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Background The aims of this study were: to investigate the capacity of the rare disease healthcare network in Campania to diagnose patients with rare diseases during the outbreak of Covid-19; and to shed light on problematic diagnoses during this period. Methods To describe the impact of the Covid-19 pandemic on the diagnosis of patients with rare diseases, a retrospective analysis of the Campania Region Rare Disease Registry was performed. A tailored questionnaire was sent to rare disease experts to investigate major issues during the emergency period. Results Prevalence of new diagnoses of rare disease in March and April 2020 was significantly lower than in 2019 (117 versus 317, P Conclusions This study describes the effects of the Covid-19 outbreak on the diagnosis of rare disease in a single Italian region and investigates potential issues of diagnosis and management during this period.

PurposeThis study aims to focus on inter-firm collaboration, exploring the main capabilities that can make a business more or less open to collaboration; it also considers the role of both firm-specific and relationship-specific capabilities. The paper proposes a model that can be used to study how the combination of the two categories of capabilities determines a firm’s approach to collaboration.Design/methodology/approachThrough a survey of high-end hotels in tourist destinations in Italy and the USA, this paper tests variable connected with firm-specific and relationship-specific aspects, using confirmatory factor analysis.FindingsFirms with greater capabilities are less open to cooperation; weaker firms with fewer resources appear to be more inclined to cooperate, probably to gain access to resources and competencies they do not possess.Research limitations/implicationsFrom a scientific perspective, this paper suggests an analysis based on both individual and relational capabilities when deciding whether to collaborate, while most studies based on a relational view just consider relational capabilities. The study could be enlarged to other countries and contexts.Practical implicationsFrom a practical perspective, it indicates the importance of accounting for different and sometimes diverging aspects when deciding to cooperate.Social implicationsIn terms of social implications, it shows that, apart from the relational capabilities they have, potential partners can decide not to collaborate.Originality/valueThe paper suggests a method of analyzing both individual and relational capabilities when deciding whether to engage in a collaboration. It shows that firms’ behavior does not necessarily depend on the firm’s relational capabilities.

Background: The management of chronic diseases, particularly in children, requires an integrated physical and psychological approach to both sick children and their family. This is the case of Cystic Fibrosis (CF), a complex genetic chronic disease, where, a comprehensive evaluation of the emotional impact and an effective multidimensional approach are indicated. Aim: This study investigates on parenting stress in children and adolescents with CF and its determinants related to parents, children and the disease severity. Methods: The study involved 34.04% adult males and 65.96% adult females (range 21-55 years) and 47 children with CF, 54.35% males and 45.65% females (range 1-17 years). The data were obtained through a Parenting Stress Index - Short Form (PSI-SF) questionnaire. According to the PSI-SF scoring system, three types of stress were detected: a typical stress pattern (normal), a high stress pattern (increased) and a defensive response, which may be considered as a high stress feature in children which requires monitoring and clinical evaluation. Results: This study shows a significant presence of stress in females (60.23%), of subject married (84.62%), unemployed (69.23%) and with education level such as "middle School" (61.54%). Concerning children of parents with high stress, it resulted most frequent children with one sibling (53.85%). Finally, by univariate analysis, it resulted a significant positive correlation between parenting stress and disease degree of children. Instead by multivariate analysis, we found that the variables: Number of siblings and Birth order were a significant positive and negative predictor of parenting stress respectively. Conclusion: An increased stress level was detected in less than one third of parents of subjects with CF. These data may be related to the psychological support which is part of the routine management of CF care team. However, as children's features seem to act as a determinant of stress more than parental ones, the parental-child dysfunction should be the target for further integrated interventions. Background: The management of chronic diseases, particularly in children, requires an integrated physical and psychological approach to both sick children and their family. This is the case of Cystic Fibrosis (CF), a complex genetic chronic disease, where, a comprehensive evaluation of the emotional impact and an effective multidimensional approach are indicated. Aim: This study investigates on parenting stress in children and adolescents with CF and its determinants related to parents, children and the disease severity. Methods: The study involved 34.04% adult males and 65.96% adult females (range 21-55 years) and 47 children with CF, 54.35% males and 45.65% females (range 1-17 years). The data were obtained through a Parenting Stress Index – Short Form (PSI-SF) questionnaire. According to the PSI-SF scoring system, three types of stress were detected: a typical stress pattern (normal), a high stress pattern (increased) and a defensive response, which may be considered as a high stress feature in children which requires monitoring and clinical evaluation. Results: This study shows a significant presence of stress in females (60.23%), of subject married (84.62%), unemployed (69.23%) and with education level such as “middle School” (61.54%). Concerning children of parents with high stress, it resulted most frequent children with one sibling (53.85%). Finally, by univariate analysis, it resulted a significant positive correlation between parenting stress and disease degree of children. Instead by multivariate analysis, we found that the variables: Number of siblings and Birth order were a significant positive and negative predictor of parenting stress respectively. Conclusion: An increased stress level was detected in less than one third of parents of subjects with CF. These data may be related to the psychological support which is part of the routine management of CF care team. However, as children’s features seem to act as a determinant of stress more than parental ones, the parental-child dysfunction should be the target for further integrated interventions.

