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This review aims to provide a comprehensive overview of the literature on the oral side effects caused by radiotherapy for head and neck cancers. Various treatments are examined to mitigate these sequelae, and a protocol is proposed for dentists and dental hygienists to manage oncological patients. A literature search was conducted to select relevant articles addressing the effects of radiotherapy treatments on the oral cavity, with a particular focus on the development of mucositis, candidiasis, changes in salivary pH, trismus, fibrosis, and alterations in the oral biofilm. PubMed and MedLine were used as search engines, with keyword combinations including: head and neck cancer, mucositis, candida, dental care, dental hygiene, epidemiology, oral microbiome, biofilm, trismus, fibrosis, and salivary pH. A total of 226 articles were identified, spanning the period from 1998 to 2023. Articles deemed inappropriate or in languages other than English or Italian were excluded. A management protocol for oncological patients was proposed, divided into two phases: home-based and professional. Despite the advancements in intensity-modulated radiation therapy, it is impossible to completely avoid damage to healthy tissues. Preventive education and counseling in the dental chair, ongoing motivation, and education about oral hygiene are crucial to combine a good therapeutic outcome with an improved quality of life for the patient.

Blood-brain barrier dysfunction might be driven by peripheral inflammation. TNFα inhibitors (TNF-α i ) are occasionally associated with a wide spectrum of neurological immuno-mediated disorders. However, patients with systemic autoimmune disorders, including rheumatoid arthritis (RA), might be prone to develop further organ-specific, including central nervous system (CNS), autoimmunity. Here we report the case of a patient, affected by RA and treated with etanercept, who suddenly developed focal neurological symptoms. Cerebrospinal fluid, magnetic resonance imaging (MRI), and positron emission tomography (PET)/MRI findings are reported and support the diagnosis of TNF-α i -associated aseptic meningitis., Competing Interests: AM received a travel grant from Novartis, Sanofi-Genzyme, and Biogen. MP received a travel grant from Novartis, Genzyme, Biogen, Teva, Almirall and Sanofi-Genzyme; he has been a consultant for Sanofi-Genzyme, Novartis., Biogen. FR serves as an advisory board member of Biogen-Idec and has received funding for travel and speaker honoraria from Merck Serono, Biogen Idec, Sanofi-Aventis, Teva and Bayer Schering Pharma. PG reports grants and personal fees from Novartis, grants and personal fees from Almirall, grants and personal fees from Biogen Idec, grants and personal fees from Sanofi Genzyme, grants and personal fees from Teva, grants and personal fees from Merck Serono, grants from University of Padova, grants from Italian Ministry of Public Health, grants from Veneto Region of Italy, grants from Italian Association for Multiple Sclerosis, outside the submitted work. The remaining 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 © 2024 Kassabian, Facco, Miscioscia, Carraro, Rinaldi, Gallo and Puthenparampil.)

Background/Objectives : The literature reports that emotional disorders in asthmatic children and their parents may affect asthma control. This research explores the baseline psychological well-being of asthmatic children and their mothers' and fathers' psychological functioning, focusing on the influence of the parents' anxiety and separation anxiety on children's asthma. Methods : In this cross-sectional study, we enrolled children with non-severe asthma and their parents, and a group of healthy children and their parents. The asthmatic children underwent anamnestic investigation, including asthma control and spirometry. Then, both the asthmatic and control triads filled a survey assessing their psychological functioning. Results : Among the 40 asthmatic children enrolled (8-18 years old), most had good clinical control maintained with GINA (Global Initiative for Asthma) therapy step 1-2 (14 patients, 35%) or step 3-4 (26 patients, 65%); 12 patients (30%) had at least one steroid course in the year before enrollment. They exhibited normal psychological adjustment but elevated levels of general (U = 179,500; p < 0.001) and state anxiety (U = 170,000; p < 0.001) compared to healthy peers. Additionally, the asthmatic children's mothers displayed higher levels of separation anxiety compared to the fathers (t = -2.865, p = 0.006). Increased separation anxiety in the mothers corresponded to a history of at least one exacerbation in the previous year. Conclusions : The asthmatic children exhibited normal psychological adjustment with higher general and state anxiety. Also, their mothers showed greater levels of separation anxiety compared to their fathers. Lastly, higher mothers' separation anxiety corresponded to a history of at least one exacerbation in the previous year. The influence of the parents' psychological well-being on the children's asthma control was previously unexplored.

Adherent cells perceive mechanical feedback from the underlying matrix and convert it into biochemical signals through a process known as mechanotransduction. The response to changes in the microenvironment relies on the cell's mechanical properties, including elasticity, which was recently identified as a biomarker for various diseases. Here, we propose the design, development, and characterization of a new system for the measurement of adherent cells' strain drop , a parameter correlated with cells' elasticity. To consider the interplay between adherent cells and the host extracellular matrix, cell stretching was combined with adhesion on substrates with different stiffnesses. The technique is based on the linear stretching of silicone chambers, high-speed image acquisition, and feedback for image centering. The system was characterized in terms of the strain homogeneity, impact of collagen coating, centering capability, and sensitivity. Subsequently, it was employed to measure the strain drop of two osteosarcoma cell lines, low-aggressive osteoblast-like SaOS-2 and high-aggressive 143B, cultured on two different substrates to recall the stiffness of the bone and lung extracellular matrices. Results demonstrated good substrate homogeneity, a negligible effect of the collagen coating, and an accurate image centering. Finally, the experimental results showed an average strain drop that was lower in the 143B cells in comparison with the SaOS-2 cells in all the tested conditions.

T-cell large granular lymphocyte leukemia (T-LGLL) is a chronic lymphoproliferative disorder characterized by the clonal expansion of T-cell large granular lymphocytes (T-LGL). Immunophenotypic and genotypic features contribute to discriminate symptomatic (CD8+ STAT3-mutated T-LGLL) from clinically indolent patients, this latter group including CD8+ wildtype (wt), CD4+ STAT5B-mutated and wt cases. T-LGL lymphoproliferation is sustained both by somatic gain-offunction mutations (i.e., STAT3 and STAT5B) and by pro-inflammatory cytokines, but little information is available on the activity of T-LGLL non-leukemic cells. In this study, we characterized pro-inflammatory cells in the peripheral blood of T-LGLL patients and analyzed their role in supporting the leukemic growth. In symptomatic patients we found that cell populations not belonging to the leukemic component showed a discrete pro-inflammatory pattern. In particular, CD8+ STAT3-mutated cases showed a skewed Th17/Treg ratio and an abnormal distribution of monocyte populations characterized by increased intermediate and non-classical monocytes. We also demonstrated that monocytes released high levels of interleukin-6 after CCL5 stimulation, a chemokine specifically expressed only by leukemic LGL. Conversely, in asymptomatic cases an altered distribution of monocyte populations was not detected. Moreover, T-LGLL patients' monocytes showed abnormal activation of signaling pathways, further supporting the different pathogenic role of monocytes in patients in discrete clinical settings. Altogether, our data contribute to deepening the knowledge on the different cell subtypes in T-LGLL, focusing particularly on non-leukemic cell populations and thus offering the rationale for new therapeutic strategies.

