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The post-operative pediatric cerebellar mutism syndrome (CMS) affects about one-third of children and adolescents following surgical removal of a posterior fossa tumor (PFT). According to the Posterior Fossa Society consensus working definition, CMS is characterized by delayed-onset mutism/reduced speech and emotional lability after cerebellar or 4th ventricle tumor surgery in children, and is frequently accompanied by additional features such as hypotonia and oropharyngeal dysfunction/dysphagia. The main objective of this work was to develop a diagnostic scale to grade CMS duration and severity. Thirty consecutively referred subjects, aged 1–17 years (median 8 years, IQR 3–10), were evaluated with the proposed Post-Operative Pediatric CMS Survey after surgical resection of a PFT and, in case of CMS, for 30 days after the onset (T0) or until symptom remission. At day 30 (T1), CMS was classified into mild, moderate, or severe according to the proposed scale. CMS occurred in 13 patients (43%, 95% C.I.: 25.5–62.6%), with mild severity in 4 cases (31%), moderate in 4 (31%), and severe in 5 (38%). At T1, longer symptom persistence was associated with greater severity (p = 0.01). Greater severity at T0 predicted greater severity at T1 (p = 0.0001). Children with a midline tumor location and those aged under 5 years at diagnosis were at higher risk of CMS (p = 0.025 and p = 0.008, respectively). In conclusion, the proposed scale is a simple and applicable tool for estimating the severity of CMS at its onset, monitoring its course over time, and providing an early prognostic stratification to guide treatment decisions. What is Known:• Post-operative pediatric Cerebellar Mutism Syndrome (CMS) is a complex phenomenon with a wide spectrum of symptoms that may manifest in children undergoing the resection of a posterior fossa tumor (PFT) and that can result into long-term impairment. What is New:• This study developed and pilot-tested an easily applicable diagnostic and severity scale to grade the duration and the severity of symptoms of the CMS.• The proposed scale was found to be a sensitive instrument to identify even mild CMS presentations.• By scoring not only the duration but also the severity of symptoms the scale allows a more accurate prognostic stratification for an optimal planning of clinical and rehabilitative interventions.

Cesium-halide perovskite quantum dots (QDs) have gained tremendous interest as quantum emitters in quantum information processing applications due to their optical and photophysical properties. However, engineering excitonic states in quantum dots requires a deep knowledge of the coherent dynamics of their excitons at a single-particle level. Here, we use femtosecond time-resolved two-photon near-field scanning optical microscopy (NSOM) to reveal coherences involving a single cesium lead bromide perovskite QD (CsPbBr3) at room temperature. We show that, compared to other nonperovskite nanoparticles, the electronic coherence on a single perovskite QD has a relatively long lifetime of ca. 150 fs, whereas CdSe QDs have exciton coherence times shorter than 75 fs at room temperature. One possible explanation for the longer coherence time observed for the CsPbBr3 perovskite system is related to the exciton fine structure of these perovskite QDs compared to other nanoparticles. These perovskite QDs exhibit interesting optical properties that differ from those of the traditional QDs including bright triplet exciton states. In fact, due to the small amplitude of the energy gap fluctuations of dipole-allowed triplet states in perovskite QDs, the coherent superposition could be preserved for longer times. Furthermore, single-particle excitation approach implemented in this work allows us to remove effects of heterogeneity that are usually present in ensemble averaging experiments at room temperature. The realization of quantum-mechanical phase-coherence of a charge carrier that can operate at room temperature is an issue of great importance for the potential application of coherent electronic phenomena in electronic and optoelectronic devices. These interesting findings provide further evidence of the great potential of these perovskite QDs as candidates for quantum computing and information processing applications.

Building on the argument that corporate boards are responsible for the creation and leveraging of a firm’s intellectual capital (IC), this study empirically examines the relation between boardroom characteristics—namely board size, director independence, leadership structure and gender diversity—and IC efficiency. Additionally, we propose that the family firm (FF) status is a specific condition that moderates the effect of board features on IC efficiency. We test the above propositions using data on 113 nonfinancial firms continuously listed on the Italian stock exchange over the period 2011–2016. The empirical results indicate that (1) IC efficiency is significantly lower in FFs, which challenges previous research claiming that FFs have some performance advantages over non-FFs and (2) that board size and director independence have an opposite effect in FFs and non-FFs (positive and negative, respectively), suggesting that the role of individual board mechanisms as drivers of (or brakes on) IC efficiency is contingent on firm characteristics. This paper extends the empirical literature supporting the link between board composition and IC efficiency, which has been scant and inconclusive. Furthermore, the literature has seldom considered the firm contingencies potentially affecting this relation. Regarding practical implications, our findings indicate that there is no one best way of structuring corporate boards that can fit all firm conditions; specifically, the results call into question conventional ‘best practices’ of board composition that emphasise director independence, suggesting that this governance mechanism may not have a consistent effect on organisational outcomes such as IC efficiency.

Central nervous system (CNS) involvement has been variously studied in pediatric neuromuscular disorders (NMDs). The primary goal of this study was to assess cognitive functioning in NMDs, and secondary aims were to investigate possible associations of cognitive impairment with motor impairment, neurodevelopmental delay, and genotype. This was a cross-sectional study of 43 pediatric patients, affected by six NMDs. Myotonic dystrophy type 1 (DM1) and glycogen storage disease type 2 (GSD2) patients had a delay on the Bayley-III scales. On Wechsler scales, DMD and DM1 patients showed lower FSIQ scores, with an intellectual disability (ID) in 27% and 50%, respectively. FSIQ was normal in Becker muscular dystrophy (BMD), GSD2, and hereditary motor sensory neuropathy (HMSN) patients, while higher individual scores were found in the spinal muscular atrophy (SMA) group. In the DM1 cohort, lower FSIQ correlated with worse motor performance (ρ = 0.84, p < 0.05), and delayed speech acquisition was associated with ID (p = 0.048), with worse cognitive impairment in the congenital than in the infantile form (p = 0.04). This study provides further evidence of CNS in some NMDs and reinforces the need to include cognitive assessment in protocols of care of selected pediatric NMDs.

Purpose The COVID-19 pandemic and related lockdown measures drastically changed health care and emergency services utilization. This study evaluated trends in emergency department (ED) access for seizure-related reasons in the first 8 weeks of lockdown in Italy. Methods All ED accesses of children (

Introduction: Genetic neuromuscular diseases (NMDs) constitute a heterogeneous group of rare conditions, including some of the most disabling conditions in childhood. Recently, advanced technologie...

