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Abstract Background The current Italian scenario of pediatric palliative care (PPC) services is characterized by inadequate coverage of the territory. Therefore, it is important to improve the referral of patients to the most appropriate setting (community care, general PPC, or specialized PPC) and to improve the delivery of PPC care. Methods Aiming at obtaining information about the referrals to the Padua Pediatric Hospice that could help estimate the investments needed to improve the provision of care, a retrospective analysis has been carried out. The rate of proper referral and discharge, the number of patients followed at the hospice, the mortality rate, and the length of follow-up were analyzed, and, when possible, data were stratified by oncological and non-oncological diseases. Results The analysis showed that of the 870 patients referred to the Padua Pediatric Hospice between 2008 and 2022, 76% were affected by non-oncological conditions. 82% of patients referred were taken in charge and most of the remaining patients have been inappropriately referred. The analysis showed a growing number of total referrals, which increased by 195% from 2008 to 2022. An increase in proper referrals and referrals of non-oncological patients was observed alongside a decrease in oncological patient referrals and a trend toward a decrease in discharge rates. A decreased mortality was observed in patients with non-oncological conditions, with only 6% of deceased patients in 2022. Moreover, a longer survival with a median follow-up length of 43 months was observed among patients with non-oncological conditions who were followed up at the Padua Pediatric Hospice for more than 12 months. Conversely, the short survival rate observed for oncological patients suggests that those patients should have been referred to PPC earlier to benefit from palliative care for longer periods. Conclusions Considering these data, it is expected that the number of patients needing PPC services will steadily increase in the next years. Hence, there is a need to invest resources to provide the best care delivery model encompassing specific pathways for the transition into adulthood, the establishment of networks within all the Italian regions, and an efficient referral to the more suitable setting of care.

Abstract The physics of a single Josephson junction coupled to a resistive environment is a long-standing fundamental problem at the center of an intense debate, strongly revived by the advent of superconducting platforms with high-impedance multimode resonators. Here we investigate the emergent criticality of a junction coupled to a multimode resonator when the number of modes is increased. We demonstrate how the multimode environment renormalizes the Josephson and capacitive energies of the junction so that in the thermodynamic limit the charging energy dominates when the impedance is larger than the resistance quantum and is negligible otherwise, independently from the bare ratio between the two energy scales and the compact or extended nature of the phase of the junction. Via exact diagonalization, we find that the transition surprisingly stems from a level anticrossing involving not the ground state, but the first excited state, whose energy gap vanishes in the thermodynamic limit. We clarify the nature of the two phases by pointing at a different behavior of the ground and excited states and we show that at the transition point the spectrum displays universality not only at low frequencies. In agreement with recent experiments, we reveal striking spectral signatures of the phase transition.

Pediatric palliative care (PPC) is defined as “the active care of the child’s body, quality of life, mind and spirit, also giving support to the family”. PPC should be established once a diagnosis of life-limiting or life-threatening disease is reached and should continue as long as necessary. Therefore, pediatric palliative care (PPC) can continue for years, also given the improved care approaches for children with life-limiting or life-threatening diseases. Over time, the child may grow to become a young adult, and when this happens, the transition to adult healthcare services must be undertaken. This article discusses possible interventions, fostering an efficient transition from pediatric to adult palliative care. A narrative review presents issues, experiences, and existing programs. A “Perspectives” section presents opinions and proposals by the authors. The transition process is not limited to a change from pediatric to adult services. Rather, it includes the entire process of the development of the child and requires interdisciplinary management with proper planning and collaboration among professionals of pediatric and adult teams.