Aldosterone plays a key role in controlling blood pressure (BP) values by maintaining body salt, water, and fluid homeostasis. Excess aldosterone production is associated with arterial hypertension, cardiovascular and metabolic diseases, partly via generation of an inflammatory state followed by fibrotic changes in the organs that are target of hypertension. Aldosterone exerts genomic effects that are known to involve activation of the mineralocorticoid receptor (MR). Other aldosterone effects, including those usually defined as 'rapid' or 'non genomic', involve additional receptors as the G-protein coupled estrogen receptor (GPER). To date, the receptor(s) implicated in the inflammatory action of aldosterone in cells of the innate and adaptive immunity are unknown. Considering the potential role of T-lymphocytes in adaptive immunity in arterial hypertension and related hypertension-mediated organ damage (HMOD), we herein investigated and quantified the expression of the MR and GPER in human CD4 + and CD8 + T-cells. Results provided compelling evidence for the presence at the mRNA and protein level and suggest a functional role of these receptors in the two T-lymphocyte subtypes, thus indicating that they can represent a potential target for modulation of steroid hormone-induced inflammation and ensuing HMOD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Nitric oxide (NO) is produced within the airways and released with exhalation. Nasal NO (nNO) can be measured in a non-invasive way, with different devices and techniques according to the age and cooperation of the patients. Here, we conducted a narrative review of the literature to examine the relationship between nNO and some respiratory diseases with a particular focus on primary ciliary dyskinesia (PCD). A total of 115 papers were assessed, and 50 were eventually included in the review. nNO in PCD is low (below 77 nL/min), and its measurement has a clear diagnostic value when evaluated in a clinically suggestive phenotype. Many studies have evaluated the role of NO as a molecular mediator as well as the association between nNO values and genotype or ciliary function. As far as other respiratory diseases are concerned, nNO is low in chronic rhinosinusitis and cystic fibrosis, while increased values have been found in allergic rhinitis. Nonetheless, the role in the diagnosis and prognosis of these conditions has not been fully clarified.

PET/MR imaging is a one-stop shop technique for pediatric diseases allowing not only an accurate clinical assessment of tumors at staging and restaging but also the diagnosis of neurologic, inflammatory, and infectious diseases in complex cases. Moreover, applying PET kinetic analyses and sequences such as diffusion-weighted imaging as well as quantitative analysis investigating the relationship between disease metabolic activity and cellularity can be applied. Complex radiomics analysis can also be performed., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Children with inherited and/or acquired respiratory disorders often arrive in adolescence and adulthood with diminished lung function that might have been detected and prevented had better mechanisms been available to identify and to assess progression of disease. Fortunately, advances in genetic assessments, low-cost diagnostics, and minimally- invasive novel biomarkers are being developed to detect and to treat respiratory diseases before they give rise to loss of life or lung function. This paper summarizes the Developing Biomarkers for Pulmonary Health sessions of the National Heart, Lung, and Blood Institute- sponsored 2021 Defining and Promoting Pediatric Pulmonary Health workshop. These sessions discussed genetic testing, pulse oximetry, exhaled nitric oxide, and novel biomarkers related to childhood lung diseases., (Copyright © 2023 by the American Academy of Pediatrics.)

Background : Asthma is the most common chronic condition in children. It is a complex non-communicable disease resulting from the interaction of genetic and environmental factors and characterized by heterogeneous underlying molecular mechanisms. Metabolomics, as with the other omic sciences, thanks to the joint use of high-throughput technologies and sophisticated multivariate statistical methods, provides an unbiased approach to study the biochemical-metabolic processes underlying asthma. The aim of this narrative review is the analysis of the metabolomic studies in pediatric asthma published in the past 10 years, focusing on the prediction of asthma development, endotype characterization and pharmaco-metabolomics. Methods : A total of 43 relevant published studies were identified searching the MEDLINE/Pubmed database, using the following terms: "asthma" AND "metabolomics". The following filters were applied: language (English), age of study subjects (0-18 years), and publication date (last 10 years). Results and Conclusions : Several studies were identified within the three areas of interest described in the aim, and some of them likely have the potential to influence our clinical approach in the future. Nonetheless, further studies are needed to validate the findings and to assess the role of the proposed biomarkers as possible diagnostic or prognostic tools to be used in clinical practice.

Background: Primary ciliary dyskinesia (PCD) is characterized by impaired mucociliary clearance that results in accumulation of mucus and bacteria in the airways. Lower respiratory tract infections lead to airway remodeling and lung function impairment. The aim of our narrative review is to discuss available data on lung function in PCD children, focusing on risk factors for lung function impairment., Methods: Relevant published studies searching MEDLINE/Pubmed are included in this narrative review, using these terms: "primary ciliary dyskinesia" and "pulmonary function test" or "spirometry" or "lung function". Filters were language (English) and age of study subjects (0-18 years)., Results and Conclusions: The majority of recent published studies showed normal spirometric values in PCD children, even if some authors described a pulmonary impairment. Together with spirometry, Lung Clearance Index has been applied for detecting peripheral airway disease, and it might have a role in early mild lung disease assessment. Studies on lung function trajectories after PCD diagnosis showed a significant heterogeneity, with some patients maintaining reasonably good lung function, whereas others showing a decline. Further studies are needed to analyze lung function prospectively from childhood into adulthood, and to evaluate whether lung function trajectories are affected by PCD clinical phenotype, ultrastructural ciliary defect or genetic background.

Due to the COVID-19 pandemic, many families had to manage new difficulties, especially those of chronically ill children. More and more research has focused on the negative effects of the pandemic on psychological wellbeing, while less is known about the resources. The present study aimed to explore the role of time spent with mothers in chronically ill children's populations during the COVID-19 pandemic. Moreover, it explored the differences in mothers' and children's psychosocial functioning in three clinical populations. Four groups were recruited and compared: 7-15 year old children with asthma (45), type 1 diabetes (52), and cancer (33), as well as their healthy counterparts (41), and their respective mothers. They were administered standardized questionnaires and ad hoc surveys assessing psychological wellbeing and worries. Children of the four groups scored significantly differently with respect to the concerns for contagion, internalizing symptoms, and prosocial behaviors; mothers had worries about the consequences of their children's contagion related to the chronic illness, as well as time with the child. The multiple linear regression model showed an association of being affected by cancer, suffering from type 1 diabetes, and spending less time with the child with an increase in children's internalizing problems. Time with mothers seemed to be a resource for psychological wellbeing during the pandemic. Clinical implications are discussed.

