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Abstract Background Regional lymph nodes are frequently sampled in cats with suspected intestinal lymphoma; however, their diagnostic value has not been explored. Objectives To investigate whether histologic and immunohistochemical analysis of mesenteric lymph nodes correlates with the diagnosis of intestinal lymphoma in cats. Animals One hundred 2 client‐owned cats diagnosed with intestinal lymphoma. Methods Retrospective study. The inclusion criteria required a full‐thickness biopsy of the small intestine and concurrent excision of mesenteric lymph nodes. Histologic and immunophenotypic analyses were performed on intestinal biopsies and corresponding lymph nodes. Selected nodal samples diagnosed with reactive lymph nodes underwent clonality testing. Results Transmural T‐cell lymphomas, encompassing small and large cell types, were predominant (64 cases, 62.7%), with large B‐cell lymphomas being more frequently transmural (68.8%) than mucosal (31.2%). Among all lymph nodes examined, 44 (43.1%; 95% CI: 33.9%‐52.8%) exhibited neoplastic infiltration. Among cases of small cell lymphoma, 51 out of 72 (70.8%; 95% CI: 59.4%‐80.1%) showed no nodal involvement. Clonality results correctly identified 19/30 (63.3%; 95% CI: 45.5%‐78.2%) reactive lymph nodes. Concerns were raised regarding clonal identification in the remaining cases and potential misdiagnoses based on phenotypic characteristics. Conclusion and Clinical Importance The study underscores the potential drawbacks of relying solely on mesenteric lymph nodes for diagnosing intestinal lymphomas in cats, particularly small cell subtypes. It emphasizes the importance of full‐thickness biopsies for assessing transmural infiltration and recommends caution when utilizing mesenteric lymph nodes for histologic, immunohistochemical and clonality evaluations in mucosal lymphomas. Despite limitations, this research highlights the need for comprehensive diagnostic strategies in cats with intestinal lymphoma.

Glioblastoma (GBM) is a primary tumor in the central nervous system with poor prognosis. It exhibits elevated glucose uptake and lactate production. This metabolic state of aerobic glycolysis is known as the Warburg effect. N6‐isopentenyladenosine (iPA), a natural cytokine modified with an isopentenyl moiety derived from the mevalonate pathway, has well‐established anti‐tumor activity. It inhibits cell proliferation in glioma cells, inducing cell death by apoptosis and/or necroptosis. In the present study, we found that iPA inhibits aerobic glycolysis in unmodified U87MG cells and in the same cell line engineered to over‐express wild‐type epidermal growth factor receptor (EGFR) or EGFR variant III (vIII), as well as in a primary GBM4 patient‐derived cell line. The detection of glycolysis showed that iPA treatment suppressed ATP and lactate production. We also evaluated the response of iPA treatment in normal human astrocyte primary cells, healthy counterpart cells of the brain. Aerobic glycolysis in treated normal human astrocyte cells did not show significant changes compared to GBM cells. To determine the mechanism of iPA action on aerobic glycolysis, we investigated the expression of certain enzymes involved in this metabolic pathway. We observed that iPA reduced the expression of pyruvate kinase M2 (PKM2), which plays a key role in the regulation of aerobic glycolysis, promoting tumor cell proliferation. The reduction of PKM2 expression is a result of the inhibition of the inhibitor of nuclear factor kappa‐B kinase subunit, beta/nuclear factor‐kappa B pathway upon iPA treatment. In conclusion, these experimental results show that iPA may inhibit aerobic glycolysis of GBM in stabilized cell lines and primary GBM cells by targeting the expression and activity of PKM2.

Abstract The security of data communications is one of the crucial challenges that our society is facing today. Quantum Key Distribution (QKD) is one of the most prominent methods for guaranteeing ultimate security based on the laws of quantum physics. In this work, the results obtained during the Italian Industry 4.0 Quantum Testbed (II4QuTe) project are reported where the authors realised a QKD testbed securely connecting the Competence Industry Manufacturing 4.0 (CIM4.0) located in Torino and a TIM edge node located 10 km away from the testbed. The edge node accommodates the server providing computation capabilities for managing the real‐time data generated by the machines within the CIM4.0 digital factory pilot line, thus gracefully integrating QKD with the MEC (Multi‐access Edge Computing) paradigm. The experiment was conducted for more than 69 h, establishing an average key generation rate of 5.125 keys/s (AES‐256 keys) and demonstrating the stability of the entire end‐to‐end encryption system.