Background In addition to morphological and cytogenetic features, acute myeloid leukemias are characterized by mutations that can be used for target-therapy; also the minimal/measurable residual disease (MRD) could be an important prognostic factor. The purpose of this retrospective study was to investigate if somatic mutations could represent an additional prognostic value in respect of MRD alone. Method At baseline, 98 patients were tested for NPM1, FLT3, and for WT1 expression; 31 for ASXL1, TET2, IDH1, IDH2, N-RAS, WT1, c-KIT, RUNX1, and DNMT3A. The same genes have been also tested after induction and consolidation. Results Overall, 60.2% of our patients resulted mutated: 24.5% carried mutations of FLT3-ITD, 38.7% of NPM1, 48.4% of c-KIT, 25.8% of N-RAS and 19.3% of IDH2. The probability of achieving a complete response (CR) was higher for younger patients, with low ELN risk score, NPM1-mutated, with low WT1 levels, and without FLT3. The presence of additional mutations represented a poor predictive factor: only 19% of these cases achieved CR in comparison to 43% of subjects without any of it. Concerning survival, it was conditioned by a lower ELN risk score, younger age, reduction > 1 log of the NPM1 mutational burden, disappearance of FLT3 mutations and lower WT1 expression. Regarding the role of the additional mutations, they impaired the outcome of 20% of the already MRD-negative patients. Concerning the possibility of predicting relapse, we observed an increase of the NPM1 mutational burden at the time-point immediately preceding the relapse (about 2 months earlier) in 50% of subjects. Similarly concerning WT1, an increase of its expression anticipated disease recurrence in 64% of cases. Conclusions We demonstrated that additional somatic mutations are able to impair outcome of the already MRD-negative subjects. About MRD, we suggest a prognostic role also for the WT1 expression. Finally, we considered as relevant the assessment of NPM1 quantity clearance instead of the presence/absence of mutations alone. Still remains in doubt the utility in terms of long-term prognosis of a baseline more complex mutational screening; we could hypothesize that it would be useful for those patients where other markers are not available or who reached the MRD negativity. Electronic supplementary material The online version of this article (10.1186/s12935-019-0807-0) contains supplementary material, which is available to authorized users.

BACKGROUND: The post-operative Pediatric Cerebellar Mutism Syndrome (CMS) affects about one-third of children and adolescents following surgical removal of a posterior fossa tumor (PFT). According to the Posterior Fossa Society consensus working definition, CMS is characterized by delayed onset mutism/reduced speech and emotional lability after cerebellar or 4th ventricle tumor surgery in children, with additional common features that include hypotonia and oropharyngeal dysfunction/dysphagia. The main objective of this work was to propose a diagnostic scale to grade CMS duration and severity.METHOD: Thirty consecutive subjects, aged 1-17 years (median 8 years, IQR 7) were evaluated with the proposed Post-Operative Pediatric CMS Survey after surgical resection of a PFT and, in cases of CMS, for the next 30 days after the onset (T0) or until symptom remission. At day 30th (T1), CMS was classified into mild, moderate, or severe according to the proposed Scale.RESULTS: CMS occurred in 13 patients (43.3%, 95% C.I.: 25.5-62.6%), with mild severity in 4 cases (31%), moderate in 4 (31%), and severe in 5 (38%). At T1, longer symptom persistence was associated with greater severity (p=0.01). Greater severity at T0 predicted greater severity at T1 (p=0.0001). Children with a midline tumor location and those aged under 5 years at diagnosis were at higher risk of CMS (p=0.025 and p=0.008, respectively).CONCLUSIONS: The proposed scale is a simple and applicable tool for estimating the severity of CMS at its onset, monitoring its course over time, and providing an early prognostic stratification to guide treatment decisions.

Introduction The aim of this study was to report 36-month longitudinal changes using the North Star Ambulatory Assessment (NSAA) in ambulant patients affected by Duchenne muscular dystrophy amenable to skip exons 44, 45, 51 or 53. Materials and methods We included 101 patients, 34 had deletions amenable to skip exon 44, 25 exon 45, 19 exon 51, and 28 exon 53, not recruited in any ongoing clinical trials. Five patients were counted to skip exon 51 and 53 since they had a single deletion of exon 52. Results The difference between subgroups (skip 44, 45, 51 and 53) was significant at 12 (p = 0.043), 24 (p = 0.005) and 36 months (p≤0.001). Discussion Mutations amenable to skip exons 53 and 51 had lower baseline values and more negative changes than the other subgroups while those amenable to skip exon 44 had higher scores both at baseline and at follow up. Conclusion Our results confirm different progression of disease in subgroups of patients with deletions amenable to skip different exons. This information is relevant as current long term clinical trials are using the NSAA in these subgroups of mutations.

OBJECTIVE: By forcing closure of schools, curtailing outpatient services, and imposing strict social distancing, the COVID-19 pandemic has abruptly affected the daily life of millions worldwide, with still unclear consequences for mental health. This study aimed to evaluate if and how child and adolescent psychiatric visits to hospital emergency departments (EDs) changed during the pandemic lockdown, which started in Italy on February 24, 2020. METHODS: We examined all ED visits by patients under 18 years of age in the 7 weeks prior to February 24, 2020, and in the subsequent 8 weeks of COVID-19 lockdown at two urban university hospitals, in Turin and Rome, Italy. ED visits during the corresponding periods of 2019 served as a comparison using Poisson regression modeling. The clinician's decision to hospitalize or discharge home the patient after the ED visit was examined as an index of clinical severity. RESULTS: During the COVID-19 lockdown, there was a 72.0% decrease in the number of all pediatric ED visits (3,395) compared with the corresponding period in 2019 (12,128), with a 46.2% decrease in psychiatric visits (50 vs 93). The mean age of psychiatric patients was higher in the COVID-19 period (15.7 vs 14.1 years). No significant changes were found in hospitalization rate or in the prevalence distribution of the primary reason for the psychiatric ED visit (suicidality, anxiety/mood disorders, agitation). CONCLUSIONS: In the first 8 weeks of the COVID-19-induced social lockdown, the number of child and adolescent psychiatric ED visits significantly decreased, with an increase in patient age. This decrease does not appear to be explained by severity-driven self-selection and might be due to a reduction in psychiatric emergencies or to the implementation of alternative ways of managing acute psychopathology.