Background: since December 2019, the world has become victim of the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The aim of our narrative review is to analyze the impact of COVID-19 in children suffering from chronic lung disease (CLD)., Methods: we searched the MEDLINE/Pubmed database using the terms "SARS-CoV-2" or "COVID-19" or "Coronavirus Diseases 2019"; AND "chronic lung diseases" or "chronic respiratory diseases" or "asthma" or "cystic fibrosis" or "primary ciliary dyskinesia" or "bronchopulmonary dysplasia"; and limiting the search to the age range 0-18 years., Results and Conclusions: although COVID-19 rarely presents with a severe course in children, CLD may represent a risk factor; especially when already severe or poorly controlled before SARS-CoV-2 infection. On the other hand, typical features of children with CLD (e.g., the accurate adoption of prevention measures, and, in asthmatic patients, the regular use of inhaled corticosteroids and T2 inflammation) might have a role in preventing SARS-CoV-2 infection. Moreover, from a psychological standpoint, the restrictions associated with the pandemic had a profound impact on children and adolescents with CLD.

Lung function is a central issue in diagnosis and determination of asthma severity and asthma control has been previously reported to improve after a stay in mountain environment for at least 2 weeks. No data are available for shorter periods of stay, in particular for small airways during a stay at altitude. The aim of this study is to focus on changes in respiratory function, regarding both the central airways and the peripheral airways in the first 2 weeks of stay in a mountain environment in asthmatic children. In this study, 66 asthmatic children (age: 14 ± 2.8 years) were evaluated through spirometric and oscillometric tests at the time of arrival at the Istituto Pio XII, Misurina (BL), Italy, 1756 m above sea level (T0), after 24 h (T1), and 168 h (T2) of stay. FEV1%, FEF25%-75%, and FEV1/FVC increased significantly from T0 value both at T1 and T2 (respectively, p = 0.0002, p < 0.0001, p = 0.0002). Oscillometry showed a significant improvement in R5, R20, and R5-20 at both T1 and T2 as compared to T0 (respectively, p = 0.0001, p = 0.0002, and p = 0.049). Reactance at 5 Hz (X5) improved significantly at T2 versus T0, p = 0.0022. The area under reactance curve between Fres and 5 Hz (AX) was significantly reduced (p = 0.0001) both at T1 and T2 as compared to T0. This study shows an improvement in respiratory indices as soon as after 24 h of stay at altitude, persisting in the following week., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

A growing number of scientific papers focus on the description and quantification of the detrimental effects of pollution exposure on human health. The respiratory system is one of the main targets of these effects and children are potentially a vulnerable population. Many studies analyzed the effects of short- and long-term exposure to air pollutants on children's respiratory function. Aim of the present narrative review is to summarize the results of the available cohort studies which investigated how lung function of children and adolescents is affected by exposure to air pollution. In addition, an overview is provided on the association, in children, between pollution exposure and exhaled breath biomarkers, as possible indicators of the pathogenetic mechanisms involved in pollution-related lung damages. The identified cohort studies suggest that, beside the possible impact of recent exposure, early and lifetime exposure are the variables most consistently associated with a reduction in lung function parameters in both children and adolescents. As for the effect of air pollution exposure on exhaled breath biomarkers, the available studies show an association with increased exhaled nitric oxide, with increased concentrations of malondialdehyde and 8-isoprostane in exhaled breath condensate (EBC), and with EBC acidification. These studies, therefore, suggest lung inflammation and oxidative stress as possible pathogenetic mechanisms involved in pollution related lung damages. Taken together, the available data underscore the importance of the development and application of policies aimed at reducing air pollutant concentration, since the protection of children's lung function can have a beneficial impact on adults' respiratory health in the future., (© 2022 IOP Publishing Ltd.)

Background: While it has been described that adults can develop long-lasting deterioration in pulmonary function (PF) after coronavirus disease 19 (COVID-19), regardless of disease severity, data on the long-term pneumological impact of SARS-CoV-2 infection in children are lacking., Methods: Performing a single-center, prospective, observational study on children aged 6-18 years with a previous diagnosis of asymptomatic/mild COVID-19, we evaluated the long-term impact of mild severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children., Results: A total of 61 subjects underwent spirometry after a mean time of 10 ± 4 months from asymptomatic or mild infection. None of the children reported any respiratory symptoms, needed any inhaled therapy, or had abnormal lung function., Conclusions: In our study, we observed that children and adolescents did not develop chronic respiratory symptoms and did not present lung function impairment after asymptomatic or mild SARS-CoV-2 infection.

The measurement of biological tissues' dielectric properties plays a crucial role in determining the state of health, and recent studies have reported microwave biosensing to be an innovative method with great potential in this field. Research has been conducted from the tissue level to the cellular level but, to date, cellular adhesion has never been considered. In addition, conventional systems for diagnosing tumor aggressiveness, such as a biopsy, are rather expensive and invasive. Here, we propose a novel microwave approach for biosensing adherent cancer cells with different malignancy degrees. A circular patch resonator was designed adjusting its structure to a standard Petri dish and a network analyzer was employed. Then, the resonator was realized and used to test two groups of different cancer cell lines, based on various tumor types and aggressiveness: low- and high-aggressive osteosarcoma cell lines (SaOS-2 and 143B, respectively), and low- and high-aggressive breast cancer cell lines (MCF-7 and MDA-MB-231, respectively). The experimental results showed that the sensitivity of the sensor was high, in particular when measuring the resonant frequency. Finally, the sensor showed a good ability to distinguish low-metastatic and high-metastatic cells, paving the way to the development of more complex measurement systems for noninvasive tissue diagnosis.

Mucopolysaccharidosis type II (MPS II) is a multisystemic lysosomal storage disorder caused by deficiency of the iduronate 2-sulfatase enzyme. Currently, enzyme replacement therapy (ERT) with recombinant idursulfase is the main treatment available to decrease morbidity and improve quality of life. However, infusion-associated reactions (IARs) are reported and may limit access to treatment. When premedication or infusion rate reductions are ineffective for preventing IARs, desensitization can be applied. To date, only two MPS II patients are reported to have undergone desensitization. We report a pediatric patient with recurrent IARs during infusion successfully managed with gradual desensitization. Our protocol started at 50% of the standard dosage infused at concentrations from 0.0006 to 0.06 mg/ml on weeks 1 and 2, followed by 75% of the standard dosage infused at concentrations from 0.0009 to 0.09 mg/ml on weeks 3 and 4, and full standard dosage thereafter, infused at progressively increasing concentrations until the standard infusion conditions were reached at 3 months. Our experience can be used in the management of MPS II patients presenting IARs to idursulfase infusion, even when general preventive measures are already administered., Competing Interests: The authors declare no conflict of interest., (© 2022 The Authors.)