Abstract Background There has been a growing interest in studying the value of physical exercise in children with disabilities or chronic health conditions because of evidence of improvement in quality of life, social acceptance, and physical functioning. However, only scant evidence exists for routine sports activities in children requiring pediatric palliative care (PPC), and in most cases, such evidence has been collected in oncological patients. The Pediatric Hospice of Padua is the referral center for PPC in the Veneto region (northern Italy). Starting from the experience of this PPC center, this pilot study aims to describe the personal experience of children and young people who practice physical activity and their caregivers’ perspectives, focusing particularly on the emotional and social impact of exercise and sports practice. Methods Patients involved in at least one regular and structured sports activity were included in the pilot analysis. Two different ICF-CY (International Classification of Functioning, Disability and Health-Children and Youth Version) scales (“Body Function” and “Activity and Participation”) were filled out to assess the children’s global functional competence. Two online ad hoc questionnaires were created and administered to children, when able to respond, and caregivers. Results A total of 9% of patients reported being involved in a sports activity. All children who played sports did not have indications of cognitive retardation. The most practiced sport was swimming. The use of standardized methods such as ICF-CY shown that severe motor impairments do not limit sports accessibility. Questionnaires result suggest that sports are a positive experience for both children needing PPC and their parents. Children encourage other children to do sports and can find the positive side even in difficulties. Conclusion Since PPC is encouraged as early as the diagnosis of incurable pathologies, the inclusion of sports activities in the context of a PPC plan should be considered from the perspective of improving quality of life.

Abstract Background Medical cannabis may be a useful tool for managing treatment-resistant epilepsy and chronic pain, which affect many patients in pediatric palliative care (PPC); however, little evidence is available in this setting. Case presentation We aimed to describe a clinical experience in a setting where high-level evidence may not be obtained. We report our clinical experience in a pediatric palliative care department in Italy. Caregivers reported changes in intensity and frequency of pain and epilepsy events. Six patients received a titrated plant extract of cannabis sativa for 1 year. Only mild and transient adverse events occurred: drowsiness, euphoria, restlessness and tachycardia; the resolution was either spontaneous or obtained by modifying the administration schedule. Treatment was never discontinued. No overdoses occurred. All patients experienced seizures during the pre-treatment observation period, and obtained a reduction in seizure frequency, although with variable extent while receiving cannabis. In addition, a benefit on pain was observed, based on the caregiver’s evaluation, and a reduction of analgesic use. Conclusion Our experience suggests that a titrated plant extract preparation of medical cannabis may be useful to control treatment-resistant pain and epilepsy in PPC patients.

The proper assessment of needs and outcomes in pediatric palliative care (PPC) is imperativeto ensure the best possible service to patients and families. However, given the multidimensionalnature of PPC, the low number of patients in this setting, the heterogeneity of diseases, the presenceof cognitive impairment in many patients, and the physiological development of children, outcomescan be complex and difficult to measure. Consequently, in this context, the use of standardizedand validated tools to assess the needs of children and families, to assess symptom severity, andto estimate the quality of PPC service represent a current need. Even if efforts have been made tostandardize approaches and tools for palliative care in adults, to our knowledge, a similar comprehensiveassessment of PPC has not yet been conducted to date. This narrative review provides anoverview and discusses the evaluation of tools currently applied in PPC, with an educational intentfor healthcare providers. We found that several instruments are available to assess different dimensionsof PPC. We proposed a classification into eligibility tools, patient and family needs assessmenttools, and care assessment tools. At present, two main eligibility tools exist, the PaPaS Scale and theACCAPED Scale questionnaire. Most of the tools for patient and family needs assessment have notbeen specifically validated in the PPC setting, and many may be more readily applied in researchsettings rather than in daily practice. Similar considerations can be made for tools assessing QoL,while tools assessing PPC service quality seem to be easily applied. Efforts to develop new specifictools and validate existing ones are undoubtedly advocated. However, in the patient’s best interest,PPC healthcare providers should start using available tools, regardless of their validation status.

The possibility of improving dental restorative materials is investigated through the addition of two different types of fillers to a polymeric resin. These fillers, consisting of porous alumina and TiO2 nanotubes, are compared based on their common physicochemical properties on the nanometric scale. The aim was to characterize and compare the surface morphological properties of composite resins with different types of fillers using analytical techniques. Moreover, ways to optimize the mechanical, surface, and aesthetic properties of reinforced polymer composites are discussed for applications in dental treatments. Filler-reinforced polymer composites are the most widely used materials in curing dental pathologies, although it remains necessary to optimize properties such as mechanical resistance, surface characteristics, and biocompatibility. Anodized porous alumina nanoparticles prepared by electrochemical anodization offer a route to improve mechanical properties and biocompatibility as well as to allow for the controlled release of bioactive molecules that can promote tissue integration and regeneration. The inclusion of TiO2 nanotubes prepared by hydrothermal treatment in the resin matrix promotes the improvement of mechanical and physical properties such as strength, stiffness, and hardness, as well as aesthetic properties such as color stability and translucency. The surface morphological properties of composite resins with anodized porous alumina and TiO2 nanotube fillers were characterized by Atomic Force Microscopy (AFM), Scanning Electron Microscopy (SEM), and X-ray chemical analysis. In addition, the stress–strain behavior of the two composite resins is examined in comparison with enamel and dentin.

