Nurturing the next generation of pediatric physician scientists: the Padova Physician Scientist Research Training for pediatric residents.

Less than 2% of physicians complete a research training (PhD) after the residency with a declining trend in those pursuing a clinical scientist pathway in pediatrics. The exposure to research methodology during the clinical training may play a role in engaging the next generations of pediatric physician scientist. Herein, we describe the experience of the Padova Physician Scientist Research Training (PPSRT) of the pediatric residency program at the University of Padova. The PPSRT was addressed to residents attending PGY2 to PGY4 of the pediatric program and consisted of two cores: a general one including in person or virtual lectures about research methodology in pediatrics including design of a clinical trial, writing of a scientific paper and statistical methods, and a subspecialties core for the discussion of research challenges in each area and the scientific writing activities. The perceived barriers to a research training and an evaluation of the program were assessed by an anonymized questionnaire. Sixty-four out 150 residents registered for the research training with 62/64 completing the two cores. The major perceived barrier to research during clinical training was the absence of protected time (89%) followed by the lack of specific funds (37%). The group activities lead to the publication of 24 papers.    Conclusion: This is the first experience in the Italian pediatric training of a dedicated research program within the frame of postgraduate medical education. Our report highlights the need for protected time to promote research interest and nurture a new generation of physician scientists. What is Known: • Training to medical research is not part of residency program. • The declining trend of physician scientists might be reverted by early exposure to research methodology and challenges during residency. What is New: • An early exposure to research training during pediatric residency increases the research engagement of pediatric residents. • The lack of protected time for research is perceived as the major barrier to research training during residency.

Vaccination practices in pediatric transplantation: A survey among member centers of the European reference network TransplantChild.

BACKGROUND: There is considerable variation in vaccination practices between pediatric transplant centers. This study aims to evaluate active immunization attitudes and practices among ERN-TransplantChild centers and identify potential areas of improvement that could be addressed by shared evidence-based protocols. METHODS: A cross-sectional questionnaire of attitudes and practices toward immunization of pediatric SOT and HSCT candidates and recipients was sent to a representative member of multidisciplinary teams from 27 European centers belonging to the ERN-TransplantChild. RESULTS: A total of 28/62 SOT programs and 6/12 HSCT programs across 21 European centers participated. A quarter of centers did not have an on-site protocol for the immunizations. At the time of transplantation, pediatric candidates were fully immunized (80%-100%) in 57% and 33% of the SOT and HSCT programs. Variations in the time between vaccine administration and admission to the waiting list were reported between the centers, with 2 weeks for inactivated vaccines and variable time (2-4 weeks) for live-attenuated vaccines (LAVs). Almost all sites recommended immunization in the post-transplant period, with a time window of 4-8 months for the inactivated vaccines and 16-24 months for MMR and Varicella vaccines. Only five sites administer LAVs after transplantation, with seroconversion evaluated in 80% of cases. CONCLUSIONS: The immunization coverage of European pediatric transplant recipients is still inconsistent and far from adequate. This survey is a starting point for developing shared evidence-based immunization protocols for safe vaccination among pediatric transplant centers and generating new research studies.

A pilot study on sports activities in pediatric palliative care: just do it.

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

Intratracheal administration of mesenchymal stem cell-derived extracellular vesicles reduces lung injuries in a chronic rat model of bronchopulmonary dysplasia.

Early therapeutic effect of intratracheally (IT)-administered extracellular vesicles secreted by mesenchymal stem cells (MSC-EVs) has been demonstrated in a rat model of bronchopulmonary dysplasia (BPD) involving hyperoxia exposure in the first 2 postnatal weeks. The aim of this study was to evaluate the protective effects of IT-administered MSC-EVs in the long term. EVs were produced from MSCs following GMP standards. At birth, rats were distributed in three groups: (a) animals raised in ambient air for 6 weeks (n = 10); and animals exposed to 60% hyperoxia for 2 weeks and to room air for additional 4 weeks and treated with (b) IT-administered saline solution (n = 10), or (c) MSC-EVs (n = 10) on postnatal days 3, 7, 10, and 21. Hyperoxia exposure produced significant decreases in total number of alveoli, total surface area of alveolar air spaces, and proliferation index, together with increases in mean alveolar volume, mean linear intercept and fibrosis percentage; all these morphometric changes were prevented by MSC-EVs treatment. The medial thickness index for <100 µm vessels was higher for hyperoxia-exposed/sham-treated than for normoxia-exposed rats; MSC-EV treatment significantly reduced this index. There were no significant differences in interstitial/alveolar and perivascular F4/8-positive and CD86-positive macrophages. Conversely, hyperoxia exposure reduced CD163-positive macrophages both in interstitial/alveolar and perivascular populations and MSC-EV prevented these hyperoxia-induced reductions. These findings further support that IT-administered EVs could be an effective approach to prevent/treat BPD, ameliorating the impaired alveolarization and pulmonary artery remodeling also in a long-term model. M2 macrophage polarization could play a role through anti-inflammatory and proliferative mechanisms.

IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.

Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.

Sodium Thiosulfate for Protection from Cisplatin-Induced Hearing Loss.

BACKGROUND: Cisplatin chemotherapy and surgery are effective treatments for children with standard-risk hepatoblastoma but may cause considerable and irreversible hearing loss. This trial compared cisplatin with cisplatin plus delayed administration of sodium thiosulfate, aiming to reduce the incidence and severity of cisplatin-related ototoxic effects without jeopardizing overall and event-free survival. METHODS: We randomly assigned children older than 1 month and younger than 18 years of age who had standard-risk hepatoblastoma (≤3 involved liver sectors, no metastatic disease, and an alpha-fetoprotein level of >100 ng per milliliter) to receive cisplatin alone (at a dose of 80 mg per square meter of body-surface area, administered over a period of 6 hours) or cisplatin plus sodium thiosulfate (at a dose of 20 g per square meter, administered intravenously over a 15-minute period, 6 hours after the discontinuation of cisplatin) for four preoperative and two postoperative courses. The primary end point was the absolute hearing threshold, as measured by pure-tone audiometry, at a minimum age of 3.5 years. Hearing loss was assessed according to the Brock grade (on a scale from 0 to 4, with higher grades indicating greater hearing loss). The main secondary end points were overall survival and event-free survival at 3 years. RESULTS: A total of 109 children were randomly assigned to receive cisplatin plus sodium thiosulfate (57 children) or cisplatin alone (52) and could be evaluated. Sodium thiosulfate was associated with few high-grade toxic effects. The absolute hearing threshold was assessed in 101 children. Hearing loss of grade 1 or higher occurred in 18 of 55 children (33%) in the cisplatin-sodium thiosulfate group, as compared with 29 of 46 (63%) in the cisplatin-alone group, indicating a 48% lower incidence of hearing loss in the cisplatin-sodium thiosulfate group (relative risk, 0.52; 95% confidence interval [CI], 0.33 to 0.81; P=0.002). At a median of 52 months of follow-up, the 3-year rates of event-free survival were 82% (95% CI, 69 to 90) in the cisplatin-sodium thiosulfate group and 79% (95% CI, 65 to 88) in the cisplatin-alone group, and the 3-year rates of overall survival were 98% (95% CI, 88 to 100) and 92% (95% CI, 81 to 97), respectively. CONCLUSIONS: The addition of sodium thiosulfate, administered 6 hours after cisplatin chemotherapy, resulted in a lower incidence of cisplatin-induced hearing loss among children with standard-risk hepatoblastoma, without jeopardizing overall or event-free survival. (Funded by Cancer Research UK and others; SIOPEL 6 ClinicalTrials.gov number, NCT00652132 ; EudraCT number, 2007-002402-21 .).

Protecting youth from the vaping epidemic.

E-cigarettes (e-cigs) have been initially proposed as an aid to smoke cessation in adults, whereas they turned into a paradoxical preferential gateway to tobacco and nicotine initiation for adolescents naïve to tobacco. More than 25% of US school-age students is an e-cigs user with a steep rise over the past years. A marketing strategy on media and social network targeting youths, in the absence of rules to protect the pediatric users, resulted in an unprecedented trend up in tobacco consumption among adolescents and gave rise to a new generation of nicotine-addicted teenagers. Flavored e-cigs liquids and aerosols contain airway irritants and toxicants, that, in turn, produced an increase in asthma prevalence and its exacerbations among adolescents. In addition, since August 2019 an outbreak of e-cigarette, or vaping, product use-associated lung injury (EVALI) has been described. In view of this, e-cigs must no longer be considered harmless, especially in adolescents never used a tobacco product before. This is a call-for-action to establish effective rules and campaigns targeting youths aimed to limit their access to e-cigs, thereby preserving the potential benefit in quitting tobacco addiction described in adults. Behavioral and educational actions, out of the conventional primary care setting, have been described as a model for a youth-centered campaign. We call for stricter regulations on e-cigs products, with respect to their marketing to the youngest ones, along with public health and primary care interventions that could curb the spread of this "vaping" epidemic.