Wheezing, asthma, and respiratory infections (RTI) are among the most common causes of morbidity in children and their economic and social burden could be significantly reduced by specific prevention strategies. Epidemiological studies suggest that lower levels of some nutrients are associated with higher prevalence of these conditions, but the possible protective effect of early supplementation with these nutrients has not yet been established. Aim of our review is to synthetize the available scientific evidence on the role of supplementation with pre- and probiotics, vitamin D, fish and poly-unsaturated fatty acids (PUFA), vitamin A, C, and E, given during the first year of life, in the prevention of wheezing, asthma and RTI. We searched studies published on this topic in the PubMed database between January 2000 and September 2021. As for pre- and probiotics, most of the studies showed that an early supplementation had no protective effect toward the development of asthma and wheezing, while conflicting results were reported on their role in the reduction of RTI. As for vitamin D, the available data suggest that early and regular (on a daily or weekly base) supplementation of vitamin D during infancy could have a role in the prevention of RTI, while most studies showed no effect in the prevention of wheezing or asthma. Finally, early introduction of fish in the diet in most studies has proved protective toward wheezing and asthma development., 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 © 2022 Trivillin, Zanella, Castaldo, Prati, Zanconato, Carraro and Ferraro.)

The treatment of cutaneous and subcutaneous localizations from breast cancer (BC) is still a therapeutic challenge. Electrochemotherapy (ECT) is one of the available options, and it is characterized by the association between the administration of a chemotherapic agent (Bleomycin) with the temporary raise of permeability of the cellular membrane induced by the local administration of electrical impulses (electroporation). ECT represents an effective therapy for loco-regional control of this disease. This study aimed to investigate the predictive factors of response in cutaneous and subcutaneous localizations from breast cancer treated with ECT. We decided to evaluate the response to this treatment in 55 patients who underwent ECT between January 2013 and March 2020 at our Institute. We performed a monocentric retrospective cohort study. ECT was administered following the ESOPE (European Standard Operative Procedure of Electrochemotherapy) guidelines, a set of criteria updated in 2018 by a panel of European experts on ECT who defined the indications for selecting the patients who can benefit from the ECT treatment and the ones for technically performing the procedure. The responses were evaluated with the RECIST criteria (Response Evaluation Criteria in Solid Tumor). We found after 12 weeks of treatment a complete response (CR) in 64% of our patients. From the analysis divided for subgroups of covariates is emerged that lower BMI, reduced body surface, and absence of previous radiation treatment could be predictive for a better complete response. This study suggests that the efficacy of the ECT treatment is related to the concurrent systemic therapies while administering ECT. The association between ECT and immunotherapy has offered better results than the association between ECT and chemotherapy (p-value = 0.0463). So, ECT is a valuable tool in the treatment of cutaneous and subcutaneous metastases from breast cancer and its efficacy in local control of these lesions improves when it is well planned in a therapeutic scenario., Competing Interests: Author FT was employed by company IGEA S.p.A. The remaining 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 © 2021 Russano, Del Fiore, Di Prata, Pasqual, Marconato, Campana, Spina, Gianesini, Collodetto, Tropea, Dall’Olmo, Carraro, Parisi, Galuppo, Scarzello, De Terlizzi, Rastrelli and Mocellin.)

There is growing interest for studying how early-life influences the development of respiratory diseases. Our aim was to apply metabolomic analysis to urine collected at birth, to evaluate whether there is any early metabolic signatures capable to distinguish children who will develop acute bronchiolitis and/or recurrent wheezing. Urine was collected at birth in healthy term newborns. Children were followed up to the age of 3 years and evaluated for the development of acute bronchiolitis and recurrent wheezing (≥3 episodes). Urine were analyzed through a liquid-chromatography mass-spectrometry based untargeted approach. Metabolomic data were investigated applying univariate and multivariate techniques. 205 children were included: 35 had bronchiolitis, 11 of whom had recurrent wheezing. Moreover, 13 children had recurrent wheezing not preceded by bronchiolitis. Multivariate data analysis didn't lead to reliable classification models capable to distinguish children with and without bronchiolitis or with recurrent wheezing preceded by bronchiolitis neither by PLS for classification (PLS2C) nor by Random Forest (RF). However, a reliable signature was discovered to distinguish children who later develop recurrent wheezing not preceded by bronchiolitis, from those who do not (MCCoob = 0.45 for PLS2C and MCCoob = 0.48 for RF). In this unselected birth cohort, a well-established untargeted metabolomic approach found no biochemical-metabolic dysregulation at birth associated with the subsequent development of acute bronchiolitis or recurrent wheezing post-bronchiolitis, not supporting the hypothesis of an underlying predisposing background. On the other hand, a metabolic signature was discovered that characterizes children who develop wheezing not preceded by bronchiolitis.

The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in a fair percentage of CLL patients, no information on resistance mechanisms is available in patients lacking these mutations. The heat shock protein of 70 kDa (HSP70) and its transcription factor heat shock factor 1 (HSF1) play a role in mediating the survival and progression of CLL, as well as taking part in drug resistance in various cancers. We demonstrated that resveratrol and related phenols were able to induce apoptosis in vitro in leukemic cells from CLL untreated patients by acting on the HSP70/HSF1 axis. The same was achieved in cells recovered from 13 CLL patients failing in vivo ibrutinib treatment. HSP70 and HSF1 levels decreased following in vitro treatment, correlating to apoptosis induction. We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients.

The "Veneto Cancer Registry" records melanoma as the most common cancer diagnosed in males and the third common cancer in females under 50 years of age in the Veneto Region (Italy). While melanoma is rare in children, it has greater incidence in adolescents and young adults (AYA), but literature offers only few studies specifically focused on AYA melanoma. The aim of this study was to describe the characteristics, surgical treatment, and prognosis of a cohort of AYA melanoma in order to contribute to the investigation of this malignancy and provide better patient care. This retrospective cohort study included 2,752 Caucasian patients (702 AYA and 2,050 non-AYA patients) from the Veneto Region who were over 15 years of age at diagnosis, and who received diagnosis and/or treatment from our institutions between 1998 and 2014. Patients were divided in adolescents and youth (15-25 years), young adults (26-39 years) and adults (more than 39 years) for the analysis. We found statistically significant differences in gender, primary site, Breslow thickness, ulceration, pathologic TNM classification (pTNM) stage and tumor subtype among the age groups. Disease-specific survival and disease-free survival were also different among the age groups. Our findings suggest that the biological behavior of melanoma in young people is different to that in adults, but not such as to represent a distinct pathological entity. Additional and larger prospective studies should be performed to better evaluate potential biological and cancer-specific differences between AYAs and the adult melanoma population., 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 © 2021 Del Fiore, Russo, Ferrazzi, Monico, Cavallin, Filoni, Tropea, Russano, Di Prata, Buja, Collodetto, Spina, Carraro, Cappellesso, Nicolè, Chiarion-Sileni, Pigozzo, Dall’Olmo, Rastrelli, Vecchiato, Benna, Menin, Di Carlo, Bisogno, Dei Tos, Alaibac and Mocellin.)

