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Background and Purpose: The Active Connection Matrixes (ACMs) are unsupervised artificial adaptive systems able to extract from digital images features of interest (edges, tissue differentiation, etc.) unnoticeable with conventional systems. In this proof-of-concept study, we assessed the potentiality of ACMs to increase measurement precision of morphological structures (e.g., stenosis and lumen diameter) and to grasp morphological features (arterial walls) from quantitative coronary angiography (QCA), unnoticeable on the original images.Methods: Archive images of QCA and intravascular ultrasound (IVUS) of 10 patients (8 men, age 69.1 ± 9.7 years) who underwent both procedures for clinical reasons were retrospectively analyzed. Arterial features derived from “IVUS images,” “conventional QCA images,” and “ACM-reprocessed QCA images” were measured in 21 coronary segments. Portions of 1-mm length (263 for lumen and 526 for arterial walls) were head-to-head compared to assess quali-quantitative between-methods agreement.Results: When stenosis was calculated on “ACM-reprocessed QCA images,” the bias vs. IVUS (gold standard) did not improve, but the correlation coefficient of the QCA–IVUS relationship increased from 0.47 to 0.83. When IVUS-derived lumen diameters were compared with diameters obtained on ACM-reprocessed QCA images, the bias (−0.25 mm) was significantly smaller (p < 0.01) than that observed with original QCA images (0.58 mm). ACMs were also able to extract arterial wall features from QCA. The bias between the measures of arterial walls obtained with IVUS and ACMs, although significant (p < 0.01), was small [0.09 mm, 95% CI (0.03, 0.14)] and the correlation was fairly good (r = 0.63; p < 0.0001).Conclusions: This study provides proof of concept that ACMs increase the measurement precision of coronary lumen diameter and allow extracting from QCA images hidden features that mirror well the arterial walls derived by IVUS.

This randomized double-blinded, placebo-controlled clinical trial evaluated the progression of intima-media thickness of common carotid artery (cIMT) and the effect of phytoestrogen therapy on atherosclerosis development in early and late postmenopausal women. The 2-year cIMT progression was evaluated in 315 early postmenopausal women aged 40−55 years and in 231 late postmenopausal women aged 60−69 years free of cardiovascular disease. B-mode ultrasound was done at baseline and after 12 and 24 months of follow-up. The study revealed no significant changes in the rate of cIMT progression in 315 early postmenopausal women. By contrast, a statistically significant difference in the rate of atherosclerosis development was observed in late postmenopausal women treated with phytoestrogens compared to placebo (p = 0.008). The rate of cIMT progression in the placebo group was 0.019 mm/year led to a significant increase of cIMT during the observation period (p = 0.012), while the rate of cIMT progression in phytoestrogen late postmenopausal recipients was 0.011 mm/year, and total change did not reach statistical significance during the follow-up period (p = 0.101). These results suggest that late postmenopausal women can be a suitable cohort for trials assessing the anti-atherosclerosis effects of phytoestrogen preparations. In particular, the beneficial effect of phytoestrogens on cIMT progression was demonstrated in late postmenopausal women.

A case study from eastern Australia is used to demonstrate methods for subsurface high-grading and development-concept optimisation in Coal Seam Gas resource plays. We discuss two aspects of subsurface high-grading: (1) improved prediction of net coal using 2D seismic data, and (2) structure-geological analysis and mapping of the fracture network. Net-coal predictions across the study area focused on the upper Juandah Coal Measures interval of the Jurassic Walloon Coal Measures. There is a positive relationship between extracted and normalised upper Juandah Coal Measures seismic-amplitude strength and net coal in the wells. Areas with considerable amplitude dimming commonly coincide with reflector 'washout' areas mapped from seismic data and are interpreted as channel incisions into otherwise continuous coal seams. Integration of seismic and well data can improve the mapping of net coal and help optimise the placement of appraisal wells, reducing the number of unexpected or difficult-to-interpret well finds. It may also guide delineation of resource-classification domains in a more robust manner than mapping from well data alone. Fractures in coal seams of the study area are mostly bed-perpendicular joints and cleats. Three sets of fractures/cleats are identified in the coal beds: a dominant set and two more localised sets. Fracture intensity was mapped per set using well data and then combined. Fracture maps are deemed useful as an indication of permeability anisotropy, and hence the expected shape of well drainage areas, as opposed to indicating a range of permeability values. Based on the fracture interpretations, it may be possible to optimise the development concept of specific areas, i.e. varying well spacing and/or drilling wells slanted perpendicular to dominant fracture strike. Use of 2D seismic data to qualitatively indicate net-coal trends in the Walloon Coal Measures. The correlation coefficient between seismic amplitude and net coal is strong enough to guide well placement and resource delineation. Fracture intensity mapping from borehole images may indicate permeability anisotropy of the coals rather than absolute permeability values. [ABSTRACT FROM AUTHOR]

