Australian clinical consensus guideline for the subacute rehabilitation of childhood stroke.

Childhood stroke results in long-term, multifaceted difficulties, affecting motor, cognitive, communication, and behavioral domains of function which impact on participation and quality of life. The Childhood Stroke Consensus Rehabilitation Guideline was developed to improve the care of children with stroke by providing health professionals with recommendations to assist in their rehabilitative treatment. Clinical questions were formulated to inform systematic database searches from 2001 to 2016, limited to English and pediatric studies. SIGN methodology and the National Health and Medical Research Council system were used to screen and classify the evidence. The Grade of Recommendation, Assessment, Development and Evaluation system was used to grade evidence as strong or weak. Where evidence was inadequate or absent, a modified Delphi consensus process was used to develop consensus-based recommendations. The guideline provides 56 recommendations (1 evidence-based recommendation and 55 consensus recommendations). These relate to the framework of rehabilitation service delivery as well as domain-specific rehabilitation treatment strategies for each domain of function. It is anticipated that this guideline will provide health professions with recommendations to improve the subacute care of children with stroke both in Australia and internationally.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. Ensemble docking makes use of MD results by docking compound databases into representative protein binding-site conformations, thus taking into account the dynamic properties of the binding sites. We also describe preliminary results obtained for 24 systems involving eight proteins of the proteome of SARS-CoV-2. The MD involves temperature replica exchange enhanced sampling, making use of massively parallel supercomputing to quickly sample the configurational space of protein drug targets. Using the Summit supercomputer at the Oak Ridge National Laboratory, more than 1 ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to 10 configurations of each of the 24 SARS-CoV-2 systems using AutoDock Vina. Comparison to experiment demonstrates remarkably high hit rates for the top scoring tranches of compounds identified by our ensemble approach. We also demonstrate that, using Autodock-GPU on Summit, it is possible to perform exhaustive docking of one billion compounds in under 24 h. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and artificial intelligence (AI) methods to cluster MD trajectories and rescore docking poses.

Supercomputer-Based Ensemble Docking Drug Discovery Pipeline with Application to Covid-19.

We present a supercomputer-driven pipeline for in-silico drug discovery using enhanced sampling molecular dynamics (MD) and ensemble docking. We also describe preliminary results obtained for 23 systems involving eight protein targets of the proteome of SARS CoV-2. THe MD performed is temperature replica-exchange enhanced sampling, making use of the massively parallel supercomputing on the SUMMIT supercomputer at Oak Ridge National Laboratory, with which more than 1ms of enhanced sampling MD can be generated per day. We have ensemble docked repurposing databases to ten configurations of each of the 23 SARS CoV-2 systems using AutoDock Vina. We also demonstrate that using Autodock-GPU on SUMMIT, it is possible to perform exhaustive docking of one billion compounds in under 24 hours. Finally, we discuss preliminary results and planned improvements to the pipeline, including the use of quantum mechanical (QM), machine learning, and AI methods to cluster MD trajectories and rescore docking poses.

A comparison of doctors', parents' and children's reports of health states and health-related quality of life in children with chronic conditions.

BACKGROUND: Health-related quality of life is an important outcome. Self-report is the gold standard, but in the paediatric setting we often rely on proxy reporting. Our understanding of the differences between self- and proxy reports and the factors that influence them is limited. These differences can impact on treatment choices and the patient-doctor relationship. OBJECTIVE: To evaluate differences between children's, parents' and doctors' perceptions of health states and health-related quality of life in children with chronic illness and explore factors which explain these differences. METHODS: Consecutive families attending eligible clinics at a tertiary paediatric centre were invited to complete the Health Utilities Index (HUI) 23 questionnaire. Percentage agreement and kappas were calculated as a measure of the agreement between pairs. Chi-squared tests or Fisher's exact test, if appropriate, were performed to determine if there was an association between level of agreement and participant variables. RESULTS: Data were collected for 130 parent-doctor pairs, 59 child-parent pairs and 59 child-doctor pairs. Overall health-related quality of life scores did not differ between responders, but there was poorer agreement for subjective domains. Doctor-child agreement was lower than parent-child agreement. Children with a diagnosis of cerebral palsy or chronic neurological condition were more likely to have lower inter-rater agreement for both subjective and objective domains. On the HUI2, agreement was lower for parent-child pairs when the father was the respondent. For child-doctor pairs, an increased frequency of patient-doctor visits and doctors' seniority were predictors of poorer agreement on the HUI3 and HUI2 respectively. CONCLUSIONS: We identified factors associated with level of agreement for self- and proxy reporting on the HUI23. Parent-child agreement was higher than doctor-child agreement. Patients with significant pain or emotional distress and patients with a diagnosis of severe cerebral palsy or chronic neurological conditions were more susceptible to under-reporting of subjective aspects of well-being by doctors and parents and may benefit from formal assessment of health-related quality of life in the clinical setting.

Zolpidem for persistent vegetative state--a placebo-controlled trial in pediatrics.

