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Background: The current Italian scenario of pediatric palliative care (PPC) services is characterized by inadequate coverage of the territory. Therefore, it is important to improve the referral of patients to the most appropriate setting (community care, general PPC, or specialized PPC) and to improve the delivery of PPC care., Methods: Aiming at obtaining information about the referrals to the Padua Pediatric Hospice that could help estimate the investments needed to improve the provision of care, a retrospective analysis has been carried out. The rate of proper referral and discharge, the number of patients followed at the hospice, the mortality rate, and the length of follow-up were analyzed, and, when possible, data were stratified by oncological and non-oncological diseases., Results: The analysis showed that of the 870 patients referred to the Padua Pediatric Hospice between 2008 and 2022, 76% were affected by non-oncological conditions. 82% of patients referred were taken in charge and most of the remaining patients have been inappropriately referred. The analysis showed a growing number of total referrals, which increased by 195% from 2008 to 2022. An increase in proper referrals and referrals of non-oncological patients was observed alongside a decrease in oncological patient referrals and a trend toward a decrease in discharge rates. A decreased mortality was observed in patients with non-oncological conditions, with only 6% of deceased patients in 2022. Moreover, a longer survival with a median follow-up length of 43 months was observed among patients with non-oncological conditions who were followed up at the Padua Pediatric Hospice for more than 12 months. Conversely, the short survival rate observed for oncological patients suggests that those patients should have been referred to PPC earlier to benefit from palliative care for longer periods., Conclusions: Considering these data, it is expected that the number of patients needing PPC services will steadily increase in the next years. Hence, there is a need to invest resources to provide the best care delivery model encompassing specific pathways for the transition into adulthood, the establishment of networks within all the Italian regions, and an efficient referral to the more suitable setting of care., (© 2024. The Author(s).)

Background: Children with medical complexity (CMC) often require multiple medications, leading to polypharmacy, which seems to be linked to adverse effects, administration errors, and increased caregiver burden. This study aimed to describe the prevalence of polypharmacy, medication burden, off-label drug use, and associated costs., Methods: Conducted at the Pediatric Palliative Care Center of Padua, Italy, from August to October 2021, this cross-sectional observational study included patients up to 23 years old with at least one prescribed drug. Data were collected from medical records and caregiver interviews. Drug costs were collected from the Italian Medicine Agency. Descriptive statistical analysis was performed. For comparisons among categorical variables, the Chi-square test was used, and for those among continuous variables, the ANOVA test was used., Results: This study analyzed treatment regimens of 169 patients with a median age of 12.5 years (0.3-23). Polypharmacy was present in 52.7% of patients, and medication burden was observed in 44.4%, both varying significantly by primary diagnosis ( p < 0.001). The median daily cost per patient was EUR 2.2 (IQR 0.9-7.1), with significant variation among subgroups. Only 34.6% of prescriptions were off-label., Conclusions: polypharmacy and medication burden are frequent among our CMC population, with some differences according to primary diagnosis.