Calcium is an essential element for human health, with key roles in the prevention and therapy of multifactorial conditions. Calcium dietary intake is often insufficient in the general population. The aim of this study was to perform a clinical audit for general practitioners (GPs) to understand the efficacy of training intervention on doctors' awareness about dietary calcium and supplements.General practice outpatients were enrolled (Before Clinical Audit, BCA) from the same sanitary district, and calcium dietary intake was evaluated with a validated questionnaire, also collecting information about the consumption of calcium and vitamin D supplements. Then, a training intervention with a frontal lesson and discussion with GPs involved was performed. After one month of this intervention, a second outpatient enrolment was performed (Post Clinical Audit, PCA) in the same general practices to evaluate differences in nutritional suggestions and supplement prescription by GPs. In BCA, the calcium dietary intake was low, with nobody reaching 1000 mg as suggested by the guidelines. Only 6.6% and 24.5% took calcium and vitamin D supplements, respectively; in the PCA, these percentages increased to 28% and 78% for calcium and vitamin D supplements, respectively (p 0.01 PCA vs BCA). There were no differences in calcium dietary intake between BCA and PCA.Training intervention on GPs was successful to sensitize them regarding calcium intake problems; GPs tended to increase the prescription of supplements but not to suggest changes in dietary habits.

Elderly individuals with chronic disorders tend to develop inflammaging, a condition associated with elevated levels of blood inflammatory markers, and increased susceptibility to chronic disease progression. Native and adaptive immunity are both involved in immune system senescence, kidney fibrosis and aging. The innate immune system is characterized by a limited number of receptors, constantly challenged by self and non-self stimuli. Circulating and kidney resident myeloid and lymphoid cells are all equipped with pattern recognition receptors (PRRs). Recent reports on PRRs show kidney overexpression of toll-like receptors (TLRs) in inflammaging autoimmune renal diseases, vasculitis, acute kidney injury and kidney transplant rejection. TLR upregulation leads to proinflammatory cytokine induction, fibrosis, and chronic kidney disease progression. TLR2 blockade in a murine model of renal ischemia reperfusion injury prevented the escape of natural killer cells and neutrophils by inflammaging kidney injury. Tumor necrosis factor-α blockade in endothelial cells with senescence-associated secretory phenotype significantly reduced interleukin-6 release. These findings should encourage experimental and translational clinical trials aimed at modulating renal inflammaging by native immunity blockade.