Aim: Early onset of psychopathology is often an index of a more severe clinical course and worse prognosis. This review examined the course of bipolar disorder (BD) with onset in childhood and adolescence, with a focus on persistence of symptoms, severity of illness, comorbidity, and functional impairment. Methods: The databases of PubMed, Embase, and PsycInfo were systematically searched for publications since 1990 reporting on long-term (12 months or longer) assessments of patients with early onset BD. Results: Forty-two relevant publications were identified, which reported on data derived from 15 different patient cohorts, including 7 prospective research psychopathology studies, 4 medical record reviews, 2 follow-ups of clinical trial samples, 1 managed care database, and 1 nationwide registry, for a total of 10,187 patients. The length of follow-ups ranged from 1.0 to 15 years. Diagnostic stability of BD ranged from 73% to 100% over ten years. Recovery rate from an index episode was 81.5–100% and recurrence rate was 35–67%. Suicide attempt cumulative prevalence in five years was 18–20%. Earlier age at the first episode predicted a more severe clinical course. Conclusions: Early onset BD persists over time through adolescence, with homotypic diagnostic continuity over the years, but heterogeneity in the severity of the clinical course. Whether early identification and treatment improves distal prognosis remains to be further investigated.

INTRODUCTION/AIMS: We aim to describe 12-month functional and motor outcome performance in a cohort of participants with congenital myotonic dystrophy (CDM). METHODS: CDM participants performed the Six Minute Walk Test (6MWT), 10 Meter Run, 4 Stair Climb, Grip Strength and Lip Force at baseline and 12 month visits. Parents completed the Vineland Adaptive Behavior Scale. RESULTS: Forty-seven participants, aged 0 to 13 years old, with CDM were enrolled. 6MWT, 10 Meter Run and 4 Stair Climb were completed in >85% of eligible participants. The only significant difference between mean baseline and 12-month performance was an improvement in 6MWT in children 3–6 years old (p=0.008). This age group also had the largest mean % improvement in performance in all other timed functional testing. In children >7 years, the slope of change on timed functional tests decreased or plateaued, with further reductions in performance in children ≥10 years. Participants with CTG repeat lengths 1000. DISCUSSION: 6MWT, 10 Meter Run and 4 Stair Climb were the most feasible measures. Our findings are consistent with the clinical profile and prior cross-sectional data, helping to establish reasonable expectations of functional trajectories in this population as well as identifying points in which therapeutic interventions may be best studied. Further study of outcomes in children >10 years old and

Background: The coronavirus disease 2019 (COVID-19) has abruptly changed the life of millions in the areas stricken by the pandemic as movements and social contacts have been severely restricted. We assessed the psychological impact of COVID-19 on adults and children, with special attention to health care workers (HCWs). Methods: On March 20-26, 2020, a self-rated online survey was conducted in Italy. Psychological impact was assessed with the Impact of Event Scale-Revised (IES-R) in adults, and the Children Revised Impact of Event Scale-Revised-13 items (CRIES-13) in their 8- to 18-year-old offspring. Linear mixed-effects models were applied to the data, accounting for age, sex, education, and other demographic characteristics. Outcomes: Data were available from 2,419 adults (78·4% females, mean age 38·1 ± 13·1 year; 15·7% HCW) and 786 children (50·1% male, mean age 12·3 ± 3·2). Median (IQR) for IES-R score was 30·0 (21·0-40·0), corresponding to mild psychological impact, with 33.2% reporting severe psychological impact. IES-R scores were lower in HCW (29·0) than non-HCW (31·0), but HCW involved in COVID-19 care had higher scores (33·0 [26·0-43·2]) than uninvolved HCW (28·0 [19·0-36·0]). Median CRIES-13 score was 21·0 (11·0-32·0), with 30·9% of the children at high risk for post-traumatic stress disorder. Parent and child scores were correlated. Interpretation: Up to 30% of adult and children in the pandemic area are at high risk for post-traumatic stress disturbances. The risk is greater for HCW directly involved in COVID-19 care and their children. Funding Statement: None. Declaration of Interests: Authors declare they have no conflict of interests. Ethics Approval Statement: Expedited approval was obtained from the institutional ethics committee.

Background and AimsThe pathogenesis of Crohn’s disease [CD] is still unclear. Disorders in the mucosal immunoregulation and its crosstalk with the microbiota may represent an important component in tissue injury. We aimed to characterize the molecular immune response distribution within the ileal layers and to evaluate the correlated microbiota in pathological/healthy settings comparing first surgery/relapse clinical conditions.MethodsWe enrolled 12 CD patients. A comprehensive analysis of an ileal mucosa, submucosa and serosa broad-spectrum cytokine panel was performed through a multiplex approach. In addition, ileal microbiota composition was assessed through next generation sequencing.ResultsWe observed a distinct profile [of IL1-α, IL-1β, IL-4, IL-8, ICAM-1, E-Selectin, P-Selectin, IP-10, IL 6 and IL 18] across the CD vs healthy ileal layers; and a different distribution of IFN- γ, P-Selectin, IL-27 and IL-21 in first surgery vs relapse patients. In addition, the phylum Tenericutes, the family Ruminococcaceae, and the genera Mesoplasma and Mycoplasma were significantly enriched in the pathological setting. Significant microbiota differences were observed between relapse and first surgery patients regarding the class Bacteroidia, and the genera Prevotella, Flavobacterium, Tepidimonas and Escherichia/Shigella. Finally, the abundance of the genus Mycoplasma was positively correlated with IL-18.ConclusionsWe describe a dissimilarity of cytokine distribution and microbiota composition within CD and adjacent healthy ileal tissue layers and between first operation and surgical relapse. Our results give potential insight into the dynamics of the gut microbiota–immune axis in CD patients, leading to detection of new biomarkers.

The aim was to assess 3-year longitudinal data using 6MWT in 26 ambulant boys affected by DMD carrying nonsense mutations and to compare their results to other small mutations. We also wished to establish, within the nonsense mutations group, patterns of change according to several variables. Patients with nonsense mutations were categorized according to the stop codon type newly created by the mutation and also including the adjacent 5' (upstream) and 3' (downstream) nucleotides. No significant difference was found between nonsense mutations and other small mutations (p 0.05) on the 6MWT. Within the nonsense mutations group, there was no difference in 6MWT when the patients were subdivided according to: Type of stop codon, frame status of exons involved, protein domain affected. In contrast, there was a difference when the stop codon together with the 3' adjacent nucleotide ("stop+4 model") was considered (p 0.05) with patients with stop codon TGA and 3' adjacent nucleotide G (TGAG) having a more rapid decline. Our finding suggest that the stop+4 model may help in predicting functional changes. This data will be useful at the time of interpreting the long term follow up of patients treated with Ataluren that are becoming increasingly available.

What happens when corporate financing/investment decisions are made in contexts dominated by strong uncertainty and particular risk?

