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BACKGROUND: Aggressive fluid or blood component transfusion for severe hemorrhagic shock may restore macrocirculatory parameters, but not always improve microcirculatory perfusion and tissue oxygen delivery. We established an ovine model of hemorrhagic shock to systematically assess tissue oxygen delivery and repayment of oxygen debt; appropriate outcomes to guide Patient Blood Management. METHODS: Female Dorset-cross sheep were anesthetized, intubated, and subjected to comprehensive macrohemodynamic, regional tissue oxygen saturation (StO2), sublingual capillary imaging, and arterial lactate monitoring confirmed by invasive organ-specific microvascular perfusion, oxygen pressure, and lactate/pyruvate levels in brain, kidney, liver, and skeletal muscle. Shock was induced by stepwise withdrawal of venous blood until MAP was 30 mm Hg, mixed venous oxygen saturation (SvO2) 4 mM. Resuscitation with PlasmaLyte® was dosed to achieve MAP > 65 mm Hg. RESULTS: Hemorrhage impacted primary outcomes between baseline and development of shock: MAP 89 ± 5 to 31 ± 5 mm Hg (P

Objective and design Our prospective study assesses the role of detailed lung ultrasound (LUS) features to discriminate the etiological diagnosis of acute lower respiratory tract infection (ALRTI) in children. Methodology We analyzed patients aged from 1 month to 17 years admitted between March 2018 and April 2020 who were hospitalized for ALRTI. For all patients, history, clinical parameters, microbiological data, and lung ultrasound data were collected. Patients were stratified into three main groups (“bacterial”, “viral”, “atypical”) according to the presumed microbial etiology and LUS findings evaluated according to the etiological group. Nasopharyngeal swabs were obtained from all patients. A qualitative diagnostic test developed by Nurex S.r.l. was used for identification of bacterial and fungal DNA in respiratory samples. The Seegene Allplex™ Respiratory assays were used for the molecular diagnosis of viral respiratory pathogens. In addition, bacterial culture of blood and respiratory samples were performed, when indicated. Results A total of 186 children with suspected ALRTI (44% female) with an average age of 6 were enrolled in the study. We found that some ultrasound findings as size, number and distribution of consolidations, the position and motion of air bronchograms, pleural effusions and distribution of vertical artifacts significantly differ (p Conclusion Our study provides a detailed analysis of LUS features able to predict the ALRTI ethology in children. These findings may help the physicians to better manage a child with ALRTI and to offer personalized approach, from diagnosis to treatment and follow-up.

Background Although children with special health care needs (CSHCN) represent a minority of the population, they go through more hospitalizations, more admissions to the Emergency Department (ED), and receive a major number of medical prescriptions, in comparison to general pediatric population. Objectives of the study were to determine the reasons for admission to the ED in Italian CSHCN, and to describe the association between patient’s demographic data, clinical history, and health services requirements. Methods Ad hoc web site was created to collect retrospective data of 3479 visits of CSHCN to the ED in 58 Italian Hospitals. Results Seventy-two percent of patients admitted to ED were affected by a previously defined medical condition. Most of the ED admissions were children with syndromic conditions (54%). 44.2% of the ED admissions were registered during the night-time and/or at the weekends. The hospitalization rate was of 45.6% among patients admitted to the ED. The most common reason for admission to the ED was the presence of respiratory symptoms (26.6%), followed by gastrointestinal problems (21.3%) and neurological disorders (18.2%). 51.4% of the access were classified as ‘urgent’, with a red/yellow triage code. Considering the type of ED, 61.9% of the visits were conducted at the Pediatric EDs (PedEDs), 33.5% at the Functional EDs (FunEDs) and 4.6% at the Dedicated EDs (DedEDs). Patients with more complex clinical presentation were more likely to be evaluated at the PedEDs. CSHCN underwent to a higher number of medical procedures at the PedEDs, more in comparison to other EDs. Children with medical devices were directed to a PedED quite exclusively when in need for medical attention. Subjects under multiple anti-epileptic drug therapy attended to PedEDs or FunEDs generally. Patients affected by metabolic diseases were more likely to look for medical attention at FunEDs. Syndromic patients mostly required medical attention at the DedEDs. Conclusions Access of CSHCN to an ED is not infrequent. For this reason, it is fundamental for pediatricians working in any kind of ED to increase their general knowledge about CHSCN and to gain expertise in the management of such patients and their related medical complexity.

Fever is the most common problem of children admitted to emergency department (ED). The management of febrile patients ≤ 60 d old admitted to the Pediatric Emergency Department in the last 5 y was evaluated, applying the invasive bacterial infection (IBI) score proposed to evaluate the reliability and safety of this score in the authors' setting. Medical records of 280 patients with fever reported and/or detected in ED were retrospectively analyzed. A total of 166 patients were enrolled, whose average IBI score was 2.98 IBI score

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer with the majority of cases being of B lineage [1]. B-cell precursor ALL (BCP-ALL) is a heterogeneous disease in which risk ass...