Background: One of the main challenges for paediatric palliative care (PPC) is the management of concomitant, different and severe symptoms that frequently affect the quality of life of PPC patients and are often refractory to commonly used pharmacological treatments. Consequently, many efforts are still needed to find the best therapeutic options to handle these refractory conditions. Since the first synthesis of ketamine in the 1960s, its pharmacokinetic and pharmacodynamic properties have been largely investigated and its potential wide range of clinical applications has become clear. However, this molecule still receives poor attention in some areas, including in children and PPC. This narrative review analyses the use of ketamine in children and the potential extension of its applications in PPC in order to provide new options for treatment in the PPC setting. Methods: Scientific papers published before October 2020 on MEDLINE, EMBASE and the Cochrane Library were considered. The cited references of the selected papers and the authors’ personal collections of literature were reviewed. The terms “palliative care”, “ketamine”, “neuropathic pain”, “procedural pain”, “status epilepticus”, “refractory pain” and “child”, adding “age: birth–18 years” on a further filter were used for the search. Discussion: The use of ketamine in PPC should be more widely considered due to its overall favourable safety profile and its efficacy, which are supported by an increasing number of studies, although in settings different from PPC and of mixed quality. Ketamine should be proposed according to a case-by-case evaluation and the specific diagnosis and the dosage and route of administration should be tailored to the specific needs of patients. Furthermore, there is evidence to suggest that ketamine is safe and efficacious in acute pain. These findings can prompt further research on the use of ketamine for the treatment of acute pain in PPC. Conclusion: Ketamine could be a suitable option after the failure of conventional drugs in the treatment of different refractory conditions in PPC.

Abstract The association between the metabolic profile and inflammatory cytokines in psoriasis is poorly understood. We analyzed the metabolic and cytokine/chemokine profiles in serum and skin from patients with new-onset psoriasis and healthy subjects (n = 7/group) by HR-MAS NMR and Bio-Plex immunoassay. Immuno-metabolic correlation matrix was analyzed in skin and serum to identify a potential immune-metabolic signature. Metabolomics analysis showed a significant increase in ascorbate and a decrease in scyllo-inositol, and a trend towards an increase in eight other metabolites in psoriatic skin. In serum, there was a significant increase of dimethylglycine and isoleucine. In parallel, psoriatic skin exhibited an increase of early inflammatory cytokines (IL-6, IL-8, TNF-α, IL-1β) and correlation analysis highlighted some major clusters of immune-metabolic correlations. A cluster comprising scyllo-inositol and lysine showed correlations with T-cell cytokines; a cluster comprising serine and taurine showed a negative correlation with early inflammatory cytokines (IL-6, G-CSF, CCL3). A strong positive correlation was enlightened between glutathione and inflammatory cytokines/angiogenesis promoters of psoriasis. The integration of metabolic and immune data indicated a molecular signature constituted by IL-6, IL1-ra, DMG, CCL4, Ile, Gly and IL-8, which could discriminate patients and healthy subjects and could represent a candidate tool in the diagnosis of new-onset psoriasis.

Abstract Background Breast cancer (BC) presents important physical and psychological challenges that should be appropriately addressed through continuous, integrated and individualized rehabilitation programs after treatment. In this study, we aimed to collect more information on the rehabilitation patterns and utilization of healthcare services by women with BC. Methods We retrospectively analyzed data from two archives of the Lazio Regional Health System Database to assess rehabilitation patterns in women diagnosed with BC in the Lazio region (Italy) in 2008. Results A total of 5538 women diagnosed with BC were considered in the present study. Most patients (81.7%) received outpatient rehabilitative care, consisting mainly of pathology-related interventions and, more rarely, disability-related interventions (mainly motor rehabilitation and rarely cognitive or psychological therapy). Few patients followed an inpatient (1.3%) or an intensive outpatient rehabilitation program (1.0%). Conclusion Most patients do not receive adequate rehabilitation care during the first year after diagnosis. More information and better rehabilitation services should be provided to help patients with BC access rehabilitation programs. The study also suggests the importance of psychosocial and cognitive interventions, which is a major unmet need in women with BC.

