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Background: Diagnosis of nevoid melanoma (NeM) is often difficult because NeM closely resembles a common nevus clinically and histologically. Methods: A retrospective study was conducted on 110 patients diagnosed with and/or treated for primary nevoid melanoma at the Veneto Institute of Oncology and at the University Hospital of Padua from August 1999. Results: Mean Breslow thickness was of 1.4 mm. Sentinel lymph node biopsy was conducted in nearly half of the patients, and positivity was detected in 16.7% of them. Twenty-four clinical and 23 dermoscopic pictures were collected. Papular and macular lesions prevailed over nodular and plaque-type lesions. Different hues of brown, pink, and red color were most represented. Twenty nevus-like NeMs and four multicomponent-pattern NeMs were observed. The Most frequent dermoscopic patterns for nevus-like NeM were atypical pigmented reticulum, irregular globules and dots, and hyperpigmented blotches. Atypical vessels, asymmetric peripheric striae, blue-white veil, and areas of regression were less frequent and prevailed in multicomponent pattern NeM. A structureless pattern was also featured. Many patients in the series had multiple melanomas. However, none of them had numerous multiple nevoid melanomas. Conclusions: NeM should not be regarded as a separate biological entity from classical melanoma, and the same histological and clinical prognostic factors apply to NeM. Clinically and dermoscopically, it often resembles benign nevi, although some clues such as evolution and some dermoscopic patterns could suggest malignancy. Clinical suspicion might prove crucial to further pathological analysis and recognition.

Introduction: Despite global immunization efforts, rubella remains a public health concern, particularly in high- and middle-income countries. This study focused on rubella seroprevalence in the province of Florence, Italy, aiming to identify susceptibility clusters, especially among women in their childbearing age., Methods: A cross-sectional study was conducted between April 2018 and December 2019, enrolling 430 adult subjects (age over 18 years). Serum samples were collected, and anti-rubella antibodies were quantified using the ELISA test. Data were analyzed descriptively and compared by sex, nationality, and age groups using statistical tests., Results: The overall rubella seroprevalence was high (92.3%), with no significant differences between genders or nationalities. Among childbearing-age females (18-49 years), the highest seroprevalence was observed in the 30-39 age group (94.1%). However, susceptibility clusters exceeding the 5% threshold set by WHO were identified, especially in females aged 40-49 years (7.0%)., Conclusions: Despite high overall seroprevalence, the study identified pockets of susceptibility, even in childbearing age women. Continuous monitoring, targeted immunization strategies, and public health interventions are recommended to maintain rubella elimination, emphasizing the importance of sustained vaccination efforts to protect vulnerable populations.

Objectives: There is little experience in the use of the WHO Standards for improving the quality of care (QOC) for children at the facility level. We describe the use of 75 WHO Standard based Quality Measures to assess paediatric QOC, using service users as a source of data, in Italy., Study Design: In a cross-sectional study including 12 hospitals, parents/caregivers of admitted children completed a validated questionnaire including 75 Quality Measures: 40 pertinent to the domain of experience of care; 25 to physical/structural resources; 10 to COVID-19 reorganisational changes. Univariate and multivariate analyses were conducted., Results: Answers from 1482 service users were analysed. Physical resources was the domain with the higher frequency of reported gaps in QOC, with key gaps (higher rates of responders reporting need for improvement and low variability across centres) being: (1) quality of meals (48.1%; range across facilities: 35.3%-61.7%); (2) presence of cooking areas (50.9%; range: 34.6%-70.0%); (3) spaces for family/friends (51.3%; range: 31.8%-77.4%). For experience of care , the most critical gap was the information on the rights of the child (76.6%; range: 59.9%-90.4%), with most other Quality Measures showing an overall frequency of reported need for improvement ranging between 5% and 35%. For reorganisational changes due to COVID-19 an improvement was felt necessary by <25% of responders in all Quality Measures, with low variability across centres. At the multivariate analyses, factors significantly associated with the QOC Index largely varied by QOC domain., Conclusions: The use of the 75 prioritised Quality Measures, specific to service users' perspective, enabled the identification of both general and facility-specific gaps in QOC. Based on these findings, quality improvement initiatives shall focus on a core list of selected Quality Measures common to all facilities, plus on an additional list of Quality Measures as more relevant in each facility., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Machines powered by artificial intelligence (AI) are increasingly taking over tasks previously performed by humans alone. In accomplishing such tasks, they may intentionally commit 'AI crimes', ie engage in behaviour which would be considered a crime if it were accomplished by humans. For instance, an advanced AI trading agent may-despite its designer's best efforts-autonomously manipulate markets while lacking the properties for being held criminally responsible. In such cases (hard AI crimes) a criminal responsibility gap emerges since no agent (human or artificial) can be legitimately punished for this outcome. We aim to shift the 'hard AI crime' discussion from blame to deterrence and design an 'AI deterrence paradigm', separate from criminal law and inspired by the economic theory of crime. The homo economicus has come to life as a machina economica , which, even if cannot be meaningfully blamed, can nevertheless be effectively deterred since it internalises criminal sanctions as costs., (© The Author(s) 2024. Published by Oxford University Press.)

Inherited macular dystrophies (iMDs) are a group of genetic disorders, which affect the central region of the retina. To investigate the genetic basis of iMDs, we used single-molecule Molecular Inversion Probes to sequence 105 maculopathy-associated genes in 1352 patients diagnosed with iMDs. Within this cohort, 39.8% of patients were considered genetically explained by 460 different variants in 49 distinct genes of which 73 were novel variants, with some affecting splicing. The top five most frequent causative genes were ABCA4 (37.2%), PRPH2 (6.7%), CDHR1 (6.1%), PROM1 (4.3%) and RP1L1 (3.1%). Interestingly, variants with incomplete penetrance were revealed in almost one-third of patients considered solved (28.1%), and therefore, a proportion of patients may not be explained solely by the variants reported. This includes eight previously reported variants with incomplete penetrance in addition to CDHR1 :c.783G>A and CNGB3 :c.1208G>A. Notably, segregation analysis was not routinely performed for variant phasing-a limitation, which may also impact the overall diagnostic yield. The relatively high proportion of probands without any putative causal variant (60.2%) highlights the need to explore variants with incomplete penetrance, the potential modifiers of disease and the genetic overlap between iMDs and age-related macular degeneration. Our results provide valuable insights into the genetic landscape of iMDs and warrant future exploration to determine the involvement of other maculopathy genes.

This article investigates the conceptual connection between argumentation and explanation in the law and provides a formal account of it. To do so, the methods used are conceptual analysis from legal theory and formal argumentation from AI. The contribution and results are twofold. On the one hand, we offer a critical reconstruction of the concept of legal argument, justification, and explanation of decision-making as it has been elaborated in legal theory and, above all, in AI and law. On the other hand, we propose some definitions of explanation in the context of formal legal argumentation, showing a connection between formal justification and explanation. We also investigate the notion of stable normative explanation developed elsewhere in Defeasible Logic and extend some complexity results. Our contribution is thus mainly conceptual, and it is meant to show how notions of explanation from literature on explainable AI and legal theory can be modeled in an argumentation framework with structured arguments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Rotolo and Sartor.)