Accidental swallowing of foreign bodies is a common problem among the pediatric population (6 months to 3 years), especially if the foreign body (FB) presents a sharp end that could potentially lead to perforation of the gastrointestinal (GI) tract, resulting in infection and complications. We report the case of a 2-year-old, admitted to the Emergency Department of our hospital after ingesting two FBs classifiable as sharp objects, specifically two metal nails, both approximately 4-cm long, which had been swallowed in one go, as reported by the parents. The patient had been previously admitted to another hospital in the same region, where the Emergency Department (ED) doctors took an X-ray to confirm the ingestion. The foreign bodies ingestion was thus confirmed, and they were, according to their report, located in the GI tract over the stomach. The patient has been monitored through all of his stay in the hospital and the progression of the foreign bodies has been documented with serial X-rays. Since neither clinical nor radiological signs of perforation were present, putting the FBs in the small bowel, a non-operative expectant management was followed. After 4 days of admission, the patient had passed one of the two FBS and later on the second one, without any complication. Thereafter the patient was discharged. The management of sharp gastrointestinal foreign objects ingestion is still debated, and the data of the current literature are poor. A number of case reports and small case series describe successful conservative management for the majority of ingested sharp objects. According to the literature data, our report confirms that the ingestion of sharp objects and relatively big objects in a baby can be successfully non-operatively managed, even despite the age of the patient and though the FBs are multiple.

Background L-asparaginase (L-ASP) is a key component of acute lymphoblastic leukemia (ALL) treatment, but its use in clinical practice raises challenges to clinicians due to a relatively high incidence of drug-related adverse events, mainly in adult patients. In the past years the use of ASP in adult population has been mainly limited due to a poor knowledge of its safety profile and to an approximate management of ASP-related toxicity. Recently the development of pediatric-inspired treatment protocols for adult ALL has led to a wider use of ASP and since 2010 in Italy three national treatment protocols including Pegylated asparaginase (Peg-ASP) have been sequentially developed for adolescents, young adults and adults with Philadelphia-negative (Ph-) ALL. Methods With the aim to better understand the approach adopted in Italian centers for the management and prevention of Peg-ASP toxicity in adult ALL and to provide practical, consensus-based recommendations, a board of 6 Italian clinicians, with known expertise in adult ALL, designed 41 consensus statements on current challenges on the management of Peg-ASP associated toxicity. A group of 19 clinical experts in the field then rated these statements using the 5-point Likert-type scale (1 = strongly disagree; 5 = strongly agree). Results The main Peg-ASP related issues identified by the board included: 1) clinician’s attitudes; 2) toxicity profile; 3) hypersensitivity reactions; 4) hepatic toxicity; 5) hepatic and/or metabolic toxicity; 6) hemorrhagic/thrombotic toxicity; 7) pancreatitis; 8) metabolic toxicity management and prevention; 9) activity levels monitoring. Overall, participants agreed on most statements, except those addressing the potential contraindications to the treatment with Peg-ASP, such as patients with a diagnosis of chronic liver disease or the subsequent administrations of the drug in patients who had previously developed chemical pancreatitis or severe metabolic toxicity. Participants agreed that adult patients with ALL should receive Peg-Asp because this drug is essential to improve treatment results. Conclusions The panel agreed that a critical evaluation of specific risk factors for each patient is crucial in order to reduce the risk of adverse events and specific advices in the management of Peg-ASP toxicities are reported.

Chest pain is a common cause to admission to the pediatric emergency department and often leads to an extensive cardiac evaluation. The objective of this study was to evaluate the usefulness of the troponin (TN) plasma level determination in the initial phase of the differential diagnosis of chest pain in children.This is a retrospective observational study on 107 patients, aged 0 to 19 years, admitted for chest pain to the pediatric emergency department of our institution. Demographics, clinical data, and patient outcomes were analyzed. Troponin values of0.03 ng/mL but0.1 ng/mL were considered suspected for cardiac pathology, whereas levels of0.1 ng/mL were indicative of cardiac pathology. In these latter patients, an echocardiographic examination was also performed.Only 99 patients were evaluated with electrocardiogram (ECG). In 91 of 99 patients of our series, both TN determination and ECG recording were performed. Troponin was higher than the cutoff value (0.03 ng/mL) in 9 patients (9.1%). Only 2 of the 9 patients who presented high TN values showed a nonpathological ECG, whereas 16 (17.5%) of 91 patients in whom both ECG and TN determination were performed had ECG abnormalities without a simultaneous elevation of TN. Of the 26 patients who had medical history and suggestive targets of cardiac pathology, only in 6 (23.1%) of them the diagnosis was confirmed. The final diagnosis of the 99 patients was idiopathic chest pain in 45.4% of cases.Even with the low cost and the relatively easiness for the plasma level determination, TN should be measured only in children with chest pain associated to familiar history suggestive of cardiovascular disease and/or clinical symptoms and/or ECG alterations.Chest pain is a common cause to admission to the pediatric emergency department and often leads to an extensive cardiac evaluation. The objective of this study was to evaluate the usefulness of the troponin (TN) plasma level determination in the initial phase of the differential diagnosis of chest pain in children.This is a retrospective observational study on 107 patients, aged 0 to 19 years, admitted for chest pain to the pediatric emergency department of our institution. Demographics, clinical data, and patient outcomes were analyzed. Troponin values of0.03 ng/mL but0.1 ng/mL were considered suspected for cardiac pathology, whereas levels of0.1 ng/mL were indicative of cardiac pathology. In these latter patients, an echocardiographic examination was also performed.Only 99 patients were evaluated with electrocardiogram (ECG). In 91 of 99 patients of our series, both TN determination and ECG recording were performed. Troponin was higher than the cutoff value (0.03 ng/mL) in 9 patients (9.1%). Only 2 of the 9 patients who presented high TN values showed a nonpathological ECG, whereas 16 (17.5%) of 91 patients in whom both ECG and TN determination were performed had ECG abnormalities without a simultaneous elevation of TN. Of the 26 patients who had medical history and suggestive targets of cardiac pathology, only in 6 (23.1%) of them the diagnosis was confirmed. The final diagnosis of the 99 patients was idiopathic chest pain in 45.4% of cases.Even with the low cost and the relatively easiness for the plasma level determination, TN should be measured only in children with chest pain associated to familiar history suggestive of cardiovascular disease and/or clinical symptoms and/or ECG alterations.