Abstract Background We report the clinical outcomes observed in our patients with SMA type 1 or 2 receiving nusinersen, and we comment on the ethical implications of this treatment, in line with our results and those reported by Audic et al. in their analysis published in the Orphanet Journal of Rare Diseases. Methods We analyzed records of all children with a genetically diagnosed SMA and clinically confirmed diagnosis of SMA Type 1 or 2 to whom nusinersen was offered. Follow-up lasted 30 months. Results Among the 17 children with SMA type 1, 6 interrupted treatment with nusinersen due to adverse events or lack of efficacy. Of the remaining 11 patients, 9 are responding to therapy, though multidisciplinary complex care is still required. All those children started nusinersen at a very early age. Eighteen patients with SMA type 2 received nusinersen; five required treatment interruption. The other 13 patients are still on nusinersen therapy, and 6 are responders. Among the seven non-responders, only two met the inclusion criteria of the pivotal trial. Conclusions Our analysis further supports the findings reported in the study by Audic et al. We believe that a wider use of nusinersen in clinical practice would require a comprehensive assessment of its actual benefits weighed against the discomfort caused to patients, as well as the identification of the patients who may obtain the best benefits from this treatment.

Background: The once-daily oral combination of daclatasvir (DCV) and sofosbuvir (SOF), with or without ribavirin (RBV), is effective and well tolerated in patients with hepatitis C virus (HCV). However, further field-practice studies are necessary to investigate the effectiveness and safety of the DCV+SOF combination in diverse subpopulations of patients with HCV, including those who are more challenging to treat such as patients with a genotype 3 (G3) infection. The aim of this retrospective, multicenter, field-practice study was to investigate the therapeutic efficacy and safety of the oral combination of DCV and SOF, with or without RBV (DCV+SOF±RBV), in a large unselected cohort of patients with chronic HCV infection (CHC). Patients and methods: Consecutive patients received DCV+SOF±RBV for 12 or 24 weeks. The efficacy endpoint was sustained virological response at 12 weeks after the end of treatment (SVR12). Safety factors were also considered. Results: A total of 620 patients were included in this study; the predominant genotype was G3 (55.3%). Of the total sample, 248 (40%) patients were treated with DCV+SOF+RBV and 372 (60%) did not receive RBV. The majority of patients assessed at week 12 (98%, 596/608) achieved SVR12. Among G3 patients, 98.8% (335/339) achieved SVR12. The most common adverse event was elevated bilirubin (30.6%), recorded in 4.9% of cases as a grade 3–4 adverse event. Conclusion: This study shows the high pan-genotypic effectiveness and safety of the DCV+SOF±RBV combination in a large, unselected sample of CHC patients with G1–4, including a wide proportion of G3 CHC patients.

Approximately 95% of patients receiving radiotherapy (RT) will ultimately develop radiation-induced dermatitis (RID) during or after the course of treatment, with major consequences on quality of life and treatment outcomes. This paper reviews the pathophysiology of RID and currently used topical products for the prevention and treatment of RID. Although there is no consensus on the appropriate management, recent evidence suggests that the use of topical products supports to protect and promote tissue repair in patients with RID. Basic recommendations include advice to wear loose clothing, using electric razors if necessary, and avoiding cosmetic products, sun exposure or extreme temperatures. Based on mechanisms involved and on the clinical characteristics of oncological patients, the profile of the ideal topical product for addressing RID can be designed; it should have limited risk of adverse events, systemic adsorption and drug–drug interactions, should be characterized by multiple clinical activities, with a special focus on localized pain, and should have a careful formulation as some vehicles can block the RT beam.