Abstract Circulating extracellular vesicles and particles (EVPs) are being investigated as potential biomarkers for early cancer detection, prognosis, and disease monitoring. However, the suboptimal purity of EVPs isolated from peripheral blood plasma has posed a challenge of in‐depth analysis of the EVP proteome. Here, we compared the effectiveness of different methods for isolating EVPs from healthy donor plasma, including ultracentrifugation (UC)‐based protocols, phosphatidylserine‐Tim4 interaction‐based affinity capture (referred to as “PS”), and several commercial kits. Modified UC methods with an additional UC washing or size exclusion chromatography step substantially improved EVP purity and enabled the detection of additional proteins via proteomic mass spectrometry, including many plasma membrane and cytoplasmic proteins involved in vesicular regulation pathways. This improved performance was reproduced in cancer patient plasma specimens, resulting in the identification of a greater number of differentially expressed EVP proteins, thus expanding the range of potential biomarker candidates. However, PS and other commercial kits did not outperform UC‐based methods in improving plasma EVP purity. PS yielded abundant contaminating proteins and a biased enrichment for specific EVP subsets, thus unsuitable for proteomic profiling of plasma EVPs. Therefore, we have optimized UC‐based protocols for circulating EVP isolation, which enable further in‐depth proteomic analysis for biomarker discovery.

Abstract Background Breast cancer patients are commonly treated with sequential administrations of epirubicin–cyclophosphamide (EC) and paclitaxel (TAX). The chronic effect of this treatment induces skeletal muscle alterations, but the specific effect of each chemotherapy agent is unknown. This study aimed to investigate the effect of EC or TAX administration on skeletal muscle homeostasis in breast cancer patients. Methods Twenty early breast cancer patients undergoing EC followed by TAX chemotherapies were included. Two groups of 10 women were established and performed vastus lateralis skeletal muscle biopsies either before the first administration (pre) of EC (50 ± 14 years) or TAX (50 ± 16 years) and 4 days later (post). Mitochondrial respiratory capacity recording, reactive oxygen species production, western blotting and histological analyses were performed. Results Decrease in muscle fibres cross‐sectional area was only observed post‐EC (−25%; P

Abstract The Gulf of Trieste, is a shallow semi‐enclosed sea of about 500 km2 in the north‐eastern part of the Adriatic Sea. The coastal and marine areas of the Italian region Friuli Venezia Giulia, which borders most of the Gulf of Trieste, are subject to significant pressure from human activities, especially in terms of maritime traffic, ports, industry, fishing and tourism. But they are also characterised by natural areas of high environmental value. We wanted to understand the human impact on these coastal and marine areas in order to better inform sustainable management. To carry out the analysis, we collected a range of anthropogenic (human) and environmental data, from which we produced a series of indicator maps. By combining the various indicators, we created two subsequent maps: the seabed vulnerability map and the marine environment vulnerability map in the area as a whole. The analysis has highlighted areas with different degrees of environmental vulnerability due to human development and identified the most critical areas in the Gulf of Trieste with high anthropogenic pressure. Both maps show that human impacts affect large areas of the seabed and marine environment, while those with minimal or non‐existent impacts are very limited and are related mainly to areas with high levels of existing protection and conservation. The seabed vulnerability map shows that the biggest problems are related to discharge of dredging sludge, mollusc fishing with dredgers and turbo blowers, and anchoring boats. Furthermore, the presence of anthropogenic elements on the seabed can damage the natural environment and even permanently alter the natural shape and structure of the seabed. The marine environment vulnerability map shows that ports, urbanisation, industrial activities, maritime traffic and fishing pressure affect the entire study area. The vulnerability maps are a useful analytical tool to identify the most critical areas where possible actions can be planned to maintain a healthy and sustainable productive marine environment and to manage and resolve the conflicts between economic development and environmental health. Read the free Plain Language Summary for this article on the Journal blog.