Since the 1980s, the development of a pharmacology based on nerve growth factor (NGF) has been postulated for the therapy of Alzheimer’s disease (AD). This hypothesis was based on the rescuing effect of the neurotrophin on the cholinergic phenotype of the basal forebrain neurons, primarily compromised during the development of AD. Subsequently, the use of NGF was put forward to treat a broader spectrum of neurological conditions affecting the central nervous system, such as Parkinson’s disease, degenerative retinopathies, severe brain traumas and neurodevelopmental dysfunctions. While supported by solid rational assumptions, the progress of a pharmacology founded on these hypotheses has been hampered by the difficulty of conveying NGF towards the brain parenchyma without resorting to invasive and risky delivery methods. At the end of the last century, it was shown that NGF administered intranasally to the olfactory epithelium was able to spread into the brain parenchyma. Notably, after such delivery, pharmacologically relevant concentration of exogenous NGF was found in brain areas located at considerable distances from the injection site along the rostral-caudal axis. These observations paved the way for preclinical characterization and clinical trials on the efficacy of intranasal NGF for the treatment of neurodegenerative diseases and of the consequences of brain trauma. In this review, a summary of the preclinical and clinical studies published to date will be attempted, as well as a discussion about the mechanisms underlying the efficacy and the possible development of the pharmacology based on intranasal conveyance of NGF to the brain.

Background Very few studies describe factors associated with COVID-19 diagnosis in children. Aim We here describe characteristics and risk factors for COVID-19 diagnosis in children tested in 20 paediatric centres across Italy. Methods We included cases aged 0–18 years tested between 23 February and 24 May 2020. Our primary analysis focused on children tested because of symptoms/signs suggestive of COVID-19. Results Among 2,494 children tested, 2,148 (86.1%) had symptoms suggestive of COVID-19. Clinical presentation of confirmed COVID-19 cases included besides fever (82.4%) and respiratory signs or symptoms (60.4%) also gastrointestinal (18.2%), neurological (18.9%), cutaneous (3.8%) and other unspecific influenza-like presentations (17.8%). In multivariate analysis, factors significantly associated with SARS-CoV-2 positivity were: exposure history (adjusted odds ratio (AOR): 39.83; 95% confidence interval (CI): 17.52–90.55; p Conclusion Recommendations for SARS-CoV-2 testing in children should consider the evidence of broader clinical features. Exposure history, fever and anosmia/ageusia are strong risk factors in children for positive SARS-CoV-2 testing, while other symptoms did not help discriminate positive from negative individuals. This study confirms that COVID-19 was a mild disease in the general paediatric population in Italy. Further studies are needed to understand risk, clinical spectrum and outcomes of COVID-19 in children with pre-existing conditions.

This letter describes a cohort of 100 children younger than 18 years of age with RT-PCR-confirmed Covid-19 who were assessed in 17 pediatric emergency departments in Italy. The descriptive results are compared with previously published results involving children in China and the United States.

Kawasaki disease (KD) is a childhood vasculitis of unknown etiology. The present study describes a case of KD shock syndrome that occurred in an infant (age, 16 months) following 7 days of high fever and persistent rash characterized by target-like and purpuric skin lesions. The child developed neurological manifestations such as altered consciousness and irritability. Consequently, brain magnetic resonance imaging (MRI) was performed, revealing an inflammatory involvement of the anterior perforated substance and the hypothalamus. Cerebral involvement on brain MRI is rarely described in KD but when reported is characterized mostly by cerebral vasculitis. We illustrate for the first time in KD an inflammation in the brain not related to vasculitis, reporting peculiar neuroradiological findings. This last aspect has fascinated us in light of recent evidence about the immunological spectrum of Multisystem Inflammatory Syndrome in Children (MIS-C) and Kawasaki-like syndrome in the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) outbreak.

The causal connection between serum biomarkers and COVID-19 severity or pathogenicity in children is unclear. The aim of this study was to describe clinical and immunological features of children affected by COVID-19. The secondary aim was to evaluate whether these cytokines could predict severity of COVID-19. All children (aged 0−18) admitted to the Pediatric Emergency Department and tested with nasopharyngeal swab for SARS-CoV-2 were recruited and assigned to three groups: COVID-19, other infections, control group. Clinical and laboratory data of these patients, including circulating cytokine levels, were analyzed in three groups. Fever was the most frequent symptom in COVID-19 (67.3%). Neutropenia was found in the COVID-19 group (p &lt, 0.05), no difference was observed for lymphocyte counts in the three groups. Higher levels of IL-6 and TNF-alpha were found in the COVID-19 group compared to other infections and control groups (p = 0.014 and p = 0.001, respectively). Whereas, in the COVID-19 group, no difference was observed as for the same cytokines among sub-groups of different disease severity (p = 0.7 and p = 0.8). Serum levels of IL-6 and TNF-alpha were higher in COVID-19 children than in children with other infectious diseases, but those levels did not correlate with disease severity. Clinical studies in a large pediatric population are necessary to better define the role of the immune-mediated response in SARS-CoV-2 infections in children.