Knowledge of health related quality of life (HRQOL) in the immediate phase following DMD diagnosis has not been well-characterized. It is important to understand HRQOL early in disease for both clinical care and studies of treatment. The relationship between parent-proxy and child self-report HRQOL and their associations with medical, psycho-social and behavioral symptoms deserve study. In this study HRQOL was measured using the PedsQL inventory in parent/caregiver and corticosteroid-naïve boys (ages 4 to 7 years) participating in the FOR-DMD study. Agreement between the parent-proxy report and the boys' self-report HRQOL was measured using intraclass correlation coefficients (ICCs). Factors associated with HRQOL, including standardized psychosocial and behavioral measures in this cross-sectional sample, were explored using correlations. The results showed that the level of agreement between 70 dyads of child self-report and parent-proxy ratings of HRQOL was poor for the generic PedsQL total score (ICC=0.48, 95% CI (0.23, 0.66)) and its subscale scores, and was similarly low for the neuromuscular disease module (ICC=0.24, 95% CI (0.00, 0.45)). Parents rated their child's HRQOL as poorer than the children rated themselves in all scales. Psychosocial outcome measures were more highly associated with HRQOL measures than disease severity or patient demographic variables. In the early phases of DMD, child and parent-proxy HRQOL ratings were discordant. In early DMD, psychosocial and behavioral aspects appear to be more relevant to HRQOL than disease severity factors.

Although childhood-onset psychiatric disorders are often considered as distinct and separate from each other, they frequently co-occur, with partial overlapping symptomatology. Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) commonly co-occur with each other and with other mental disorders, particularly disruptive behavior disorders, oppositional defiant disorder/conduct disorder (ODD/CD). Whether these associated comorbidities represent a spectrum of distinct clinical phenotypes is matter of research. The aim of our study was to describe the clinical phenotypes of youths with ADHD with and without ASD and/or ODD/CD, based on neuropsychological and psychopathological variables. One-hundred fifty-one participants with ADHD were prospectively recruited and assigned to four clinical groups, and assessed by means of parent-reported questionnaires, the child behavior checklist and the behavior rating inventory of executive functions. The ADHD alone group presented a greater impairment in metacognitive executive functions, ADHD+ASD patients presented higher internalizing problems and deficits in Shifting tasks, and ADHD+ODD/CD subjects presented emotional-behavioral dysregulation. Moreover, ADHD+ASD+ODD/CD individuals exhibited greater internalizing and externalizing problems, and specific neuropsychological impairments in the domains of emotional regulation. Our study supports the need to implement the evaluation of the psychopathological and neuropsychological functioning profiles, and to characterize specific endophenotypes for a finely customized establishment of treatment strategies.

The intensive use of online space has generated extensive benefits. However, it has exposed society to malicious behaviors, causing a global expansion of computer-based criminal activities. In this respect, the aim of this chapter is twofold. First, it explores the economic costs and benefits faced by private firms in the context of their investments in cybersecurity and personal data security activities. Second, it analyzes how the recent legislative innovations on network security, information systems, and the protection of personal data may affect firms’ organization of activities to reduce the risk of security breaches. This study examines the issue utilizing a case-study approach of an Italian firm (Leonardocompany S.p.A.) in the security sector.

OBJECTIVE The objective of this study was to examine psychopathology and its impact on adaptive functioning in a sample of patients affected by Noonan syndrome (NS), a genetically heterogeneous condition with systemic manifestations. METHOD Forty-two subjects affected by NS (23 males and 19 females), aged 5 to 21 years (mean 12.6 ± SD 5.1), were assessed for nonverbal cognitive abilities, with dimensional measures of psychopathology, adaptive functioning, and family quality of life. RESULTS The nonverbal intelligence quotient (IQ) mean was 99.4 ± SD 22.2, with 3 subjects (8%, 95% confidence interval [CI], 1.6%-20.9%) showing cognitive impairment (IQ

Because of increasing survival rates in pediatric oncology, attention is focusing on cancer and its treatment-related side effects. Rehabilitation may reduce their impact. However, the literature does not provide strong evidence regarding rehabilitation pathways. Therefore, the Italian Association of Pediatric Hematology and Oncology organized a consensus conference on the role of rehabilitation of motor impairments in children/adolescents affected by leukemia, central nervous system, and bone tumors to define recommendations for daily practice. The grading of recommendation assessment, developing and evaluation (GRADE) method was used in order to formulate questions, select outcomes, evaluate evidence, and create recommendations. This paper includes the results on the rehabilitation assessment.

SARS-CoV-2 is the viral agent responsible for the pandemic that in the first months of 2020 caused about 400,000 deaths. Among compounds proposed to fight the SARS-CoV-2-related disease (COVID-19), tyrosine kinase inhibitors (TKIs), already effective in Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) and chronic myeloid leukemia (CML), have been proposed on the basis of their antiviral action already demonstrated against SARS-CoV-1. Very few cases of COVID-19 have been reported in Ph+ ALL and in CML Italian cohorts; authors suggested that this low rate of infections might depend on the use of TKIs, but the biological causes of this phenomenon remain unknown. In this study, the CML model was used to test if TKIs would sustain or not the viral replication and if they could damage patient immunity. Firstly, the infection and replication rate of torquetenovirus (TTV), whose load is inversely proportional to the host immunological control, have been measured in CML patients receiving nilotinib. A very low percentage of subjects were infected at baseline, and TTV did not replicate or at least showed a low replication rate during the follow-up, with a mean load comparable to the measured one in healthy subjects. Then, after gene expression profiling experiments, we found that several “antiviral” genes, such as CD28 and IFN gamma, were upregulated, while genes with “proviral” action, such as ARG-1, CEACAM1, and FUT4, were less expressed during treatment with imatinib, thus demonstrating that TKIs are not detrimental from the immunological point of view. To sum up, our data could offer some biological explanations to the low COVID-19 occurrence in Ph+ ALL and CML patients and sustain the use of TKIs in COVID-19, as already proposed by several international ongoing studies.

Graphical abstract, COVID-19 is a medical emergency, with 20 % of patients presenting with severe clinical manifestations. From the pathogenetic point of view, COVID-19 mimics two other well-known diseases characterized by cytokine storm and hyper-activation of the immune response, with consequent organ damage: acute graft-versus-host disease (aGVHD) and macrophage activation syndrome (MAS). Hematologists are confident with these situations requiring a prompt therapeutic approach for switching off the uncontrolled cytokine release; here, we discuss pros and cons of drugs that are already employed in hematology in the light of their possible application in COVID-19. The most promising drugs might be: Ruxolitinib, a JAK1/2 inhibitor, with a rapid and powerful anti-cytokine effect, tyrosine kinase inhibitors (TKIs), with their good anti-inflammatory properties, and perhaps the anti-Cd26 antibody Begelomab. We also present immunological data from gene expression experiments where TKIs resulted effective anti-inflammatory and pro-immune drugs. A possible combined treatment algorithm for COVID-19 is here proposed.