Coenzyme Q (CoQ) is a redox lipid that fulfills critical functions in cellular bioenergetics and homeostasis. CoQ is synthesized by a multi-step pathway that involves several COQ proteins. Two steps of the eukaryotic pathway, the decarboxylation and hydroxylation of position C1, have remained uncharacterized. Here, we provide evidence that these two reactions occur in a single oxidative decarboxylation step catalyzed by COQ4. We demonstrate that COQ4 complements an Escherichia coli strain deficient for C1 decarboxylation and hydroxylation and that COQ4 displays oxidative decarboxylation activity in the non-CoQ producer Corynebacterium glutamicum. Overall, our results substantiate that COQ4 contributes to CoQ biosynthesis, not only via its previously proposed structural role but also via the oxidative decarboxylation of CoQ precursors. These findings fill a major gap in the knowledge of eukaryotic CoQ biosynthesis and shed light on the pathophysiology of human primary CoQ deficiency due to COQ4 mutations., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Chronic kidney disease mineral bone disorder (CKD-MBD) is a condition characterized by alterations of calcium, phosphate, parathyroid hormone (PTH), and fibroblast growth factor 23 (FGF-23) metabolism that in turn promote bone disorders, vascular calcifications, and increase cardiovascular (CV) risk. Nephrologists' awareness of diagnostic, prognostic, and therapeutic tools to manage CKD-MBD plays a primary role in adequately preventing and managing this condition in clinical practice., Methods: A national survey (composed of 15 closed questions) was launched to inquire about the use of bone biomarkers in the management of CKD-MBD patients by nephrologists and to gain knowledge about the implementation of guideline recommendations in clinical practice., Results: One hundred and six Italian nephrologists participated in the survey for an overall response rate of about 10%. Nephrologists indicated that the laboratories of their hospitals were able to satisfy request of ionized calcium levels, 105 (99.1%) of both PTH and alkaline phosphatase (ALP), 100 (94.3%) of 25(OH)D, and 61 (57.5%) of 1.25(OH) 2 D; while most laboratories did not support the requests of biomarkers such as FGF-23 (intact: 88.7% and c-terminal: 93.4%), Klotho (95.3%; soluble form: 97.2%), tartrate-resistant acid phosphatase 5b (TRAP-5b) (92.5%), C-terminal telopeptide (CTX) (71.7%), and pro-collagen type 1 N-terminal pro-peptide (P1NP) (88.7%). As interesting data regarding Italian nephrologists' behavior to start treatment of secondary hyperparathyroidism (sHPT), the majority of clinicians used KDOQI guidelines ( n  = 55, 51.9%). In contrast, only 40 nephrologists (37.7%) relied on KDIGO guidelines, which recommended referring to values of PTH between two and nine times the upper limit of the normal range., Conclusion: Results point out a marked heterogeneity in the management of CKD-MBD by clinicians as well as a suboptimal implementation of guidelines in Italian clinical practice., Competing Interests: J.B. and M.C. are members of the ckj editorial board. M.F. reports other financial or non-financial interest from Amgen, Abiogen, and Vifor. M.Ga. received payment for lectures/presentation from Baxter, Medtronic, Amicus, BD, Sanofi, Vifor Pharma and support for meetings/travel from Astellas, Sanofi. G.C. received payment for lectures/presentation from Amgen, Vifor, AstraZeneca, Boehringer. G.LM. received payment for lectures/presentation fro Astellas, Vifor, Hansa, Biopharma, Eli-Lily, Travere, GlaxoSmithKline. T.N. received grant support from Amgen and consulting fees from Pharmacosmos. S.F. received consulting fees from Amgen, Myovant, UCB, Amolyt, Radius, Agovos and payment for lectures/presentation from Amgen, UCB, Gedeon Richter. J.B. received consulting fees, payment for lectures/presentation and support for attending meetings and/or travel from AMGEN, Abbvie, Sanofi, CSL-Vifor, Astra-Zeneca, Rubió. M.H. received grants from Diaverum, Resverlogix. M.C.M. received payment for lectures/presentation from Amgen, Vifor Pharma, Abiogen. G.T. reports other financial or non-financial interest from Amgen, Biotest, ABBVIE, Janssen-Cilag, Alexion. The remaining authors have no conflicts of interest to disclose., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Background: We report the 4-year follow-up in type I patients treated with nusinersen and the changes in motor, respiratory and bulbar function in relation to subtype, age and SMN2 copy number., Methods: The study included SMA 1 patients with at least one assessment after 12, 24 and 48 months from the first dose of nusinersen. The assessments used were Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and the Hammersmith Infant Neurological Examination (HINE-II)., Results: Forty-eight patients, with ages ranging from 7 days to 12 years (mean 3.3 years, SD 3.6 years) were included in the study. The CHOP INTEND and HINE-II scores significantly increased between baseline and 48 months (p < 0.001). When age at starting treatment subgroups (<210 days, <2 years, 2-4 years, 5-11 years, ≥12 years) were considered, the CHOP INTEND increased significantly in patients younger than 4 years at treatment, while the HINE-2 increased significantly in patients younger than 2 years at treatment. In a mixed-model analysis, age, nutritional and respiratory status were predictive of changes on both scales while SMN2 copy number and decimal classification were not., Conclusions: Our results confirm the safety profile previously reported and support the durability of the efficacy of nusinersen at 4 years with an overall stability or mild improvement and no evidence of deterioration over a long period of time., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background: Efficacy and safety of onasemnogene abeparvovec (OA) for Spinal Muscular Atrophy infants under 7 months and <8.5 kg has been reported in clinical trials. This study examines efficacy and safety predictors in a wide age (22 days-72 months) and weight (3.2-17 kg) range, also including patients previously treated with other drugs., Methods: 46 patients were treated for 12 months between January 2020 and March 2022. Safety profile was also available for another 21 patients with at least 6 month follow-up after OA infusion. 19/67 were treatment naïve when treated with OA. Motor function was measured with the CHOP-INTEND., Findings: CHOP-INTEND changes varied among age groups. Baseline score and age at OA treatment best predicted changes. A mixed model post-hoc analysis showed that in patients treated before the age of 24 months the CHOP-INTEND changes were already significant 3 months after OA while in those treated after the age of 24 months the difference was only significant 12 months after OA. Adverse events occurred in 51/67. The risk for elevated transaminases serum levels was higher in older patients. This was also true for weight and for pre-treatment with nusinersen when analysed individually. A binomial negative regression analysis showed that only age at OA treatment had a significant effect on the risk of elevated transaminases., Interpretation: Our paper describes OA 12-month follow-up showing efficacy across various age and weight groups not targeted by clinical trials. The study identifies prognostic factors for safety and efficacy in treatment selection., Funding: None., Competing Interests: No author has received financial support for the present manuscript. MP, GC, SM, RM, CP reported personal fees from Biogen, Novartis and Roche outside the submitted work; BB reported personal fees from Biogen and Novartis outside the submitted work; AdA reported personal fees from AveXis outside the submitted work; FR reported personal fees from Biogen outside the submitted work; DG, DL, CD, CT reported personal fees from Novartis outside the submitted work; MF reported personal fees from Sanofi and Amicus outside the submitted work; SC reported personal fees from Novartis and Scholar Rock outside the submitted work; RDS reported personal fees from Biogen and Roche outside the submitted work; RF reported personal fees from AveXis, Biogen, Capricor, families of SMA, Ionis Pharmaceuticals, Novartis, Roche, and ScholarRock outside the submitted work; EM reported personal fees from Biogen, Roche, Novartis, Scholar Rock, Epirium and Cytochinetics outside the submitted work; AC, AV, VAS, CA, CB, AP, RO, MR, IB, MS, CD, EA, CT, NB, EB have nothing to disclose., (© 2023 Published by Elsevier Ltd.)