The aim of this prospective, analytic study is to evaluate if dietary approach can improve the body mass index (BMI) in a total of N = 152 patients with SB. BMI levels were evaluated stratifying patients by gender and age classes. Patients with BMI ≥ 25 have been randomized (1:1) in two groups: the “diet” group that received a dietary program and the “no diet” group that did not receive any program. Patients have been observed at the beginning of the study (T0), and again at the end of the study, 1 year later (T1). The main objective of the study was to evaluate BMI score in SB patients and how it could be influenced by dietary changes. A total of 36.8% patients were classified as overweight or obese. Females present a mean BMI level higher than male, and patients older than 20 years old present the highest mean BMI. The “diet” group BMI decreased from 29.7 (± 3.8) to 27.7 (± 3.7) during the year of program. The mean BMI in the “no diet” group decreased from 30.3 (± 4.6) to 29.2 (± 4.7). There was a statistically significant difference in BMI level between groups (p

Clofarabine (CLO) and cyclophosphamide (CY) combinations were tested in late stage refractory/relapsed (R/R) acute lymphoblastic leukemia (ALL) with disappointing results and high-grade toxicity. We designed a sequential 5-day combination of CLO 40 mg/m

Aim To assess the impact of the coronavirus disease 2019 (COVID‐19) outbreak on pediatric emergency department (ED) visits for acute bronchiolitis during the epidemic season. Methods A retrospective analytical cross‐sectional study was performed in our hospital, analyzing medical charts of all children under 2 years of age with a diagnosis of acute bronchiolitis admitted to our ED in the last years. Demographics and clinical data of patients affected with acute bronchiolitis during the 2020–2021 season—COVID‐19 outbreak—were compared to those of the 5 previous years. Results We observed an average drop of 84% of the rate of acute bronchiolitis managed by pediatricians in ED in 2020–2021 compared with bronchiolitis seasons of 5 previous years. We also reported, during the COVID‐19 outbreak, a higher number of children affected by acute bronchiolitis referred to ED as Emergency Consultations who required hospitalization. Regarding etiological agents, no differences in respiratory virus circulation, especially RSV, were observed in the two groups. The multivariate analysis showed no correlation between the diagnosis of RSV bronchiolitis and COVID‐19 period or prematurity; lower age was associated with an increased likelihood of exhibiting RSV bronchiolitis (odds ratio 0.9; 95% confidence interval 0.86–0.95 p

BackgroundNo study has described factors associated with COVID-19 diagnosis in children.AimDescribe characteristics and risk factors for COVID-19 diagnosis in children tested in 20 pediatric centers across Italy.MethodsCases aged 0-18 years tested for SARS-CoV-2 between February 23 and May 24 2020 were included. Our primary analysis focused on children tested because of COVID-19 suggestive symptoms.ResultsAmong 2494 children tested for SARS-CoV-2, 2148 (86.1%) had symptoms suggestive of COVID-19. Clinical presentation of SARS-CoV-2 included - beside fever (82.4%) and respiratory signs or symptoms (60.4%) – also gastrointestinal (18.2%), neurological (18.9%), cutaneous (3.8%) and other flu-like presentations (17.8%). In multivariate analysis, factors significantly associated with SARS-CoV-2 were: exposure history (adjusted OR 39.83 95%CI 17.52-90.55 pConclusionRecommendations for SARS-CoV-2 testing in children should be updated based on the evidence of broader clinical features. Exposure history, fever, and anosmia/ageusia are strong risk factors for COVID-19 in children, while other symptoms don’t seem helping discriminating in between the SARS-CoV-2 positive and the negative cases. This study confirm that COVID-19 is a mild disease in the general population of children in Italy. Further studies are needed to understand the risk, clinical spectrum and outcomes of COVID-19 in children with specific preexisting conditions.

This study aims to evaluate the efficacy of the PECARN Rule (PR) in reducing radiological investigations in children with mild traumatic head injury in comparison with current clinical practice. A retrospective study was performed in our hospital between July 2015 and June 2020. Data of all children Conclusion: We demonstrated the safety and validity of the PR in our setting with 100% sensitivity in both age groups in identifying patients with ciTBI and theoretically in reducing performed CT scans by 29%. Therefore, in patients classified in the low-risk category, it is a duty not to expose the child to ionizing radiation. What is Known:• CT is the gold standard to identify intracranial pathology in children with head injury but CT imaging of head-injured children expose them to higher carcinogenic risk.• PECARN Rules support doctors in identifying children with ciTBI in order to reduce exposure to ionizing radiation. What is New:• We demonstrate the safety and validity of the PR with 100% sensitivity in both age groups in identifying patients with ciTBI.• In our setting, the application of PECARN Rule would theoretically have allowed us to reduce the CT scan by 29%.