The skin is the largest organ in the human body; beyond its regulatory and sensory roles, it is meant to protect and act like a barrier against foreign matter. Products intended to restore the skin health should reintegrate the structure of the stratum corneum in which the corneocytes are surrounded by the intercellular lipid lamellae that maintain both corneum integrity and skin permeability barrier. Capilen is a specific liposomal formulation based on a technology through which highly concentrated fresh plant extracts are conveyed into a jelly-like liposomal vehicle and combined with plant-derived omega-3, -6, -7, and -9 fatty acids, phospholipids, and precursors of ceramides. Its components have been widely investigated and produced clinical benefits in atopic dermatitis, bedsores, scars, inflammatory lesions of the skin, and generally whenever signs of xerosis cutis were present. Liposomes contribute to restore the surface lipid layer of the skin and to deliver substances in the activity site. This liposomal cream was proven to limit and delay the occurrence of radiodermatitis in breast cancer patients, and as an add-on provided complete healing of bedsore lesions in geriatric subjects.

We investigate the various physical mechanisms that underlie the dynamical instability of a quantized vortex array at the interface between two counter-propagating superflows in a two-dimensional Bose–Einstein condensate. Instabilities of markedly different nature are found to dominate in different flow velocity regimes. For moderate velocities where the two flows are subsonic, the vortex lattice displays a quantized version of the hydrodynamic Kelvin–Helmholtz instability (KHI), with the vortices rolling up and co-rotating. For supersonic flow velocities, the oscillation involved in the KHI can resonantly couple to acoustic excitations propagating away in the bulk fluid on both sides. This makes the KHI rate to be effectively suppressed and other mechanisms to dominate: For finite and relatively small systems along the transverse direction, the instability involves a repeated superradiant scattering of sound waves off the vortex lattice; for transversally unbound systems, a radiative instability dominates, leading to the simultaneous growth of a localized wave along the vortex lattice and of acoustic excitations propagating away in the bulk. Finally, for slow velocities, where the KHI rate is intrinsically slow, another instability associated to the rigid lateral displacement of the vortex lattice due to the vicinity of the system's boundary is found to dominate.

Exercise-released extracellular vesicles (EVs) are emerging as a novel class of exerkines that promotes systemic beneficial effects. However, slight differences in the applied exercise protocols in terms of mode, intensity and duration, as well as the need for standardized protocols for EV isolation, make the comparison of the studies in the literature extremely difficult. This work aims to investigate the EV amount and EV-associated miRNAs released in circulation in response to different physical exercise regimens. Healthy individuals were subjected to different exercise protocols: acute aerobic exercise (AAE) and training (AT), acute maximal aerobic exercise (AMAE) and altitude aerobic training (AAT). We found a tendency for total EVs to increase in the sedentary condition compared to trained participants following AAE. Moreover, the cytofluorimetric analysis showed an increase in CD81+/SGCA+/CD45− EVs in response to AAE. Although a single bout of moderate/maximal exercise did not impact the total EV number, EV-miRNA levels were affected as a result. In detail, EV-associated miR-206, miR-133b and miR-146a were upregulated following AAE, and this trend appeared intensity-dependent. Finally, THP-1 macrophage treatment with exercise-derived EVs induced an increase of the mRNAs encoding for IL-1β, IL-6 and CD163 using baseline and immediately post-exercise EVs. Still, 1 h post-exercise EVs failed to stimulate a pro-inflammatory program. In conclusion, the reported data provide a better understanding of the release of circulating EVs and their role as mediators of the inflammatory processes associated with exercise.

Background: Unresectable or metastatic cutaneous squamous cell cancers (cSCCs) are rare but potentially life-threatening diseases. In this setting, systemic therapy has a palliative intent with limited benefit, but there is no established consensus regarding the proper management of this tumour. This retrospective study aimed to review outcomes in patients with non-curable cSCC treated with platinum-based chemotherapy and cetuximab. Methods: We considered 12 consecutive patients treated between June 2010 and March 2016. All patients had received previous treatment for the local disease. Results: The overall response rate was 50%, and the disease control rate was 67%. Median progression-free survival and overall survival were 6.6 (95% confidence interval [CI]: 1.9–8.4) and 14.6 (95% CI: 9.4–20.1) months, respectively. The median duration of response was 4.8 months (95% CI: 1.2–5.9). The most frequent toxicities were skin reactions (58%; grade 3: 25%) and anaemia (10%). No grade 4 toxicities were observed. Conclusions: Cetuximab and platinum-based chemotherapy were shown to be feasible and active in cSCC, with an acceptable toxicity profile, even if with a limited duration of response.