Machine learning can be used for social good. The employment of artificial intelligence in smart agriculture has many benefits for the environment: it helps small farmers (at a local scale) and policymakers and cooperatives (at regional scale) to take valid and coordinated countermeasures to combat climate change. This article discusses how artificial intelligence in agriculture can help to reduce costs, especially in developing countries such as Côte d'Ivoire, employing only low-cost or open-source tools, from hardware to software and open data. We developed machine learning models for two tasks: the first is improving agricultural farming cultivation, and the second is water management. For the first task, we used deep neural networks (YOLOv5m) to detect healthy plants and pods of cocoa and damaged ones only using mobile phone images. The results confirm it is possible to distinguish well the healthy from damaged ones. For actions at a larger scale, the second task proposes the analysis of remote sensors, coming from the GRACE NASA Mission and ERA5, produced by the Copernicus climate change service. A new deep neural network architecture (CIWA-net) is proposed with a U-Net-like architecture, aiming to forecast the total water storage anomalies. The model quality is compared to a vanilla convolutional neural network.

SRSF1 (also known as ASF/SF2) is a non-small nuclear ribonucleoprotein (non-snRNP) that belongs to the arginine/serine (R/S) domain family. It recognizes and binds to mRNA, regulating both constitutive and alternative splicing. The complete loss of this proto-oncogene in mice is embryonically lethal. Through international data sharing, we identified 17 individuals (10 females and 7 males) with a neurodevelopmental disorder (NDD) with heterozygous germline SRSF1 variants, mostly de novo, including three frameshift variants, three nonsense variants, seven missense variants, and two microdeletions within region 17q22 encompassing SRSF1. Only in one family, the de novo origin could not be established. All individuals featured a recurrent phenotype including developmental delay and intellectual disability (DD/ID), hypotonia, neurobehavioral problems, with variable skeletal (66.7%) and cardiac (46%) anomalies. To investigate the functional consequences of SRSF1 variants, we performed in silico structural modeling, developed an in vivo splicing assay in Drosophila, and carried out episignature analysis in blood-derived DNA from affected individuals. We found that all loss-of-function and 5 out of 7 missense variants were pathogenic, leading to a loss of SRSF1 splicing activity in Drosophila, correlating with a detectable and specific DNA methylation episignature. In addition, our orthogonal in silico, in vivo, and epigenetics analyses enabled the separation of clearly pathogenic missense variants from those with uncertain significance. Overall, these results indicated that haploinsufficiency of SRSF1 is responsible for a syndromic NDD with ID due to a partial loss of SRSF1-mediated splicing activity., Competing Interests: Declaration of interests I.M.W. is an employee of GeneDx, LLC. J.R.L. has stock ownership in 23andMe, is a paid consultant for the Regeneron Genetics Center, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine receives revenue from clinical genetic testing conducted at Baylor Genetics (BG) Laboratories. J.R.L. serves on the Scientific Advisory Board of BG., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

This article's main contributions are twofold: 1) to demonstrate how to apply the general European Union's High-Level Expert Group's (EU HLEG) guidelines for trustworthy AI in practice for the domain of healthcare and 2) to investigate the research question of what does "trustworthy AI" mean at the time of the COVID-19 pandemic. To this end, we present the results of a post-hoc self-assessment to evaluate the trustworthiness of an AI system for predicting a multiregional score conveying the degree of lung compromise in COVID-19 patients, developed and verified by an interdisciplinary team with members from academia, public hospitals, and industry in time of pandemic. The AI system aims to help radiologists to estimate and communicate the severity of damage in a patient's lung from Chest X-rays. It has been experimentally deployed in the radiology department of the ASST Spedali Civili clinic in Brescia, Italy, since December 2020 during pandemic time. The methodology we have applied for our post-hoc assessment, called Z-Inspection®, uses sociotechnical scenarios to identify ethical, technical, and domain-specific issues in the use of the AI system in the context of the pandemic.

Introduction: Robot-assisted radical prostatectomy (RARP) long-term oncologic outcomes were published in few studies. This paper provides a complete overview of RARP long-term oncologic and functional results produced in an Italian spoke hospital., Methods: From December 2004 to December 2010, 300 consecutive patients with prostate cancer were treated with extraperitoneal RARP. Biochemical recurrence-free survival (BCRFS), salvage therapy-free survival (STFS), prostate cancer specific survival (PCa-SS), and overall survival (OS) were estimated using the Kaplan-Meier analysis and log-rank test. Cox proportional hazard regression analysis was performed to identify predictors of BCR and ST. Crude rates of continence and potency recovery after surgery were reported., Results: Median follow-up was 135.6 months (IQR 20-184). At 15 years, BCR-FS, ST-FS, PCa-SS, and OS rates were 78% (95% CI 0.73-0.83), 85% (95% CI 0.81 -0.89), 98% (95% CI 0.97-100), and 89% (95% CI 0.84-0.94), respectively. On multivariate analysis, biopsy ISUP grade ⩾2, clinical stage ⩾pT3a, D'Amico high-risk patients subgroup, pathologic ISUP grade ⩾2, and multifocal/extensive positive margins were independent predictors of BCR. The same risk factors plus D'Amico intermediate risk patients subgroup were independent predictors of ST. After surgery, 280 (93.3%) and 93 (35.2%) patients experienced continence and potency recovery, respectively. The retrospective nature of the analysis and some selection biases represent the principal limitations of the study., Conclusion: The results showed in the present study match those obtained in referral centers and this is an evidence against the general belief that best prostate cancer care in provided in high volume hospitals and against centralization. Adverse characteristics of the tumor remain the best predictors of BCR and ST.

Epigenetic mechanisms play important roles in the neurobiology of substance use disorder. In particular, bromodomain and extra-terminal domain (BET) proteins, a class of histone acetylation readers, have been found to regulate cocaine conditioned behaviors, but their role in the behavioral response to other drugs of abuse remains unclear. To address this knowledge gap, we examined the effects of the BET inhibitor, JQ1, on nicotine, amphetamine, morphine, and oxycodone conditioned place preference (CPP). Similar to previous cocaine studies, systemic administration of JQ1 caused a dose-dependent reduction in the acquisition of amphetamine and nicotine CPP in male mice. However, in opioid studies, JQ1 did not alter morphine or oxycodone CPP. Investigating the effects of JQ1 on other types of learning and memory, we found that JQ1 did not alter the acquisition of contextual fear conditioning. Together, these results indicate that BET proteins play an important role in the acquisition of psychostimulant-induced CPP but not the acquisition of opioid-induced CPP nor contextual fear conditioning., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: The aim of this study is to improve the performance of machine learning (ML) models in predicting response of non-small cell lung cancer (NSCLC) to stereotactic body radiation therapy (SBRT) by integrating image features from pre-treatment computed tomography (CT) with features from the biologically effective dose (BED) distribution., Materials and Methods: Image features, consisting of crafted radiomic features or machine-learned features extracted using a convolutional neural network, were calculated from pre-treatment CT data and from dose distributions converted into BED for 80 NSCLC lesions over 76 patients treated with robotic guided SBRT. ML models using different combinations of features were trained to predict complete or partial response according to response criteria in solid tumors, including radiomics CT (Rad CT ), radiomics CT and BED (Rad CT,BED ), deep learning (DL) CT (DL CT ), and DL CT and BED (DL CT,BED ). Training of ML included feature selection by neighborhood component analysis followed by ensemble ML using robust boosting. A model was considered as acceptable when the sum of average sensitivity and specificity on test data in repeated cross validations was at least 1.5., Results: Complete or partial response occurred in 58 out of 80 lesions. The best models to predict the tumor response were those using BED variables, achieving significantly better area under curve (AUC) and accuracy than those using only features from CT, including a Rad CT,BED model using three radiomic features from BED, which scored an accuracy of 0.799 (95% confidence intervals (0.75-0.85)) and AUC of 0.773 (0.688-0.846), and a DL CT,BED model also using three variables with an accuracy of 0.798 (0.649-0.829) and AUC of 0.812 (0.755-0.867)., Conclusion: According to our results, the inclusion of BED features improves the response prediction of ML models for lung cancer patients undergoing SBRT, regardless of the use of radiomic or DL features., (© 2021 American Association of Physicists in Medicine.)