Early recognition of Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) cases could impact on the management and outcome of this subset of B-lineage ALL. In order to assess the prognostic value of the Ph-like status in a pediatric-inspired, minimal residual disease (MRD)- driven trial, we screened 88 B-lineage ALL cases negative for major fusion genes (BCR-ABL1, ETV6-RUNX1, TCF3-PBX1 and KTM2Ar) enrolled in the GIMEMA LAL1913 front-line protocol for adult BCR/ABL1-negative ALL. The screening - performed using the “BCR/ABL1-like predictor” - identified 28 Ph-like cases (31.8%), characterized by CRLF2 overexpression (35.7%), JAK/STAT pathway mutations (33.3%), IKZF1 (63.6%), BTG1 (50%) and EBF1 (27.3%) deletions, and rearrangements targeting tyrosine kinases or CRLF2 (40%). The correlation with outcome highlighted that: i) the complete remission rate was significantly lower in Ph-like compared to non-Phlike cases (74.1% vs. 91.5%, P=0.044); ii) at time point 2, decisional for transplant allocation, 52.9% of Ph-like cases versus 20% of non-Ph-like were MRD-positive (P=0.025); iii) the Ph-like profile was the only parameter associated with a higher risk of being MRD-positive at time point 2 (P=0.014); iv) at 24 months, Ph-like patients had a significantly inferior event-free and disease-free survival compared to non-Ph-like patients (33.5% vs. 66.2%, P=0.005 and 45.5% vs. 72.3%, P=0.062, respectively). This study documents that Ph-like patients have a lower complete remission rate, event-free survival and disease-free survival, as well as a greater MRD persistence also in a pediatric-oriented and MRD-driven adult ALL protocol, thus reinforcing that the early recognition of Ph-like ALL patients at diagnosis is crucial to refine risk-stratification and to optimize therapeutic strategies. Clinicaltrials gov. Identifier: 02067143.

Phlebotonics’ effects were evaluated to reduce time-to-stop bleeding and anal irritation in 130 patients who complained of hemorrhoidal disease (HD); bleeding and pain after hemorrhoidectomy (31 patients) and hemorrhoidal thrombosis (34 patients) in the short time. Sixty patients were randomized to receive the routine treatment (both conservative and surgical) (control Group C). The treated group (both conservative and surgical) was divided into two subgroups: one treated with flavonoids (Group A, n = 73), the other with Centella (Group B, n = 66). Time-to-stop bleeding was checked at baseline and checkups (0 up to day 42). Healing was estimated with Kaplan-Meier method, the Kruskal-Wallis test estimated changes in the VAS scores. The HD median time-to-stop bleeding was 2 weeks for Groups A and B; 3 weeks for Group C. VAS scores comparison among Groups (irritation): A vs C, p = 0.007; B vs C, p = 0.041; and A vs B, p = 0.782 resulted respectively. As for operated hemorrhoids, the time-to-stop bleeding was 3 and 4 weeks in Groups A and B and 5 in Group C. Histopathology showed an association between flavonoids and piles’ fibrosis (p = 0.008). Phlebotonics in HD, as well as after surgery, showed significant beneficial effects. Flavonoids are the most effective phlebotonics against bleeding and anal irritation.

Objectives- We prospectively analyzed children with acute chest pain and clinical suspicion of pneumothorax (PNX) evaluated at the pediatric Emergency Department. Methods- After clinical examination and before Chest X-Ray, children underwent LUS to evaluate the presence of PNX. We enrolled 70 children, 13 (18,57%) received a final diagnosis of PNX. Results- In all 13 (100%) patients LUS showed the “bar-code sign”, the absence of lung sliding and the absence of B lines while in 12 (92,3%) there was the lung point, giving a diagnosis of PNX. All cases had PNX features on CXR. The “bar-code sign”, the absence of lung sliding and the absence of B lines had a sensitivity of 100% and a specificity of 100%. The “bar-code sign” had a positive predictive value of 100% and a negative predictive value of 100% for the detection of PNX. Conclusions- LUS is highly accurate in detecting or excluding pneumothorax in children with acute chest pain evaluated in the pediatric emergency department.

Background Suspending ordinary care activities during the COVID-19 pandemic made it necessary to find alternative routes to comply with care recommendations not only for acute health needs but also for patients requiring follow-up and multidisciplinary visits. We present the ‘Contactless’ model, a comprehensive operational tool including a plurality of services delivered remotely, structured according to a complexity gradient, aimed to cover diagnostic procedures and monitor disease progression in chronic pediatric patients. Methods A multidisciplinary and multiprofessional project team was recruited, in collaboration with patients’ associations, to map a panel of available Evidence-Based solutions and address individual needs in full respect of the concept of personalized medicine. The solutions include a number of services from videoconsultations to more structure videotraining sessions. Results A modular framework made up of four three Macro-levels of complexity - Contactless Basic, Intermediate and Advanced - was displayed as an incremental set of services and operational planning establishing each phase, from factors influencing eligibility to the delivery of the most accurate and complex levels of care. Conclusion The multimodal, multidisciplinary ‘Contactless’ model allowed the inclusion of all Units of our Pediatric Department and families with children with disability or complex chronic conditions. The strengths of this project rely on its replicability outside of pediatrics and in the limited resources needed to practically impact patients, caregivers and professionals involved in the process of care. Its implementation in the future may contribute to reduce the duration of hospital admissions, money and parental absence from work.

Botulism is a neuroparalytic syndrome caused by a neurotoxin produced by Clostridium botulinum. We describe a patient with neurological symptoms associated with intoxication by Clostridium botulinum and infection by SARSCoV2. This report underlines that it is mandatory, even in case of SARS-CoV-2 positivity, to investigate all the causes of a clinical pattern.