In this paper several statistical learning algorithms are used to predict the maximal length of fatigue cracks based on a sample composed of 31 observations. The small-data regime is still a problem for many professionals, especially in the areas where failures occur rarely. The analyzed object is a high-pressure Nozzle of a heavy-duty gas turbine. Operating parameters of the engines are used for the regression analysis. The following algorithms are used in this work: multiple linear and polynomial regression, random forest, kernel-based methods, AdaBoost and extreme gradient boosting and artificial neural networks. A substantial part of the paper provides advice on the effective selection of features. The paper explains how to process the dataset in order to reduce uncertainty; thus, simplifying the analysis of the results. The proposed loss and cost functions are custom and promote solutions accurately predicting the longest cracks. The obtained results confirm that some of the algorithms can accurately predict maximal lengths of the fatigue cracks, even if the sample is small.

Background Severe immune-related Adverse Events (irAEs) develop in 10–27% of patients treated with Immune-Oncology (IO) [Powles (Lancet 391:748–757, 2018); Galsky (Lancet 395:1547–1557, 2020); Haanen (Ann Oncol 28:119–142, 2017)]. The aim of our study was to evaluate efficacy and clinical outcome of metastatic renal cell carcinoma (mRCC) patients who stopped Immune Checkpoint Inhibitors (ICIs) due to early Grade (G) 3-G4 irAEs. Methods We retrospectively collected data from 204 mRCC patients treated with ICIs in 6 Italian referral centers adhering to the Meet-Uro group, between February 2017 and January 2020. To properly weight the results, patients who did not report early G3–G4 toxicities have been included as control group. Primary endpoint was to evaluate 6 months Progression Free Survival (PFS) after early treatment interruption for Grade (G) 3–4 toxicities compared to the control group. Secondary endpoints were to evaluate Time to treatment failure (TTF) and overall survival (OS) in both groups. All statistical analyses were performed using SPSS software (version 19.00, SPSS, Chicago). Results 18/204 (8.8%) patients had early treatment interruption for serious (G3-G4) irAEs. Early was defined as interruption of IO after only one or two administrations. Immune related nephritis and pancreatitis were the most common irAE that lead to treatment interruption. 6/18 patients received IO-IO combination whereas 12/18 patients antiPD1. In the study group, 12/18 (66.6%) were free from progression at 6 months since IO interruption, TTF was 1.6 months (95% CI 1.6–2.1), mPFS was 7.4 months (95% CI 3.16–11.6) and mOS was 15.5 months (5.1–25.8). In the control group 111/184 (60.3%) patients were free from progression at 6 months, TTF was 4.6 months (95% CI 3.5–5.6), mPFS was 4.6 months (95% CI 3.5–5.6) and mOS was 19.6 months (95% CI 15.1–24.0). In the overall population, mPFS was 5.0 months (95% CI 4.0–5.9) and mOS was 19.6 months (95% CI 15.1–24.0). Conclusions ICIs seem to maintain efficacy even after early interruption due to severe irAE.

The Multi-Attribute Method (MAM) Consortium was initially formed as a venue to harmonize best practices, share experiences, and generate innovative methodologies to facilitate widespread integration of the MAM platform, which is an emerging ultra-high-performance liquid chromatography-mass spectrometry application. Successful implementation of MAM as a purity-indicating assay requires new peak detection (NPD) of potential process- and/or product-related impurities. The NPD interlaboratory study described herein was carried out by the MAM Consortium to report on the industry-wide performance of NPD using predigested samples of the NISTmAb Reference Material 8671. Results from 28 participating laboratories show that the NPD parameters being utilized across the industry are representative of high-resolution MS performance capabilities. Certain elements of NPD, including common sources of variability in the number of new peaks detected, that are critical to the performance of the purity function of MAM were identified in this study and are reported here as a means to further refine the methodology and accelerate adoption into manufacturer-specific protein therapeutic product life cycles.