Introduction: Pediatric flexible laryngotracheal bronchoscopy (FB) is an integral part of diagnostics and treatment at tertiary pediatric respiratory centers., Aim: FBs performed between 2013 and 2018 at our Pediatric Allergy and Respiratory Medicine Unit of the Department of Women's and Children's Health at Padua University were examined in terms of the indications, findings, and adverse events., Materials and Methods: The electronic medical records of pediatric patients who underwent FB at least once between 1 January 2013 and 31 December 2018 were considered. Patients' clinical data, indications for FB, anatomical findings, information derived from bronchoalveolar lavage (BAL) and bronchial brushing, and possible adverse events were analyzed., Results: There were 447 pediatric FBs performed in 428 patients (aged from 1 month to 18 years) for diagnostic purposes (92.4%), to clear secretions (3.6%), or to monitor a known condition (4.0%). The main indications were recurrent lower respiratory tract infections (LRTI, 32.2%) and chronic wet cough (9.4%). Lower airway malacia was the most common abnormal finding in these two groups (36.1% and 28.6%, respectively). BAL bacterial culture was positive in 55 children (39.6%) with recurrent LRTI and in 25 (59.5%) with chronic wet cough, being Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis the microorganisms most commonly isolated. FB proved a safe procedure and was well tolerated., Conclusions: Pediatric FB is an essential tool at our tertiary pediatric respiratory center. It helps establish the anatomical conditions underlying several chronic respiratory conditions and any correlated microbiological findings, with a significant impact on further patient management., (© 2021 The Authors. Pediatric Pulmonology Published by Wiley Periodicals LLC.)

The biology of plasma cell dyscrasias (PCD) involves both genetic and immune-related factors. Since genetic lesions are necessary but not sufficient for Multiple Myeloma (MM) evolution, several authors hypothesized that immune dysfunction involving both B and T cell counterparts plays a key role in the pathogenesis of the disease. The aim of this study is to evaluate the impact of cornerstone treatments for Multiple Myeloma into immune system shaping. A large series of 976 bone marrow samples from 735 patients affected by PCD was studied by flow analysis to identify discrete immune subsets. Treated MM samples displayed a reduction of CD4+ cells (p<0.0001) and an increase of CD8+ (p<0.0001), CD8+/DR+ (p<0.0001) and CD3+/CD57+ (p<0.0001) cells. Although these findings were to some extent demonstrated also following bortezomib treatment, a more pronounced cytotoxic polarization was shown after exposure to autologous stem cell transplantation (ASCT) and Lenalidomide (Len) treatment. As a matter of fact, samples of patients who received ASCT (n=110) and Len (n=118) were characterized, towards untreated patients (n=138 and n=130, respectively), by higher levels of CD8+ (p<0.0001 and p<0.0001, respectively), CD8+/DR+ (p=0.0252 and p=0.0001, respectively) and CD3+/CD57+ cells (p<0.0001 and p=0.0006, respectively) and lower levels of CD4+ lymphocytes (p<0.0001 and p=0.0005, respectively). We demonstrated that active MM patients are characterized by a relevant T cell modulation and that most of these changes are therapy-related. Current Myeloma treatments, notably ASCT and Len treatments, polarize immune system towards a dominant cytotoxic response, likely contributing to the anti-Myeloma effect of these regimens., 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 © 2021 Barilà, Pavan, Vedovato, Berno, Lo Schirico, Arangio Febbo, Teramo, Calabretto, Vicenzetto, Gasparini, Fregnani, Manni, Trimarco, Carraro, Facco, Piazza, Semenzato and Zambello.)

Background: The lockdown imposed by the COVID-19 pandemic resulted in a completely different style of life with possible effects on the attitude toward their disease in patients with chronic lung disease, such as asthma. The aim of our study was to investigate in asthmatic children the level of asthma control and the maintenance therapy used during the lockdown., Methods: Among asthmatic children attending our clinic, we identified those who had been prescribed the same therapy in March-April 2019 and March-April 2020. The level of asthma control (GINA-score) and the maintenance therapy used during the lockdown (March-April 2020) were compared with those of March-April 2019. We separately analyzed a small group of children with severe asthma treated with Omalizumab during the lockdown., Results: We enrolled 92 asthmatic children (67 males). Compared to 2019, in 2020 a higher proportion of children modified their maintenance therapy (38% vs. 15.2%, p < .001), with a significant increase in both the proportion of children who increased (p = .033) and in that of children who decreased their therapy (p = .026). The level of control resulted as significantly higher in 2020 (March p = .023; April p = .007). Also, the 13 children treated with Omalizumab showed a good level of control in 2020., Conclusions: In asthmatic children, the COVID-19 pandemic lockdown had a significant impact on their asthma control and on their attitude toward maintenance therapy., (© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Italy was the first European country to fight the Covid-19 outbreak. To limit the transmission of the virus, the Italian Government imposed strict domestic quarantine policies and temporary closure of non-essential businesses and schools from March 10th,2020. Although more and more literature is exploring the impact of the pandemic on non-referred children and families, only a few studies are focused on the psychosocial impact of Covid-19 in chronically ill children and their caregivers. The present study investigates asthma control and children and mothers' psychological functioning (i.e.: psychological well-being, fear of contagion, and mothers' Covid-19 related fears) in 45 asthmatic children aged 7-to-14, compared to a control sample. The subjects were administered an online survey after the lockdown (from 28th May to 23rd August 2020). The analysis shows that asthmatic children presented higher concern in relation to contagion, however, no difference in psychological functioning was displayed between the two cohorts. Mothers reported more Covid-19 related fears, and greater worries according to the resumption of their children's activities. Moreover, they indicated a global worsening of their psychological well-being during the lockdown. Furthermore, regarding the clinical sample, the multivariate regression model showed that a worsening of mothers' psychological and children's physical well-being was associated with a worsening of children's psychological well-being during the lockdown. The results of this study indicate that mothers of asthmatic children can be more prone to experience psychological fatigue in a pandemic scenario. Special programs should be developed to support caregivers of chronically ill children.