OBJECTIVE: The aim of this study was to determine if zolpidem is associated with improved responsiveness or regional cerebral perfusion in patients with persistent vegetative states. METHODS: Following ethics approval, children with persistent vegetative state were enrolled in a prospective, double-blind, placebo-controlled randomised trial. Patients underwent 2 treatments of 4 days, separated by 10 days. Each child received either a daily dose of zolpidem or placebo with a dosage of 0.14-0.2 mg/kg. Responsiveness and regional cerebral perfusion were the outcomes of interest. These were assessed using the Rancho levels of cognitive functioning scale, the coma/near-coma scale and F (18)-FDG positron emission tomography. These were conducted at baseline and after completion of the treatments. RESULTS: 3 children were enrolled. The Rancho assessment scales showed no change with treatment. The coma/near-coma scale showed a tendency to increase with zolpidem, suggesting reduced responsiveness - when compared to baseline or placebo. The positron emission tomography scans showed no significant changes between treatments. CONCLUSION: Zolpidem was associated with a tendency towards reduced responsiveness in patients with persistent vegetative states. There were no objective changes on positron emission tomography suggestive of an associated increase in cerebral blood flow with zolpidem. It would appear that zolpidem does not offer a beneficial effect in this setting.

Survey of paediatric case management practices in Australia for children and young people with acquired brain injury (ABI).

AIM: To investigate the characteristics of paediatric acquired brain injury (ABI) case managers and their organizations in Australia, and to determine the ways in which case managers deliver their service, maintain professional development and evaluate outcomes. METHODS: Postal survey of 57 known paediatric ABI case managers working at 24 separate organizations in Australia. RESULTS: Out of 40 questionnaires returned (70%), the majority of respondents had been providing case management for over 5 years (55%). Co-ordination of services was ranked the most important component of case management, with services most frequently delivered by telephone. Evaluation of case management outcomes was reported by only 52% of the case managers. Whilst the majority of case managers had received some form of training (83%), this varied widely from informal in-house training, to workshops run by insurance companies and government agencies. DISCUSSION: This survey provides information about current case management practices for children with ABI in Australia. Detailing what case managers do is a first step towards developing controlled research designs which are required to demonstrate whether case management is effective in terms of clinical outcomes and cost-benefit.

Obesity in children and adolescents with acquired brain injury.

OBJECTIVES: To measure the prevalence of obesity and to assess associated clinical factors in children and adolescents with acquired brain injury (ABI). STUDY DESIGN: This cross-sectional study included 88 subjects aged between 2.4-17.7 years attending the Brain Injury Clinic at a tertiary paediatric hospital. Body mass index (BMI) and BMI z-scores were calculated. Obesity and overweight were defined using the International Obesity Taskforce cut-points. Associations were examined between BMI z-scores and the following: ABI severity, mobility level, duration from injury and presence of radiological injury. RESULTS: The prevalence of obesity in this population (obese = 15%) was higher than those in Australian children and adolescents (1995 National Nutrition Survey) while the prevalence of overweight (19.3%) was comparable. There was a linear trend for the participants to have a higher BMI z-score with increasing level of mobility (F = 6.91, df 1.70, p = 0.011). CONCLUSION: There is no data about obesity in children and adolescents with ABI. The study with limited statistical power suggests that obesity is prevalent in this population and increases with increasing level of mobility. Further studies are required to address the issue of obesity and related complications in this population.

Status dystonicus and Hallervorden-Spatz disease: treatment with intrathecal baclofen and pallidotomy.

Severe dystonia or status dystonicus is a life threatening disorder that develops in patients with both primary and secondary dystonia. We present the case of a 9-year-old boy with Hallervorden-Spatz disease (HVS) who developed status dystonicus, failing to respond to high dose oral therapy with multiple antidystonic agents. High dose intravenous sedating agents combined with endotracheal intubation and mechanical ventilation were required to control the spasms. Alleviation of the spasms was achieved by a combination of temporary intrathecal baclofen infusions and bilateral pallidotomy. Although it could be argued this is a situation where only palliative measures should be used, we believe a relatively aggressive approach was justified. It relieved the intense pain associated with the spasms and allowed the child to be discharged home without the prolonged stay in intensive care, morbidity and mortality, which characterize status dystonicus.

Continuous intrathecal baclofen infusion for children with cerebral palsy: a pilot study.

OBJECTIVES: To determine whether continuous intrathecal baclofen infusion (CIBI) would decrease spasticity and improve function in children with spastic cerebral palsy. DESIGN: Prospective study with measurement of changes from baseline assessed at regular intervals for 6 months following the intervention. PATIENTS: Two subjects aged 8 and 9 years with cerebral palsy. Inclusion criteria included severe spasticity and age greater than 4 years. STUDY CENTRE: Department of Rehabilitation, The Children's Hospital at Westmead, Westmead, New South Wales, Australia. RESULTS: Both subjects had clinically significant reductions in lower limb spasticity from a single intrathecal dose of baclofen (screening procedure), and had intrathecal pumps implanted. An intensive physical therapy programme was provided for both subjects in the 1-3-month period after commencing CIBI, in order to maximize functional gains. Modified Ashworth Scale scores remained reduced during the 6-month study period. There was a clinically significant increase in upper limb function for Subject 1. Gross Motor Function Measure scores decreased from 22% to 19% for Subject 1, and increased from 6% to 10% for Subject 2 over the study period. Paediatric Evaluation of Disability Inventory scores for Subject 1 showed a reduction in the level of caregiver assistance required, while Subject 2 showed significant improvement in the functional mobility domain. The major changes noted in the parent questionnaires were reduction in tone, increased range of motion and reduced time taken helping with activities of daily living such as toilet and dressing. No significant side-effect was seen after the screening procedure or after continuous intrathecal infusion. Both subjects' parents felt their child was improved following the intervention. CONCLUSIONS: Children with spastic cerebral palsy can have their spasticity effectively reduced with CIBI. In this study of two children, the clinical improvements were encouraging, and it is proposed that CIBI may be of benefit to those patients whose level of spasticity severely interferes with function. Further studies using multidimensional assessment approaches, with larger numbers of children, are warranted.