The virus species Protoparvovirus carnivoran 1 encompasses pathogens that infect both domestic and wild carnivores, including feline panleukopenia virus. We identified and characterized feline panleukopenia virus strains in a Marsican brown bear (Ursus arctos marsicanus) and a crested porcupine (Hystrix cristata) in Italy, extending the known host range of this virus.

Abstract Photonic platforms are promising for implementing neuromorphic hardware due to their high processing speed, low power consumption, and ability to perform parallel processing. A ubiquitous device in integrated photonics, which has been extensively employed for the realization of optical neuromorphic hardware, is the microresonator. The ability of CMOS-compatible silicon microring resonators to store energy enhances the nonlinear interaction between light and matter, enabling energy efficient nonlinearity, fading memory and the generation of spikes via self-pulsing. In the self-pulsing regime, a constant input signal can be transformed into a time-dependent signal based on pulse sequences. Previous research has shown that self-pulsing enables the microresonator to function as an energy-efficient artificial spiking neuron. Here, we extend the experimental study of single and coupled microresonators in the self-pulsing regime to confirm their potential as building blocks for scalable photonic spiking neural networks. Furthermore, we demonstrate their potential for introducing all-optical long-term memory and event detection capabilities into integrated photonic neural networks. In particular, we show all-optical long-term memory up to at least 10 μs and detection of input spike rates, which is encoded into different stable self-pulsing dynamics.

Abstract The effects of cosmological expansion on quantum bosonic states are investigated, using quantum information theory. In particular, a generic Bogoliubov transformation of bosonic field modes is considered and the state change on a single mode is regarded as the effect of a quantum channel. Properties and capacities of this channel are thus explored in the framework of f(Q) non-metric gravity. The reason is that non-metric gravity can be considered under the standard of gauge theories with all the advantages of such a formulation. As immediate result, we obtain that the information on a single-mode state appears better preserved, whenever the number of particles produced by the cosmological expansion is small. Specifically, we investigate a power law f(Q) model, leaving unaltered the effective gravitational coupling, and minimise the corresponding particle production. We thus show how to optimise the preservation of classical and quantum information, stored in bosonic mode states in the remote past. Finally, we compare our findings with those obtained in General Relativity.

Abstract Glioblastoma remains one of the deadliest brain malignancies. First-line therapy consists of maximal surgical tumor resection, accompanied by chemotherapy and radiotherapy. Malignant cells escape surgical resection by migrating into the surrounding healthy brain tissue, where they give rise to the recurrent tumor. Based on gene expression, tumor cores can be subtyped into mesenchymal, proneural, and classical tumors, each being associated with differences in genetic alterations and cellular composition. In contrast, the adjacent brain parenchyma where infiltrating malignant cells escape surgical resection is less characterized in patients. Using spatial transcriptomics (n = 11), we show that malignant cells within proneural or mesenchymal tumor cores display spatially organized differences in gene expression, although such differences decrease within the infiltrated brain tissue. Malignant cells residing in infiltrated brain tissue have increased expression of genes related to neurodevelopmental pathways and glial cell differentiation. Our findings provide an updated view of the spatial landscape of glioblastomas and further our understanding of the malignant cells that infiltrate the healthy brain, providing new avenues for the targeted therapy of these cells after surgical resection.