Inherited retinal diseases (IRDs) are a heterogeneous group of conditions that include retinitis pigmentosa (RP) and Leber congenital amaurosis (LCA) and early-onset severe retinal dystrophy (EO[S]RD), which differ in severity and age of onset. IRDs are caused by mutations in >250 genes. Variants in the RPE65 gene account for 0.6-6% of RP and 3-16% of LCA/EORD cases. Voretigene neparvovec is a gene therapy approved for the treatment of patients with an autosomal recessive retinal dystrophy due to confirmed biallelic RPE65 variants ( RPE65 -IRDs). Therefore, the accurate molecular diagnosis of RPE65 -IRDs is crucial to identify 'actionable' genotypes-i.e., genotypes that may benefit from the treatment-and is an integral part of patient management. To date, hundreds of RPE65 variants have been identified, some of which are classified as pathogenic or likely pathogenic, while the significance of others is yet to be established. In this review, we provide an overview of the genetic diagnostic workup needed to select patients that could be eligible for voretigene neparvovec treatment. Careful clinical characterization of patients by multidisciplinary teams of experts, combined with the availability of next-generation sequencing approaches, can accelerate patients' access to available therapeutic options.

Background: The Prognostic Nutritional Index (PNI) is a parameter of nutritional and inflammation status related to toxicity in cancer treatment. Since data for head and neck cancer are scanty, this study aims to investigate the association between PNI and acute and late toxicity for this malignancy., Methods: A retrospective cohort of 179 head and neck cancer patients treated with definitive radiotherapy with induction/concurrent chemotherapy was followed-up (median follow-up: 38 months) for toxicity and vital status between 2010 and 2017. PNI was calculated according to Onodera formula and low/high PNI levels were defined according to median value. Odds ratio (OR) for acute toxicity were calculated through logistic regression model; hazard ratios (HR) for late toxicity and survival were calculated through the Cox proportional hazards model., Results: median PNI was 50.0 (interquartile range: 45.5-53.5). Low PNI was associated with higher risk of weight loss > 10% during treatment (OR = 4.84, 95% CI: 1.73-13.53 for PNI < 50 versus PNI ≥ 50), which was in turn significantly associated with worse overall survival, and higher risk of late mucositis (HR = 1.84; 95% CI:1.09-3.12). PNI predicts acute weight loss >10% and late mucositis., Conclusions: PNI could help clinicians to identify patients undergoing radiotherapy who are at high risk of acute and late toxicity.

The aim of this study was to test validity and reliability of the adapted version of the Nutrition Literacy Assessment Instrument (NLit) for Italian people (NLit-IT). An observational cross-sectional study was conducted, involving a convenience sample of adults ( n = 74). To explore the validity of the tool, we considered both diet quality as an outcome of NL, and health literacy (HL) as a construct that presents similarities and differences with NL. Diet quality was measured by adherence to the Mediterranean Diet (Med diet) through the validated Mediterranean Diet Literature-based adherence score (MEDI-Lite). The relationship between NL level and adherence to Med diet was assessed by linear regression analysis and computing correlations between NLit-IT and MEDI-Lite scores (Spearman's Rho). Additionally, we evaluated the correlation between NLit-IT score and the level of HL (Spearman's Rho). Internal consistency and reliability were measured by Cronbach's alpha and intraclass correlation coefficient (ICC) respectively. Internal consistency (ρT = 0.78; 95% CI, 0.69-0.84) and reliability (ICC = 0.68, 95% CI, 0.46-0.85) were confirmed. In addition, NLit-IT total score was correlated with MEDI-Lite score (Rho = 0.25; p -value = 0.031) and multivariate regression analysis confirmed that NL significantly contributed to MEDI-Lite score (R 2 = 0.13; β = 0.13; p -value = 0.008). There was no significant association between the level of HL and NL. In conclusion, NLit-IT showed validity and reliability as a measure of NL for Italian people.

Serosurveys may help to assess the transmission dynamics in high-risk groups. The aim of the study was to assess the SARS-CoV-2 antibody seroprevalence in people who had performed essential activities during the lock-down period in the Province of Prato (Italy), and to evaluate the risk of exposure to SARS-CoV-2 according to the type of service. All the workers and volunteers of the Civil Protection, employees of the municipalities, and all the staff of the Health Authority of the Province of Prato were invited to be tested with a rapid serological test. A total of 4656 participants were tested. SARS-CoV-2 antibodies were found in 138 (2.96%) cases. The seroprevalence in health care workers, in participants involved in essential support services and in those who worked from home were 4.1%, 1.4% and 1.0%, respectively. Health care workers experienced higher odds of seropositivity (OR 4.38, 95%CI 2.19-10.41) than participants who were assigned to work-from-home; no significant seropositivity differences were observed between support services and work-from-home groups. A low circulation of SARS-CoV-2 was observed among participants performing different essential activities. Findings highlighted the risk of in-hospital transmission in healthcare workers and that community support services may increase the risk of seropositivity to a limited extent in low incidence areas.

Microplastics (plastics <5 mm) contamination is of worldwide concern and represents a threat to the environment, biota, and humans. Also, they are potential carriers of other contaminants, increasing their adverse effects. In this study, it was analyzed for the first time the chemical composition and abundance of microplastics (MPs) in the commercial shrimp Pleoticus muelleri. Fibers were the predominant plastics (mean: 1.31 fibers g -1 wet weight) in the abdominal muscle of the shrimps being black, the dominant colour. μ-Raman showed that fibers were composed of polyethylene (PE), polypropylene (PP), and cellulose. Also, weathering and topography of the fibers were analyzed through wide-field confocal microscopy. C, O, Si, Al, K, as well as Fe, Zn, S, Ba, Br, and Ti on the plastic surface were detected with SEM/EDS, indicating potential carriers of contaminants. CAPSULE: The shrimp Pleoticusmuelleri ingests fibers with different chemical elements adsorbed on the plastic surface., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: While many evidence-based pathways have been introduced to drive quality improvements in cancer care, most of these do not include evidence about their affordability. The main aim of this study was to provide an estimation of the overall budget to cover all the needs of melanoma patients in Veneto Region, managed according to the clinical pathway defined by the Rete Oncologica Veneta. A second objective is to conduct a cost-consequence analysis, comparing two different treatments., Methods: A very detailed whole-disease model was developed describing the patient's pathway from diagnosis through the first year of follow-up. Each procedure involved in the model was associated with a likelihood measure and a cost. The model can be used to estimate the expected direct costs associated with melanoma., Results: We can observe that 0 and I stage, despite accounting for a huge percentage of new melanoma cases are characterized by a small percentage of the total costs. Stage III can be considered as the most expensive stage accounting for 54% of the total costs with a 12% of patients. Finally, the stage IV patients, although very few accounts for almost the 7% of the total costs. Regarding the cost-consequence analysis, it was estimated that the therapies introduced in 2016 led to an approximately 14% increase in the total costs., Conclusions: Modeling a clinical pathway with a high level of detail enables to identify the main sources of spending. The consequent analysis can thus help policymakers to plan the future resources allocation.