Background: There has been a growing interest in studying the value of physical exercise in children with disabilities or chronic health conditions because of evidence of improvement in quality of life, social acceptance, and physical functioning. However, only scant evidence exists for routine sports activities in children requiring pediatric palliative care (PPC), and in most cases, such evidence has been collected in oncological patients. The Pediatric Hospice of Padua is the referral center for PPC in the Veneto region (northern Italy). Starting from the experience of this PPC center, this pilot study aims to describe the personal experience of children and young people who practice physical activity and their caregivers' perspectives, focusing particularly on the emotional and social impact of exercise and sports practice., Methods: Patients involved in at least one regular and structured sports activity were included in the pilot analysis. Two different ICF-CY (International Classification of Functioning, Disability and Health-Children and Youth Version) scales ("Body Function" and "Activity and Participation") were filled out to assess the children's global functional competence. Two online ad hoc questionnaires were created and administered to children, when able to respond, and caregivers., Results: A total of 9% of patients reported being involved in a sports activity. All children who played sports did not have indications of cognitive retardation. The most practiced sport was swimming. The use of standardized methods such as ICF-CY shown that severe motor impairments do not limit sports accessibility. Questionnaires result suggest that sports are a positive experience for both children needing PPC and their parents. Children encourage other children to do sports and can find the positive side even in difficulties., Conclusion: Since PPC is encouraged as early as the diagnosis of incurable pathologies, the inclusion of sports activities in the context of a PPC plan should be considered from the perspective of improving quality of life., (© 2023. The Author(s).)

Objective: Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. The aim of this study was to assess the prevalence of SMA and treatment prescription in Italy., Methods: An online survey was distributed to 36 centers identified by the Italian government as referral centers for SMA. Data on the number of patients with SMA subdivided according to age, type, SMN2 copy number, and treatment were collected., Results: One thousand two hundred fifty-five patients with SMA are currently followed in the Italian centers with an estimated prevalence of 2.12/100,000. Of the 1,255, 284 were type I, 470 type II, 467 type III, and 15 type IV with estimated prevalence of 0.48, 0.79, 0.79 and 0.02/100,000, respectively. Three patients with SMA 0 and 16 presymptomatic patients were also included. Approximately 85% were receiving one of the available treatments. The percentage of treated patients decreased with decreasing severity (SMA I: 95.77%, SMA II: 85.11%, SMA III: 79.01%)., Discussion: The results provide for the first time an estimate of the prevalence of SMA at the national level and the current distribution of patients treated with the available therapeutical options. These data provide a baseline to assess future changes in relation to the evolving therapeutical scenario., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

The main consequence of the COVID-19 pandemic has been to increase the distance between patients and their doctors and to limit the opportunities to compare experiences and clinical cases in the medical community. Based on this, we adopted a strategy to create networks with the ambition to break down these distances and to unify the process of care and management. Here we report the results and perspectives of our efforts and studies. A summary of the presentations on the topic, held during the webinars organized for macro-areas by the Italian Association of Myology with the aim of raising awareness among "non-expert doctors" who deal with neuromuscular disorders in the era of COVID-19 was collected and here reported. Although the macro-areas responded in different way to the problems of neuromuscular patients in the era of COVID-19, they all have tried to create a network between doctors and opportunity for education and information, with the secondary outcome to have shared process of care and management. Telemedicine, virtual meetings and the strengthening of national and international networks, through research projects, were the nodal and common points. Due to their complexity, neuromuscular diseases had already taught clinicians the importance of multidisciplinary confrontation. COVID-19 has further strengthened the need to create links between clinicians and experts, even of different nationalities, in order to guarantee to patients the best possible care, but above all, access and continuity of care even in critical periods. Adequate answers have been given to these problems, though there is still a lot to improve., (©2021 Gaetano Conte Academy - Mediterranean Society of Myology, Naples, Italy.)

Nusinersen is the first oligonucleotide-based drug that is approved for the treatment of spinal muscular atrophy. In January 2020, the WHO declared COVID-19 a pandemic and nusinersen-provider centers had to postpone planned infusions for some children along with other related interventions. Considering the important contribution that the intrathecal infusions and other support activities could have on the quality of life of spinal muscular atrophy patients and their families, this emergency could have a relevant impact on the course of the pathology. The present work aims to assess the clinical and social issues that arise for spinal muscular atrophy children in care at the referral pediatric palliative care Centre of Padua (Veneto) from a delay in nusinersen infusions, resulting from the contingent COVID-19 restrictions. This evaluation has been carried out in both the short and long term after the first lockdown period and can be considered as a "proxy" of a situation of a possible delay in administration or management of infusions, due to other different causes., Competing Interests: LG and SP were employed by the company Polistudium Srl. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Agosto, Salamon, Giacomelli, Papa, Benedetti and Benini.)

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by muscle atrophy and weakness. SMA type 1 (SMA1) is the most severe form: affected infants are unable to sit unaided; SMA type 2 (SMA2) children can sit, but are not able to walk independently. The Standards of Care has improved quality of life and the increasing availability of disease-modifying treatments is progressively changing the natural history; so, the clinical assessment of nutritional status has become even more crucial. Aims of this multicenter study were to present the growth pattern of treatment-naïve SMA1 and SMA2, and to compare it with the general growth standards., Results: Body Weight (BW, kg) and Supine Length (SL, cm) were collected using a published standardized procedure. SMA-specific growth percentiles curves were developed and compared to the WHO reference data. We recruited 133 SMA1 and 82 SMA2 (48.8% females). Mean ages were 0.6 (0.4-1.6) and 4.1 (2.1-6.7) years, respectively. We present here a set of disease-specific percentiles curves of BW, SL, and BMI-for-age for girls and boys with SMA1 and SMA2. These curves show that BW is significantly lower in SMA than healthy peers, while SL is more variable. BMI is also typically lower in both sexes and at all ages., Conclusions: These data on treatment-naïve patients point toward a better understanding of growth in SMA and could be useful to improve the clinical management and to assess the efficacy of the available and forthcoming therapies not only on motor function, but also on growth., (© 2021. The Author(s).)