Medullary thyroid carcinoma (MTC) is a rare malignant neoplasia with a variable clinical course, with complete remission often difficult to achieve. Genetic alterations lead to fundamental changes not only in hereditary MTC but also in the sporadic form, with close correlations between mutational status and prognosis. In recent years, microRNAs (miRNAs) have become highly relevant as crucial players in MTC etiology. Current research has focused on their roles in disease carcinogenesis and development, but recent studies have expounded their potential as biomarkers and response predictors to novel biological drugs for advanced MTC. One such element which requires greater investigation is their mechanism of action and the molecular pathways involved in the regulation of gene expression. A more thorough understanding of these mechanisms will help realize the promising potential of miRNAs for MTC therapy and management.

The term children interstitial lung diseases (chILD) refers to a heterogeneous group of rare diseases that diffusely affect the lung. ChILD specific to children younger than 2 years of age include diffuse developmental disorders, growth abnormalities, specific conditions of undefined etiology (neuroendocrine cell hyperplasia of infancy and pulmonary interstitial glycogenosis) and surfactant protein disorders. Clinical manifestations are highly variable, ranging from the absence of relevant symptoms to a severe onset. Most commonly, chILD presents with nonspecific respiratory signs and symptoms, such as dyspnea, polypnea, dry cough, wheezing, recurrent respiratory infections and exercise intolerance. In the diagnostic approach to a child with suspected ILD, chest high resolution computed tomography and genetic tests play a central role. Then, if the diagnosis remains uncertain, laryngotracheal-bronchoscopy and lung biopsy are needed. Pharmacological treatment is mostly empiric and based on anti-inflammatory and immunomodulatory drugs including corticosteroids, hydroxychloroquine and azithromycin. Despite chILD overall rarity, pediatric pulmonologists must be familiar with these diseases in order to carry out a timely diagnosis and patient treatment.

Background: "breathomics" enables indirect analysis of metabolic patterns underlying a respiratory disease. In this study, we analyze exhaled breath condensate (EBC) in asthmatic children before (T0) and after (T1) a three-week course of inhaled beclomethasone dipropionate (BDP)., Methods: we recruited steroid-naive asthmatic children for whom inhaled steroids were indicated and healthy children, evaluating asthma control, spirometry and EBC (in asthmatics at T0 and T1). A liquid-chromatography-mass-spectrometry untargeted analysis was applied to EBC and a mass spectrometry-based target analysis to urine samples., Results: metabolomic analysis discriminated asthmatic ( n = 26) from healthy children ( n = 16) at T0 and T1, discovering 108 and 65 features relevant for the discrimination, respectively. Searching metabolomics databases, seven putative biomarkers with a plausible role in asthma biochemical-metabolic processes were found. After BDP treatment, asthmatic children, in the face of an improved asthma control ( p < 0.001) and lung function ( p = 0.01), showed neither changes in EBC metabolomic profile nor in urinary endogenous steroid profile., Conclusions: "breathomics" can discriminate asthmatic from healthy children, with prostaglandin, fatty acid and glycerophospholipid as putative markers. The three-week course of BDP-in spite of a significant clinical improvement-was not associated with changes in EBC metabolic arrangement and urinary steroid profile.

Background: Available diagnostics often fail to distinguish viral from bacterial causes of pediatric community-acquired pneumonia (pCAP). Metabolomics, which aims at characterizing diseases based on their metabolic signatures, has been applied to expand pathophysiological understanding of many diseases. In this exploratory study, we used the untargeted metabolomic analysis to shed new light on the etiology of pCAP., Methods: Liquid chromatography coupled with mass spectrometry was used to quantify the metabolite content of urine samples collected from children hospitalized for CAP of pneumococcal or viral etiology, ascertained using a conservative algorithm combining microbiological and biochemical data., Results: Fifty-nine children with CAP were enrolled over 16 months. Pneumococcal and viral cases were distinguished by means of a multivariate model based on 93 metabolites, 20 of which were identified and considered as putative biomarkers. Among these, six metabolites belonged to the adrenal steroid synthesis and degradation pathway., Conclusions: This preliminary study suggests that viral and pneumococcal pneumonia differently affect the systemic metabolome, with a stronger disruption of the adrenal steroid pathway in pneumococcal pneumonia. This finding may lead to the discovery of novel diagnostic biomarkers and bring us closer to personalized therapy for pCAP., (© 2019 Wiley Periodicals, Inc.)

Chronic obstructive respiratory disorders such as asthma and chronic obstructive pulmonary disease (COPD) have their roots in the womb. Together with a genetic predisposition, prenatal and early-life factors, including maternal smoking, prematurity, and bronchopulmonary dysplasia (BPD), have a pivotal role in later respiratory health. Then, inappropriate responses to respiratory viruses (especially respiratory syncytial virus and rhinovirus) and early allergic sensitization are the strongest contributors to the inception of wheezing and early-onset asthma. There is an urgent need for early disease biomarkers to identify profiles at higher risk of chronic respiratory conditions. Applying the "-omic" technologies to urine, blood and breath condensate, and non-invasive inflammometry seem promising in this regard. The description of specific risk profiles may be the key to the use of targeted personalized therapies., (© 2020 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Sleep and circadian rhythm disorders are common amongst medical inpatients. They are caused by a mixture of factors, including noise, loss of habitual daily routines, and abnormal exposure to light, which tends to be insufficient in the day and too high at night. The aim of the present study was to test the efficacy of morning light therapy plus night short-wavelength filter glasses on sleep quality/timing, and sleepiness/mood over the daytime hours, in a group of well-characterized medical inpatients. Thirty-three inpatients were enrolled and randomized (2:1) to either treatment ( n = 22; 13 males, 48.3 ± 13.3 years) or standard of care ( n = 11; 8 males, 56.9 ± 12.9 years). On admission, all underwent a baseline assessment of sleep quality/timing and diurnal preference. During hospitalization they underwent monitoring of sleep quality/timing (sleep diaries and actigraphy), plus hourly assessment of sleepiness/mood during the daytime hours on one, standard day of hospitalization. Patients in the treatment arm were administered bright light through glasses immediately after awakening, and wore short-wavelength filter glasses in the evening hours. Treated and untreated patients were comparable in terms of demographics, disease severity/comorbidity, diurnal preference and pre-admission sleep quality/timing. During hospitalization, sleep diaries documented a trend for a lower number of night awakenings in treated compared to untreated patients (1.6 ± 0.8 vs. 2.4 ± 1.3, p = 0.057). Actigraphy documented significantly earlier day mode in treated compared to untreated patients (06:39 ± 00:35 vs. 07:44 ± 00:40, p = 0.008). Sleepiness during a standard day of hospitalization, recorded between 09:30 and 21:30, showed physiological variation in treated compared to untreated patients, who exhibited a more blunted profile. The level of sleepiness reported by treated patients was lower over the 09:30-14:30 interval, i.e., soon after light administration (interaction effect: F = 2.661; p = 0.026). Mood levels were generally higher in treated patients, with statistically significant differences over the 09:30-14:30 time interval, i.e., soon after light administration (treatment: F = 5.692, p = 0.026). In conclusion, treatment with morning bright light and short-wavelength filter glasses in the evening, which was well tolerated, showed positive results in terms of sleepiness/mood over the morning hours and a trend for decreased night awakenings., (Copyright © 2020 Formentin, Carraro, Turco, Zarantonello, Angeli and Montagnese.)