Abstract Arginine and lysine, frequently appearing as a pair on histones, have been proven to carry diverse modifications and execute various epigenetic regulatory functions. However, the most context‐specific and transient effectors of these marks, while significant, have evaded study as detection methods have thus far not reached a standard to capture these ephemeral events. Herein, a pair of complementary photo‐arginine/δ‐photo‐lysine (R‐dz/K‐dz) probes is developed and involve these into histone peptide, nucleosome, and chromatin substrates to capture and explore the interactomes of Arg and Lys hPTMs. By means of these developed tools, this study identifies that H3R2me2a can recruit MutS protein homolog 6 (MSH6), otherwise repelDouble PHD fingers 2 (DPF2), Retinoblastoma binding protein 4/7 (RBBP4/7). And it is disclosed that H3R2me2a inhibits the chromatin remodeling activity of the cBAF complex by blocking the interaction between DPF2 (one component of cBAF) and the nucleosome. In addition, the novel pairs of H4K5 PTMs and respective readers are highlighted, namely H4K5me‐Lethal(3)malignant brain tumor‐like protein 2 (L3MBTL2), H4K5me2‐L3MBTL2, and H4K5acK8ac‐YEATS domain‐containing protein 4 (YEATS4). These powerful tools pave the way for future investigation of related epigenetic mechanisms including but not limited to hPTMs.

Key Clinical Message Spinal cord compression from non‐Hodgkin lymphoma (NHL) should be considered as a potential diagnosis in cases of acute signs of myelopathy in pediatric patients. Abstract Spinal cord compression in pediatric non‐Hodgkin lymphoma (NHL) is a rare presentation with potential diagnostic challenges. We report on two pediatric patients with NHL who exhibited myelopathy signs as initial presentation. Considering NHL as a differential diagnosis in pediatric patients presenting with spinal cord compression is crucial for optimizing the outcome of these patients.

Abstract Midostaurin is used in combination with chemotherapy to treat patients with newly diagnosed FLT3‐mutated acute myeloid leukemia. Chemotherapy‐induced neutropenia exposes these patients to a significant risk of invasive fungal infections (IFIs). International guidelines recommend primary antifungal prophylaxis with posaconazole (PCZ) but nested analysis of a phase III trial showed that strong PCZ inhibition of CYP3A4 diminished midostaurin metabolism and increased midostaurin plasma levels; however, midostaurin‐related adverse events (AEs) were only moderately exacerbated. We conducted a prospective multicenter real‐life study to evaluate (i) how often concerns around PCZ‐midostaurin interactions made the hematologist prescribe antifungals other than PCZ, (ii) how remarkably PCZ increased midostaurin plasma levels, and (iii) how significantly PCZ‐midostaurin interactions influenced hematologic and safety outcomes of induction therapy. Although the hematologists were blinded to pharmacokinetic findings, as many as 16 of 35 evaluable patients were prescribed antifungal prophylaxis with micafungin, weak CYP3A4 inhibitor, in place of PCZ (p

Abstract Introduction Chronic obstructive pulmonary disease (COPD) is commonly diagnosed and managed in primary care but there is evidence that this has been suboptimal, with low confidence expressed in providing interventions requiring behaviour change. The aim of this study was to determine the acceptability of a general practitioner (GP)–physiotherapist partnership in the diagnosis and management of COPD in primary care and to explore the experiences of participants during the implementation of the model. Methods Semi‐structured interviews were conducted with physiotherapists (n = 3), GPs (n = 2), practice nurses (PNs) (n = 2) and patients (n = 12) who had participated in the InNovaTivE Gp‐physiotheRapist pArTnErship for copD (INTEGRATED) trial. We sought to explore participants' views about their experiences and perceived benefits, barriers and facilitators to the implementation of this model of care. Interviews were transcribed, coded and thematically analysed. Synthesis of the data was guided by the Theoretical Domains Framework for clinician interviews and the health belief model for patient interviews. Results All clinicians felt that this integrated model helped to optimise care for patients with COPD by facilitating evidence‐based practice. GPs and PNs valued the physiotherapist's knowledge and skills relating to diagnosis and management, which was reported to complement their own management and improve patient outcomes. Patients reported a sense of empowerment following their appointments and acknowledged improved self‐management skills. However, physiotherapists reported many patients were already engaging in positive health behaviours. Responses were mixed on the effectiveness of the model in facilitating teamwork between clinicians with different perspectives concerning management, communication pathways and logistical issues, such as time and room availability, being cited as barriers. Conclusions An experienced cardiorespiratory physiotherapist embedded into a small number of primary care practices to work in partnership with GPs for COPD diagnosis and management was acceptable and viewed as beneficial for patients. Barriers relating to logistics and resources remain, which must be addressed to optimise implementation. Patient or Public Contribution Patient input was obtained from qualitative feedback from a prior study conducted by two authors and was used to refine the model of care to determine the added value of a physiotherapist integrated into the primary care team. This feedback was also used to refine the interview guides utilised in this study determine the acceptability of this model of care. We had health service involvement from the rehabilitation service of the local health district who were directly involved in determining study aims and establishing the project around the priorities for their chronic disease integration service. For example, this project aimed to engage with a less severe patient population in primary care who would benefit from pulmonary rehabilitation. The findings from this study will be used to further tailor the model of care to the needs of the public and patients. Trial Registration: ACTRN12619001127190