Aim: In complex congenital heart diseases (CHD), patients may remain affected by significant morbidity and mortality after surgery. We analysed the end-of-life (EoL) care in children with severe CHD who died in our institution and investigated perspectives of parents and health-care professionals (HCPs)., Methods: Medical records of all children (age < 18 years old) affected by a severe CHD who died in a tertiary cardiac care centre were reviewed. Subsequently, a cross-sectional questionnaire-based study of parents and HCPs of children involved in the study was designed., Results: In total, 30 children died (median age: 45 days; range: 15 days to 3.4 years). Of them, 97% (31/32) died in an intensive care unit setting and were intubated and sedated at EoL. A total of 77% (23/30) died without parents being present at bedside. Eighteen families and 10 HCPs were interviewed. For 61% of the parents (11/18) and 70% of the clinicians (7/10), the goal of therapy at the EoL was 'to lessen your child's suffering as much as possible'. Overall, 44% of parents (8/18) and 50% of HCPs recognised that their child had no chance of survival 'a few days before the child died'., Conclusions: We believe that these data suggest an unconscious reluctance to change goals of care in EoL, shifting from intensive care to comfort and quality of life., (© 2020 Paediatrics and Child Health Division (The Royal Australasian College of Physicians).)

Background: Body composition assessment is paramount for spinal muscular atrophy type I (SMA I) patients, as weight and BMI have proven to be misleading for these patients. Despite its importance, no disease-specific field method is currently available, and the assessment of body composition of SMA I patients requires reference methods available only in specialized settings., Objective: To develop predictive fat mass equations for SMA I children based on simple measurements, and compare existing equations to the new disease-specific equations., Design: Demographic, clinical and anthropometric data were examined as potential predictors of the best candidate response variable and non-linear relations were taken into account by transforming continuous predictors with restricted cubic splines. Alternative models were fitted including all the dimensions revealed by cluster analysis of the predictors. The best models were then internally validated, quantifying optimism of the obtained performance measures. The contribution of nusinersen treatment to the unexplained variability of the final models was also tested., Results: A total of 153 SMA I patients were included in the study, as part of a longitudinal observational study in SMA children conducted at the International Center for the Assessment of Nutritional Status (ICANS), University of Milan. The sample equally represented both sexes (56% females) and a wide age range (from 3 months to 12 years, median 1.2 years). Four alternative models performed equally in predicting fat mass fraction (fat mass/body weight). The most convenient was selected and further presented. The selected model uses as predictors sex, age, calf circumference and the sum of triceps, suprailiac and calf skinfold thicknesses. The model showed high predictive ability (optimism corrected coefficient of determination, R 2  = 0.72) and internal validation indicated little optimism both in performance measures and model calibration. The addition of nusinersen as a predictor variable did not improve the prediction. The disease-specific equation was more accurate than the available fat mass equations., Conclusions: The developed prediction model allows the assessment of body composition in SMA I children with simple and widely available measures and with reasonable accuracy., Competing Interests: Conflict of interest Some authors (EB, CB, AD) of this publication are members of the European Reference Network for Neuromuscular Diseases (ERN EURO-NMD). GiBa has received speaker and consultancy honoraria from AveXis, Inc., Roche, PTC, and Sarepta Therapeutics, but he received no funding for this specific study. All the other authors declare no conflicts of interest., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Knowledge on resting energy expenditure (REE) in spinal muscular atrophy type I (SMAI) is still limited. The lack of a population-specific REE equation has led to poor nutritional support and impairment of nutritional status., Objective: To identify the best predictors of measured REE (mREE) among simple bedside parameters, to include these predictors in population-specific equations, and to compare such models with the common predictive equations., Methods: Demographic, clinical, anthropometric, and treatment variables were examined as potential predictors of mREE by indirect calorimetry (IC) in 122 SMAI children consecutively enrolled in an ongoing longitudinal observational study. Parameters predicting REE were identified, and prespecified linear regression models adjusted for nusinersen treatment (discrete: 0 = no; 1 = yes) were used to develop predictive equations, separately in spontaneously breathing and mechanically ventilated patients., Results: In naïve patients, the median (25th, 75th percentile) mREE was 480 (412, 575) compared with 394 (281, 554) kcal/d in spontaneously breathing and mechanically ventilated patients, respectively (P = 0.009).In nusinersen-treated patients, the median (25th, 75th percentile) mREE was 609 (592, 702) compared with 639 (479, 723) kcal/d in spontaneously breathing and mechanically ventilated patients, respectively (P = 0.949).Both in spontaneously breathing and mechanically ventilated patients, the best prediction of REE was obtained from 3 models, all using as predictors: 1 body size related measurement and nusinersen treatment status. Nusinersen treatment was correlated with higher REE both in spontaneously breathing and mechanically ventilated patients. The population-specific equations showed a lower interindividual variability of the bias than the other equation tested, however, they showed a high root mean squared error., Conclusions: We demonstrated that ventilatory status, nusinersen treatment, demographic, and anthropometric characteristics determine energy requirements in SMAI. Our SMAI-specific equations include variables available in clinical practice and were generally more accurate than previously published equations. At the individual level, however, IC is strongly recommended for assessing energy requirements. Further research is needed to externally validate these predictive equations., (Copyright © The Author(s) 2020.)

Microorganisms that release plant-available phosphate from natural soil phosphate stores may serve as biological alternatives to costly and environmentally damaging phosphate fertilizers. To explore this possibility, we engineered a collection of root bacteria to release plant-available orthophosphate from phytate, an abundant phosphate source in many soils. We identified 82 phylogenetically diverse phytase genes, refactored their sequences for optimal expression in Proteobacteria , and then synthesized and engineered them into the genomes of three root-colonizing bacteria. Liquid culture assays revealed 41 engineered strains with high levels of phytate hydrolysis. Among these, we identified 12 strains across three bacterial hosts that confer a growth advantage on the model plant Arabidopsis thaliana when phytate is the sole phosphate source. These data demonstrate that DNA synthesis approaches can be used to generate plant-associated strains with novel phosphate-solubilizing capabilities. IMPORTANCE Phosphate fertilizers are essential for high-yield agriculture yet are costly and environmentally damaging. Microbes that release soluble phosphate from naturally occurring sources in the soil are appealing, as they may reduce the need for such fertilizers. In this study, we used synthetic biology approaches to create a collection of engineered root-associated microbes with the ability to release phosphate from phytate. We demonstrate that these strains improve plant growth under phosphorus-limited conditions. This represents a first step in the development of phosphate-mining bacteria for future use in crop systems., (Copyright © 2019 Shulse et al.)