The importance of age as prognostic factor for the outcome of patients with hepatoblastoma: Analysis from the Children's Hepatic tumors International Collaboration (CHIC) database.

PURPOSE: Treatment outcomes for hepatoblastoma have improved markedly in the contemporary treatment era, principally due to therapy intensification, with overall survival increasing from 35% in the 1970s to 90% at present. Unfortunately, these advancements are accompanied by an increased incidence of toxicities. A detailed analysis of age as a prognostic factor may support individualized risk-based therapy stratification. METHODS: We evaluated 1605 patients with hepatoblastoma included in the CHIC database to assess the relationship between event-free survival (EFS) and age at diagnosis. Further analysis included the age distribution of additional risk factors and the interaction of age with other known prognostic factors. RESULTS: Risk for an event increases progressively with increasing age at diagnosis. This pattern could not be attributed to the differential distribution of other known risk factors across age. Newborns and infants are not at increased risk of treatment failure. The interaction between age and other adverse risk factors demonstrates an attenuation of prognostic relevance with increasing age in the following categories: metastatic disease, AFP < 100 ng/mL, and tumor rupture. CONCLUSION: Risk for an event increased with advancing age at diagnosis. Increased age attenuates the prognostic influence of metastatic disease, low AFP, and tumor rupture. Age could be used to modify recommended chemotherapy intensity.

Relationship-based care model in paediatrics: A randomized controlled trial to implement the parents' perception of the quality of nursing care.

AIM: To evaluate whether the application of the Relationship-based care model as a new treatment, called "Take 5 min", affects the level of anxiety, depression, and perceived quality of nursing care of parents of paediatric patients and the work satisfaction of the nursing staff. DESIGN: Single-blind randomized controlled trial. METHODS: The trial was performed from February-July 2016. The trial was conducted with one intervention (N = 101) and one control group (N = 90). Nurses applied the treatment named "Take 5 Minutes", which consisted of dedicating some short time (from 5 to 10 min) to the relationship with the parents using specifically designed communication strategies. The primary outcome was the evaluation of anxiety and depression of parents; the secondary was the parent perceived quality of nursing care. RESULTS: In the experimental group, participants had a lower level of anxiety and depression and highlighted that the effect of the "Take 5 Minutes" was proportional to the initial seriousness of parents' anxiety and depression. Higher scores for the perception of the quality of care were given from the parents of the experimental group. CONCLUSION: The "Take 5 Minutes" treatment offered to parents of paediatric patients demonstrated significant improvements in terms of their anxiety, depression, and perceived quality of nursing care. IMPACT: Caregivers of paediatric patients are subject to psychological disorders such as depression and anxiety. The communication by the nursing community is of fundamental importance in the management of anxiety and depression in the caregivers of hospitalized patients. Caregivers who received the "Take 5 Minutes" treatment demonstrated a significant decrease in anxiety and depression compared with the control group caregivers. The perceived level of quality of nursing care showed a significant increase in the group of caregivers who received the T5M treatment. The RBC model does not require extra costs for health organizations and can be applied during the usual practice of care. Practices such as T5M could become part of paediatric patient care guidelines and nurses should be trained to apply them. TRIAL REGISTRATION NUMBER: Padua Research: ID No. 10,034; ClinicalTrials.gov: ID No. NCT04199429.

Intratracheal administration of clinical-grade mesenchymal stem cell-derived extracellular vesicles reduces lung injury in a rat model of bronchopulmonary dysplasia.

Mesenchymal stem cells (MSCs) prevent the onset of bronchopulmonary dysplasia (BPD) in animal models, an effect that seems to be mediated by their secreted extracellular vesicles (EVs). The aim of this study was to compare the protective effects of intratracheally (IT) administered MSCs versus MSC-EVs in a hyperoxia-induced rat model of BPD. At birth, rats were distributed as follows: animals raised in ambient air for 2 wk ( n = 10), and animals exposed to 60% oxygen for 2 wk and treated with IT-administered physiological solution ( n = 10), MSCs ( n = 10), or MSC-EVs ( n = 10) on postnatal days 3, 7, and 10. The sham-treated hyperoxia-exposed animals showed reductions in total surface area of alveolar air spaces, and total number of alveoli ( Nalv), and an increased mean alveolar volume (Valv). EVs prompted a significant increase in Nalv ( P < 0.01) and a significant decrease in Valv ( P < 0.05) compared with sham-treated animals, whereas MSCs only significantly improved Nalv ( P < 0.05). Small pulmonary vessels of the sham-treated hyperoxia-exposed rats also showed an increase in medial thickness, which only EVs succeeded in preventing significantly ( P < 0.05). In conclusion, both EVs and MSCs reduce hyperoxia-induced damage, with EVs obtaining better results in terms of alveolarization and lung vascularization parameters. This suggests that IT-administered EVs could be an effective approach to BPD treatment.