Background: This study focuses on the application of Provan and Kenis' modes of network governance to the specific field of public healthcare networks, extending the framework to an analysis of systems in which networks are involved. Thus, the aim of this study is to analyze and compare the governance of two cancer networks in two Italian regions that underwent system reconfiguration processes due to reforms in the healthcare system., Methods: A qualitative study of two clinical networks in the Italian healthcare system was conducted. The sample for interviews included representatives of the regional administration (n = 4), network coordinators (n = 6), and general and clinical directors of health organizations involved in the two networks (n = 25). Data were collected using semi-structured interviews., Results: Our study shows that healthcare system reforms have a limited impact on network governance structures. In fact, strong inertial tendencies characterize networks, especially network administrative organization models (NAO). Networks tend to find their own balance with respect to the trade-offs analyzed using a mix of formal and informal ties. Our study confirms the general validity of Provan and Kenis' framework and shows how other specific factors and contingencies may affect the possibility that cancer networks find positive equilibria between competing needs of inclusivity and efficiency, internal and external legitimacy, and stability and flexibility. It also shows how networks react to external changes., Conclusions: Our study shows the importance of considering three factors and contingencies that may affect network effectiveness: a) the importance of looking at network governance modes not in isolation, but in relationship to the governance of regional systems; b) the influence of a specific network's governance structure on the network's ability to respond to tensions and to achieve its goals; and c) the need to take into account the role of professionals in network governance.

Although meningococcal disease has a low incidence in Italy, it is a public health concern owing to its high lethality rate and high frequency of transitory and/or permanent sequelae among survivors. The highest incidence rates are recorded in infants, children and adolescents, and most of the cases are due to Neisseria meningitidis B. In Italy, anti-meningococcal B (anti-MenB) vaccination is free for infants but, despite the considerable disease burden in adolescents, no national recommendation to vaccinate in this age-group is currently available. The aim of this study was to assess the main available scientific evidence to support the Italian health authorities in implementing a program of free anti-MenB vaccination for adolescents. We conducted an overview of the scientific literature on epidemiology, disease burden, immunogenicity and safety of available vaccines, and economic evaluations of vaccination strategies. Each case of invasive meningococcal disease generates a considerable health burden (lethality rate: 9%; up to 60% of patients experience at least one sequela) in terms of impaired quality of life for survivors and high direct and indirect costs (the mean overall cost of acute phase for a single case amounts to about EUR 13,952; the costs for post-acute and the long-term phases may vary widely depending of the type of sequela, reaching an annual cost of about EUR 100,000 in cases of severe neurological damage). Furthermore, vaccination against meningococcus B in adolescence proved cost-effective. The study highlights the need to actively offer the anti-MenB vaccination during adolescence at a national level. This would make it possible to avoid premature deaths and reduce the high costs borne by the National Health Service and by society of supporting survivors who suffer temporary and/or permanent sequelae.

Lung malignancies have been extensively characterized through radiomics and deep learning. By providing a three-dimensional characterization of the lesion, models based on radiomic features from computed tomography (CT) and positron-emission tomography (PET) have been developed to detect nodules, distinguish malignant from benign lesions, characterize their histology, stage, and genotype. Deep learning models have been applied to automatically segment organs at risk in lung cancer radiotherapy, stratify patients according to the risk for local and distant recurrence, and identify patients candidate for molecular targeted therapy and immunotherapy. Moreover, radiomics has also been applied successfully to predict side effects such as radiation- and immunotherapy-induced pneumonitis and differentiate lung injury from recurrence. Radiomics could also untap the potential for further use of the cone beam CT acquired for treatment image guidance, four-dimensional CT, and dose-volume data from radiotherapy treatment plans. Radiomics is expected to increasingly affect the clinical practice of treatment of lung tumors, optimizing the end-to-end diagnosis-treatment-follow-up chain. The main goal of this article is to provide an update on the current status of lung cancer radiomics.

COVID-19 represents a major public health issue in Italy; estimating the size of the outbreak could direct public health policies and inform us of the extent of the reorganization needed in the healthcare system, the efficacy of quarantine measures, and eventually on the achievement of herd immunity. To chart the real extent of COVID-19 infection in Italy official data need to be interpreted, considering various aspects such as the "suspected-case" definition that changed during recent months, the management of asymptomatic and untested symptomatic cases, the system for reporting deaths, and short-term fluctuations. All these aspects should be considered when reflecting on the meaning of the official COVID-19 figures in Italy. Regionalization of the healthcare system and fragmentation of data represent real challenges in the management of the COVID-19 outbreak in Italy. The authors' opinion is that transparent and accurate reporting could guide policy-making and help reorganize health services., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: To assess the potential impact of a melanoma screening programme, compared with usual care, on direct costs and life expectancy in the era of targeted drugs and cancer immunotherapy., Methods: Using a Whole Disease Model approach, a Markov simulation model with a time horizon of 25 years was devised to analyse the cost-effectiveness of a one-time, general practitioner-based melanoma screening strategy in the population aged over 20, compared with no screening. The study considered the most up-to-date drug therapy and was conducted from the perspective of the Veneto regional healthcare system within the Italian National Health Service. Only direct costs were considered. Sensitivity analyses, both one-way and probabilistic, were performed to identify the parameters with the greatest impact on cost-effectiveness, and to assess the robustness of our model., Results: Over a 25-year time horizon, the screening intervention dominated usual care. The probabilistic sensitivity analyses confirmed the robustness of these findings. The key drivers of the model were the proportion of melanomas detected by the screening procedure and the adherence of the target population to the screening programme., Conclusions: The screening programme proved to be a dominant option compared with usual care. These findings should prompt serious consideration of the design and implementation of a regional or national melanoma screening strategy within a National Health Service.

Purpose: to predict the occurrence of late subcutaneous radiation induced fibrosis (RIF) after partial breast irradiation (PBI) for breast carcinoma by using machine learning (ML) models and radiomic features from 3D Biologically Effective Dose (3D-BED) and Relative Electron Density (3D-RED). Methods: 165 patients underwent external PBI following a hypo-fractionation protocol consisting of 40 Gy/10 fractions, 35 Gy/7 fractions, and 28 Gy/4 fractions, for 73, 60, and 32 patients, respectively. Physicians evaluated toxicity at regular intervals by the Common Terminology Adverse Events (CTAE) version 4.0. RIF was assessed every 3 months after the completion of radiation course and scored prospectively. RIF was experienced by 41 (24.8%) patients after average 5 years of follow up. The Hounsfield Units (HU) of the CT-images were converted into relative electron density (3D-RED) and Dose maps into Biologically Effective Dose (3D-BED), respectively. Shape, first-order and textural features of 3D-RED and 3D-BED were calculated in the planning target volume (PTV) and breast. Clinical and demographic variables were also considered (954 features in total). Imbalance of the dataset was addressed by data augmentation using ADASYN technique. A subset of non-redundant features that best predict the data was identified by sequential feature selection. Support Vector Machines (SVM), ensemble machine learning (EML) using various aggregation algorithms and Naive Bayes (NB) classifiers were trained on patient dataset to predict RIF occurrence. Models were assessed using sensitivity and specificity of the ML classifiers and the area under the receiver operator characteristic curve (AUC) of the score functions in repeated 5-fold cross validation on the augmented dataset. Results: The SVM model with seven features was preferred for RIF prediction and scored sensitivity 0.83 (95% CI 0.80-0.86), specificity 0.75 (95% CI 0.71-0.77) and AUC of the score function 0.86 (0.85-0.88) on cross-validation. The selected features included cluster shade and Run Length Non-uniformity of breast 3D-BED, kurtosis and cluster shade from PTV 3D-RED, and 10th percentile of PTV 3D-BED. Conclusion: Textures extracted from 3D-BED and 3D-RED in the breast and PTV can predict late RIF and may help better select patient candidates to exclusive PBI., (Copyright © 2020 Avanzo, Pirrone, Vinante, Caroli, Stancanello, Drigo, Massarut, Mileto, Urbani, Trovo, el Naqa, De Paoli and Sartor.)