Background: Respiratory muscle weakness associated with scoliosis in type-2 spinal muscular atrophy (SMA) leads to respiratory impairment. Spinal brace, generally utilized to slow scoliosis progression and support sitting, could worsen lung function and hamper cough maneuvers., Case Series: Six home-treated type-2 SMA children (aged 6-15 years, subtype 2.1-2.5) were assessed to evaluate time-dependent influence of "static-balanced brace" on pulmonary function. Lung function tests, including peak expiratory flow (PEF), peak cough flow (PCF), maximal static inspiratory pressure (MIP), maximal static expiratory pressure (MEP), forced vital capacity (FVC), were performed. PEF, MEP, FVC parameters were higher in tests after wearing braces three-hours, PCF slightly higher and MIP slightly lower compared to upon awakening values., Clinical Rehabilitation Impact: "Static-balanced brace" did not impair lung function in our sample of six type-2 SMA children; in addition, it seemed to support cough maneuvers. Double assessment is determinant for decisions concerning use/non-use of brace differently from the usual one time evaluation procedure (base level compared to level wearing brace).

The prevalence of children on long-term ventilation (LTV) at home has increased in many countries. In Italy, there are 4.3/100,000 population younger than 18 years. Pediatric palliative care (PPC) network provides high-level care for these patients. In December 2003, in the northeast region of Italy, the regional authority promoted and developed a regional network for PPC, a regional network dedicated to the management of pediatric patients with life-limiting and life-threatening diseases. Characterization of LTV children population and description of care offered to them by a regional PPC network, based on the experience of the Veneto region were collected in a regional database. The regional database and evaluation of families' satisfaction, by means of a questionnaire, were longitudinally analyzed. We studied 56 children on LTV. The main involved diseases were neuromuscular diseases and myopathy. All patients had major comorbidities. Mean age was 4.5 years. The median age of starting ventilation was 3.9 years. The initial type of ventilation was invasive mechanical ventilation in 31 patients and noninvasive ventilation in 25 of them. The overall average frequency of hospitalizations for acute episodes was 0.7 admissions per year and the median duration of staying was 6 days. The median duration of staying in the intensive care unit (ICU) was significantly reduced after the opening of a residential solution (the pediatric hospice) (5 vs. 39 days). PPC network can offer global care to children on LTV. The availability of a residential structure into the PPC network seems to reduce the number and duration of hospital stays, especially in ICU, of this population, with likely cost savings. Further studies are necessary to confirm this hypothesis.

Aim: This study described end-of-life care for children affected by spinal muscular atrophy type 1 (SMA1), which is characterised by progressive muscle weakness and develops in the first six months of life., Methods: We retrospectively analysed 17 children (13 boys) who attended the University of Padua's paediatric palliative care centre in Italy from March 2000 to March 2015. All the children received supportive care without proactive respiratory intervention to prolong survival., Results: The median age at admission was 3.57 months, and the median age at death was 6.80 months. The most frequent symptoms were dyspnoea and pain. In the last 72 hours of life, 15/17 children required more intense doses of morphine and, or, benzodiazepines for intractable dyspnoea and pain, but deep palliative sedation was not needed. Airway suction to manage secretions and nasogastric tubes was required in all cases. The place of death was previously planned by the parents in all cases - home, hospital or hospice - and 15/17 deaths occurred in that place. We also interviewed 16 of the 17 parents after their child died., Conclusion: Our study found that symptom management and psychological support for families were the cornerstones of end-of-life care for children with SMA1., (©2017 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

We report our clinical experience on the effect of Scrambler Therapy (ST) for a child with acute mixed pain refractory to pharmacological treatment. ST, recently proposed as an alternative treatment for chronic neuropathic pain in adults, is a noninvasive approach to relieve pain, by changing pain perception at brain level. It is safe and has no side effects. Further research is needed to assess its efficacy for acute pain and for paediatric population.

We describe a case of a paediatric patient affected by mandibular fibrous dysplasia (FD) with severe and chronic pain who was successfully treated with zoledronic acid (ZOL): a third-generation bisphosphonate. Further research is needed to assess its safety and efficacy as a treatment option for FD in the paediatric population., Competing Interests: The authors declare they have no conflict of interests regarding the publication of this paper.

Unlabelled: Pediatric palliative care represents the ideal response to life-limiting and life-threatening diseases and requires a specific and multidisciplinary training. This study aims at evaluating in Italy the training programs offered in pain therapy and pediatric palliative care, the exposure, and the personal experience concerning end-of-life care management. The data have been obtained through a survey addressed to all the residents specializing in pediatrics in Italy. Three hundred forty-eight of 1,200 residents from 33 of the 41 schools of pediatrics existing in Italy responded to the questionnaire. One hundred seventy-four of them (50 %) declared they received training in end-of-life care at least once: 146 during their graduation course of medicine, 84 during the pediatric residency, and 54 in both occasions. Sixty percent of respondents were present at one death at least, with an increasing percentage in the last years of residency (91.5 % in the fifth year) but only 12 % were directly involved in the management (36.2 % in the fifth year); 5.7 % managed at least one communication of death; 12.6 % followed sedo-analgesia protocols. Only 11 % of residents felt ready to face end-of-life care management., Conclusion: The training in end-of-life care in Italy is not currently satisfactory. Further efforts are therefore required to create a comprehensive and multidisciplinary training.