Short-term outcomes of paediatric liver transplant recipients after transition to Adult Healthcare Service.

BACKGROUND & AIMS: Survival rates after liver transplantation (LT) in paediatric recipients have significantly improved over time. However, data regarding outcomes after transition from Paediatric to Adult Healthcare Service (AHS) are still lacking. Therefore, we aimed to prospectively evaluate the outcome of LT recipients after transition, to access patients' non-adherence and identify potential risk factors for non-adherence. METHODS: All consecutive adolescent LT recipients moving to the AHS at Padua University Hospital were evaluated between 2010 and 2015. Demographic data, liver function tests, incidence of acute or chronic rejection episodes and adherence to medical prescription, were prospectively evaluated. An educational pilot study was implemented since 2015 to foster adherence during transition. RESULTS: In all, 32 patients (M/F 16/16, median age: 23 years) were evaluated. Median interval time between LT and transition was 15 years (range: 1-26 years). The main indication for LT was biliary atresia (31%), whereas immunosuppression regimen was tacrolimus-based in 75%. After a median follow-up of 29 months (range: 12-83), no significant modifications of liver function tests were observed. Biopsy-proven chronic rejection was diagnosed in 6/32 (18%) of patients, who had higher standard deviation of tacrolimus trough level than patients without (1.5 vs 1, P = .03). Non-adherence was reported in 8/32 (25%) of patients and was significantly associated with alcohol consumption (P = .003). Patient and graft survival were 96% and 93%, respectively. CONCLUSIONS: Adolescent LT patients who undergo transition to the AHS have good long-term outcomes. However, a multidisciplinary approach aiming at fostering adherence should be used.

Metabolomics reveals new metabolic perturbations in children with type 1 diabetes.

OBJECTIVE: Using an untargeted metabolomics approach we investigated the metabolome of children with type 1 diabetes (T1D) in comparison with healthy peers and explored the contribution of HbA1c and clinical features to the observed difference. RESEARCH DESIGN AND METHODS: We enrolled children with T1D aged 6-15 years, attending the pediatric diabetes clinic of University of Padova (Italy). Healthy controls were enrolled on voluntary basis and matched for age, sex, pubertal status, body mass index (BMI). We performed a liquid chromatography and mass spectrometry analysis (LC-MS) on fasting urinary samples of the 2 groups. RESULTS: A total of 56 patients with T1D aged (11.4 ± 2.2) years, and 30 healthy controls (10.7 ± 2.8) years were enrolled. We identified 59 urinary metabolites having a higher level in children with T1D, mainly represented by gluco- and mineralcorticoids, phenylalanine and tryptophan catabolites (kynurenine), small peptides, glycerophospholipids, fatty acids, and gut bacterial products. We did not find any association between HbA1c, pubertal status, disease duration, and metabolome profile within the case group. CONCLUSIONS: T1D profoundly disrupts the metabolome of pediatric patients. The excess of cortisol and aldosterone may contribute to the development of macrovascular complications in adulthood, while the increase of tryptophan derivates may have a role in neuronal damage associated to hyperglycemia. Determinants of such findings, other than HbA1c, should be explored.

Hepatoblastoma in children aged less than six months at diagnosis: A report from the SIOPEL group.