This suspect case focuses on investigating the presence of halite (NaCl) crystals on the clothing of a deceased individual to determine whether they resulted from immersion in seawater or residual absorption after immersion (i.e., the crystals were left on the clothing after contact with the victim’s wet body). Thirteen clothing samples were collected from various garments worn by the victim and were subjected to optical stereomicroscopy, Scanning Electron Microscopy (SEM), coupled with Energy Dispersive Spectroscopy (EDS), and Simultaneous Thermal Analysis (STA). Optical stereomicroscopy revealed numerous white-colored, vitreous, and greasy luster microcrystals dispersed between fabric fibers, with higher concentrations observed near the hem seams and metal rivets. These microcrystals exhibited predominantly cubic and irregular morphologies. Additionally, sandy particles and organic elements, such as plant fragments and micro seashells, were detected, indicative of coastal environment exposure. SEM-EDS analysis confirmed the presence mainly of sodium and chlorine in stoichiometric ratios consistent with halite, with crystals exhibiting amorphous, needle-shaped, or cubic morphologies. Furthermore, STA analysis identified weight loss events attributed to organic decomposition and halite decomposition at high temperatures, corroborating SEM-EDS findings. The distribution and characteristics of halite crystals, along with other trace elements, support the hypothesis of immersion in seawater while wearing clothing. Specifically, the higher concentrations of halite crystals near thicker fabric portions and metal rivets suggest slower drying rates and longer evaporation times, indicative of immersion rather than residual absorption after swimming. This finding not only helps in determining the victim’s exposure to seawater but also establishes a methodology for distinguishing between different sources of halite residue on clothing. Overall, the comprehensive mineralogical characterization of halite crystals on clothing samples, using best practices of forensic mineralogy, provides valuable forensic insights related to the circumstances that led to the victim’s death. This approach aided investigators in reconstructing the sequence of events, enhancing the accuracy of forensic reconstructions. Moreover, this study contributes to the broader field of forensic geoscience by demonstrating the practical applications of mineralogical analysis in criminal investigations, potentially guiding future research and improving investigative techniques in similar cases.

Abstract We propose a compartmental model for investigating smoking dynamics in an Italian region (Tuscany). Calibrating the model on local data from 1993 to 2019, we estimate the probabilities of starting and quitting smoking and the probability of smoking relapse. Then, we forecast the evolution of smoking prevalence until 2043 and assess the impact on mortality in terms of attributable deaths. We introduce elements of novelty with respect to previous studies in this field, including a formal definition of the equations governing the model dynamics and a flexible modelling of smoking probabilities based on cubic regression splines. We estimate model parameters by defining a two-step procedure and quantify the sampling variability via a parametric bootstrap. We propose the implementation of cross-validation on a rolling basis and variance-based Global Sensitivity Analysis to check the robustness of the results and support our findings. Our results suggest a decrease in smoking prevalence among males and stability among females, over the next two decades. We estimate that, in 2023, 18% of deaths among males and 8% among females are due to smoking. We test the use of the model in assessing the impact on smoking prevalence and mortality of different tobacco control policies, including the tobacco-free generation ban recently introduced in New Zealand.

Bluetongue (BT) and Epizootic Hemorrhagic Disease (EHD) are two notifiable animal diseases transmitted to ruminants by small hematophagous midges belonging to the Culicoides genus. The etiological agents, Bluetongue virus (BTV) and Epizootic hemorrhagic disease virus (EHDV), are both members of the Sedoreoviridae family and Orbivirus genus, which include double-stranded (ds) RNA segmented genomes (10 segments). By the end of the summer 2023, first's outbreaks of EHD were reported from the south west of France, concurrently with unexpectedly severe BT cases in Central France and Corsica. Within a few weeks, numerous BT and EHD outbreaks were recorded with significant sanitary and economic impact on cattle and sheep farms (no sanitary impact of EHD for sheep). Using a customized SISPA approach and the nanopore sequencing technology we successfully recovered genomic sequences from viral isolates and blood samples from infected animals from EHD and BT outbreaks. Three different viruses were responsible for these outbreaks: EHDV-8, BTV-8 and BTV-4. The EHDV-8 strain detected in France corresponded to the strain circulating in Tunisia, Sardinia and Spain since 2021 and 2022. A new BTV-8 strain of unknown origin, clearly different from the enzootic strain circulating in France since 2015, was responsible of the BT outbreaks in domestic ruminants in 2023 on both mainland France and Corsica. A second BTV, BTV-4, also involved in BT outbreaks in Corsica, corresponded to a BTV-4 strain occasionally detected on Corsica island since 2016, suggesting either a new introduction of this strain or a silent circulation on the field. The exceptional nature of orbivirus epizootics in France in 2023, including new introduction, emergence or incursions, raises numerous questions regarding BTV and EHDV dynamics and epidemiology and stresses out the need to identify factors involved in these emergences.