Aim: The aim of this study was to determine the safety and the efficacy of paediatrician-administered propofol in children undergoing different painful procedures., Methods: We conducted a retrospective study over a 12-year period in three Italian hospitals. A specific training protocol was developed in each institution to train paediatricians administering propofol for painful procedures., Results: In this study, 36,516 procedural sedations were performed. Deep sedation was achieved in all patients. None of the children experienced severe side effects or prolonged hospitalisation. There were six calls to the emergency team (0.02%): three for prolonged laryngospasm, one for bleeding, one for intestinal perforation and one during lumbar puncture. Nineteen patients (0.05%) developed hypotension requiring saline solution administration, 128 children (0.4%) needed O2 ventilation by face mask, mainly during upper endoscopy, 78 (0.2%) patients experienced laryngospasm, and 15 (0.04%) had bronchospasm. There were no differences in the incidence of major complications among the three hospitals, while minor complications were higher in children undergoing gastroscopy., Conclusion: This multicentre study demonstrates the safety and the efficacy of paediatrician-administered propofol for procedural sedation in children and highlights the importance of appropriate training for paediatricians to increase the safety of this procedure in children., (©2013 Foundation Acta Paediatrica. Published by John Wiley & Sons Ltd.)

Objectives: Pain is the most common reason for admission to the Emergency Department (ED) in patients with sickle cell disease (SCD). It can be associated with severe complications and impairs quality of life. Pain management in the ED should be well-defined and aggressive. The objective of this study was to evaluate pain management in the pediatric ED of a country recently facing SCD and to identify priority areas of intervention., Methods: The charts of SCD children who had accessed the ED from January 2003 to December 2010 were retrospectively reviewed. Pain management was compared before and after 2008. During 2008, educational events on SCD-pain management involved the ED personnel., Results: Twenty-three/28 patients (82%) accessed the ED for/with pain, of a total of 96/185 accesses for/with pain. Mean age was 5.9 years (range, 8 mo to 17.9 y). Fifty-four percent of the episodes resulted in hospital admissions, with a mean length of stay of 6.2 days. Pain was scored in 30% of the episodes; analgesics were administered in 50%. After the educational interventions, high score at triage was assigned more frequently (72% vs. 40%), waiting time for analgesics administration reduced (64 vs. 87 min), and use of Visual Analogue Scale increased (50% vs. 8%)., Discussion: Pain represents the main reason for admission to the ED in children with SCD even in countries recently facing SCD. Educational interventions obtained significant but still limited improvement in pain management. The diffusion of national guidelines with defined pain evaluation and treatment protocols represents a priority to further ameliorate care of SCD children.

Purpose: The quality of life of children with cancer can be affected by the experience of cancer-related pain, treatment-related pain, procedural pain, generalized pain, and long-term chronic pain, and the consequences may be permanent. Treatment-related pain and procedural pain are often reportedly the most painful experiences relating to their illness. Procedural pain treatment is therefore now considered essential. This multicenter survey investigated how procedural pain is managed at Italian Pediatric Hematology-Oncology Centers., Methods: From April to October 2010, questionnaires were collected from the directors and/or referent of the Italian Centers of Pediatric Hematology-Oncology about the management of lumbar punctures, bone marrow aspirates, and biopsies., Results: We received responses from 67% of the centers (which performed a total of 13,271 procedures per year). Fifty percent of the procedures were performed in the operating room. The sedation-analgesia was provided "almost always" for 84% of procedures. Non-pharmacological treatments were used in 55% of the centers. The specialist who practiced analgesia was the anesthetist in 83.3% of the cases., Conclusions: A nationwide multicentre survey has been conducted for the first time to verify the management of procedural pain in Pediatric Hematology-Oncology patients. The results indicate that many aspects in the management of procedural pain appear consistent with the international guidelines. Some problems still remain, including the inability to ensure adequate sedation-analgesia in all the patients--often due to the lack of adequate staff, the frequent use of the operating room, and an underdeveloped use of non-pharmacological therapies.

Pain management should be warranted for all children in every situation. Italian legislation proposes a model for pain assistance based on specialized tertiary centers which provide direct clinical management for complex cases and assure continuous cooperation with hospitals and family pediatricians for managing painful conditions every day. The Procedural Pain Service of the University of Padua Department of Pediatrics applies such model for procedural pain management. We describe activities of Service since January 1, 2006 on two levels: education and training for territorial services and sedation-analgesia when required for invasive and painful procedures. Since 2006 to date, the Service team produced an internal protocol for procedural sedation, developed two master courses, and organized a training program for procedural pain management in the territorial context. Procedural sedation-analgesia service provided overall 10,832 sedations to perform 14,264 procedures for 3,815 patients, median age of 6 years old. The most frequently performed procedures were lumbar puncture and bone marrow aspiration, followed by gastroscopy and bronchoscopy. Most frequently administered drug combinations were local analgesia + intravenous midazolam alone or midazolam and propofol or midazolam and propofol and ketamine; most frequently used non-pharmacological methods were distraction using cartoons and bubbles. Minor adverse events were recorded in 281 cases (2.5%), the most common being desaturation (2.1%). In conclusion, our model functions on two integrated levels, and it can be considered generally applicable as a solution for pain management.