Purpose Methylphenidate (MPH), the first-line medication in children with attention-deficit/hyperactivity disorder (ADHD), is associated with increased risk of sleep disorders. Melatonin has both hypnotic and chronobiotic properties that influence circadian rhythm sleep disorders. This study explores the effectiveness of melatonin in children with ADHD who developed sleep problems after starting MPH. Patients and methods This study, based on a clinical database, included 74 children (69 males, mean age 11.6±2.2 years) naturalistically treated with MPH (mean dosage 33.5±13.5 mg/d). The severity of sleep disorder (sleep onset delay) was recorded at baseline and after a follow-up of at least 4 weeks using a seven-point Likert scale according to the Clinical Global Impression Severity score. Effectiveness of melatonin on sleep (mean dosage 1.85±0.84 mg/d) after 4 weeks was assessed using a seven-point Likert scale according to the Clinical Global Impression Improvement (CGI-I) score, and patients who scored 1 (very much improved) or 2 (much improved) were considered responders. Results Clinical severity of sleep disorders was 3.41±0.70 at the baseline and 2.13±1.05 after the follow-up (P

Background Pompe disease (PD) is a rare condition caused by mutations in gene encoding for the enzyme alpha-glucosidase, resulting in an abnormal intracellular accumulation of glycogen. The disease clinical spectrum ranges from severe infantile forms to adult-onset forms with minor limitations. Since 2000 enzyme replacement therapy (ERT) is available and disease natural history has changed, with prolonged survival and evidence of myopathic features. Methods In this study, we monitored disease progression up to three years in eight young patients with PD. Based on the literature data and the long term personal experience, we selected validated functional scales for neuromuscular disorders and compared the results to identify a simple and reliable protocol for the follow-up of children with PD. Moreover, we evaluated cognitive functions using developmental/cognitive tests. Results Based on study results, we suggest that motor functions in children with PD could be better assessed by Chop Intend, MFM20 (Motor Function Measure Scale for Neuromuscular Diseases 20) and NSAA (North Star Ambulatory Assessment), according to age and functional level. Evaluation should be completed with ROM (Range Of Motion) measurement, MRC (Medical Research Council) evaluation and 6MWT (6 Minute Walk test) when possible. Conclusions The proposed protocol seems to be reliable and should be done every six months, because of the progressive natural history of the disease, the rapid changes typical of developmental age and the need to document ERT effects. About cognitive functions, additional tests to classical intelligence scales (WISC, WPPSI) should be useful to better describe specific neuropsychological profile.

Objectives Biallelic mutations in the SLC25A19 gene impair the function of the thiamine mitochondrial carrier, leading to two distinct clinical phenotypes. Homozygosity for the c.530G > C mutation is invariably associated to Amish lethal microcephaly. The second phenotype, reported only in 8 patients homozygous for different non-Amish mutations (c.373G > A, c.580T > C, c.910G > A, c.869T > A, c.576G > C), is characterized by bilateral striatal necrosis and peripheral polyneuropathy. We report a new patient with the non-Amish SLC25A19 phenotype showing compound heterozygosity for the new variant c.673G > A and the known mutation c.373G > A. Case presentation The natural history of non-Amish SLC25A19 deficiency is characterized by acute episodes of fever-induced encephalopathy accompanied by isolated lactic acidosis and Leigh-like features at magnetic resonance imaging (MRI). Acute episodes are prevented by high-dose thiamine treatment (600 mg/day). As shown in the new case, both mild clinical signs and basal ganglia involvement can precede the acute encephalopathic onset of the disease, potentially allowing treatment anticipation and prevention of acute brain damage. Peripheral axonal neuropathy, observed in 7 out of 9 patients, is not improved by thiamine therapy. In two early treated patients, however, peripheral neuropathy did not occur even on long-term follow-up, suggesting a potential preventive role of treatment anticipation also at the peripheral level. Conclusions Non-Amish SLC25A19 deficiency is an extra-rare cause of Leigh syndrome responsive to thiamine treatment. Ex adiuvantibus thiamine treatment is mandatory in any patient with Leigh-like features.

To define the role of spleen stiffness (SS) and liver stiffness (LS) in myelofibrosis and other Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs), we studied, by ultrasonography (US) and elastography (ES), 70 consecutive patients with myelofibrosis (MF) (no.43), essential thrombocythemia (ET) (no.10), and polycythemia vera (PV) (no.17). Overall, the median SS was not different between patients with MF and PV (p = 0.9), however, both MF and PV groups had significantly higher SS than the ET group (p = 0.011 and p = 0.035, respectively) and healthy controls (p &lt, 0.0001 and p = 0.002, respectively). In patients with MF, SS values above 40 kPa were significantly associated with worse progression-free survival (PFS) (p = 0.012, HR = 3.2). SS also correlated with the extension of bone marrow fibrosis (BMF) (p &lt, 0.0001). SS was higher in advanced fibrotic stages MF-2, MF-3 (W.H.O. criteria) than in pre-fibrotic/early fibrotic stages (MF-0, MF-1) (p &lt, 0.0001) and PFS was significantly different in the two cohorts, with values of 63% and 85%, respectively (p = 0.038, HR = 2.61). LS significantly differed between the patient cohort with MF and healthy controls (p = 0.001), but not between the patient cohorts with ET and PV and healthy controls (p = 0.999 and p = 0.101, respectively). We can conclude that organ stiffness adds valuable information to the clinical work-up of MPNs and could be employed to define patients at a higher risk of progression.

Background Role of erythropoietin (EPO) in the treatment of late anemia in patients with Chronic Myeloid Leukemia (CML) is still undefined. Methods Fifty CML patients treated at 14 institutions with frontline imatinib for at least 12 months and in stable complete cytogenetic response who developed a late chronic anemia treated with EPO were retrospectively evaluated. Results Median time from imatinib start to EPO treatment was 42.2 months [interquartile range (IQR) 20.8-91.9]. Median Hb value at EPO starting time was 9.9 g/dL (IQR 8.9-10.3): Eleven patients (22.0%) were transfusion dependent. Alpha-EPO (40 000 UI weekly) was employed in 37 patients, beta-EPO (30 000 UI weekly) in 9 patients, zeta-EPO (40 000 UI weekly) in 2 patients, and darbepoetin (150 mcg/weekly) in the remaining 2 patients. On the whole, 41 patients (82.0%) achieved an erythroid response, defined as a stable (>3 months) improvement >1.5 g/dL of Hb level, and 9 patients (18.0%) indeed resulted resistant. Among responding patients, 10 relapsed after a median time from EPO start of 20.7 months (IQR 10.8-63.7). No EPO-related toxicity was observed. Conclusions Results of EPO treatment for late chronic anemia during long-lasting imatinib therapy are encouraging, with a high rate of response.