Abstract Background Pulmonary embolism (PE) is one of the most common causes of death from cardiovascular disease. Although deep vein thrombosis (DVT) is the leading cause of PE, its prognostic role is unclear. This study investigated the incidence and prognostic value of DVT in predicting in‐hospital mortality (IHM) in patients admitted from the emergency department (ED) for PE. Methods This retrospective cohort study was conducted in the ED of a third‐level university hospital. Patients over 18 years admitted for PE between 1 January 2018 and 31 December 2022 were included. Results Five hundred and thirty patients (mean age 73.13 years, 6% IHM) were included. 69.1% of cases had DVT (36.4% unilateral femoral vein, 3.6% bilateral, 39.1% unilateral popliteal vein, 2.8% bilateral, 45.7% distal vein thrombosis and 7.4% iliocaval involvement). Patients who died in hospital had a higher Pulmonary Embolism Severity Index (PESI) (138.6 vs. 99.65, p II, right ventricular dysfunction, increased blood markers of myocardial damage and involvement of the iliocaval venous axis were independent predictors of IHM on multivariate analysis. Conclusions Although further studies are needed to confirm the prognostic role of DVT at PE, involvement of the iliocaval venous axis should considered to be a sign of a higher risk of IHM and may be a key factor in prognostic stratification.

Abstract Several modeling tools commonly used for supporting flood risk assessment and management are highly effective in representing physical phenomena, but provide a rather limited understanding of the multiple implications that flood risk and flood risk reduction measures have on highly complex systems such as urban areas. In fact, most of the available modeling tools do not fully account for this complexity—and related uncertainty—which heavily affects the interconnections between urban systems evolution and flood risk, ultimately resulting in an ineffective flood risk management. The present research proposes an innovative methodological framework to support decision‐makers involved in an urban regeneration process at a planning/strategic level, accounting for the multi‐dimensional implications of flood risk and of different flood risk management strategies. The adopted approach is based on the use of System Thinking principles and participatory System Dynamics modeling techniques, and pursues an integration between scientific and stakeholder knowledge. Reference is made to one of the case studies of the CUSSH and CAMELLIA projects, namely Thamesmead (London), a formerly inhospitable marshland currently undergoing a process of urban regeneration, and perceived as being increasingly vulnerable to flooding. It represents an interesting opportunity for building a replicable modeling approach to integrate urban development dynamics with flood risk, ultimately supporting policy and decision‐makers in identifying mitigation/prevention measures and understanding how they could help achieve multi‐dimensional benefits (e.g., environmental, social and economic).

Abstract Objective Sleep impairment is one of the most common comorbidities affecting people with epilepsy (PWE). The bidirectional relation between epilepsy and sleep has been widely established. Several studies investigated subjective sleep quality and daytime vigilance in PWE, highlighting frequent complaints of sleep fragmentation, difficulties in falling asleep, and daytime sleepiness. The present study aimed to evaluate sleep structure in drug‐naive PWE, distributed on the basis of epilepsy type, and compared with controls. Methods This observational study included adult patients newly diagnosed with epilepsy and drug‐naive as well as a control group of healthy subjects. All PWE and controls underwent a dynamic 24‐h EEG with signals for sleep recording to evaluate sleep architecture, structure, continuity, and fragmentation. Results Twenty‐four PWE were included and distributed in two groups based on epilepsy type. Eleven patients were included in the generalized epilepsy group (63.6% male; 34.91 ± 9.80 years) and 13 patients in the focal epilepsy group (53.8% male; 38.69 ± 12.74 years). The control group included 16 subjects (56.3% male; 32.75 ± 12.19 years). Patients with generalized or focal epilepsy had a significantly lower sleep efficiency than controls. Moreover, both patient groups presented the alteration of markers of sleep fragmentation and loss of continuity, with higher indices of sleep stage transitions and arousal. Finally, the two patient groups presented less REM sleep than controls. Significance This study highlighted the alteration of sleep quality, continuity, and stability in both patients with focal or generalized epilepsy compared with controls, also in the absence of ictal events. This sleep impairment resulted in the reduction of REM sleep. Therefore, these findings may be explained by the increase in awakenings and sleep stage shifts, which may be attributed to both sleep networks impairment and neurotransmission dysfunction in PWE, and also possibly triggered by paroxysmal interictal abnormalities.