Background: Hepatitis B still represents a health concern, although safe and effectivevaccines have been available since 1982. Italy introduced a program of universal vaccination againsthepatitis B in 1991. The aim of this study was to assess the immunity levels towards hepatitis B in asample of sera from the pediatric and adolescent population in the province of Florence, CentralItaly, twenty-seven years after the implementation of universal vaccination., Methods: A total of 165sera samples were collected from the resident population of Florence aged 1-18 years. The anti-HBsand anti-HBc enzyme-linked immunosorbent Assay (ELISA) tests were performed on all samples.The anamnestic and vaccination status data were also collected., Results: Seroprevalence of anti-HBswas approximately 60%, with children aged 1-5 years having the highest positivity rate (81.6%),and decreasing trends in the older age groups. The zero prevalence of anti-HBc shows that thedetected protective immunity is mainly due to vaccination, and natural infection was not reportedin the studied population., Conclusions: The seroprevalence of anti-HBs and the lack of anti-HBc inthis study highlights that immunity levels have been derived mainly from immunization. Thisconfirms how vaccination dramatically reduced circulation of the hepatitis B virus in Italy in thepediatric and adolescent population twenty-seven years after implementation of the mandatoryuniversal program.

Purpose: The purpose of study is to investigate the dosimetry of electron intraoperative radiotherapy (IOERT) of the Intraop Mobetron 2000 mobile LINAC in treatments outside of the breast. After commissioning and external validation of dosimetry, we report in vivo results of measurements for treatments outside the breast in a large patient cohort, and investigate if the presence of inhomogeneities can affect in vivo measurements., Methods and Materials: Applicator factors and profile curves were measured with a stereotactic diode. The applicators factors of the 6 cm flat and beveled applicators were also confirmed with radiochromic films, parallel-plate ion chamber and by an external audit performed with ThermoLuminescent Dosimeters (TLDs). The influence of bone on dose was investigated by using radiochromic films attached to an insert equivalent to cortical bone, immersed in the water phantom. In vivo dosimetry was performed on 126 patients treated with IOERT using metal oxide-silicon semiconductor field effect transistors (MOSFETs) placed on the tumor bed., Results: Relatively small differences were found among different detectors for measurements of applicator factors. In the external audit, the agreement with the TLD was mostly within ±0.2%. The largest increase of dose due to the presence of cortical bone insert was +6.0% with energy 12 MeV and 3 cm applicator. On average, in vivo dose was significantly (+3.1%) larger than prescribed dose., Conclusion: IOERT in applications outside the breast results in low discrepancies between in vivo and prescribed doses, which can be also explained with the presence of tissue inhomogeneity., (Copyright © 2019 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

9-Hydroxystearic acid (9-HSA) is an endogenous cellular lipid that possesses antiproliferative and selective effects against cancer cells. A series of derivatives were synthesized in order to investigate the effect of the substituent in position 9 and on the methyl ester functionality on the biological activity. The two separate enantiomers of methyl 9-hydroxystearate and of methyl 9-aminostearate showed antiproliferative activity against the HT29 cell line. This indicates the importance of position 9 groups being able to make hydrogen bonding with the molecular target. Further, this effect must be preserved when the carboxy group of 9-HSA is esterified. The biological tests showed that the amines, contrarily to methyl esters, resulted in cytotoxicity. A deep investigation on the effect of methyl ( R )-9-hydroxystearate on HT29 cells showed an antiproliferative effect acting through the CDKN1A and MYCBP gene expression.

Background: The inadequate knowledge about vaccinations of healthcare workers, including medical doctors, has certainly contributed to the spread of the vaccine hesitancy. Therefore, it is essential to improve the level of knowledge of future doctors. The aim of the study is to evaluate the impact of a course about vaccinations on the knowledge of medical students., Methods: Medical students were asked to complete an anonymous questionnaire before and after a seminar on vaccination that they willingly attended. The two questionnaires contained the same 10 questions about vaccines. Only the students who had attended the lecture were allowed to fulfil the post-lecture questionnaires through the learning management system (LMS) called "Moodle". A descriptive statistical analysis of the data collected through the comparative evaluation of the answers before and after the seminar was performed. Mann-Whitney test for two independent samples was used to compare medians score before and after the interventions., Results: A total of 100 medical students filled the pre-lecture questionnaire and 81 of them completed the post-lecture questionnaire. Knowledge of the students on the indication of the MMR (Measles-Mumps-Rubella) vaccine strongly improved after the seminar. Moreover, the number of students who would recommend vaccination for pertussis and influenza during pregnancy increased significantly by 37% and 19% respectively after the seminar and those aware of the need for Herpes Zoster vaccination over the age of 65 increased by 22%., Discussion: For future doctors, a thorough knowledge about vaccinations is increasingly required in order to deal with vaccine hesitancy. Extracurricular seminars about vaccines, provided in the second half of the course of study, can have a highly positive impact., (©2019 Pacini Editore SRL, Pisa, Italy.)

Introduction : Vaccination is a crucial tool for the primary prevention of infectious diseases. Thanks to widespread vaccination, in the last century smallpox has been eradicated, and the Americas and Europe have become polio-free. Areas covered : The aim of our study was to assess vaccination coverage in childhood up to booster preschool age in order to update the analysis on European trends of immunization coverage in the last nine years (2009-2017) and to assess the impact of different national policies on vaccine uptake. Expert opinion : Despite the good results, several EU countries are going through unprecedented outbreaks of vaccine-preventable diseases due to insufficient coverage. The increase of vaccine hesitancy has made it difficult to reach and maintain high rates of vaccination coverage. Enforcing mandatory vaccinations is one of the strategies adopted by some countries, like Italy and France, to increase coverage. However, each country should find the most suitable way to keep up with vaccination coverages according to own cultural and organizational background.

Introduction: Although the benefits of vaccinations have been extensively demonstrated, vaccination coverage remains unsatisfactory as result of many people's poor knowledge and negative perception of vaccination.We evaluated the impact of an education course on vaccinations in a population of pregnant women., Methods: A total of 214 pregnant women were invited to participate in this project, which was undertaken at the Obstetrics and Gynaecology Department of Careggi University Hospital in Florence (Italy). Anonymous questionnaires were administered to women before and after the intervention.A descriptive and statistical analysis was carried out in order to compare the responses obtained before and after the intervention., Results: Adherence to the initiative was good (98%): initially, the respondents were not hostile to vaccinations, though many (43%) were poorly or insufficiently informed. The educational intervention had a positive impact. After the intervention, the number of women who rated their level of knowledge of vaccinations as poor or insufficient had decreased by 30% and the number of "hesitant" respondents had decreased with respect to all aspects of the study, especially the decision to be vaccinated during pregnancy., Conclusions: Hesitancy stems from a lack of accurate information. Healthcare professionals need to improve their communication skills. Appropriate education during pregnancy, when women are more receptive, may have a highly positive impact. These observations need to be considered in the planning of courses to prepare pregnant women for delivery also in other maternal-foetal centres in Italy.