The purpose of this paper is to assess whether a relation exists between stock market valuation and the extent to which Italian listed companies disclose information on their digitalization initiatives. The authors posit that the disclosure of digitalization-related information is a form of intellectual capital disclosure, which provides potentially value-relevant information to investors. Additionally, it is assumed that the reputation for corporate sustainability affects the relation between digitalization disclosure and stock market valuation. To test the aforementioned hypotheses, the authors first quantified the extent of digitalization disclosure by content-analysing the annual reports of 75 Italian listed companies for the years 2011–2017, and then they examined the value relevance of digitalization-related information accounting for the role of corporate sustainability. Empirical results suggest 1) that stock market participants incorporate digitalization-related information into their business valuation process, and 2) that firms with better reputation for corporate sustainability achieve higher valuations from disclosing their digitalization efforts. The potential contribution of this study is manifold: first, it extends prior research on the value relevance of IC disclosure by broadening its scope to include digitalization-related disclosure and evidencing the (moderating) role of corporate sustainability in firm valuation; second, it provides some empirical substance to the discussion on how to measure the value a company extracts from digitalization efforts; and third, it may support the case for increased non-financial disclosure as called for by accounting regulators and standard setters.

Purpose In Italy, most children and adolescents affected by oncological diseases are treated in one of the centers within the Italian Association of Pediatric Hematology and Oncology (AIEOP). AIEOP relies on groups of experts; each of them develops interventions in their specific field of expertise to improve the diagnostic, therapeutic, and assistance pathway of patients and families. Although rehabilitation is an important field in pediatric oncology, until recently there was no working group dedicated to it. This study intends to show the steps that led to the creation of the rehabilitation working group in AIEOP. Methods First of all, a survey to identify the various rehabilitation approaches applied throughout Italian centers was sent via email to 39 AIEOP centers that provide rehabilitation. Results Answers received from 31 centers showed a lack of homogeneity in rehabilitation methods in terms of type of treatment, number of patients, and outcome measurement. Conclusions Some results of the survey were chosen as basic criteria of clinical best practice on which to build the first rehabilitation working-group at the national level to be proposed to the AIEOP commission.

Background and Rationale: Among the key players in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS), microglia and T regulatory lymphocytes (Treg) are candidate cells for modifying the course of the disease. The gut microbiota (GM) acts by shaping immune tolerance and regulating the Treg number and suppressive function, besides circulating neuropeptides, and other immune cells that play in concert through the gut-brain axis. Previous mouse models have shown an altered enteric flora in early stage ALS, pointing to a possible GM role in ALS pathogenesis. Fecal Microbial Transplantation (FMT) is a well-known therapeutic intervention used to re-establish the proper microenvironment and to modulate enteric and systemic immunity. Methods: We are going to perform a multicenter randomized double-blind clinical trial employing FMT as a therapeutic intervention for ALS patients (NCT0376632). Forty-two ALS patients, at an early stage, will be enrolled with a 2:1 allocation ratio (28 FMT-treated patients vs. 14 controls). Study duration will be 12 months per patient. Three endoscopic procedures for intestinal biopsies in FMT and control groups are predicted at baseline, month 6 and month 12; at baseline and at month 6 fresh feces from healthy donors will be infused at patients in the intervention arm. The primary outcome is a significant change in Treg number between FMT-treated patients and control arm from baseline to month 6. Secondary outcomes include specific biological aims, involving in-depth analysis of immune cells and inflammatory status changes, central and peripheral biomarkers of ALS, besides comprehensive analysis of the gut, saliva and fecal microbiota. Other secondary aims include validated clinical outcomes of ALS (survival, forced vital capacity, and modifications in ALSFRS-R), besides safety and quality of life. Expected Results: We await FMT to increase Treg number and suppressive functionality, switching the immune system surrounding motorneurons to an anti-inflammatory, neuroprotective status. Extensive analysis on immune cell populations, cytokines levels, and microbiota (gut, fecal and saliva) will shed light on early processes possibly leading the degenerative ALS course. Conclusions: This is the first trial with FMT as a potential intervention to modify immunological response to ALS and disease progression at an early stage.

Notwithstanding the introduction of Tyrosine Kinase Inhibitors (TKIs) revolutionized the outcome of Chronic Myeloid Leukemia (CML), one third of patients still suspends treatment for failure response. Recent research demonstrated that several BCR/ABL1-independent mechanisms can sustain resistance, but the relationship between these mechanisms and the outcome has not yet been fully understood. This study was designed to evaluate in a “real-life” setting if a change of expression of several genes involved in the WNT/BETA-CATENIN, JAK-STAT, and POLYCOMB pathways might condition the outcome of CML patients receiving TKIs. Thus, the expression of 255 genes, related to the aforementioned pathways, was measured by quantitative PCR after 6 months of therapy and compared with levels observed at diagnosis in 11 CML patients, in order to find possible correlations with quality of response to treatment and event-free-survival (EFS). These results were then re-analyzed by the principal component method (PCA) for tempting to better cluster resistant cases. After 12 months of therapy, 6 patients achieved an optimal response and 5 were “resistant;” after application of both statistical methods, it was evident that in all pathways a significant overall up-regulation occurred, and that WNT was the pathway mostly responsible for the TKIs resistance. Indeed, 100% of patients with a “low” up-regulation of this pathway achieved an optimal response vs. 33% of those who showed a “high” gene over-expression (p = 0.016). Analogously, the 24-months EFS resulted significantly influenced by the degree of up-regulation of the WNT signaling: all patients with a “low” up-regulation were event-free vs. 33% of those who presented a “high” gene expression (p = 0.05). In particular, the PCA analysis confirmed the role of WNT pathway and showed that the most significantly up-regulated genes with negative prognostic value were DKK, WNT6, WISP1, and FZD8. In conclusion, our results sustain the need of a wide and multitasking approach in order to understand the resistance mechanisms in CML.