Background An increasing number of people, including recreational trained individuals, choose not to consume animal products and follow a vegan diet. Young women in particular are switching to a vegan diet. Studies have shown no difference in performance and muscle adaptations between a balanced vegan and an omnivorous diet. However, there are hardly any studies on the transition phase from an omnivorous to a vegan diet and the potential difficulties. Therefore, this study aimed to investigate the influence of a vegan dietary transition and its effects on body composition, physical performance, and menstrual cycle in young, recreationally trained women.Methods Ten young healthy women (23.8 ± 2.0 years, 173.0 ± 5.8 cm) were recruited to participate in this 12-week controlled study (4-week omnivorous phase, 8-week vegan intervention). At the beginning and before the vegan phase, all participants were informed about a balanced diet for fitness-oriented individuals and a vegan lifestyle. They were supervised by a sports dietitian for the entire 12 weeks. Explicit instructions and regular checks on macronutrient distribution were not carried out but had to be implemented independently. The diet was documented using FDDB Extender. The training habits were not explicitly specified, but should not be changed over the entire period. At baseline (T0) and 4-week intervals (T1, T2, T3), body composition (body weight, skeletal muscle mass, fat mass) and performance (squat, countermovement jump) were tested. In addition, the menstrual cycle was examined every two days using saliva samples and a cycle diary.Results Between treatments, there was a significant decrease in absolute (T0: 94.44 ± 20.37 kcal; T3: 71.67 ± 27.64 kcal; p

Background Rapid regeneration after intense exercise is essential for competitive athletes. Based on this assumption, supplementation strategies, focusing on food supplements, are increasing to improve the recovery processes. One such supplement is cannabidiol (CBD) which is gaining more attention in competitive sports. However, the evidence is still lacking and there are no data available about the effect of a short-term chronic application.Methods A three-arm double-blind cross-over study was conducted to determine the effects of two different CBD products on performance, muscle damage and inflammatory processes in well-trained athletes. In total 17 subjects took successfully part in this study. Each subject underwent the six-day, high-intensity training protocol three times. After each training session, each subject took either a placebo or a CBD product (60 mg of oil or solubilisate). Between the intervention phases, at least four weeks of washout period was conducted. Before and after the training protocols the performance capacity in countermovement jump (CMJ), back squat (BS), bench press (BP) and 1-mile run were measured and biomarkers for muscle damage (creatine kinase, myoglobin), inflammatory processes (interleukin 6 and 10) and immune cell activity (ratios of neutrophil granulocytes, lymphocytes and, platelets) were analyzed. For statistical analyses, the current version of R and a linear mixed model was used.Results It could identify different effects of the training protocol depending on performance level (advanced or highly advanced athletes) (p

The immunization of mice with the sterile culture medium supernatants of Mycobacterium tuberculosis (Mtb) H37Rv permitted the production of several monoclonal antibodies (mAbs) specific for secreted and/or released antigens. Two mAbs bound and immunoprecipitated an 80-kDa protein that was identified by mass spectrometry as Rv1133c, the methionine synthase MetE. The protein MetE is ubiquitous among prokaryota and shows a significant sequence homology in many bacteria. We produced both the full-length recombinant MetE and its N-terminal fragment, whose sequence is more conserved among mycobacteria, to select mAbs recognizing an Mtb-specific region of MetE. Finally, we produced and selected eight mAbs that specifically detect the MetE protein in the supernatant and cell lysate of Mtb and BCG, but not other bacteria such as non-tuberculous mycobacteria (NTM), Streptococcus pneumoniae, Staphylococcus aureus, Acinetobacter baumanii, or Escherichia coli. Taking advantage of our mAbs, we studied (i) the vitamin B12 dependence for the synthesis of MetE in Mtb and NTM and (ii) the kinetics of MetE production and secretion in supernatants during the in vitro reproduced replicative, dormant, and resuscitation cycle of Mtb. Our data demonstrate that dormant Mtb, which are assumed to be prevalent in latent infections, as well as NTM do not produce and secrete MetE. Results indicate an unexpected specificity for Mtb of our anti-MetE mAbs and encourage the use of rMetE and our mAbs as tools for the immunodiagnosis of TB and its stages.