Nusinersen is the first oligonucleotide-based drug that is approved for the treatment of spinal muscular atrophy. In January 2020, the WHO declared COVID-19 a pandemic and nusinersen-provider centers had to postpone planned infusions for some children along with other related interventions. Considering the important contribution that the intrathecal infusions and other support activities could have on the quality of life of spinal muscular atrophy patients and their families, this emergency could have a relevant impact on the course of the pathology. The present work aims to assess the clinical and social issues that arise for spinal muscular atrophy children in care at the referral pediatric palliative care Centre of Padua (Veneto) from a delay in nusinersen infusions, resulting from the contingent COVID-19 restrictions. This evaluation has been carried out in both the short and long term after the first lockdown period and can be considered as a “proxy” of a situation of a possible delay in administration or management of infusions, due to other different causes.

Abstract In the pediatric setting, management of pain in the emergency department – and even in common care – is a challenging exercise, due to the complexity of the pediatric patient, poor specific training of many physicians, and scant resources. A joint effort of several Italian societies involved in pediatrics or in pain management has led to the definition of the PIPER group and the COPPER project. By applying a modified Delphi method, the COPPER project resulted in the definition of 10 fundamental statements. These may represent the basis for improving the correct management of children pain in the emergency department.

Abstract Microenvironment‐related immune and inflammatory markers, when combined with established Ki‐67 and morphology parameters, can improve prognostic prediction in gastro‐entero‐pancreatic neuroendocrine neoplasms (GEP‐NENs). Therefore, we evaluated the prognostic value of microenvironment and tumor inflammatory features (MoTIFs) in GEP‐NENs. For this purpose, formalin‐fixed paraffin‐embedded tissue sections from 350 patients were profiled by immunohistochemistry for immune, inflammatory, angiogenesis, proliferation, NEN‐, and fibroblast‐related markers. A total of 314 patients were used to generate overall survival (OS) and disease‐free survival (DFS) MoTIFs prognostic indices (PIs). PIs and additional variables were assessed using Cox models to generate nomograms for predicting 5‐year OS and DFS. A total of 36 patients were used for external validation of PIs and nomograms' prognostic segregations. From our analysis, G1/G2 versus G3 GEP‐NENs showed phenotypic divergence with immune‐inflammatory markers. HLA, CD3, CD8, and PD‐1/PD‐L1 IHC expression separated G3 into two sub‐categories with high versus low adaptive immunity‐related features. MoTIFs PI for OS based on COX‐2Tumor(T) > 4, PD‐1Stromal(S) > 0, CD8S < 1, and HLA‐IS < 1 was associated with worst survival (hazard ratio [HR] 2.50; 95% confidence interval [CI], 2.12–2.96; p < 0.0001). MoTIFs PI for DFS was based on COX‐2T > 4, PD‐1S > 4, HLA‐IS < 1, HLA‐IT < 2, HLA‐DRS < 6 (HR 1.77; 95% CI, 1.58–1.99; p < 0.0001). Two nomograms were developed including morphology (HR 4.83; 95% CI, 2.30–10.15; p < 0.001) and Ki‐67 (HR 11.32; 95% CI, 5.28–24.24; p < 0.001) for OS, and morphology (PI = 0: HR 10.23; 95% CI, 5.67–18.47; PI = 5: HR 2.87; 95% CI, 1.21–6.81; p < 0.001) and MoTIFs PI for DFS in well‐differentiated GEP‐NENs (HR 6.21; 95% CI, 2.52–13.31; p < 0.001). We conclude that G1/G2 to G3 transition is associated with immune‐inflammatory profile changes; in fact, MoTIFs combined with morphology and Ki‐67 improve 5‐year DFS prediction in GEP‐NENs. The immune context of a subset of G3 poorly differentiated tumors is consistent with activation of adaptive immunity, suggesting a potential for responsiveness to immunotherapy targeting immune checkpoints.

The incidence of pancreatic neuroendocrine tumors (panNETs) has increased worldwide in the last two decades. Given the indolent nature of these tumors, several patients are diagnosed with metastatic disease, which partially impairs the long-term efficacy of currently available treatments and reduces survival rates. The search for new therapeutic strategies for cancer patients has pushed towards the retrospective analysis of studies involving patients who concomitantly received other drugs together with standard anticancer agents. In this light, several retrospective analyses have shown that metformin use is associated with improved prognosis in patients with different tumor types treated with standard antitumor agents. Metformin, the cornerstone oral agent for the treatment of type 2 diabetes, plays a role in modulating glucose cell metabolism. Its potential ability to interfere with tumors may derive from the tight relationship between metabolic reprogramming in cancer cells and tumor progression. Indications for metformin use as an anticancer drug result from pre-clinical and clinical observations. In particular, metformin use in diabetic patients with advanced panNETs has been associated with better progression-free survival in patients treated with somatostatin analogues with or without metformin.