The purpose of this paper is to review and critically evaluate the extant academic research employing the concept of board capital, which was introduced by Hillman and Dalziel (2003) in order to explain the antecedents of effective board functioning and the resulting impact on firm performance. The emergence of a growing body of empirical literature based on the concept of board capital and the goal of identifying the main research topics and empirical strategies triggered the structured review presented in this paper. This study analyses 64 empirical articles encompassing the concept of board capital using a structured literature review methodology. We narrowed the search to articles published from 2003 to July 2019 and listed in the Scopus database. The selected articles mainly focused on the impact of board capital on firm performance and corporate social responsibility (CSR) disclosure. Other relevant but less numerous works focused on the impact of board capital on firm innovation and firm internationalization. This research also highlights the need for qualitative studies examining the actual process of board monitoring and advising on strategic issues. Additionally, findings revealed a scarcity of empirical studies addressing certain national contexts, including Italy. This study is limited with respect to the analysed time period (2003-July 2019) and to the methodological approach employed to review the selected articles. We found no evidence in published academic journals of any previous literature review on board capital research

The Polycomb gene BMI1 expression exerts a negative predictive impact on several hematological malignancies, such as acute and chronic myeloid leukemia (CML), myelofibrosis, and follicular lymphoma. As already demonstrated in CML, BMI1 is responsible for the resistance to the tyrosine kinase inhibitors (TKIs) in a BCR-ABL1-independent way. Even if, it is unknown where BMI1 in CML is expressed (in progenitors or more mature cells). We decided, therefore, to evaluate if and where the BMI1 protein is located, focusing mainly on the CD34+/CD38-/CD26+ CML progenitors. To begin we measured, by flow cytometry, the proportion of CD34+/CD26+ cells in 31 bone marrow samples from 20 CML patients, at diagnosis and during treatment with imatinib. After that the bone marrow blood smears were stained with antibodies anti-CD26, BCR-ABL1, and BMI1. These smears were observed by a confocal laser microscope and a 3D reconstruction was then performed. At diagnosis, CD34+/CD26+ cells median value/μL was 0.48; this number increased from diagnosis to the third month of therapy and then reduced during treatment with imatinib. The number and behavior of the CD26+ progenitors were independent from the BCR-ABL1 expression, but they summed up what previously observed about the BMI1 expression modulation. In this work we demonstrate for the first time that in CML the BMI1 protein is co-expressed with BCR-ABL1 only in the cytoplasm of the CD26+ precursors; on the contrary, in other hematological malignancies where BMI1 is commonly expressed (follicular lymphoma, essential thrombocytemia, acute myeloid leukemia), it was not co-localized with CD26 or, obviously, with BCR-ABL1. Once translated into the clinical context, if BMI1 is a marker of stemness, our results would suggest the combination of the BMI1 inhibitors with TKIs as an interesting object of research, and, probably, as a promising way to overcome resistance in CML patients.

The aim of the study was to establish 24 month changes in upper limb function using a revised version of the performance of upper limb test (PUL 2.0) in a large cohort of ambulant and non-ambulant boys with Duchenne muscular dystrophy and to identify possible trajectories of progression. Of the 187 patients studied, 87 were ambulant (age range: 7-15.8 years), and 90 non-ambulant (age range: 9.08-24.78). The total scores changed significantly over time (p

Background With conventional enzyme replacement therapy (ERT), the clinical prognosis of classic Pompe disease is often unsatisfactory. About half the patients treated with ERT at the recommended dosage (20 mg/kg every other week) require ventilatory support within the first years of life. The heterogeneous response to ERT has been related to different factors, including cross-reactive immunologic material (CRIM) status and age at ERT initiation. Early treatment with a standard dosage of ERT improves clinical outcome and avoids mechanical ventilation in CRIM-positive patients detected at newborn screening, not preventing persistent hyperCKemia and muscle weakness. Later treatment with higher dosages of ERT was shown to provide similar benefits in CRIM-positive patients. Here, we report the clinical and biochemical outcomes of six patients with classic Pompe disease treated with different dosages of alglucosidase alpha at different ages. Methods A standard dosage of ERT was employed in five patients, sharing a poor prognosis after transient clinical improvements, even in the case of early treatment (four died at 22.2±11.9 months and one survived but required tracheostomy and gastrostomy). Early higher dosage of alglucosidase alpha (40 mg/kg/week from 14 days) was administered to one CRIM-positive patient with fetal persistent bradycardia. Results Early higher dosage of alclucosidase alpha not only achieved normal neuromotor development but also the full correction of biochemical markers of muscle damage until 3 years of age, an unmet target with the standard dosage. Speech delay was not prevented by this approach. Conclusions We suggest that early treatment with a higher dosage of ERT may further improve clinical prognosis in classic Pompe disease.

In the current cross-sectional study, we aimed to investigate the presence and severity of "male" depressive symptoms and suicidal behaviors in psychiatric patients with and without a history of child abuse and neglect, as measured by the Childhood Trauma Questionnaire (CTQ), as well as to explore the associations among childhood maltreatment, "male depression" and suicide risk. The sample consisted of 163 consecutively admitted adult inpatients (80 men; 83 women). The patients were administered the CTQ, Gotland Male Depression Scale (GMDS), and Suicidal History Self-Rating Screening Scale (SHSS). Those with a moderate-severe childhood maltreatment history were more likely to be female (p0.05) and reported more "male depression" (p0.001) and suicidal behaviors (p0.01) as compared to those not having or having a minimal history of child abuse and neglect. In the multivariate analysis, only the minimization/denial scale of the CTQ (odds ratio=0.31; p0.001) and "male depression" (odds ratio=1.83; p0.05) were independently associated with moderate/severe history of child maltreatment. The findings suggest that exposure to abuse and neglect as a child may increase the risk of subsequent symptoms of "male depression", which has been associated with higher suicidal risk.

Objective Individuals with bipolar disorder (BD) usually report significant disability and psychosocial impairment. Both the nature and causes associated with this impairment are poorly understood. In particular, research examining the impact of pharmacotherapy on the different aspects of psychosocial functioning in bipolar patients is currently lacking. The aim of this study was to assess to what extent the psychotropic medications used during psychiatric hospitalization and at discharge can predict clinical psychosocial functioning and the severity of the illness at follow-up in inpatients with bipolar disorder (BD). Methods Patients were 71 adult BD patients contacted on average 31 months after discharge who completed at the follow-up a telephone interview based on the Health of the Nation Outcome Scales (HoNOS). Results All the subjects completed the follow-up assessment between 5 and 75 months after discharge. The mean raw score for the HoNOS-6 was 5.70 ± 5.37. Patients with more severe behavior problems more often had been prescribed atypical antipsychotics and anticonvulsants at discharge. Patients with more severe psychosocial functioning problems more often had a history of suicide attempts, and were more often prescribed anxiolytics during hospitalization and less often prescribed lithium at discharge. Conclusions Having been prescribed anxiolytics and atypical antipsychotics during hospitalization predicted reduced psychosocial functioning, whereas prescription of lithium at discharge was associated with better psychosocial functioning at follow-up. Future studies are needed in order to investigate how psychosocial functioning may be related in the long-term to pharmacological treatment in patients after discharge. Copyright © 2014 John Wiley & Sons, Ltd.