Histone deacetylases, HDACs, have been demonstrated to play a critical role in epigenetic signaling and were found to be overexpressed in several type of cancers; therefore, they represent valuable targets for anticancer therapy. 9-Hydroxystearic acid has been shown to bind the catalytic site of HDAC1, inducing G0/G1 phase cell cycle arrest and activation of the p21 WAF1 gene, thus promoting cell growth inhibition and differentiation in many cancer cells. Despite the ( R) enantiomer of 9-hydroxystearic acid (9R) displaying a promising in vitro growth-inhibitory effect on the HT29 cell line, its scarce water solubility and micromolar activity require novel solutions for improving its efficacy and bioavailability. In this work, we describe the synthesis and in vitro biological profiling of 9R keratin nanoparticles (9R@ker) obtained through an in-water drug-induced aggregation process. The anticancer activity of 9R@ker was investigated in the HT29 cell line; the results indicate an increased fluidity of cell membrane and a higher intracellular ROS formation, resulting in an unexpected S phase cell cycle arrest (25% increase as compared to the control) induced by 9R@ker with respect to free 9R and an induction of cell death.

Purpose: The purpose of this study was to implement a machine learning model to predict skin dose from targeted intraoperative (TARGIT) treatment resulting in timely adoption of strategies to limit excessive skin dose., Methods: A total of 283 patients affected by invasive breast carcinoma underwent TARGIT with a prescribed dose of 6 Gy at 1 cm, after lumpectomy. Radiochromic films were used to measure the dose to the skin for each patient. Univariate statistical analysis was performed to identify correlation of physical and patient variables with measured dose. After feature selection of predictors of in vivo skin dose, machine learning models stepwise linear regression (SLR), support vector regression (SVR), ensemble with bagging or boosting, and feed forward neural networks were trained on results of in vivo dosimetry to derive models to predict skin dose. Models were evaluated by tenfold cross validation and ranked according to root mean square error (RMSE) and adjusted correlation coefficient of true vs predicted values (adj-R 2 )., Results: The predictors correlated with in vivo dosimetry were the distance of skin from source, depth-dose in water at depth of the applicator in the breast, use of a replacement source, and irradiation time. The best performing model was SVR, which scored RMSE and adj-R 2 , equal to 0.746 [95% confidence intervals (CI), 95% CI 0.737,0.756] and 0.481 (95% CI 0.468,0.494), respectively, on the tenfold cross validation., Conclusion: The model trained on results of in vivo dosimetry can be used to predict skin dose during setup of patient for TARGIT and this allows for timely adoption of strategies to prevent of excessive skin dose., (© 2019 American Association of Physicists in Medicine.)

Introduction: About 1.25 million people worldwide die every year because of road accidents. Risk is higher when drivers use mobile phones, whereas seat belts help to prevent crash-related injury. We aimed to evaluate the prevalence, associated factors, and temporal trend of the use of seat belts and mobile phones among drivers and passengers in Florence, Italy (2005-2015)., Methods: Use of seat belts and mobile phones use was monitored via direct observation in four areas in the province of Florence. We fitted Poisson regression models with robust variance to investigate the factors associated with the use of seat belts and mobile phones use by the drivers and to explore long-term trends and seasonal patterns in the two time-series., Results: We observed a total of an overall 134,775 vehicles: seat belts were worn by 71.8% of drivers and front-seat passengers and 27.6% of back-seat passengers, while mobile phones were being used by 4.8% of drivers. Drivers were more likely to wear seat belt when transporting passengers (≥2 vs none: prevalence ratio [PR] 1.21, 95% confidence intervals [CI] 1.14-1.29) and while driving in the afternoon (PR 1.04, 95% CI 1.03-1.05), and less likely when the front-seat passenger was not wearing seat belts (PR 0.33, 95% CI 0.32-0.34). After an initial increase, seat belts use by the driver decreased over time (-0.5% each year during 2010-2015), with significant peaks and troughs in July and January, respectively. Mobile phone use by the driver was inversely associated with wearing seat belts (PR 0.67, 95% CI 0.64-0.70) and carrying passengers (≥2 vs. none PR 0.20, 95% CI 0.07-0.52). The proportion of drivers using mobile phones did not vary over time nor showed any clear seasonality., Conclusions: Drivers' risky behaviours (not wearing a seat belt and using a mobile phone) are associated, showing a global misperception of risk among a subset of drivers. The number of passengers and their behaviour is also associated with the driver's attitude. The effectiveness of primary enforcement laws has declined in Italy in recent years; therefore, other strategies should be devised and implemented., Competing Interests: The authors have declared that no competing interests exist.

Objective: We attempted to overexpress Human Histone Deacetylase 1 (HDAC1) in Escherichia coli., Results: A synthetic gene coding for HDAC1, and optimised for E. coli codon usage, was cloned into pBADHisB, generating pBAD-rHDAC1. This construct was used to transform E. coli TOP10, and the target protein was overexpressed and partially purified. According to its elution volume from a Superdex 200 column, the partially purified rHDAC1 was obtained in aggregated form, i.e., as an octamer. The dissociation of octameric HDAC1 was tested using several agents, among which sodium dodecyl sulfate was competent in partially dissociating rHDAC1 aggregates. When the enzyme activity was tested in vitro using 3 H-acetyl-labelled histones both protein samples, aggregated and dissociated, were active. Hence, our results suggest that E. coli represents an alternative system for the production of the recombinant HDAC1., Conclusions: We described a procedure for the overexpression in E. coli of recombinant HDAC1, the purification of which in active form can be successfully performed, although yielding an octameric aggregate.

Cutaneous melanoma is a major concern in terms of healthcare systems and economics. The aim of this study was to estimate the direct costs of melanoma by disease stage, phase of diagnosis, and treatment according to the pre-set clinical guidelines drafted by the AIOM (Italian Medical Oncological Association). Based on the AIOM guidelines for malignant cutaneous melanoma, a highly detailed decision-making model was developed describing the patient's pathway from diagnosis through the subsequent phases of disease staging, surgical and medical treatment, and follow-up. The model associates each phase potentially involving medical procedures with a likelihood measure and a cost, thus enabling an estimation of the expected costs by disease stage and clinical phase of melanoma diagnosis and treatment according to the clinical guidelines. The mean per-patient cost of the whole melanoma pathway (including one year of follow-up) ranged from €149 for stage 0 disease to €66,950 for stage IV disease. The costs relating to each phase of the disease's diagnosis and treatment depended on disease stage. It is essential to calculate the direct costs of managing malignant cutaneous melanoma according to clinical guidelines in order to estimate the economic burden of this disease and to enable policy-makers to allocate appropriate resources.

Correction: After publication of the article [1], it has been brought to our attention that the thirteenth author of this article has had their name spelt incorrectly. In the original article the spelling "Laura Rizzir" was used. In fact the correct spelling should be "Laura Rizzi".