Objective To decrease referrals to cardiology of patients ages 7 to 21 years with low-probability cardiac pathology who presented to primary care with chest pain by 50% within 24 months. Study Design A multidisciplinary team designed and implemented an initiative consisting of 1) a decision support tool (DST), 2) educational sessions, 3) routine feedback to improve use of referral criteria, and 4) patient family education. Four pediatric practices, comprising 34 pediatricians and 7 nurse practitioners, were included in this study. We tracked progress via statistical process control charts. Results A total of 421 patients ages 7 to 21 years presented with chest pain to their pediatrician. The utilization of the DST increased from baseline of 16% to 68%. Concurrently, the percentage of low-probability cardiology referrals in pediatric patients ages 7 to 21 years who presented with chest pain decreased from 17% to 5% after our interventions. At a median follow-up time of 0.9 years (interquartile range, 0.3–1.6 years), no patient had a life-threatening cardiac event. Conclusion Our health care improvement initiative to reduce low-probability cardiology referrals for children presenting to primary care practices with chest pain was feasible, effective, and safe.

Background The glutamatergic modulator ketamine rapidly reduces depressive symptoms in individuals with treatment-resistant major depressive disorder (MDD). However, ketamine's effects on emotional processing biases remain largely unknown, and understanding these processes may help elucidate ketamine's mechanism of action. Methods Magnetoencephalography (MEG) was used to investigate ketamine's effects on early visual responses to affective stimuli in individuals with MDD (n=31) and healthy volunteers (HVs; n=24). Participants were enrolled in a double-blind, placebo-controlled, crossover clinical trial and were assessed at baseline and after subanesthetic-dose ketamine and placebo-saline infusions. During MEG recording, participants completed an emotional evaluation task in which they indicated the sex or emotional valence (happy-neutral or sad-angry) of facial stimuli. Source-localized event-related field (ERF) M100 and M170 amplitudes and latencies were extracted from regions of interest. Linear fixed effects models examined interactions between diagnosis, stimulus valence, and drug session for behavioral and MEG data. Results In baseline behavioral analyses, MDD participants exhibited higher accuracy for sad-angry than happy-neutral faces, and HVs responded faster to happy-neutral than sad-angry faces. In the MEG post-infusion analyses, calcarine M100 amplitudes were larger in MDD than HV participants post-placebo but became more similar post-ketamine. Finally, fusiform M170 amplitudes were associated with antidepressant response in MDD participants. Limitations The modest sample size and the need to collapse across responses to happy and neutral faces to increase statistical power limit the generalizability of the findings. Conclusions Ketamine rapidly altered emotional stimulus processing in MDD, laying the groundwork for future investigations of biomarkers of antidepressant treatment response. Clinical Trial Clinicaltrials.gov, NCT#00088699

Cloud segmentation of remotely sensed multispectral images is an important topic not only for weather forecast but, more in general, for establishing when the sensed data actually relate to the soil so that can be reliably used for some monitoring purpose. In this work, leveraging on the capability of convolutional neural networks to accurately approximate complex relationships between raw data and higher-level products, we propose a U-Net-like solution conceived for Sentinel-2 images. In order to face the scarsity of training data, a proper domain adaptation strategy has been pursued, which resorts to a labeled Landsat-8 dataset. Preliminary results show a consistent improvement over standard tools.

Residual stresses induced by the welding processes may, in some cases, result in significant warping and distortions that can endanger the integrity of the welded structures. This document reports an investigation of the welding process to make a dissimilar T-joint through an advanced Finite Element (FE) modelling and a dedicated laboratory test. The T-joint consisted of two plates of dissimilar materials, AISI304 and S275JR steels, both having a thickness of 5 mm, welded through a Shielded Metal Arc Welding (SMAW). Thermocouples were used to acquire the temperature variations during welding. In parallel, an FE model was built and the welding process was simulated through the “element birth and death” technique. Numerical and experimental outcomes were compared in terms of temperature distributions during welding and in terms of distortion at the end of the final cooling, showing that the FE model was able to provide a high level of accuracy.

