifungal drugs was investigated by E-test method. Results. Among the 1154 enrolled patients, 62 (5.3%) were positive for Scedosporium/Lomentospora species (median age: 27y; range 8-64y; 33 male). Out of 1977 samples, 93 were positive for Scedosporium/Lomentospora species, and 13 (13.9%) were recovered only on SceSel agar. According to molecular analyses, isolation rates of each species were: S. apiospermum 53.1%, S. boydii 37.5%, L. prolificans 6.3% and S. aurantiacum 3.1%. Amphotericin B minimum inhibitory concentration (MIC) values were above or equal to 2 mg/L in all strains. Voriconazole MIC values were below or equal to 0.38 mg/L in almost all strains, proving this drug to be the most effective antimycotic for members of Scedosporium species. Otherwise, Lomentospora prolificans showed to be resistant to all considered antifungal drugs, only Voriconazole seems to be active on some Lomentospora prolificans isolates. Conclusions. Our results suggest that SceSel agar should be used in combination with routine media as standard microbiological protocol and procedures are not always adequate to isolate Scedosporium and Lomentospora species in CF respiratory samples. Molecular identification and susceptibility tests are needed, especially for strains isolated from critical patients and those considered for transplantation, as they might develop invasive scedosporiosis.

Pediatric acute myeloid leukemia is a clonal disorder characterized by malignant transformation of the hematopoietic stem cell. The incidence and the outcome remain inferior when compared to pediatric ALL, although prognosis has improved in the last decades, with 80% overall survival rate reported in some studies. The standard therapeutic approach is a combined cytarabine and anthracycline-based regimen followed by consolidation with allogeneic stem cell transplantation (allo-SCT) for high-risk AML and allo-SCT for non-high-risk patients only in second complete remission after relapse. In the last decade, several drugs have been used in clinical trials to improve outcomes in pediatric AML treatment.