In response to the uncertainty and volatility arising from renewable sources, there is a growing need for enhanced flexibility within the energy system to maintain a continuous balance between power generation and demand. In this context, interest is growing around the so-called Multi-Energy Systems (MES) where different energy vectors coexist and optimally interact through conversion technologies and energy networks, creating additional flexibility opportunities. Nevertheless, there exists a gap in research regarding the impact of the network on flexibility availability. Typically, these complex systems are treated as power nodes or energy hubs without comprehensive network considerations. For this reason, the paper aims to propose a methodology and a tool to evaluate flexibility in a Multi-Energy System, considering not only the individual devices in place and the users' demands but also their interactions with the physical energy network. In detail, a simulation-based methodology is developed and described, and finally tested on a Case Study. As a result, both the physical and operational flexibilities (UP-flex and DOWN-flex) of the system regarding the electrical vector were obtained analytically and graphically. Particular attention was given to the evolution of key temperatures within the district heating network and the thermal power produced by the central unit in various flexibility scenarios. The outcomes demonstrate the utility of this tool for defining flexibility boundaries and profiles, as well as for assessing whether the flexibility demanded by grid operators aligns with the physical constraints of the network.

Abstract Background Multisystem inflammatory syndrome in children (MIS-C) shows a significant overlap of symptoms with other hyper-inflammatory diseases such as Kawasaki disease (KD), but the real difference of the two conditions is still matter of debate. Coronary artery lesions (CAL) are the most relevant complication in KD. Nonetheless, CAL, myocarditis, pericarditis, arrhythmia are the main cardiovascular complications in MIS-C. A close clinical assessment is mandatory, both at the diagnosis and during the follow-up, by ECG and echocardiography. Cardiac magnetic resonance (MRI) adds important data to ultrasound findings. However, cardiac MRI studies in MIS-C are limited to a small number of cohorts. Methods We enrolled 20 children (age:1–16 years; 11 F; 9 M) with cardiac involvement secondary to MIS-C, all evaluated by cardiac MRI. Results 8 children showed pathological cardiac MRI: 2 showed pericardial effusion; 2 showed myocardial oedema; 1 showed aortic insufficiency; 3 showed delayed enhancement (one for acute myocarditis with oedema; 2 for myocardial fibrosis). Delayed enhancement was reduced significantly 5.6-9 months after the first MRI evaluation. 25% of patients with pathological MRI had CAL associated with valvular insufficiency of 2 valves. 17% of patients with normal MRI had CAL, associated with valvular insufficiency of 1 valve in 1 patient. The correlations between haematological, clinical, cardiologic parameters, treatment, did not reach the statistical significance. 4 patients were treated with anakinra. Among those, 2 patients showed a normal cardiac MRI. Cardiac lesions resolved in all the patients during the follow-up. Some patients with pathological cardiac MRI could not underwent a control with MRI, for the low compliance. However, echocardiography and ECG, documented the resolution of the pathological data in these cases. Conclusions A higher risk of CAL was documented in patients with an association of other cardiac lesions. Cardiac MRI is difficult to perform routinely; however, it is useful for evaluating the acute myocardial damage and the outcome of patients with MIS-C.

Epizootic haemorrhagic disease (EHD), caused by the EHD virus (EHDV), is a vector-borne viral disease transmitted through Culicoides biting midges. EHDV comprises seven serotypes (1, 2, and 4–8), with EHDV-8 having recently emerged and spread in Europe over the last two years. Such event has raised concerns about the significant threat posed by EHDV-8 to livestock industry. In this study, an inactivated vaccine against EHDV-8 (vEHDV8-IZSAM) was developed. Safety and efficacy of the vaccine were evaluated in calves through clinical, serological, and virological monitoring following experimental challenge.The vaccine was proven safe, with only transient fever and localized reactions observed in a few animals, consistent with adjuvanted vaccine side effects. vEHDV8-IZSAM elicited a robust humoral response, as evidenced by the presence of neutralizing antibodies. After challenge with a virulent isolate, viraemia and clinical signs were evidenced in control animals but in none of the vaccinated animals.This study highlights the potential of vEHDV8-IZSAM as a safe and highly effective vaccine against EHDV-8 in cattle. It offers protection from clinical disease and effectively prevents viraemia. With the recent spread of EHDV-8 in European livestock, the use of an inactivated vaccine could be key in protecting animals from clinical disease and thus to mitigate the economic impact of the disease. Further investigations are warranted to assess the duration of the induced immunity and the applicability of this vaccine in real-world settings. Accordingly, joint efforts between public veterinary institutions and pharmaceutical companies are recommended to scale up vaccine production.