Non-alcoholic steatohepatitis (NASH) is a chronic and progressive form of non-alcoholic fatty liver disease. Its global incidence is increasing and makes NASH an epidemic and a public health threat. Non-alcoholic fatty liver disease is associated with major morbidity and mortality, with a heavy burden on quality of life and liver transplant requirements. Due to repeated insults to the liver, patients are at risk for developing hepatocellular carcinoma. The progression of NASH was initially defined according to a two-hit model involving an initial development of steatosis, followed by a process of lipid peroxidation and inflammation. In contrast, current evidence proposes a “multi-hit” or “multi-parallel hit” model that includes multiple pathways promoting progressive fibrosis and oncogenesis. This model includes multiple cellular, genetic, immunological, metabolic, and endocrine pathways leading to hepatocellular carcinoma development, underscoring the complexity of this disease.

Frailty represents a state of vulnerability to multiple internal physiologic factors, as well as external pressures, and has been associated with clinical outcomes. We aim to understand the impact of frailty on patients admitted with hepatocellular carcinoma (HCC) by using the validated Hospital Frailty Risk Score, which is implemented in several hospitals worldwide. We conducted a nation-wide retrospective cohort study to determine the effect of frailty on the risk of in-patient mortality, hepatic encephalopathy, length of stay and cost. Frailty was associated with a 4.5-fold increased risk of mortality and a 2.3-fold increased risk of hepatic encephalopathy. Adjusted Cox regression showed that frailty was correlated with increased risk of in-patient mortality (hazard ratio: 2.3, 95% CI 1.9–2.8, p < 0.001). Frail HCC patients had longer hospital stay (median 5 days) vs. non-frail HCC patients (median 3 days). Additionally, frail patients had higher total costs of hospitalization ($40,875) compared with non-frail patients ($31,667). Frailty is an independent predictor of hepatic encephalopathy and in-patient mortality. Frailty is a surrogate marker of hospital length of stay and cost.

We investigate the stability of vortices in two-dimensional Bose–Einstein condensates. In analogy with rotating space-times and with a careful account of boundary conditions, we show that the dynamical instability of multiply quantized vortices in trapped condensates persists in untrapped, spatially homogeneous geometries and has an ergoregion nature with some modification due to the peculiar dispersion of Bogoliubov sound. Our results open perspectives to the physics of vortices in trapped condensates, where multiply quantized vortices can be stabilized by interference effects and singly charged vortices can become unstable in suitably designed trap potentials. We show how superradiant scattering can be observed also in the short-time dynamics of dynamically unstable systems, providing an alternative point of view on dynamical (in)stability phenomena in spatially finite systems.

：Protein carbonylation (PC) is a marker of reactive oxygen species-mediated alterations induced by external stimuli such as UV and blue light irradiation. In this study, we investigated the protective effect of Vitachelox®, a mixture of three standardized natural extracts rich in polyphenols, against PC induced by blue light irradiation in human keratinocytes. We tested eight experimental conditions, including Vitachelox® 0.01% and 0.005% w/v, used for 6 or 24 h before irradiation, and a solution of N-acetylcysteine (NAC) as positive control of protection. PC was evaluated by fluorescence microscopy in situ and by absolute quantification (Carbonyl Score) upon protein extraction and separation. Both the in situ visualization study and the carbonyl score showed a considerable increase in protein oxidative damage upon blue light irradiation, and a decrease in PC in the presence of Vitachelox®. In particular, Vitachelox® 0.005% showed superior results compared to NAC in terms of carbonyl score and protein quality, and it was estimated to exert a protective action against blue-light irradiation ranging from 72% (24 h) to 82% (6 h). The protective antioxidant effect of Vitachelox®, together with the anti-inflammatory and anti-microbial properties previously reported, make this natural active ingredient a valuable tool in the maintenance of healthy skin.