Purpose: To correlate radiation dose to the risk of severe radiologically-evident radiation-induced lung injury (RRLI) using voxel-by-voxel analysis of the follow-up computed tomography (CT) of patients treated for lung cancer with hypofractionated helical Tomotherapy., Methods and Materials: The follow-up CT scans from 32 lung cancer patients treated with various regimens (5, 8, and 25 fractions) were registered to pre-treatment CT using deformable image registration (DIR). The change in density was calculated for each voxel within the combined lungs minus the planning target volume (PTV). Parameters of a Probit formula were derived by fitting the occurrences of changes of density in voxels greater than 0.361gcm -3 to the radiation dose. The model's predictive capability was assessed using the area under receiver operating characteristic curve (AUC), the Kolmogorov-Smirnov test for goodness-of-fit, and the permutation test (P test )., Results: The best-fit parameters for prediction of RRLI 6months post RT were D 50 of 73.0 (95% CI 59.2.4-85.3.7)Gy, and m of 0.41 (0.39-0.46) for hypofractionated (5 and 8 fractions) and D 50 of 96.8 (76.9-123.9)Gy, and m of 0.36 (0.34-0.39) for 25 fractions RT. According to the goodness-of-fit test the null hypothesis of modeled and observed occurrence of RRLI coming from the same distribution could not be rejected. The AUC was 0.581 (0.575-0.583) for fractionated and 0.579 (0.577-0.581) for hypofractionated patients. The predictive models had AUC>upper 95% band of the P test ., Conclusions: The correlation of voxel-by-voxel density increase with dose can be used as a support tool for differential diagnosis of tumor from benign changes in the follow-up of lung IMRT patients., (Copyright © 2017 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Rectal resection is technically one of the most demanding laparoscopic procedures, requiring additional training and expertise of both surgeons and institutions. The literature has shown that laparoscopic procedures can be appropriate for the treatment of rectal cancer (RC), in terms of safety, outcome and efficiency, but results may not always be directly transferable to the general population. This study aimed to investigate the use of laparoscopic rectal cancer resections in a north-eastern Italian region (the Veneto) and to see how the characteristics of patients and hospitals are associated with the use of laparoscopy. This was a retrospective cohort study based on administrative data collected from 2007 to 2014 in the Veneto region (north-east Italy). In the period considered (2007-2014), 4953 rectal resections were performed for RC in Veneto hospitals, accounting for 35% of the total 14,243 surgical procedures involving the rectum, and resulting in 76,739 days in hospital [mean length of stay-post-operative (MLOS) 15.5 ± 11.1 days]. Patients were a mean 67.9 ± 11.7 years old (68 ± 12.7 for women, 67.9 ± 11 for men), while the subgroup of patients undergoing laparoscopic procedures was on average 2 years younger (66.5 ± 11.8 vs 68.8 ± 11.5; p < 0.05). The four main findings of this study are: (1) the increasing rates of laparoscopic procedures for RC resection at all the hospitals in our geographical area, rising up to 52% in 2014. This is probably related to not only to availability of better equipment but surely to a growing expertise of surgeons; (2) the esteem of proportion of laparoscopically treated RC; (3) the significant difference between the laparoscopic and open surgical approach in terms of mean length of hospital stay after RC resection, making the laparoscopic approach cost-effective generally speaking; and (4) the disparities in hospitals' use of laparoscopy by patients' age group: Laparoscopic surgery is safe also in the elderly population but it is not so widely offers in Veneto Region hospitals, and it's probably due to the lack of experience about this approach in frail/old patients.

Vaginal lactobacilli offer protection against recurrent urinary and vaginal infections. The precise mechanisms underlying the interaction between lactobacilli and the host epithelium remain poorly understood at the molecular level. Deciphering such events can provide valuable information on the mode of action of commensal and probiotic bacteria in the vaginal environment. We investigated the effects exerted by five Lactobacillus strains of vaginal origin (Lactobacillus crispatus BC1 and BC2, Lactobacillus gasseri BC9 and BC11 and Lactobacillus vaginalis BC15) on the physical properties of the plasma membrane in a cervical cell line (HeLa). The interaction of the vaginal lactobacilli with the cervical cells determined two kinds of effects on plasma membrane: (1) modification of the membrane polar lipid organisation and the physical properties (L. crispatus BC1 and L. gasseri BC9); (2) modification of α5β1 integrin organisation (L. crispatus BC2, L. gasseri BC11 and L. vaginalis BC15). These two mechanisms can be at the basis of the protective role of lactobacilli against Candida albicans adhesion. Upon stimulation with all Lactobacillus strains, we observed a reduction of the basal oxidative stress in HeLa cells that could be related to modifications in physical properties and organisation of the plasma membrane. These results confirm the strictly strain-specific peculiarities of Lactobacillus and deepen the understanding of the mechanisms underlying the health-promoting role of this genus within the vaginal ecosystem.

The myeloproliferative neoplasms are chronic myeloid cancers divided in Philadelphia positive (Ph+), chronic myeloid leukemia, or negative: polycythemia vera (PV) essential thrombocythemia (ET), and primary myelofibrosis (PMF). Most Ph negative cases have an activating JAK2 or MPL mutation. Recently, somatic mutations in the calreticulin gene (CALR) were detected in 56-88% of JAK2/MPL-negative patients affected by ET or PMF. The most frequent mutations in CARL gene are type-1 and 2. Currently, CALR mutations are evaluated by sanger sequencing. The evaluation of CARL mutations increases the diagnostic accuracy in patients without other molecular markers and could represent a new therapeutic target for molecular drugs.We developed a novel detection assay in order to identify type-1 and 2 CALR mutations by PNA directed PCR clamping. Seventy-five patients affected by myeloproliferative neoplasms and seven controls were examined by direct DNA sequencing and by PNA directed PCR clamping. The assay resulted to be more sensitive, specific and cheaper than sanger sequencing and it could be applied even in laboratory not equipped for more sophisticated analysis. Interestingly, we report here a case carrying both type 1 and type2 mutations in CALR gene.

Meningioma 1 (MN1) gene overexpression has been reported in acute myeloid leukaemia (AML) patients and identified as a negative prognostic factor. In order to characterize patients presenting gene overexpression and to verify if MN1 transcript could be a useful marker for minimal residual disease detection, MN1 was quantified in 136 AML patients with different cytogenetic risk and in 50 normal controls. In 20 patients bearing a fusion gene transcript suitable for minimal residual disease quantitative assessment and in 8 patients with NPM1 mutation, we performed a simultaneous analysis of MN1 and the fusion-gene transcript or NPM1 mutation during follow-up. Sequential MN1 and WT1 analysis was also performed in 13 AML patients lacking other molecular markers. The data obtained show that normal cells consistently express low levels of MN1 transcript. In contrast, high levels of MN1 expression are present in 47% of patients with normal karyotype and in all cases with inv(16). MN1 levels during follow-up were found to follow the pattern of other molecular markers (fusion gene transcripts, NPM1 and WT1). Increased MN1 expression in the BM during follow up was always found to be predictive of an impending hematological relapse.