In a bolted joint, the preload level resulting from the tightening torque represents a very important parameter governing the stresses distributions involving the joint under the real loading conditions. This paper deals with the development of a Finite Element (FE) model for the investigation of the effects of some selected preload levels on the stress-strain states affecting both bolt and plate in a single lap joint. The aim of this FE model is to support the design phase of strain gauges instrumented bolt to evaluate experimentally the rate of tensile load applied to the joint that the bolt absorbs with different preloads. The test article consists of two steel plates, a steel bolt and an aluminum nut. The results herein presented showed firstly that, without bolt preload, the tensile load applied to the joint is completely transferred to the bolt and that the load transferred to the bolt almost linearly decreases as the preload increases. Moreover, at a selected preload level, the transversal and longitudinal stresses (with respect to the load direction) increase as the tensile load increases, while the stress along the plate thickness direction decreases, reaching negative values. On the other hand, at a selected tensile load level, the transversal and longitudinal stresses as well as the stress along the thickness direction decrease as the preload level increases. Predicting the mechanical behaviour of the only bolted joint, if the same bolt model will be used to simulate the mechanical behaviour in a hybrid single-lap joint, possible imperfections of the model will have to certainly be linked to the modelling of the adhesive.

Over the last 20 years, different therapies have been considered as the mainstay for the treatment of patients with metastatic renal cell carcinoma (mRCC). Since angiogenesis is a key mechanism in the pathogenesis of renal carcinoma, research is still focusing on the inhibition of new vessel growth through the development of novel and potent tyrosine kinase inhibitors (TKIs), such as cabozantinib. On the other hand, a new therapeutic scenario has opened up in the forefront with immunotherapy. Immune checkpoint inhibitors (ICIs), which already represent a standard treatment option in pretreated mRCC patients, are revolutionizing the frontline therapeutic armamentarium of mRCC. Upfront combination immunotherapy as well as combinations of immunotherapy with targeted agents showed to significantly improved outcomes of mRCC patients compared to single-agent TKIs. ICIs are associated with long-lasting responses. Nonetheless, several unmet needs remain, as a small proportion of patients shows primary refractoriness to immunotherapy. Multiple treatment strategies combining different mechanisms of action or targeting immune escape pathways are emerging with the aim to improve response rates and survival outcomes. This review summarizes current immunotherapeutic targets and therapies approved for mRCC, while examining mechanisms of resistance and future directions, with the aim to address novel treatment strategies and help in improving the management of this tumor.

We report a preliminary experience of adjuvant therapy with Hemoperfusion (HP) in patients with Severe Acute Respiratory Syndrome-CoronaVirus 2 (SARS-CoV2) pneumonia. Currently, there are no approved treatments for CoronaVirus Disease 19 (COVID-19); however, therapeutic strategies based on the preclinical evidence include supportive measures, such as oxygen supplementation, antiviral, and anticoagulant agents. Despite these treatments, 10% of patients worsen and develop severe acute respiratory distress syndrome (ARDS). Since the pathogenic mechanism of ARDS is an uncontrolled inflammatory state, we speculate that removing inflammation effectors from blood may contrast tissue injury and improve clinical outcome. In a scenario of dramatic medical emergency, we conducted an observational study on 9 consecutive patients hospitalized in COVID Intensive Care Unit, where 5 of 9 consecutive patients were treated with HP, due to the emergency overload made it impossible to deliver blood purification in the other 4 patients. COVID-19 was diagnosed through the identification of virus sequences by reverse transcription-PCR on respiratory specimens. All patients had severe pneumonia requiring continuous positive airway pressure. HP was started in all patients 6–7 days after hospital admission. The treated patients (T) received 2 consecutive sessions of HP using CytoSorb cartridge. Our results show a better clinical course of T compared to control patients (C), in fact all T except 1 survived, and only 2 of them were intubated, while all C required intubation and died. Lymphocytopenia worsened in C but not in T. C-reactive protein decreased in both patients, but to a greater extent in T. IL-6, IL-8, and TNF-α decreased after HP, IL-10 did not change. Respiratory function remained stable and did not worsen in T compared to C. The limited sample size and observational study design preclude a sound statement about the potential effectiveness of HP in COVID-19 patients, but our experience suggests a potential therapeutic role of adjuvant CytoSorb HP in the early course of CO­VID-19 pneumonia. A randomized clinical trial is ongoing.