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes (TREX1, RNASEH2B, RNASEH2C, RNASEH2A, ADAR1, SAMHD1, IFIH1) have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in RNASEH2B, SAMHD1 and IFIH1 gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in RNASEH2B and a lower frequency of mutations in TREX1 than those seen in international series. RNASEH2B mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.

Epilepsy is the most common comorbidity in patients with brain tumors. Study Aims: To define characteristics of brain tumor-related epilepsy (BTRE) patients and identify patterns of care. Nationwide, multicenter retrospective cohort study. Medical records of BTRE patients seen from 1/1/2010 to 12/31/2011, followed for at least one month were examined. Information included age, sex, tumor type/treatments, epilepsy characteristics, antiepileptic drugs (AEDs). Time to modify first AED due to inefficacy and/or toxicity was assessed with the Kaplan-Meier method and Cox proportional hazard models were used to identify predictors of treatment outcome. Enrolled were 808 patients (447 men, 361 women) from 26 epilepsy centers. Follow-up ranged 1 to 423 months (median 18 months). 732 patients underwent surgery, 483 chemotherapy (CT), 508 radiotherapy. All patients were treated with AEDs. Levetiracetam was the most common drug. 377 patients (46.7%) were still on first drug at end of follow-up, 338 (41.8%) needed treatment modifications (uncontrolled seizures, 229; side effects, 101; poor compliance, 22). Treatment discontinuation for lack of efficacy was associated with younger age, chemotherapy, and center with 20 cases. About one-half of patients with BTRE were on first AED at end of follow-up. Levetiracetam was the most common drug. A non enzyme-inducing AED was followed by a lower risk of drug discontinuation for SE.

This paper investigates the interplay between board-level governance characteristics, ownership concentration and firm performance in the Italian corporate landscape, which is characterized by high (though varying) degrees of ownership concentration. The empirical setting of this study is the Italian stock market and specifically a sample of non-financial firms included in FTSE MIB and mid-cap index of Milan stock exchange, spanning a five-year time period from 2011 up to 2015. We regressed an accounting proxy for firm performance, namely the return-on-asset (ROA) ratio, on several board-level governance variables and specifically board size, board independence, CEO-chairman duality and audit committee (ACD) full independence. In doing so, we also controlled for the impact of different levels of ownership concentration by partitioning the sample into firms with lower and-higher-than-median values of ownership concentration (OC). The empirical results indicate that board characteristics differently impact performance in firms with lower levels of OC compared to firms with higher OC. Specifically, in lower-OC firms, board independence and AC full independence have a negative impact, whereas CEO duality (either alone or interacted with board independence) has a positive impact on performance. Conversely, higher-OC firms benefit from a large board size and are negatively affected by AC independence, while the remaining variables are not significant. The key insight to be gained from our evidence is that the individual and interaction effects of board-level mechanisms may be contingent on the presence of other governance mechanisms (in this instance, the degree of ownership concentration). As such, this research adds to the existing literature questioning the ‘one-size-fits-all’ approach to corporate boards. In terms of practical implications, our findings support the notion that firms might consider the potential interaction and substitution effects between governance mechanisms and structure boards accordingly

First-line nilotinib in chronic myeloid leukemia is more effective than imatinib to achieve early and deep molecular responses, despite poor tolerability or failure observed in one-third of patients. The toxicity and efficacy of tyrosine kinase inhibitors might depend on the activity of transmembrane transporters. However, the impact of transporters genes polymorphisms in nilotinib setting is still debated. We investigated the possible correlation between single nucleotide polymorphisms of hOCT1 (rs683369 [c.480C>G]) and ABCB1 (rs1128503 [c.1236C>T], rs2032582 [c.2677G>T/A], rs1045642 [c.3435C>T]) and nilotinib efficacy and toxicity in a cohort of 78 patients affected by chronic myeloid leukemia in the context of current clinical practice. The early molecular response was achieved by 81% of patients while 64% of them attained deep molecular response (median time, 26 months). The 36-month event-free survival was 86%, whereas 58% of patients experienced toxicities. Interestingly, hOCT1 and ABCB1 polymorphisms alone or in combination did not influence event-free survival or the adverse events rate. Therefore, in contrast to data obtained in patients treated with imatinib, hOCT1 and ABCB1 polymorphisms do not impact on nilotinib efficacy or toxicity. This could be relevant in the choice of the first-line therapy: patients with polymorphisms that negatively condition imatinib efficacy might thus receive nilotinib as first-line therapy.

International audience; The neuromuscular junction (NMJ) is one of the best-studied cholinergic synapses. Inherited defects of peripheral neurotransmission result in congenital myasthenic syndromes (CMS5), a clinically and genetically heterogeneous group of rare diseases with fluctuating fatigable muscle weakness as the clinical hallmark. Whole-exome sequencing and Sanger sequencing in six unrelated families identified compound heterozygous and homozygous mutations in SLC5A7 encoding the presynaptic sodium-dependent high-affinity choline transporter 1 (CHT), which is known to be mutated in one dominant form of distal motor neuronopathy (DHMN7A). We identified 11 recessive mutations in SLC5A7 that were associated with a spectrum of severe muscle weakness ranging from a lethal antenatal form of arthrogryposis and severe hypotonia to a neonatal form of CMS with episodic apnea and a favorable prognosis when well managed at the clinical level. As expected given the critical role of CHT for multisystemic cholinergic neurotransmission, autonomic dysfunctions were reported in the antenatal form and cognitive impairment was noticed in half of the persons with the neonatal form. The missense mutations induced a near complete loss of function of CHT activity in cell models. At the human NMJ, a delay in synaptic maturation and an altered maintenance were observed in the antenatal and neonatal forms, respectively. Increased synaptic expression of butyrylcholinesterase was also observed, exposing the dysfunction of cholinergic metabolism when CHT is deficient in vivo. This work broadens the clinical spectrum of human diseases resulting from reduced CHT activity and highlights the complexity of cholinergic metabolism at the synapse.