Rationale: Alcoholism is a complex disorder in which diverse pathophysiological processes contribute to initiation and progression, resulting in a high degree of heterogeneity among patients. Few pharmacotherapies are presently available, and patient responses to these are variable. The nociceptin/orphanin FQ (NOP) receptor has been suggested to play a role both in alcohol reward and in negatively reinforced alcohol seeking. Previous studies have shown that NOP-receptor activation reduces alcohol intake in genetically selected alcohol-preferring as well as alcohol-dependent rats. NOP activation also blocks stress- and cue-induced reinstatement of alcohol-seeking behavior., Objectives: Here, we aimed to examine a novel, potent, and brain-penetrant small-molecule NOP-receptor agonist, SR-8993, in animal models of alcohol- as well as anxiety-related behavior using male Wistar rats., Results: SR-8993 was mildly anxiolytic when given to naïve animals and potently reversed acute alcohol withdrawal-induced ("hangover") anxiety. SR-8993 reduced both home-cage limited access drinking, operant responding for alcohol, and escalation induced through prolonged intermittent access to alcohol. SR-8993 further attenuated stress- as well as cue-induced relapse to alcohol seeking. For the effective dose (1.0 mg/kg), non-specific effects such as sedation may be limited, since a range of control behaviors were unaffected, and this dose did not interact with alcohol elimination., Conclusion: These findings provide further support for NOP-receptor agonism as a promising candidate treatment for alcoholism and establish SR-8993 or related molecules as suitable for further development as therapeutics., Competing Interests: Compliance with ethical standardsExperiments were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals (work done at the NIAAA, NIH) or the European Union guidelines on the care and use of laboratory animals. All experimental procedures were approved by the local ethics committee on animal research (NIAAA ACUC and the Research Animal Ethics Board in Linköping).Funding and disclosuresThe work presented here was supported by a grant from the National Institutes of Health to C. Wahlestedt (R01-DA035055) and a grant from the Swedish Research Council to M. Heilig (VR grant no. 2010-3219). The authors declare no conflict of interest.

The Wilms tumor gene WT1 is a useful marker of clonal hematopoiesis and it has been shown to be a good marker of residual disease and it reflects the response to therapy. Although myelofibrosis is characterized by mutations of JAK2 and calreticulin (CALR), these mutations are not useful to monitor response to therapy. In this study we demonstrated that in patients affected by myelofibrosis WT1 correlates with the International Prognostic Scoring System (IPSS) score at diagnosis. Furthermore WT1 is a good marker of response to JAK2 inhibitors especially for patients without blasts and for patients who develop anemia or thrombocytopenia not for progression but as therapy related toxicity. Finally, WT1 transcript reduction can mirror a benefit of therapy on the disease burden. This study demonstrated that WT1 is a good marker for monitoring the response to therapy in patients affected by myelofibrosis., (© 2016 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Interest in chronic conditions reflects their role as the first cause of death and disability in developed countries; improving the management of these conditions is a priority for health care services. The aim of this study was to establish which sociodemographic factors influence adherence to standards of care for chronic heart failure (CHF). A generalized multilevel structural equation model was developed and applied to a sample of patients with CHF obtained from administrative data flows in six Italian regions to ascertain any associations between adherence to standards of care for CHF and sociodemographic variables. Indicators of compliance were adherence to beta-blocker therapy (BB-A) and Angiotensin Convertin Enzime inhibitor/Angiotensin Receptor Blocker therapy (ACE-A), and creatinine and electrolyte testing (CNK-T). All indicators were computed over a one-year follow-up. Among a cohort of 24,997 patients, the BB-A rate was 40.4%, the ACE-A rate 61.1%, and the CNK-T rate 57.0%. Factors found associated with adherence were gender, age, and citizenship. Our study shows an inadequate adherence to standards of care for CHF, particularly associated with certain sociodemographic characteristics. This suggests the need to improve the role of primary care in managing this chronic condition. The measures considered only apply to patients with a reduced Left Ventricular Ejection Fraction, hence a limitation of this analysis is the lack of information on left ventricular ejection.

Growing evidence indicates that targeting nociceptin receptor (NOP) signaling may have therapeutic efficacy in treating alcohol and opioid addiction. However, little is known about the therapeutic value of selective NOP agonists for the treatment of cocaine dependence. Recently, we identified a highly selective, brain-penetrant NOP small molecule agonist (SR-8993), and using this compound, we previously showed that nociceptin receptor activation attenuated consolidation of fear-related memories. Here, we sought to determine whether SR-8993 also affects the rewarding properties of cocaine. Using a conditioned place preference (CPP) procedure, we show that SR-8993 (3 or 10 mg/kg) failed to disrupt acquisition or expression of cocaine CPP (7.5 or 15 mg/kg) in C57BL/6 mice. Additionally, SR-8993 did not affect rate of extinction or reinstatement (yohimbine- and cocaine-induced) of cocaine CPP. These studies indicate that selective activation of NOP may not be sufficient in reducing behavioral responses to cocaine., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Alkynyl(triphenylphosphine)gold(i) complexes carrying variously substituted propargylic amines have been synthesized and fully characterized in solution and solid state. High levels of toxicity (i.e. micromolar range) were recognized for a series of cancer cell lines with particular emphasis on HT29, IGROV1, HL60 and I407. In particular the lead compound 3ab was identified as the most active compound in all cell lines (IC50: 1.7-7.9 μM).

Purpose: To introduce volumetric modulated arc therapy treatments (VMAT) with simultaneous integrated boost (SIB) for pancreatic cancer and describe dosimetric results on a large patient series., Methods and Materials: 45 patients with pancreatic malignancies were treated with 18 MV single-arc VMAT. Image guidance was performed with daily online kilo-volt cone-beam computed tomography (CBCT). The conformity index (CI) and homogeneity index (HI) to the target volumes, PTV45Gy and PTV54Gy, and dose-volume indices to OARs from the QUANTEC task group were reported. The risk of clinical nephritis was evaluated using normal tissue complication probability (NTCP). Treatments were verified in-phantom with the Delta4 system., Results: Average CI was 1.06 with 95% confidence intervals (95% CI) of 0.97-1.22 for PTV45Gy and 1.17 (0.66-1.61) for PTV54Gy. HI of PTV54Gy was 1.06 (1.04-1.10). OAR constraints were achieved in all patients, except for kidneys V12Gy of 48 (35.4-72.3)%. NTCP of the kidneys was 0.98 (0.6-1.7)%. Kidneys V12Gy and V20Gy were inversely related to PTV54Gy CI and maximum dose. All in-phantom tests had gamma pass rates exceeding 95% with global 3% dose difference and 3 mm distance to agreement. Patient shifts measured with CBCT had 95% CI of -0.8, +0.8 in the RL, -0.7, +0.8 in the SI, and -0.8, +0.7 cm in the AP directions., Conclusions: Dosimetric results of VMAT were excellent on PTVs and organs at risk. The kidneys represent the dose-limiting organ at risk for this technique. NTCP indicates that this technique is safe from radiation-induced side effects to the kidneys., (Copyright © 2015 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: Interprofessional Education (IPE) implies how to achieve successful teamwork, and is based on collaborative practice which enhance occasions for relationships between two or more healthcare professions. This study evaluates the effectiveness of IPE in changing attitudes after a training recently introduced to medical education for second-year students at the University of Padova, Italy., Methods: All medical students following a new program for IPE were enrolled in this study. The Interdisciplinary Education Perception Scale (IEPS) was administered before and after training, according to observation-based and practice-based learning. Data were analysed with Student's paired t-test and Wilcoxon's signed rank test., Results: 277 medical students completed both questionnaires. Statistically significant improvements were found in students' overall attitudes as measured by the IEPS and four subscale scores. Gender-stratified analyses showed that improvements were observed only in female students in subscale 4 ("Understanding Others' Values"). Students who had a physician and/or health worker in their family did not show any improvement in subscales 2 ("Perceived need for cooperation") or 4 ("Understanding Others' Values")., Conclusions: Our results indicate that IPE training has a positive influence on students' understanding of collaboration and better attitudes in interprofessional teamwork. More research is needed to explore other factors which may influence specific perceptions among medical students.