Introduction: The broadening of targeted and immunotherapeutic strategies markedly impacted on the management of acute lymphoblastic leukemia (ALL). The advent of tyrosine kinase inhibitors (TKIs) changed the history of Philadelphia-chromosome positive (Ph+) ALL. Nowadays, almost all Ph+ ALL patients treated with TKIs achieve a complete hematologic response, and most become minimal residual disease negative. In Ph- ALL, genomic profiling studies have identified a subtype associated with a high relapse risk and a transcriptional profile similar to that of Ph+ ALL, the so-called Ph-like ALL. Given the high prevalence of kinase-activating lesions in this subset, there is compelling evidence from experimental models and clinical observations favoring TKI administration.Areas covered: We discuss the main findings exploring the efficacy of TKIs in ALL.Expert opinion: The use of more potent TKIs will further enhance the inhibitory activity on leukemia cells and increase the possibility of eradicating the disease at a molecular level. In the future, 'combined' approaches of different inhibitors may be considered to prevent/avoid resistance and/or mutations. A rapid identification of Ph-like ALL patients is needed to propose early TKI-based intervention. Several questions remain open, including the initial TKI choice in Ph+ ALL and whether Ph-like ALL patients might benefit from immunotherapy.

Invasive diagnostics and minor surgical procedures with deep sedation on pediatric patients, such as fibroscopic examination, have increased over the past decade. The aim of this study was to evaluate the usefulness and safety of an anesthesiological technique, based on the use of midazolam and ketamine, conducted in spontaneous breathing on a population of pediatric patients with suspected tracheobronchial pathologies. Pediatric patients from birth to 18 years old who underwent sedation diagnostic fibroscopy between April 2018 and March 2019, were enrolled. The anesthesiological technique provided was the intravenous administration of midazolam 0.2 mg/kg and ketamine 2 mg/kg in spontaneous breathing using a face mask with support of O2 and air. Vital signs such as Heart rate (HR), Systolic and Diastolic blood pressure (PAS and PAD) and Arterial oxygen saturation were recorded at the beginning of the procedure, 10 minutes and 30 minutes from the start. Other parameter evaluated were patient’s level of consciousness, quality of the procedure, major and minor complications, adequate recovery of the waking state. Sixteen patients were enrolled, 12 males and 4 females aged between 2 days of life and 7 years. Laryngomalacia tracheomalacia, tracheoesophageal fistula, and congenital airway malformations were the most frequent diseases. As for vital signs: the HR has gone from an average value of 133.4 ± 16.26 bpm at T0 to an average value of 129.3 ± 16.55 bpm at T10 and 133.7 ± 17.35 bpm at T30; PAS and PAD had not significant variations. Among drugs available for the fibroscopic examinations, the combined use of intravenous midazolam 0.2 mg/kg and ketamine 2 mg/kg is safe and well tolerated, reducing the anxiety associated with the examination, without major complications. The current literature is lacking in studies that have included such small and low weight patients. It would be interesting to make a comparison between various sedation techniques in order to identify the safest for the pediatric population.

Acute pain is one of the most common symptoms in children admitted to the Pediatric Emergency Department (PED) and its management represents a real clinical challenge for pediatricians. Different painful procedures can be very stressful for young children and their perception of pain can be enhanced by emotional factors, such as anxiety, distress, or anger. Adequate procedural sedation reduces anxiety and emotional trauma for the patient, but it reduces also stress for operators and the time for procedures. We have reviewed the literature on this topic and the drugs covered in these papers were: midazolam, fentanyl, ketamine, and dexmedetomidine. There are several routes of administering for these drugs to provide analgesia and anxiolysis to children: oral, parenteral, or intranasal (IN). Intravenous (IV) sedation, since it involves the use of needles, can be stressful; instead, IN route is a non-invasive procedure and generally well tolerated by children and it has become increasingly widespread. Some medications can be administered by a mucosal atomizer device (MAD) or by drops. The benefits of the atomized release include less drug loss in the oropharynx, higher cerebrospinal fluid levels, better patient acceptability, and better sedative effects. IN midazolam has a sedative, anxiolytic and amnesic effect, but without analgesic properties. Fentanyl and ketamine are mainly used for pain control. Dexmedetomidine has anxiolytic and analgesic properties. In conclusion, IN analgo-sedation is a simple, rapid and painless option to treat pain and anxiety in the PED requiring brief training on the administration process and experience in sedation.

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Ph+ acute lymphoblastic leukemia patients, was based on a dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or chemotherapy and/or allogeneic transplantation in patients not reaching a complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and 9 p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved a complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained a complete molecular response. Among non-complete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months, range 3-40.1), 13 during consolidation and 4 post-transplant. ABL1 mutations (5 T315I, 3 V299L, 1 E281K and 1 G254E) were found in 10/13 relapsed cases. With a median follow-up of 57.4 months (range: 4.2-75.6), overall survival and disease-free survival are 56.3% and 47.2%. A better diseasefree survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (p=0.005 and p=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemo-free induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up. EudraCT 2010-019119-39

In Ph+ acute lymphoblastic leukaemia (Ph+ ALL), minimal residual disease (MRD) is the most relevant prognostic factor. Currently, its evaluation is based on quantitative real-time polymerase chain reaction (Q-RT-PCR). Digital droplet PCR (ddPCR) was successfully applied to several haematological malignancies. We analyzed 98 samples from 40 Ph+ ALL cases, the majority enrolled in the GIMEMA LAL2116 trial: 10 diagnostic samples and 88 follow-up samples, mostly focusing on positive non-quantifiable (PNQ) or negative samples by Q-RT-PCR to investigate the value of ddPCR for MRD monitoring. DdPCR BCR/ABL1 assay showed good sensitivity and accuracy to detect low levels of transcripts, with a high rate of reproducibility. The analysis of PNQ or negative cases by Q-RT-PCR revealed that ddPCR increased the proportion of quantifiable samples (p