In this paper we describe the validation of a focus reduction neutralization test (FRNT) to quantitate human SARS-CoV-2 neutralizing antibodies by using the CTL Immunospot S6 Universal Analyzer. We employed a previously published protocol and compared its performances to a well-established and traditional serum-neutralization assay (SN). To assess diagnostic sensitivity, a total number of 201 human sera positive by SN for SARS-CoV-2 NAbs were processed: 196/201 tested positive by FRNT50 (97.51 %). A diagnostic specificity of 100 % was obtained by evaluating 206 negative serum samples. Repeatability of the test was evaluated by determining the intra and inter-assay coefficient of variation (CV). A standard deviation of 0.83 and a CV of 13 % were evidenced demonstrating an acceptable reproducibility of the assay. Moreover, a Cohen's Kappa of 0.975 was obtained proving an extremely high level of agreement between the FRNT protocol and the SN. Despite an acceptable correlation between methods (p

The present study gathers mineralogical and isotopic geochemical data of 45 soil samples collected from the La Guardiense and Cantina di Solopaca wineries (Southern Italy) in order to provide useful information for the geotraceability of Falanghina white wine terroir. Mineralogical analyses show the ubiquitous presence of quartz, frequent and moderate contents of feldspars and phyllosilicates (i.e., illite/mica, kaolinite, and smectite). Rhizosphere soils from La Guardiense vineyards show a strontium isotope signature (87Sr/86Sr) ranging from 0.708604 to 0.711234 (average 0.710334; 1σ = 0.000943; n = 7) for the total fraction and a narrower range (from 0.706907 to 0.708807; average 0.708120; 1σ = 0.000641; n = 7) for the bioavailable one. For the rhizosphere soils collected from the vineyards of Cantina di Solopaca winery, 87Sr/86Sr ratios range from 0.708268 to 0.712413 (average 0.710145; 1σ = 0.001622; n = 8) and from 0.707968 to 0.709157 (average 0.708384; 1σ = 0.000409; n = 8) for the total and the bioavailable fraction, respectively. Actually, the bioavailable Sr fraction shows a narrower range of 87Sr/86Sr ratios compared to that of the total fraction, making the former more suitable for any study of wine traceability.

Objective: Canine distemper virus (CDV) is a highly infectious virus that represents a threat for domestic dogs and several wild species. Despite recognized in several African countries, current knowledge of its molecular epidemiology is scarce and poorly updated. Design: Twenty-two hemagglutinin sequences, obtained from symptomatic Namibian dogs from 2020 to 2023, were analysed through phylogenetic and phylodynamic analysis to characterize the local CDV epidemiology and contextualize it in the international scenario. Results: Two unrelated clades were identified, including strains sampled in different Namibian towns, in the absence of a strong geographical clustering. The ancestors of the two clades were estimated to have originated from South America, likely Brazil, and South Africa, approximately in 2000 and 2006, respectively. While the introduction from South Africa was predictable, the introduction from Brazil was unexpected. The mediation of other African countries, particularly Angola, appears to be the most likely importation pathway. Conclusions: The occurrence of multiple introduction events, likely originating from cross-border illegal animal trade between African countries, and the absence of any geographical clustering within Namibian regions, suggest a need for further investigation into its spreading pattern, as well as improved biosecurity measures to limit foreign viral introduction into the country.

Abstract Background Relapse and refractory (R/R) rates after first‐line R‐CHOP in diffuse large B cell lymphomas (DLBCL) are ~40% and ~15% respectively. Aims We conducted a retrospective real‐world analysis aimed at evaluating clinical outcomes of R/R DLBCL patients. Material and Methods Overall, 403 consecutive DLBCL patients treated in two large hematological centers in Torino, Italy were reviewed. Results At a median follow up of 50 months, 5‐year overall survival from diagnosis (OS‐1) was 66.5%, and 2‐year progression free survival (PFS‐1) was 68%. 134 (34.4%) patients relapsed (n = 46, 11.8%) or were refractory (n = 88, 22.6%) to R‐CHOP. Most employed salvage treatments included platinum salt‐based regimens in 38/134 (28.4%), lenalidomide in 14 (10.4%). Median OS and PFS after disease relapse or progression (OS‐2 and PFS‐2) were 6.7 and 5.1 months respectively. No significant difference in overall response rate, OS‐2 or PFS‐2 in patients treated with platinum‐based regimens versus other regimens was observed. By multivariate analysis, age between 60 and 80 years, germinal center B cell type cell of origin and extranodal involvement of