BACKGROUND: The purpose of this study was to evaluate clinical characteristics, treatment, and survival of children, who were diagnosed with hepatoblastoma (HB) in their first 6 months of age, enrolled in the SIOPEL 2 and 3 protocols. METHODS: Seventy-nine patients, treated between 1994 and 2006, were analyzed after stratification into three age groups: <1 month, between 1 and 3 months, and between 3 and 6 months. All received preoperative chemotherapy. RESULTS: Clinical characteristics were similar in both trials: 4 patients had pulmonary metastases at diagnosis, 4 had α-fetoprotein <100 ng/ml, 68 were operated by partial hepatectomy, and 7 received liver transplant. Chemotherapy courses were delayed in 8.5%, 8.4%, and 11.8% of cycles in the three groups. Doses were calculated according to weight for children <5 and 5-10 kg, and further reduced in 18.1%, 6.8%, and 5.9% of cycles. Acute toxicity was manageable. Long-term hearing loss was the major problem at follow-up occurring in two-thirds of children. Ten patients experienced progression or relapse, and 5 of 10 died. After a median follow-up of 5.6 years, the 5-year overall survival (OS) and event-free survival (EFS) were 91% (95% confidence interval [CI]: 84-96%) and 87% (95% CI: 78-92%), respectively. CONCLUSIONS: The 5-year OS and EFS of children <6 months of age affected by HB seem to be similar to those documented in the elder children. Dose reduction does not seem to jeopardize the long-term outcome and may explain the lower toxicity profile. Ototoxicity though appears as high as in the whole population of SIOPEL 2 and 3. The treatment for these children should be further explored in international studies, particularly focusing on prevention of hearing loss.

Neonatal mitochondrial leukoencephalopathy with brain and spinal involvement and high lactate: expanding the phenotype of ISCA2 gene mutations.

A homoallelic missense founder mutation of the iron-sulfur cluster assembly 2 (ISCA2) gene has been recently reported in six cases affected by an autosomal recessive infantile neurodegenerative mitochondrial disorder. We documented a case of a 2-month-old girl presenting with severe hypotonia and nystagmus, who rapidly deteriorated and died at the age of three months. Increased cerebral spinal fluid level of lactate, documented also at the brain spectroscopy, involvement of the cortex, restricted diffusion of white and gray matter abnormalities, sparing of the corpus callosum and extensive involvement of the spinal cord were observed. Her clinical presenting features and course as well as some neuroradiological findings mimicked those of early-onset leukoencephalopathy with brainstem and spinal cord involvement and high brain lactate (LBSL). The analysis of the mitochondrial respiratory chain function showed a reduced activity of complexes II and IV. The girl harboured two heterozygous mutations in the ISCA2 gene. A comprehensive review of the literature and a comparison with the cases of early onset LBSL enabled us to highlight significant differences in the clinical, biochemical and neuroradiological phenotype between the two conditions, which also emerged from the comparison with the other 6 reported cases of ISCA2 gene mutation previously reported. In summary, this represents the second report ever published associating ISCA2 gene mutation with a mitochondrial leukoencephalopathy, with a different genetic mechanism to the previous cases. Molecular analysis of ISCA2 should be included in the genetic panel for the diagnosis of early onset mitochondrial leukoencephalopathies.

Risk-stratified staging in paediatric hepatoblastoma: a unified analysis from the Children's Hepatic tumors International Collaboration.

BACKGROUND: Comparative assessment of treatment results in paediatric hepatoblastoma trials has been hampered by small patient numbers and the use of multiple disparate staging systems by the four major trial groups. To address this challenge, we formed a global coalition, the Children's Hepatic tumors International Collaboration (CHIC), with the aim of creating a common approach to staging and risk stratification in this rare cancer. METHODS: The CHIC steering committee-consisting of leadership from the four major cooperative trial groups (the International Childhood Liver Tumours Strategy Group, Children's Oncology Group, the German Society for Paediatric Oncology and Haematology, and the Japanese Study Group for Paediatric Liver Tumours)-created a shared international database that includes comprehensive data from 1605 children treated in eight multicentre hepatoblastoma trials over 25 years. Diagnostic factors found to be most prognostic on initial analysis were PRETreatment EXTent of disease (PRETEXT) group; age younger than 3 years, 3-7 years, and 8 years or older; α fetoprotein (AFP) concentration of 100 ng/mL or lower and 101-1000 ng/mL; and the PRETEXT annotation factors metastatic disease (M), macrovascular involvement of all hepatic veins (V) or portal bifurcation (P), contiguous extrahepatic tumour (E), multifocal tumour (F), and spontaneous rupture (R). We defined five clinically relevant backbone groups on the basis of established prognostic factors: PRETEXT I/II, PRETEXT III, PRETEXT IV, metastatic disease, and AFP concentration of 100 ng/mL or lower at diagnosis. We then carried the additional factors into a hierarchical backwards elimination multivariable analysis and used the results to create a new international staging system. RESULTS: Within each backbone group, we identified constellations of factors that were most predictive of outcome in that group. The robustness of candidate models was then interrogated using the bootstrapping procedure. Using the clinically established PRETEXT groups I, II, III, and IV as our stems, we created risk stratification trees based on 5 year event-free survival and clinical applicability. We defined and adopted four risk groups: very low, low, intermediate, and high. INTERPRETATION: We have created a unified global approach to risk stratification in children with hepatoblastoma on the basis of rigorous statistical interrogation of what is, to the best of our knowledge, the largest dataset ever assembled for this rare paediatric tumour. This achievement provides the structural framework for further collaboration and prospective international cooperative study, such as the Paediatric Hepatic International Tumour Trial (PHITT). FUNDING: European Network for Cancer Research in Children and Adolescents, funded through the Framework Program 7 of the European Commission (grant number 261474); Children's Oncology Group CureSearch grant contributed by the Hepatoblastoma Foundation; Practical Research for Innovative Cancer Control and Project Promoting Clinical Trials for Development of New Drugs and Medical Devices, Japan Agency for Medical Research; and Swiss Cancer Research grant.