We investigated MYB rearrangements (MYB-R) and the levels of MYB expression, in 331 pediatric and adult patients with T-cell acute lymphoblastic leukemia (T-ALL). MYB-R were detected in 17 cases and consisted of MYB tandem duplication (tdup) (= 14) or T cell receptor beta locus (TRB)-MYB (= 3). As previously reported, TRB-MYB was found only in children (1.6%) while MYB tdup occurred in both age groups, although it was slightly more frequent in children (5.2% vs 2.8%). Shared features of MYB-R T-ALL were a non-early T-cell precursor (ETP) phenotype, a high incidence of NOTCH1/FBXW7 mutations (81%) and CDKN2AB deletions (70.5%). Moreover, they mainly belonged to HOXA (=8), NKX2-1/2-2/TLX1 (=4), and TLX3 (=3) homeobox-related subgroups. Overall, MYB-R cases had significantly higher levels of MYB expression than MYB wild type (MYB-wt) cases, although high levels of MYB were detected in similar to 30% of MYB-wt T-ALL. Consistent with the transcriptional regulatory networks, cases with high MYB expression were significantly enriched within the TAL/LMO subgroup (P = .017). Interestingly, analysis of paired diagnosis/remission samples demonstrated that a high MYB expression was restricted to the leukemic clone. Our study has indicated that different mechanisms underlie MYB deregulation in 30%-40% of T-ALL and highlighted that, MYB has potential as predictive/prognostic marker and/or target for tailored therapy.

Philadelphia chromosome (Ph)-like (or BCR/ABL1-like) acute lymphoblastic leukemia (ALL) is a subtype of B-cell precursor acute lymphoblastic leukemia (B-ALL) with a transcriptional profile that res...

Objective and designOur prospective study is one of the largest prospective study assessing the role of detailed lung ultrasound features to discriminate the etiological diagnosis of Community acquired pneumonia (CAP) in children.MethodologyWe prospectively analysed patients aged from 1 month to 17 years admitted between March 2018 and April 2020 who were hospitalized for CAP. For all patients included in the study, history, clinical parameters, microbiological data, and lung ultrasound data were collected.Patients were stratified into three main groups (“bacterial”, “viral”, “atypical”) according to the presumed microbial aetiology and lung ultrasound findings evaluated according to the aetiological group.ResultsWe found that some ultrasound findings as size, number and distribution of consolidations, the position and motion of air bronchograms, pleural effusions and distribution of vertical artifacts significantly differ (p < 0.05) in children with bacterial, viral and atypical CAP. Conversely, clinical parameters and laboratory were not able to significantly distinguish between these groups. Chest x-ray, despite being still widely used, was the less useful tool in this discrimination.ConclusionOur study provides a detailed analysis of LUS features able to predict the etiology CAP in children. These findings may help the physicians to better manage a child with CAP and to offer personalized approach, from diagnosis to treatment and follow-up.

Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) represent a unique patient population with specific characteristics and needs. Growing evidences suggest that pediatric-inspired approaches improve the outcome in AYA. These results prompted the design of a pediatric AIEOP-BFM ALL 2000-based regimen - the GIMEMA LAL-1308 protocol - for newly diagnosed AYA (range 18-35 years) with Philadelphia negative (Ph-) ALL. The protocol included minimal residual disease (MRD) analysis at two different time-points (TP), that is, at the end of induction IA and consolidation IB, and a modulation in post-consolidation intensity according to MRD. Seventy-six patients were eligible between September 2010 and October 2014. The regimen was well tolerated, with 2.7% induction deaths and no deaths in the post-consolidation phase. The complete response (CR) rate was 92%; the 48-month overall survival (OS) and disease-free survival (DFS) were 60.3% and 60.4%. Both OS and DFS were significantly better in T-ALL than B-ALL. A molecular MRD

Background: Suspending ordinary care activities during the COVID-19 pandemic made it necessary to find alternative routes to comply with care recommendations not only for acute health needs but also for patients requiring follow-up and multidisciplinary visits. We present the ‘Contactless’ model, a comprehensive operational tool including a plurality of services delivered remotely, structured according to a complexity gradient, aimed to cover diagnostic procedures and monitor disease progression in chronic pediatric patients. Methods: A multidisciplinary and multiprofessional project team was recruited, in collaboration with patients’ associations, to map a panel of available Evidence-Based solutions and address individual needs in full respect of the concept of personalized medicine. The solutions include a number of services from videoconsultations to more structure videotraining sessions.Results: A modular framework made up of four three Macro-levels of complexity - Contactless Basic, Intermediate and Advanced - was displayed as an incremental set of services and operational planning establishing each phase, from factors influencing eligibility to the delivery of the most accurate and complex levels of care. Conclusion: The multimodal, multidisciplinary ‘Contactless’ model allowed the inclusion of all Units of our Pediatric Department and families with children with disability or complex chronic conditions. The strengths of this project rely on its replicability outside of pediatrics and in the limited resources needed to practically impact patients, caregivers and professionals involved in the process of care. Its implementation in the future may contribute to reduce the duration of hospital admissions, money and parental absence from work.