Abstract The EGFR tyrosine kinase inhibitor osimertinib has been approved for the first-line treatment of EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) patients. Despite its efficacy, patients develop resistance. Mechanisms of resistance are heterogeneous and not fully understood, and their characterization is essential to find new strategies to overcome resistance. Ceramides are well-known regulators of apoptosis and are converted into glucosylceramides (GlcCer) by glucosylceramide synthase (GCS). A higher content of GlcCers was observed in lung pleural effusions from NSCLC patients and their role in osimertinib-resistance has not been documented. The aim of this study was to determine the therapeutic potential of inhibiting GCS in NSCLC EGFR-mutant models resistant to osimertinib in vitro and in vivo. Lipidomic analysis showed a significant increase in the intracellular levels of glycosylceramides, including GlcCers in osimertinib resistant clones compared to sensitive cells. In resistant cells, the GCS inhibitor PDMP caused cell cycle arrest, inhibition of 2D and 3D cell proliferation, colony formation and migration capability, and apoptosis induction. The intratumoral injection of PDMP completely suppressed the growth of OR xenograft models. This study demonstrated that dysregulation of ceramide metabolism is involved in osimertinib-resistance and targeting GCS may be a promising therapeutic strategy for patients progressed to osimertinib.

Abstract The coronavirus disease 2019 (COVID-19) pandemic continues to represent a global public health issue. The viral main protease (Mpro) represents one of the most attractive targets for the development of antiviral drugs. Herein we report peptidyl nitroalkenes exhibiting enzyme inhibitory activity against Mpro (K i : 1–10 μM) good anti-SARS-CoV-2 infection activity in the low micromolar range (EC50: 1–12 μM) without significant toxicity. Additional kinetic studies of compounds FGA145, FGA146 and FGA147 show that all three compounds inhibit cathepsin L, denoting a possible multitarget effect of these compounds in the antiviral activity. Structural analysis shows the binding mode of FGA146 and FGA147 to the active site of the protein. Furthermore, our results illustrate that peptidyl nitroalkenes are effective covalent reversible inhibitors of the Mpro and cathepsin L, and that inhibitors FGA145, FGA146 and FGA147 prevent infection against SARS-CoV-2.

Background/Objectives: Facial pigmented skin lesions are extremely common, starting from the fourth to fifth decades, especially in South-European countries, often located in the periorbital region. These include malignant forms, Lentigo maligna (LM) and lentigo maligna melanoma (LMM), characterized by growing incidence, and a series of benign simulators, including solar lentigo (SL), pigmented actinic keratosis (PAK), seborrheic keratosis (SK) and lichen planus-like keratosis (LPK). The clinical differential diagnosis of atypical pigmented skin lesions (aPFLs) can be difficult, even for dermatologists, leading to inappropriate skin biopsies with consequent aesthetic impacts. Dermoscopy of the facial area is a specific dermoscopic field that requires dedicated training and proved to increase diagnostic accuracy in dermatologists. Since these lesions are often seen by ophthalmologists at first, we aimed to evaluate the effect of a focused dermoscopy training course on a group of ophthalmologists naïve to the use of a dermatoscope. Methods: A set of 80 periorbital pigmented skin lesions with both clinical and dermoscopic images was selected and evaluated by six ophthalmologists before and after a one-day intensive dermoscopic training course. They were required to evaluate 80 periorbital lesions one month before and after a one-day intensive dermoscopic training course, illustrating second-level diagnostic options such as reflectance confocal microscopy (RCM), obtaining a total of 480 evaluations. Specifically, they had to provide, for each case, a punctual diagnosis and a management option among dermoscopic follow-up/skin biopsy/RCM/LC-OCT. Descriptive statistics were carried out, and the accuracy (ACC), sensitivity (SE), and specificity (SP), with their 95% confidence interval (95% CI), were estimated. Results: In the pre-course test, ophthalmologists achieved 84.0% SP, 33.3% SE and 63.7% ACC, while after the course, SE increased by +9% (i.e., 41.7%), SP decreased by 4%, and ACC remained comparable, i.e., 64.6%. In the management study, the percentage of benign lesions for which a close dermoscopic follow-up was suggested significantly decreased (51.6% versus 22.2%), in parallel with an increase in the number of lesions referred for RCM. As for malignant cases, the reduction in responses “close dermoscopic follow-up” decreased from 37.0% to 9.9%, (−27%), in favor of RCM (+15%) and skin biopsy (+12%). Conclusions: The ophthalmologists proved to be very receptive in quickly metabolizing and putting into practice the concepts learned during the one-day intensive dermoscopy training course. Indeed, after only a one-day lesson, they were able to increase their SE by 9% and to improve their management strategy. The present findings highlight the importance of providing training ophthalmologists in dermoscopy during residency programs, in terms of benefits for the correct patient care.