Abstract Background Chemotherapy is extensively used to treat breast cancer and is associated with skeletal muscle deconditioning, which is known to reduce patients' quality of life, treatment efficiency, and overall survival. To date, skeletal muscle mitochondrial alterations represent a major aspect explored in breast cancer patients; nevertheless, the cellular mechanisms remain relatively unknown. This study was dedicated to investigating overall skeletal muscle mitochondrial homeostasis in early breast cancer patients undergoing chemotherapy, including mitochondrial quantity, function, and dynamics. Methods Women undergoing (neo)adjuvant anthracycline‐cyclophosphamide and taxane‐based chemotherapy participated in this study (56 ± 12 years). Two muscle biopsies were collected from the vastus lateralis muscle before the first and after the last chemotherapy administration. Mitochondrial respiratory capacity, reactive oxygen species production, and western blotting analyses were performed. Results Among the 11 patients, we found a decrease in key markers of mitochondrial quantity, reaching −52.0% for citrate synthase protein levels (P = 0.02) and −38.2% for VDAC protein levels (P = 0.04). This mitochondrial content loss is likely explained by reduced mitochondrial biogenesis, as evidenced by a decrease in PGC‐1α1 protein levels (−29.5%; P = 0.04). Mitochondrial dynamics were altered, as documented by a decrease in MFN2 protein expression (−33.4%; P = 0.01), a key marker of mitochondrial outer membrane fusion. Mitochondrial fission is a prerequisite for mitophagy activation, and no variation was found in either key markers of mitochondrial fission (Fis1 and DRP1) or mitophagy (Parkin, PINK1, and Mul1). Two contradictory hypotheses arise from these results: defective mitophagy, which probably increases the number of damaged and fragmented mitochondria, or a relative increase in mitophagy through elevated mitophagic potential (Parkin/VDAC ratio; +176.4%; P

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a hematological malignancy characterized by recurrent skin nodules, an aggressive clinical course with rapid involvement of hematological organs, and a poor prognosis with overall survival. The rarity of the disease results in a few large-scale studies, a lack of controlled clinical trials for its management, and a lack of evidence-based guidelines. Here, we present a review of unmet clinical needs on the management of BPDCN by a panel of eleven experts involved in the research and clinical practice of BPDCN. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. The panel analyzed the critical issues of diagnostic pathway, prognostic stratification, therapy for young and fit patients and elderly and unfit patients, indication for allotransplant and for autotransplant, indication for central nervous system prophylaxis, and management of pediatric BPDCN patients. For each of these issues, consensus opinions were provided and, when appropriate, proposals for advancement in clinical practice were addressed. The hope is that this comprehensive overview will serve to improve the practice of BPDCN and inform the design and implementation of new studies in the field.

Abstract Aims The role of dynamic changes in lactate concentrations on prognosis in acute heart failure has been poorly investigated. The aim of this study was to explore the predictive value of 24 h time‐weighted lactate (LACTW) in patients with acute heart failure. Methods and results Ninety‐six consecutive acute heart failure patients presenting to the Emergency Department of San Paolo Hospital, Naples, Italy, were prospectively enrolled. Arterial blood lactate was measured at admission and during the following 24 h at random time intervals. LACTW was obtained by the sum of the average lactate values among consecutive time points multiplied by the intervals between consecutive time points and dividing the sum by the total time (24 h). The outcome was a composite of need of admission to the intensive care unit, hospitalization duration >7 days, or intra‐hospital death. Admission lactate, maximum measured lactate, and LACTW were collected. Univariate and multivariate Cox regression analysis was applied to determine the hazard ratio (HR) of developing the outcome. Forty‐three patients experienced the pre‐specified outcome. In sex‐adjusted and age‐adjusted multivariable analysis, LACTW predicted the outcome occurrence (HR: 1.51, 95% confidence interval: 1.24, 1.84, P