The bone marrow microenvironment promotes proliferation and drug resistance in chronic lymphocytic leukemia (CLL). Although ibrutinib is active in CLL, it is rarely able to clear leukemic cells protected by bone marrow mesenchymal stromal cells (BMSCs) within the marrow niche. We investigated the modulation of JAK2/STAT3 pathway in CLL by BMSCs and its targeting with AG490 (JAK2 inhibitor) or Stattic (STAT3 inhibitor). B cells collected from controls and CLL patients, were treated with medium alone, ibrutinib, JAK/Signal Transducer and Activator of Transcription (STAT) inhibitors, or both drugs, in the presence of absence of BMSCs. JAK2/STAT3 axis was evaluated by western blotting, flow cytometry, and confocal microscopy. We demonstrated that STAT3 was phosphorylated in Tyr705 in the majority of CLL patients at basal condition, and increased following co-cultures with BMSCs or IL-6. Treatment with AG490, but not Stattic, caused STAT3 and Lyn dephosphorylation, through re-activation of SHP-1, and triggered CLL apoptosis even when leukemic cells were cultured on BMSC layers. Moreover, while BMSCs hamper ibrutinib activity, the combination of ibrutinib+JAK/STAT inhibitors increase ibrutinib-mediated leukemic cell death, bypassing the pro-survival stimuli derived from BMSCs. We herein provide evidence that JAK2/STAT3 signaling might play a key role in the regulation of CLL-BMSC interactions and its inhibition enhances ibrutinib, counteracting the bone marrow niche., Competing Interests: L.T. received research founding by Gilead and Janssen. The other authors declare no conflict of interest.

Purpose: The effect of combined lifestyle interventions (LSI) including dietary and physical activity on metabolic health, energy metabolism and VO 2 max in diabetic patients has provided mixed results. We evaluated the impact of 1-year caloric restriction (CR), and 12-week supervised structured exercise training (SSET) on metabolic health, RMR and VO 2 max in obese adults with type 2 diabetes., Methods: After 1-month education for LSI, 33 participants had anthropometric, biochemical and metabolic assessments. They then started CR based on RMR, and 3-month SSET during the months 1-3 (Early-SSET) or 4-6 (Late-SSET). Reassessments were planned after 3, 6 and 12 months. Using a per-protocol analysis, we evaluated parameter changes from baseline and their associations for the 23 participants (11 Early-SSET, 12 Late-SSET) who completed the study. RMR was adjusted (adjRMR) for age, sex, fat-free mass (FFM) and fat mass (FM)., Results: Compared with baseline, after 6 months we found significant increases in VO 2 max (+ 14%) and HDL-cholesterol (+ 13%), and reduction in body mass index (- 3%), FM (- 8%) and glycated hemoglobin (HbA1c, - 7%). Training-related caloric expenditure negatively correlated with changes in body weight (p < 0.001), FM (p < 0.001) and HbA1c (p = 0.006). These results were confirmed at the 12-month follow-up. Pooling together all follow-up data, adjRMR changes correlated with changes in glycemia (r = 0.29, p = 0.02), total-cholesterol (r = 0.29, p = 0.02) and VO 2 max (r = - 0.26,p = 0.02). No significant differences emerged between the Early- and Late-SSET groups., Conclusions: Combined intervention with SSET and CR improved metabolic control. Changes in metabolic health and fitness correlated with changes of adjRMR, which was reduced improving fitness, glycemia and cholesterolemia., Clinical Trial Registry: Trial registration number: NCT03785379. URL of registration: http://clinicaltrials.gov .

Background: In the context of the so-called unified airway theory, chronic rhinosinusitis (CRS) and asthma may coexist. The inflammation underlying these conditions can be studied through the aid of biomarkers. Main body: We described the main biological mediators that have been studied in pediatric CRS and asthma, and, according to the available literature, we reported their potential role in the diagnosis and management of these conditions. As for CRS, we discussed the studies that investigated nasal nitric oxide (nNO), pendrin, and periostin. As for asthma, we discussed the role of fractional exhaled nitric oxide (feNO), the role of periostin, and that of biological mediators measured in exhaled breath condensate (EBC) and exhaled air (volatile organic compounds, VOCs)., Conclusion: Among non-invasive biomarkers, nNO seems the most informative in CRS and feNO in asthma. Other biological mediators seem promising, but further studies are needed before they can be applied in clinical practice.

Given that the prevalence of pediatric IgE-mediated food allergies (FA) has followed a substantive increase in recent decades, nowadays, a research challenge is to establish whether the weaning strategy can have a role in FA prevention. In recent decades, several studies have demonstrated that delayed exposure to allergenic foods did not reduce the risk of FA, leading to the publication of recent guidelines which recommend against delaying the introduction of solid foods after 4-6 months of age, both in high- and low-risk infants, in order to prevent food allergy. In the present review, focusing on cow's milk protein, hen's eggs, peanuts, soy, wheat and fish, we describe the current scientific evidence on the relationship between timing of these foods' introduction in infants' diet and allergy development.