Pendant groups on polymers that have lower-critical solution temperature (LCST) properties experience a water-like environment below the LCST where the polymer is soluble but are less hydrated above the LCST when the polymer phase separates from solution. When these pendant groups are amphoteric groups like carboxylate salts or ammonium salts, the change in solvation that accompanies the polymer precipitation event significantly changes these groups' acidity or basicity. These changes in acidity or basicity can lead to carboxylate salts forming carboxylic acid groups by capturing protons from the bulk solvent or ammonium salts reverting to the neutral amine by release of protons to the bulk solvent, respectively. When polymers like poly(N-isopropylacrylamide) that contain a sufficient loading of such comonomers are dissolved in solutions whose pH is near the pK(a) of the pendant acid or basic group and undergo an LCST event, the LCST event can change the bulk solution pH. These changes are reversible. These effects were visually followed using common indicators with soluble polymers and or by monitoring solution pH as a function of temperature. LCST events triggered by the addition of a kosmotropic salt lead to similar reversible solution pH changes., (© 2012 American Chemical Society)

Background: COQ4 encodes a protein that organises the multienzyme complex for the synthesis of coenzyme Q(10) (CoQ(10)). A 3.9 Mb deletion of chromosome 9q34.13 was identified in a 3-year-old boy with mental retardation, encephalomyopathy and dysmorphic features. Because the deletion encompassed COQ4, the patient was screened for CoQ(10) deficiency., Methods: A complete molecular and biochemical characterisation of the patient's fibroblasts and of a yeast model were performed., Results: The study found reduced COQ4 expression (48% of controls), CoQ(10) content and biosynthetic rate (44% and 43% of controls), and activities of respiratory chain complex II+III. Cells displayed a growth defect that was corrected by the addition of CoQ(10) to the culture medium. Knockdown of COQ4 in HeLa cells also resulted in a reduction of CoQ(10.) Diploid yeast haploinsufficient for COQ4 displayed similar CoQ deficiency. Haploinsufficency of other genes involved in CoQ(10) biosynthesis does not cause CoQ deficiency, underscoring the critical role of COQ4. Oral CoQ(10) supplementation resulted in a significant improvement of neuromuscular symptoms, which reappeared after supplementation was temporarily discontinued., Conclusion: Mutations of COQ4 should be searched for in patients with CoQ(10) deficiency and encephalomyopathy; patients with genomic rearrangements involving COQ4 should be screened for CoQ(10) deficiency, as they could benefit from supplementation.

Unlabelled: Congenital central hypoventilation syndrome (CCHS) is a rare genetic disorder typically presenting in infants with an impaired automatic control of breathing, particularly during sleep, and often associated with variable patterns of autonomic nervous system dysregulations. We studied three children who had CCHS associated with episodes of severe hypoglycaemia and hyperinsulinaemia; we discuss the possible relationship with impaired dopamine-beta-hydroxylase function., Conclusion: Hypoglycaemia and hyperinsulinaemia might be suspected in children with CCHS presenting with seizures and hyperhydrosis; though, further studies are needed to confirm this association., (© 2011 The Author(s)/Acta Paediatrica © 2011 Foundation Acta Paediatrica.)

Procedural pain is an important aspect of care in pediatrics, and particularly in pediatric oncology where children often consider this to be the most painful experience during their illness. Best recommended practice to control procedural pain includes both sedative-analgesic administration and non-pharmacological treatments, practiced in an adequate and pleasant setting by skilled staff. A nationwide survey has been conducted among the Italian Centers of Pediatric Hematology-Oncology to register operators' awareness on procedural pain, state of the art procedural pain management, operators' opinions about pain control in their center, and possible barriers impeding sedation-analgesia administration. Based on indications in the literature, we discuss the results of the survey to highlight critical issues and suggest future directions for improvement. Future objectives will be to overcome differences depending on size, improve operators' beliefs about the complexity of pain experience, and promote a global approach to procedural pain.

Background: Beliefs of caregivers about patient's pain have been shown to influence assessment and treatment of children's pain, now considered an essential part of cancer treatment. Painful procedures in hematology-oncology are frequently referred by children as the most painful experiences during illness. Aim of this study was to evaluate professionals' beliefs about painfulness of invasive procedures repeatedly performed in Pediatric Hemato-Oncology Units., Methods: Physicians, nurses, psychologists and directors working in Hemato-Oncology Units of the Italian Association of Pediatric Hematology-Oncology (AIEOP) were involved in a wide-nation survey. The survey was based on an anonymous questionnaire investigating beliefs of operators about painfulness of invasive procedures (lumbar puncture, bone marrow aspirate and bone marrow biopsy) and level of pain management., Results: Twenty-four directors, 120 physicians, 248 nurses and 22 psychologists responded to the questionnaire. The score assigned to the procedural pain on a 0-10 scale was higher than 5 in 77% of the operators for lumbar puncture, 97.5% for bone marrow aspiration, and 99.5% for bone marrow biopsy. The scores assigned by nurses differed statistically from those of the physicians and directors for the pain caused by lumbar puncture and bone marrow aspiration. Measures adopted for procedural pain control were generally considered good., Conclusions: Invasive diagnostic-therapeutic procedures performed in Italian Pediatric Hemato-Oncology Units are considered painful by all the caregivers involved. Pain management is generally considered good. Aprioristically opinions about pain depend on invasiveness of the procedure and on the professional role.

The National Database of Nursing Quality Indicators (NDNQI) Pressure Ulcer Training Program was developed to improve nursing accuracy and reliability in identifying and staging pressure ulcers and differentiating hospital- and unit-acquired from community-acquired pressure ulcers. Of 5,200 individuals who completed the training program within 5 months of release, 937 provided written evaluation comments. Four major themes emerged from content analysis of the evaluation remarks: pressure ulcer and other wound pictures; accuracy and clarity of content; program design and technology; and the educational/informational experience. Reviewers most frequently commented on their positive learning experience. Program components that enhanced the educational experience included the array of pressure ulcer pictures at each stage and pictures of other wounds. Clarity of content, program design, and technological problems were barriers to reviewer satisfaction. Findings suggest the NDNQI Pressure Ulcer Training Program was effective for educating staff nurses on pressure ulcer identification and staging.

