Off-label use of medicines in neonates, infants, children, and adolescents: a joint policy statement by the European Academy of Paediatrics and the European society for Developmental Perinatal and Pediatric Pharmacology.

Health-care professionals who prescribe medicines have the professional duty to choose medicines that are in the best interest of their individual patient, irrespective if that patient is an adult or a child. However, the availability of medicines with an appropriate label for pediatric use is lagging behind those for adults, and even available pediatric drugs are sometimes not suitable to administer to children. Consequently, health-care professionals often have no other option than to prescribe off-label medicines to children. An important reason for use of off-label medicines is to improve access to (innovative) treatments or to address medical needs and preferences of patients, especially when no other options are available. However, off-label use of medicines is in general not supported by the same level of evidence as medicines licensed for pediatric use. This may result in increased uncertainty on efficacy as well as the risk for toxicity and other side effects. In addition, liability may also be of concern, counterbalanced by professional guidelines.Conclusion: The purpose of this joint EAP/ESDPPP policy statement is to offer guidance for HCPs on when and how to prescribe off-label medicines to children and to provide recommendations for future European policy.

Understanding the role of genetic variability in LRRK2 in Indian population.

BACKGROUND: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES: To resolve the role of LRRK2 in the Indian population. METHODS: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro. © 2018 International Parkinson and Movement Disorder Society.

European Training Requirements in Neonatology 2021: The ESPR, EAP, and UEMS Accredited European Syllabus for Neonatal Training.

INTRODUCTION: The European Union stipulates transnational recognition of professional qualifications for several sectoral professions, including medical doctors. The Union of European Medical Specialists (UEMS), in its "Charter on Training of Medical Specialists," defines the principles for high-level medical training. These principles are manifested in the framework for European Training Requirements (ETR), ensuring medical training reflects modern medical practice and current scientific findings. In 1998, the European Society for Paediatric Research developed the first ETR for Neonatology. We present the ETR Neonatology in its third iteration (ETR III), ratified by the European Academy of Paediatrics (EAP), and approved by UEMS in 2021. METHODS: In generating the ETR III, existing European policy documents on training requirements, including national syllabi and the European Standards of Care for Newborn Health were considered. To ensure the ETR III meets a pan-European standard of expertise in Neonatology, input from representatives from 27 European national paediatric/neonatal societies, and a European parent organisation, was sought. RESULTS: The ETR III summarises the requirements of contemporary training programs in Neonatology and offers a system for accrediting trainers and training centres. We describe the content of the ETR III training syllabus and means of gaining and assessing competency as a medical care provider in Neonatology. CONCLUSION: Graduates of courses following the ETR III Neonatology will obtain a certificate of satisfactory training completion which should be accepted by all European member states as a baseline qualification to practice as a specialist in neonatal medicine, enabling mutual recognition of status throughout Europe.

Use of ventilation/perfusion mismatch to guide individualised CPAP level selection in preterm infants: a feasibility trial.

OBJECTIVE: To measure within-subject changes in ventilation/perfusion (V'/Q') mismatch in response to a protocol of individualised nasal continuous positive airway pressure (CPAP) level selection. DESIGN: Single-arm, non-randomised, feasibility trial. SETTING: Three centres in the Children's Hospital of Philadelphia neonatal care network. PATIENTS: Twelve preterm infants of postmenstrual age 27-35 weeks, postnatal age >24 hours, and receiving a fraction of inspired oxygen (FiO2) >0.25 on CPAP of 4-7 cm H2O. INTERVENTIONS: We applied a protocol of stepwise CPAP level changes, with the overall direction and magnitude guided by individual responses in V'/Q' mismatch, as determined by the degree of right shift (kilopascals, kPa) in a non-invasive gas exchange model. Best CPAP level was defined as the final pressure level at which V'/Q' improved by more than 5%. MAIN OUTCOME MEASURES: Within-subject change in V'/Q' mismatch between baseline and best CPAP levels. RESULTS: There was a median (IQR) within-subject reduction in V'/Q' mismatch of 1.2 (0-3.2) kPa between baseline and best CPAP levels, p=0.02. Best CPAP was observed at a median (range) absolute level of 7 (5-8) cm H2O. CONCLUSIONS: Non-invasive measures of V'/Q' mismatch may be a useful approach for identifying individualised CPAP levels in preterm infants. The results of our feasibility study should be interpreted cautiously and replication in larger studies evaluating the impact of this approach on clinical outcomes is needed. TRIAL REGISTRATION NUMBER: NCT02983825.