The article reviews traditional and modern methods for prediction of gas turbine operating characteristics and its potential failures. Moreover, a comparison of Machine Learning based prediction models, including Artificial Neural Networks (ANN), is presented. The research focuses on High Pressure Compressor (HPC) recoup pressure level of 4th generation LM2500 gas generator (LM2500+G4) coupled with a 2-stage High Speed Power Turbine Module. The researched parameter is adjustable and may be used to balance net axial loads exerted on thrust bearing to ensure stable gas turbine operation, but its direct measurement is technically difficult implicating the need to indirect measurement via set of other gas turbine sensors. Input data for the research have been obtained from BHGE manufactured and monitored gas turbines and consists of real-time data extracted from industrial installations. Machine learning models trained using the data show less than 1% Mean Absolute Percentage Error (MAPE) as obtained with the use of Random Forest and Gradient Boosting Regression models. Multilayer Perceptron Artificial Neural Networks (MLP ANN) models are reviewed, and their performance checks inferior to Random Forest algorithm-based model. The importance of hyperparameter tuning and feature engineering is discussed.

In prostate cancer , there has recently been an emerging interest in mutations in genes belonging to the homologous recombination repair (HRR) pathway and in the inhibition of poly (ADP-ribose) polymerase (PARP) proteins.Mutations in the HRR genes, including BRCA1, BRCA2, and Ataxia-Telangiesctasia mutated (ATM), have been reported in prostate cancer, with different incidence in the localized and advanced settings. The PARP enzyme complex is involved in repair of DNA damage and its inhibition causes the accumulation of DNA mutations in HRR deficient cells. Several PARP inhibitors (PARPi) are under development, such as olaparib, talazoparib, niraparib, rucaparib, and veliparib. In metastatic castration resistant prostate cancer (mCRPC), olaparib has been the most studied and its clinical efficacy has been validated in a phase III clinical trial. Rucaparib and niraparib have also shown promising results in the preliminary analyzes of two phase II trials, while talazoparib is currently under development.PARPi have become part of the treatment of mCRPC. Early results of combination therapy with PARPi and new hormonal therapy are promising and are supported by a strong biological rationale. Current results need to be validated in randomized phase III-controlled trials in order to translate the use of PARPi into real world practice.

Objectives Despite the initial clinical benefit, resistance to antiangiogenic therapies develops through the activation of alternative pathways. We measured plasma levels of circulating angiogenic factors to explore their predictive role in metastatic renal cell carcinoma (mRCC) patients treated with pazopanib. Materials and methods mRCC patients receiving first-line pazopanib were prospectively enrolled. The levels of circulating interleuchine (IL)-6, IL-8, stromal derived factor-1, vascular endothelial growth factor-A, hepatocyte growth factor (HGF), osteopontin, and E-selectin were quantified at baseline and every 4 weeks until disease progression (PD). Patients were dichotomized into "low" and "high" subgroups by a cutoff point defined by the respective median circulating angiogenic factor (CAF) value at baseline. Then, association with the objective response was determined. Changes in CAF levels between baseline and PD were also compared. Results Among 25 patients included in the final data set, 6 patients were still on treatment. As best response, 12 patients presented a partial response (48%), 9 showed stable disease, and 4 showed PD. The median follow-up was 31.9 months. The median progression-free survival was 14.8 months. Low baseline levels of IL-6, IL-8, HGF, and osteopontin were found to be significantly associated with objective response. In addition, patients with low baseline levels of HGF showed longer progression-free survival and overall survival, whereas patients with low baseline levels of IL-8 showed longer overall survival. Among patients experiencing PD, the median plasma levels of stromal derived factor-1 and vascular endothelial growth factor-A were significantly higher compared with the baseline (P=0.01; P=0.011). Conversely, the median levels of E-selectin were significantly lower compared with the baseline (P=0.017). Conclusion Changes in levels of selected CAFs were associated with response/resistance to pazopanib in mRCC patients.