Cancer is the most common cause of death in adult dogs. All dogs would benefit from early diagnosis, but there are no specific guidelines regarding the schedule of cancer screening in companion animals. The aim of this study was to retrospectively evaluate the age at diagnosis in Italian oncological canine patients. A total of 14,636 canine histologically confirmed neoplastic cases were coded according to the Vet-ICD-O-canine-1 and stratified by malignancy, sex, neutering status, breed, cephalic index, body size, and tumor type. Differences in age distribution were analyzed and the influence of these variables on the time of first malignancy diagnosis was assessed using an event history analysis model. The median age at diagnosis for benign and malignant tumors was 9 and 10 years, respectively. Intact and purebred dogs were diagnosed earlier, but the median age differed significantly by breed. The earliest age at diagnosis was recorded for lymphomas and mast cell tumors. The model showed an accelerating effect of large size, brachy- and dolichocephaly, and sexual integrity in female dogs on the time of malignancy diagnosis. Our results confirm that a “one-size-fits-all” approach to cancer screening is not accurate in dogs and provide relevant data that may lead to the establishment of breed-based screening schedules.

Diagnosing atypical pigmented facial lesions (aPFLs) is a challenging topic for dermatologists. Accurate diagnosis of these lesions is crucial for effective patient management, especially in dermatology, where visual assessment plays a central role. Incorrect diagnoses can result in mismanagement, delays in appropriate interventions, and potential harm. AI, however, holds the potential to enhance diagnostic accuracy and provide reliable support to clinicians. This work aimed to evaluate and compare the effectiveness of machine learning (logistic regression of lesion features and patient metadata) and deep learning (CNN analysis of images) models in dermoscopy diagnosis and the management of aPFLs. This study involved the analysis of 1197 dermoscopic images of facial lesions excised due to suspicious and histologically confirmed malignancy, classified into seven classes (lentigo maligna—LM; lentigo maligna melanoma—LMM; atypical nevi—AN; pigmented actinic keratosis—PAK; solar lentigo—SL; seborrheic keratosis—SK; and seborrheic lichenoid keratosis—SLK). Image samples were collected through the Integrated Dermoscopy Score (iDScore) project. The statistical analysis of the dataset shows that the patients mean age was 65.5 ± 14.2, and the gender was equally distributed (580 males—48.5%; 617 females—51.5%). A total of 41.7% of the sample constituted malignant lesions (LM and LMM). Meanwhile, the benign lesions were mainly PAK (19.3%), followed by SL (22.2%), AN (10.4%), SK (4.0%), and SLK (2.3%). The lesions were mainly localised in the cheek and nose areas. A stratified analysis of the assessment provided by the enrolled dermatologists was also performed, resulting in 2445 evaluations of the 1197 images (2.1 evaluations per image on average). The physicians demonstrated higher accuracy in differentiating between malignant and benign lesions (71.2%) than in distinguishing between the seven specific diagnoses across all the images (42.9%). The logistic regression model obtained a precision of 39.1%, a sensitivity of 100%, a specificity of 33.9%, and an accuracy of 53.6% on the test set, while the CNN model showed lower sensitivity (58.2%) and higher precision (47.0%), specificity (90.8%), and accuracy (59.5%) for melanoma diagnosis. This research demonstrates how AI can enhance the diagnostic accuracy in complex dermatological cases like aPFLs by integrating AI models with clinical data and evaluating different diagnostic approaches, paving the way for more precise and scalable AI applications in dermatology, showing their critical role in improving patient management and the outcomes in dermatology.