Objectives: Little attention has been paid to the assessment of pain in children with developmental delay. The aim of this study was to explore several methods for assessing pain during venipuncture in this population of children, using classic and modified scales to evaluate the children's response to simplified tools., Methods: Sixteen children with mild or moderate developmental delay were evaluated using three standard self-rating scales (Visual Analog Scale [VAS], Eland Scale, and Faces Scale) and three modified methods (Cube Test, Modified Eland Scale, and Modified Faces Scale), recording subjective self-ratings and behavioral expressions of pain during a venipuncture procedure, apart from the initial fear. The children's pain and reaction time were assessed by an outside observer, while their pain and fear were also evaluated by the parents., Results: The VAS was used without difficulty by all the children and revealed a good consistency with the Cube Test. The parents' and neutral observer's indirect pain assessment was also consistent with the child's evaluations. The Eland Scale proved difficult to use, especially for Down's syndrome children, while its modified version was easier. Results emerging from the original and modified Faces Scales were inconsistent. Frightened children attributed higher pain scores, demonstrating that negative emotions exacerbate the experience of pain in developmentally delayed children. The patients showed a limited capacity for verbal and behavioral expression in reaction to the painful stimulus (especially the Down's cases)., Discussion: These findings support the conviction that even developmentally delayed children can use self-rating methods effectively. This sector demands further, more extensive study, including the development of simplified tools, to ensure an adequate pain assessment and optimal antalgic approach to this particular pediatric population.

Objective: To compare the efficacy and safety of intra-articular triamcinolone hexacetonide (TH) and triamcinolone acetonide (TA) in children with oligoarticular juvenile idiopathic arthritis (JIA)., Methods: One hundred and thirty joints of 85 patients undergoing intra-articular injections were randomly treated with either TH or TA depending on the availability of the drug. The efficacy of both treatments was evaluated prospectively in a blinded fashion. A good response was defined as a decrease in the articular score of > or =60% from baseline. Clinical, laboratory and immunological variables were noted in order to examine possible factors, other than treatment, predictive of the result., Results: Seventy injections were performed using TH and 60 with TA. The two groups were comparable for clinical, immunological and laboratory characteristics. The rate of response was significantly higher with TH than with TA: 81.4% vs 53.3% (P = 0.001) at 6 months, 67.1 vs 43.3% (P = 0.006) at 12 months, and 60 vs 33.3% (P = 0.002) at 24 months., Conclusion: At comparable doses TH appeared to be much more effective than TA for intra-articular use, in both short- and long-term follow-up. This result was not affected by disease duration or degree of local and systemic inflammation.

The assessment of global pain in infants and children involves the analysis of subjective, behavioural and physiological components, beyond the psychological, familiar and environmental factors that influence and modulate the manifestation of painful symptom. Therefore, researchers and clinicians need valid and reliable instruments to obtain a correct measure of pain. Although subjective indices carry out a fundamental role in the assessment of pain (instruments adjusted to the age of the child), behavioural and physiological indices should be used when intelligence deficit or serious physical handicaps exclude such possibility. Behavioural aspects, associated and correlated to physiological changes, allow to obtain a reliable enough measure of pain. In this paper, the main instruments for measuring pain in infants and children will be described, and their advantages and disadvantages underlined.

Aim: To evaluate the effects of low dose fentanyl infusion analgesia on behavioural and neuroendocrine stress response and short term outcome in premature infants ventilated for hyaline membrane disease., Methods: Twenty seven ventilated preterm infants were randomly assigned to receive a mean fentanyl infusion of 1.1 (0.08 SE) micrograms/kg/h for 75 (5) hours, and 28 untreated infants were considered a control group. A behavioural sedation score was used to assess the infants' behaviour. Urinary metanephrine and the normetanephrine:creatinine molar ratio were determined at 0, 24, 48 and 72 hours. Outcome data and ventilatory indexes were recorded for each infant., Results: The fentanyl group showed significantly lower behavioural stress scores and O2 desaturations than controls and lower urinary concentrations of metanephrine and normetanephrine at 24, 48, 72 hours. The two groups showed no significant difference in ventilatory variables or short term outcome., Conclusions: A short course of low dose fentanyl infusion reduces behavioural sedation scores, O2 desaturations and neuroendocrine stress response in preterm ventilated infants.

The aim of the present study was to evaluate the efficacy of EMLA cream (containing a eutectic mixture of local anaesthetics) in controlling pain due to arteriovenous fistula cannulation in teenagers undergoing chronic haemodialysis. The study was conducted in two phases, one prospective, the other a blind randomized trial, at the Paediatric Haemodialysis service of the Paediatrics Department of Padua University, Italy. It involved six teenagers, aged 12-18 years. Pain was measured using the visual analogue scale, indirect evaluation by nurses and a four-category verbal rating scale. Results showed that: (1) the visual analogue scale calls for an adequate training period; and (2) the EMLA cream might be effective in controlling cannulation-related pain but emotional factors, such as uncontrolled fear and stress, can interfere with the global efficacy of the analgesic approach. Copyright 1998 European Federation of Chapters of the International Association for the Study of Pain.

Pediatric intensive care units (PICUs) have been developed to provide intensive care for children between post-neonatal age and adolescence. These units have largely been developed in North America, mainly in tertiary hospitals. In Italy, critically ill children are still often nursed on adult ICU's, where medical and nursing staff often lack pediatric training. Here we report the first 5-year experience of the multidisciplinary PICU developed at the Department of Pediatrics, University of Padua, focusing on PICU and patients characteristics, as well as on the evaluation of outcome by means of the Pediatric Risk of Mortality (PRISM) score.