The 2021 European Training Requirements in Paediatric Endocrinology and Diabetes.

The aims of the 2021 European Training Requirements (ETR) in Paediatric Endocrinology and Diabetes (PED) are to (1) provide standards to harmonize training programmes in PED between different European countries, (2) establish clearly defined standards of knowledge and skills required to practice PED at the tertiary care level, (3) foster the development of a network of competent tertiary care centres for PED in Europe and globally, and (4) improve the quality of care for children and adolescents requiring PED services. This ETR in PED specifies the requirements for training institutions, trainers, and trainees. It also provides the detailed syllabus/core content that trainees are expected to achieve in order to become competent independent clinicians in PED. References to consensus guidelines produced and/or endorsed by ESPE are included. The target users are trainees in PED, trainers, and all involved with quality assurance and accreditation. The process to develop and approve this 2021 ETR has been rigorous and involved trainees and consultants in paediatric and adult Endocrinology, ESPE (Syllabus Task Force, Education and Training Committee, Council), European Academy of Paediatrics (Tertiary Care Council, Assembly), European Board of Paediatrics, and Union of European Medical Specialists. Implementing the ETR will complement professional regulatory requirements for postgraduate training in PED in different countries and allow harmonizing standards across Europe. ETR is publicly available at www.eurospe.org/education/education-training-syllabus and at https://www.uems.eu/__data/assets/pdf_file/0007/133990/UEMS-2021.17-European-Training-Requirement-in-Paediatric-Endocrinology.pdf.

Pediatric Inflammatory Multisystem Syndrome: Statement by the Pediatric Section of the European Society for Emergency Medicine and European Academy of Pediatrics.

A rise in cases with a new hyperinflammatory disease in children has been reported in Europe and in the Unites States of America, named the Pediatric Inflammatory Multisystem Syndrome-temporally associated with SARS-CoV-2 (PIMS-TS). There appears to be a wide spectrum of signs and symptoms with varying degrees of severity, including a toxic shock like presentation with hypovolaemia and shock, and a Kawasaki-like presentation with involvement of the coronary arteries. Most of these children have evidence of a previous infection with SARS-CoV-2, or a history of significant exposure, but not all. Limited data exist on the incidence of PIMS-TS, but it remains a rare condition. Early recognition and escalation of care is important to prevent the development of serious sequelae, such as coronary artery aneurysms. Clinicians assessing febrile children in primary and secondary care should include PIMS-TS in their differential diagnoses. In children fulfilling the case definition, additional investigations should be undertaken to look for evidence of inflammation and multiorgan involvement. Suspected cases should be discussed with experts in pediatric infectious diseases at an early stage, and advice should be sought from critical care in more severe cases early. There is limited consensus on treatment; but most children have been treated with immunoglobulins or steroids, and with early consideration of biologicals such anti-TNF and anti-IL1 agents. Treatment should ideally be within the context of controlled treatment trials. Clinicians are encouraged to document and share their cases using research registries.

Audit of deaths less than a week after admission through an emergency department: how accurate was the ED diagnosis and were any deaths preventable?

AIM: To review the causes of death in patients admitted via the emergency department (ED) who died within 7 days of admission and to identify any ways in which ED care could have been better. The study also aims to compare the diagnosis made in the ED and the mortality diagnosis. METHODS: A retrospective study; subjects were all patients who attended the ED over 4 months and died within 7 days of admission. The paramedics' notes, ED case cards, inpatient medical notes and details of postmortem findings were examined to identify the time and date of arrival in the ED, presenting complaint, provisional diagnosis made by the ED, treatment plan devised by the ED, diagnosis made in wards, and the cause of death as issued on death certificates or from postmortem findings. Summary sheets of cases where the care provided by the emergency department could have been improved were reviewed, errors were identified and deaths were classified as preventable or unpreventable. RESULTS: Database revealed 3521 admissions via the ED over 4 months, of which 95 cases (2.69%) died within 7 days of admission. 78 patients (82.1% of cases) were appropriately diagnosed and managed whereas 17 (17.87% of cases) were identified with deficiencies in either the diagnosis or the management provided in the ED. We reviewed the quality of care provided in the ED for these cases and rated deaths according to our preventability criteria: 5 (5.26%) deaths were unpreventable despite the deficiency in care provided in the ED; 3 (3.15%) deaths were definitely preventable; 3 (3.15%) were probably preventable; and 6 (6.31%) were possibly preventable deaths. CONCLUSION: The ED is playing a good role in the management of critically ill patients, with appropriate diagnosis and management in 82% of cases. Training of junior doctors is required to prevent occurrence of errors and thus preventable deaths, but all deaths are not preventable. New guidelines for sepsis management and management of undifferentiated clinical presentations are being introduced and we intend to audit the implications of new guidelines.