Herpes simplex virus-induced anti-N-methyl-d-aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases.

AIM: To conduct a systematic literature review on patients with biphasic disease with herpes simplex virus (HSV) encephalitis followed by anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. METHOD: We conducted a case report and systematic literature review (up to 10 December 2016), focused on differences between herpes simplex encephalitis (HSE) and anti-NMDAR encephalitis phases, age-related characteristics of HSV-induced anti-NMDAR encephalitis, and therapy. For statistical analyses, McNemar's test, Fisher's test, and Wilcoxon rank sum test were used (two-tailed significance level set at 5%). RESULTS: Forty-three patients with biphasic disease were identified (31 children). Latency between HSE and anti-NMDAR encephalitis was significantly shorter in children than adults (median 24 vs 40.5d; p=0.006). Compared with HSE, anti-NMDAR encephalitis was characterized by significantly higher frequency of movement disorder (2.5% vs 75% respectively; p<0.001), and significantly lower rate of seizures (70% vs 30% respectively; p=0.001). Compared with adults, during anti-NMDAR encephalitis children had significantly more movement disorders (86.7% children vs 40% adults; p=0.006), fewer psychiatric symptoms (41.9% children vs 90.0% adults; p=0.025), and a slightly higher median modified Rankin Scale score (5 in children vs 4 in adults; p=0.015). During anti-NMDAR encephalitis, 84.6 per cent of patients received aciclovir (for ≤7d in 22.7%; long-term antivirals in 18.0% only), and 92.7 per cent immune therapy, but none had recurrence of HSE clinically or using cerebrospinal fluid HSV polymerase chain reaction (median follow-up 7mo). INTERPRETATION: Our review suggests that movement disorder may help differentiate clinically an episode of HSV-induced anti-NMDAR encephalitis from HSE relapse. Compared with adults, children have shorter latency between HSE and anti-NMDAR encephalitis and, during anti-NMDAR encephalitis, more movement disorder, fewer psychiatric symptoms, and slightly more severe disease. According to our results, immune therapy given for HSV-induced anti-NMDAR encephalitis does not predispose patients to HSE recurrence.

An evaluation system for postgraduate pediatric residency programs: report of a 3-year experience.

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.

Diverging Concepts and Novel Perspectives in Regenerative Medicine.

Regenerative medicine has rapidly evolved, due to progress in cell and molecular biology allowing the isolation, characterization, expansion, and engineering of cells as therapeutic tools. Despite past limited success in the clinical translation of several promising preclinical results, this novel field is now entering a phase of renewed confidence and productivity, marked by the commercialization of the first cell therapy products. Ongoing issues in the field include the use of pluripotent vs. somatic and of allogenic vs. autologous stem cells. Moreover, the recognition that several of the observed beneficial effects of cell therapy are not due to integration of the transplanted cells, but rather to paracrine signals released by the exogenous cells, is generating new therapeutic perspectives in the field. Somatic stem cells are outperforming embryonic and induced pluripotent stem cells in clinical applications, mainly because of their more favorable safety profile. Presently, both autologous and allogeneic somatic stem cells seem to be equally safe and effective under several different conditions. Recognition that a number of therapeutic effects of transplanted cells are mediated by paracrine signals, and that such signals can be found in extracellular vesicles isolated from culture media, opens novel therapeutic perspectives in the field of regenerative medicine.