Probiotics are living microorganisms, which, upon oral ingestion, may prevent antibiotic-associated diarrhea (AAD) through the normalization of an unbalanced gastrointestinal flora. The objective of this study was to evaluate the benefits of a probiotic combination (Limosilactibacillus reuteri LRE02-DSM 23878 and Lacticaseibacillus rhamnosus LR04-DSM 16605) on the prevention of AAD in an outpatient pediatric setting. Questionnaires were delivered to pediatricians by each patient/parent during the visits after antibiotics and probiotics treatment to monitor physiological parameters. The primary outcome of both groups (probiotics and no probiotics treated) was the evaluation of the prevalence of AAD between the two groups. Evaluation of stool consistency using the Bristol Stool Scale (BSS) score was performed, as well as the evaluation of AAD duration, frequencies of daily evacuation, and the beginning of diarrhea and weight loss during AAD in both groups and related to antibiotic categories. Results indicated that probiotics, at the recommended dosage of 1.2 × 109 CFU (Colony Forming Unit) per day for 30 days, are associated with lower rates of AAD and a decreased number of days with diarrhea, independent of the type of antibiotic used. Moreover, the use of probiotics resulted in a normal stool consistency in a shorter time period, as evaluated by the BSS.

Background: Placement of central venous access devices is a clinical procedure associated with some risk of adverse events and with a relevant cost. Careful choice of the device, appropriate insertion technique, and proper management of the device are well-known strategies commonly adopted to achieve an optimal clinical result. However, the environment where the procedure takes place may have an impact on the overall outcome in terms of safety and cost-effectiveness. Methods: We carried out a retrospective analysis on pediatric patients scheduled for a major neurosurgical operation, who required a central venous access device in the perioperative period. We divided the patients in two groups: in group A the central venous access device was inserted in the operating room, while in group B the central venous access device was inserted in the sedation room of our Pediatric Intensive Care Unit. We compared the two groups in terms of safety and cost-effectiveness. Results: We analyzed 47 central venous access devices in 42 children. There were no insertion-related complications. Only one catheter-related bloodstream infection was recorded, in group A. However, the costs related to central venous access device insertion were quite different: €330–€540 in group A versus €105–€135 in group B. Conclusion: In the pediatric patient candidate to a major neurosurgical operation, preoperative insertion of the central venous access device in the sedation room rather than in the operating room is less expensive and equally safe.

The recent spread of the Covid‐19 infection has raised important questions within the haematology community on how best to manage and treat patients with haematological malignancies, particularly acute leukaemias. Italy has witnessed a dramatic raise in infections and death rates, that has hit in particular certain areas of the most populated Northern regions of the country (Lombardia, Veneto, Piemonte, Emilia Romagna). Within the nationwide Campus ALL programme in the last week of March we sent a questionnaire addressing different issues related to the management of adult ALL patients during the Covid‐19 pandemic to 40 haematology centres located on the entire territory.

The precursor of Nerve Growth Factor (proNGF) is the predominant form of NGF in the brain, where its tissue levels are increased in neurodegenerative diseases. proNGF exists in two main splicing variants, the long proNGF-A and the short proNGF-B. We demonstrated that proNGF-B is selectively increased in the hippocampus of rats affected by early diabetic encephalopathy and that native, purified proNGFs elicit different responses when used to stimulate PC12 cells. Therefore, the evaluation of the proNGF-B/proNGF-A ratio may be of important diagnostic and prognostic value in pathologies characterized by dysfunctions of NGF system. To date there is not clear pharmacological characterization of the different proNGFs variants, due to the lack of a proper recombinant proNGF-A. Using a bioinformatics approach, we predicted aminoacid sites involved in proNGF-A intracellular cleavage/conversion into proNGF-B, we cloned and expressed non-cleavable proNGF-A in HeLa cells and pursued a first characterization of their secretion modalities. Finally, we studied the biological effects of different proNGF-A mutants, stimulating PC12 cells with conditioned media from transfected HeLa cells. Based on our results, we propose the A73Y mutation as essential to obtaining an intact proNGF-A, limiting its conversion to proNGF-B. proNGF-A A73Y is probably released in an activity dependent manner and, when supplied to PC12 cells, shows a moderate differentiative capacity opposed to high neuroprotective potential. This preliminary study lays the foundation for future research aimed at uncovering the selective biological activities of proNGF-A and proNGF-B, and at developing pharmacological treatments that target the unbalance of proNGF system, induced by neurodegeneration.

To shed light onto the molecular basis of Philadelphia chromosome-positive acute lymphoblastic leukemia and to investigate the prognostic role of additional genomic lesions, we analyzed copy number aberrations using the Cytoscan HD Array in 116 newly diagnosed adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia enrolled in four different GIMEMA protocols, all based on a chemotherapy-free induction strategy. This analysis showed that patients with Philadelphia chromosome-positive acute lymphoblastic leukemia carry an average of 7.8 lesions/case, with deletions outnumbering gains (88% versus 12%). The most common deletions were those targeting IKZF1, PAX5 and CDKN2A/B, which were detected in 84%, 36% and 32% of cases, respectively. Patients carrying simultaneous deletions of IKZF1 plus CDKN2A/B and/or PAX5 had a significantly lower disease-free survival rate (24.9% versus 43.3%; P=0.026). The only IKZF1 isoform affecting prognosis was the dominant negative one (P=0.003). Analysis of copy number aberrations showed that 18% of patients harbored MEF2C deletions, which were of two types, differing in size: the longer deletions were associated with the achievement of a complete molecular remission (P=0.05) and had a favorable impact on disease-free survival (64.3% versus 32.1% at 36 months; P=0.031). These findings retained statistical significance also in multivariate analysis (P=0.057). KRAS deletions, detected in 6% of cases, were associated with the achievement of a complete molecular remission (P=0.009). These results indicate that in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia a detailed evaluation of additional deletions - including CDKN2A/B, PAX5, IKZF1, MEF2C and KRAS - has prognostic implications and should be incorporated in the design of more personalized treatment strategies.