KIAA0556 is a novel ciliary basal body component mutated in Joubert syndrome.

BACKGROUND: Joubert syndrome (JBTS) and related disorders are defined by cerebellar malformation (molar tooth sign), together with neurological symptoms of variable expressivity. The ciliary basis of Joubert syndrome related disorders frequently extends the phenotype to tissues such as the eye, kidney, skeleton and craniofacial structures. RESULTS: Using autozygome and exome analyses, we identified a null mutation in KIAA0556 in a multiplex consanguineous family with hallmark features of mild Joubert syndrome. Patient-derived fibroblasts displayed reduced ciliogenesis potential and abnormally elongated cilia. Investigation of disease pathophysiology revealed that Kiaa0556 (-/-) null mice possess a Joubert syndrome-associated brain-restricted phenotype. Functional studies in Caenorhabditis elegans nematodes and cultured human cells support a conserved ciliary role for KIAA0556 linked to microtubule regulation. First, nematode KIAA0556 is expressed almost exclusively in ciliated cells, and the worm and human KIAA0556 proteins are enriched at the ciliary base. Second, C. elegans KIAA0056 regulates ciliary A-tubule number and genetically interacts with an ARL13B (JBTS8) orthologue to control cilium integrity. Third, human KIAA0556 binds to microtubules in vitro and appears to stabilise microtubule networks when overexpressed. Finally, human KIAA0556 biochemically interacts with ciliary proteins and p60/p80 katanins. The latter form a microtubule-severing enzyme complex that regulates microtubule dynamics as well as ciliary functions. CONCLUSIONS: We have identified KIAA0556 as a novel microtubule-associated ciliary base protein mutated in Joubert syndrome. Consistent with the mild patient phenotype, our nematode, mice and human cell data support the notion that KIAA0556 has a relatively subtle and variable cilia-related function, which we propose is related to microtubule regulation.

Predicting early death in patients with traumatic bleeding: development and validation of prognostic model.

OBJECTIVE: To develop and validate a prognostic model for early death in patients with traumatic bleeding. DESIGN: Multivariable logistic regression of a large international cohort of trauma patients. SETTING: 274 hospitals in 40 high, medium, and low income countries PARTICIPANTS: Prognostic model development: 20,127 trauma patients with, or at risk of, significant bleeding, within 8 hours of injury in the Clinical Randomisation of an Antifibrinolytic in Significant Haemorrhage (CRASH-2) trial. External validation: 14,220 selected trauma patients from the Trauma Audit and Research Network (TARN), which included mainly patients from the UK. OUTCOMES: In-hospital death within 4 weeks of injury. RESULTS: 3076 (15%) patients died in the CRASH-2 trial and 1765 (12%) in the TARN dataset. Glasgow coma score, age, and systolic blood pressure were the strongest predictors of mortality. Other predictors included in the final model were geographical region (low, middle, or high income country), heart rate, time since injury, and type of injury. Discrimination and calibration were satisfactory, with C statistics above 0.80 in both CRASH-2 and TARN. A simple chart was constructed to readily provide the probability of death at the point of care, and a web based calculator is available for a more detailed risk assessment (http://crash2.lshtm.ac.uk). CONCLUSIONS: This prognostic model can be used to obtain valid predictions of mortality in patients with traumatic bleeding, assisting in triage and potentially shortening the time to diagnostic and lifesaving procedures (such as imaging, surgery, and tranexamic acid). Age is an important prognostic factor, and this is of particular relevance in high income countries with an aging trauma population.

A rapidly advancing mediastinal mass--overcoming tracheobronchial obstruction.

We report the case of a 7-year-old boy who presented with rapidly advancing airway obstruction secondary to mediastinal T-cell non-Hodgkins lymphoma. His brisk deterioration required transfer to the pediatric intensive care unit and intubation of the trachea. Unforeseen unilateral bronchial involvement led to gas trapping and critical pulmonary hyperinflation. Endobronchial advancement of the tracheal tube beyond the bronchial obstruction relieved pulmonary hyperinflation but subsequent one lung ventilation was poorly tolerated. We report the manufacture of a proximal 'Murphy's eye' which allowed ventilation of the contralateral lung to proceed. To the best of our knowledge this is the first time that this technique has been described in a pediatric patient.