Background: Bronchiolitis is associated with a greater risk of developing recurrent wheezing, but with currently available tools, it is impossible to know which infants with bronchiolitis will develop this condition. This preliminary prospective study aimed to assess whether urine metabolomic analysis can be used to identify children with bronchiolitis who are at risk of developing recurrent wheezing., Methods: Fifty-two infants <1 year old treated in the emergency department at University Hospital of Padova for acute bronchiolitis were enrolled (77% tested positive for respiratory syncytial virus [RSV]). Follow-up visits were conducted for 2 years after the episode of bronchiolitis. Untargeted metabolomic analyses based on mass spectrometry were performed on urine samples collected from infants with acute bronchiolitis. Data modeling was based on univariate and multivariate data analyses., Results: We distinguished children with and those without postbronchiolitis recurrent wheeze, defined as ≥3 episodes of physician-diagnosed wheezing. Pathway overrepresentation analysis pointed to a major involvement of the citric acid cycle (P < .001) and some amino acids (lysine, cysteine, and methionine; P ≤ .015) in differentiating between these 2 groups of children., Conclusion: This is the first study showing that metabolomic profiling of urine specimens from infants with bronchiolitis can be used to identify children at increased risk of developing recurrent wheezing., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Asthma is a chronic condition usually characterized by underlying inflammation. The study of asthmatic inflammation is of the utmost importance for both diagnostic and monitoring purposes. The gold standard for investigating airway inflammation is bronchoscopy, with bronchoalveolar lavage and bronchial biopsy, but the invasiveness of such procedures limits their use in children. For this reason, in the last decades there has been a growing interest for the development of noninvasive methods., Main Body: In the present review, we describe the most important non-invasive methods for the study of airway inflammation in children, focusing on the measure of the fractional exhaled nitric oxide (feNO), on the measure of the exhaled breath temperature (EBT) and on the analysis of both exhaled breath condensate (EBC) and exhaled air (Volatile Organic Compounds, VOCs), using targeted and untargeted approaches. We summarize what is currently known on the topic of exhaled biomarkers in childhood asthma, with a special emphasis on emerging approaches, underlining the role of exhaled biomarkers in the diagnosis, management and treatment of asthma, and their potential for the development of personalized treatments., Conclusion: Among non-invasive methods to study asthma, exhaled breath analysis remains one of the most interesting approaches, feNO and "-omic" sciences seem promising for the purpose of characterizing biomarkers of this disease., Competing Interests: Not applicable.Not applicable.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: Many children of preschool age present with recurrent wheezing. Most of them outgrow their symptoms, while some have early-onset asthma. Aim of this prospective preliminary study was to apply a metabolomic approach to see whether biochemical-metabolic urinary profiles can have a role in the early identification of the children with asthma., Methods: Preschool children with recurrent wheezing were recruited and followed up for 3 years, after which they were classified as cases of transient wheezing or early-onset asthma. A urine sample was collected at recruitment and analyzed using a metabolomic approach based on UPLC mass spectrometry., Results: Among 34 children aged 4.0 ± 1.1 years recruited, at the end of the 3-year follow-up, 16 were classified as having transient wheezing and 16 as cases of early-onset asthma. Through a joint multivariate and univariate statistical analyses, we identified a subset of metabolomic variables that enabled the 2 groups to be clearly distinguished. The model built using the identified variables showed an AUC = 0.99 and an AUC = 0.88 on sevenfold full cross-validation (P = .002)., Conclusions: Metabolomic urinary profile can discriminate preschoolers with recurrent wheezing who will outgrow their symptoms from those who have early-onset asthma. These results may pave the way to the characterization of early non-invasive biomarkers capable of predicting asthma development., (© 2018 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.)

Objectives: To apply metabolomic analysis of amniotic fluid in a discovery cohort to see whether a specific biochemical-metabolic profile at birth is associated with the subsequent onset of wheezing over the first year of life., Study Design: This prospective exploratory study was conducted in a healthy term-born Dutch cohort recruited at 2 hospitals in Utrecht (UMCU, Utrecht, and Diakonessenhuis, Utrecht), The Netherlands. A metabolomic approach based on mass spectrometry was applied to analyze 142 amniotic fluid samples collected at birth. The infants were followed up during their first year of life with recording any respiratory symptoms daily, and they were classified according to the onset of wheezing., Results: Orthogonally constrained projection to latent structures discriminant analysis was used to investigate differences in the metabolic profiles of the infants with (n = 86) and without (n = 56) wheezing. A search of the available databases for amniotic fluid metabolites identified by stability selection, combined with pathway analysis, highlighted the possible metabolic perturbations involved in this condition. The model built using 16 relevant variables with plausible biological significance, showed an area under the curve of 0.82 (P < .001) and an area under the curve calculated by 7-fold full cross-validation of 0.72 (P = .003), with the steroid hormone biosynthesis and the 2-phenylalanine metabolism emerging as probably perturbed pathways., Conclusions: Infants who will or will not experience wheezing in their first year of life have distinct amniotic fluid metabolomic profiles at birth. Changes occurring in biochemical-metabolic pathways in late intrauterine life may have a pathogenic role in early-onset wheezing., (Copyright © 2018 Elsevier Inc. All rights reserved.)

The diagnosis of asthma is currently based on clinical history, physical examination and lung function, and to date, there are no accurate objective tests either to confirm the diagnosis or to discriminate between different types of asthma. This consensus exercise reviews the state of the art in asthma diagnosis to identify opportunities for future investment based on the likelihood of their successful development, potential for widespread adoption and their perceived impact on asthma patients. Using a two-stage e-Delphi process and a summarizing workshop, a group of European asthma experts including health professionals, researchers, people with asthma and industry representatives ranked the potential impact of research investment in each technique or tool for asthma diagnosis and monitoring. After a systematic review of the literature, 21 statements were extracted and were subject of the two-stage Delphi process. Eleven statements were scored 3 or more and were further discussed and ranked in a face-to-face workshop. The three most important diagnostic/predictive tools ranked were as follows: "New biological markers of asthma (eg genomics, proteomics and metabolomics) as a tool for diagnosis and/or monitoring," "Prediction of future asthma in preschool children with reasonable accuracy" and "Tools to measure volatile organic compounds (VOCs) in exhaled breath.", (© 2018 John Wiley & Sons Ltd.)

The way a postgraduate medical training program is organized and the capacity of faculty members to function as tutors and to organize effective professional experiences are among the elements that affect the quality of training. An evaluation system designed to target these elements has been implemented within the framework of the Pediatric Residency Program of the University of Padua (Italy). The aim of this report is to describe some aspects of the experience gained in the first 3 years of implementation of the system (2013-2015). Data were collected using four validated questionnaires: the "Resident Assessment Questionnaire", the "Tutor-Assessment Questionnaire", the "Rotation-Assessment Questionnaire", and the "Resident Affairs Committee-Assessment Questionnaire". The response rate was 72% for the "Resident Assessment Questionnaires"; 78% for the "Tutor-/Rotation-Assessment Questionnaires" and 84% for the "Resident Affair Committee-Assessment Questionnaires". The scores collected were validated by psychometric tests., Conclusion: The high rates of completed questionnaires returned and the psychometric validation of the results collected indicate that the evaluation system reported herein can be effectively implemented. Efforts should be made to refine this system and, more importantly, to document its impact in improving the Pediatric Residency Program. What is known: • The elements that influence the quality of postgraduate training programs and the knowledge, performance, and competences of residents must be regularly assessed. • Comprehensive evaluation systems for postgraduate residency programs are not universally implemented also because quite often common guidelines and rules, well-equipped infrastructures, and financial resources are missing. What is new: • We show the feasibility of implementing an evaluation system that targets some of the key elements of a postgraduate medical training program in Italy, a European country in which the regulations governing training programs and, notably, the evaluation of residents are still being developed.