Genome-Wide Screen of Three Herpesviruses for Protein Subcellular Localization and Alteration of PML Nuclear Bodies

Herpesviruses are large, ubiquitous DNA viruses with complex host interactions, yet many of the proteins encoded by these viruses have not been functionally characterized. As a first step in functional characterization, we determined the subcellular localization of 234 epitope-tagged proteins from herpes simplex virus, cytomegalovirus, and Epstein–Barr virus. Twenty-four of the 93 proteins with nuclear localization formed subnuclear structures. Twelve of these localized to the nucleolus, and five at least partially localized with promyelocytic leukemia (PML) bodies, which are known to suppress viral lytic infection. In addition, two proteins disrupted Cajal bodies, and 19 of the nuclear proteins significantly decreased the number of PML bodies per cell, including six that were shown to be SUMO-modified. These results have provided the first functional insights into over 120 previously unstudied proteins and suggest that herpesviruses employ multiple strategies for manipulating nuclear bodies that control key cellular processes

Cognition and bimanual performance in children with unilateral cerebral palsy: Protocol for a multicentre, cross-sectional study

© 2018 The Author(s). Background: Motor outcomes of children with unilateral cerebral palsy are clearly documented and well understood, yet few studies describe the cognitive functioning in this population, and the associations between the two is poorly understood. Using two hands together in daily life involves complex motor and cognitive processes. Impairment in either domain may contribute to difficulties with bimanual performance. Research is yet to derive whether, and how, cognition affects a child's ability to use their two hands to perform bimanual tasks. Methods/Design: This study will use a prospective, cross-sectional multi-centre observational design. Children (aged 6-12 years) with unilateral cerebral palsy will be recruited from one of five Australian treatment centres. We will examine associations between cognition, bimanual performance and brain neuropathology (lesion type and severity) in a sample of 131 children. The primary outcomes are: Motor - the Assisting Hand Assessment; Cognitive - Executive Function; and Brain - lesion location on structural MRI. Secondary data collected will include: Motor - Box and Blocks, ABILHAND- Kids, Sword Test; Cognitive - standard neuropsychological measures of intelligence. We will use generalized linear modelling and structural equation modelling techniques to investigate relationships between bimanual performance, executive function and brain lesion location. Discussion: This large multi-centre study will examine how cognition affects bimanual performance in children with unilateral cerebral palsy. First, it is anticipated that distinct relationships between bimanual performance and cognition (executive function) will be identified. Second, it is anticipated that interrelationships between bimanual performance and cognition will be associated with common underlying neuropathology. Findings have the potential to improve the specificity of existing upper limb interventions by providing more targeted treatments and influence the development of novel methods to improve both cognitive and motor outcomes in children with unilateral cerebral palsy

Exploring reliability of scar rating scales using photographs of burns from children aged up to 15 years

Assessing burn scars from photographs is a common practice given the growing trend to support health service delivery via electronic media (eg, email, videoconferencing). Scar rating scales, originally designed for in-person assessment, have been used to rate scars from photographic images. Evidence for the reliability of this practice is lacking. Five raters completed three scar rating scales (Patient and Observer Scar Scale, Manchester Scar Scale, modified Vancouver Scar Scale), both in-person and using photographs on 12 participants (seven male, five female) with 18 scar areas (3 × 3 cm). Interrater reliability for the scar parameters of vascularity, color, contour, pliability, and overall opinion achieved intraclass correlation coefficient values of between 0.71 and 0.87 (in-person) and 0.72 and 0.77 (using photographs) for multiple raters. The level of agreement between in-person and photographic assessment was below acceptable levels, which brings into question construct validity when scar rating scales are used in a way for which they were not designed. Reliability estimates in this study were likely reduced by the underrepresentation of scars in the more severe range. This limitation needs to be addressed in future research. Advances are required in the development and refinement of burn scar rating scales, specifically for photographic use, given their routine use in clinical care

Blinding and bias in randomized controlled trials: when to measure the effectiveness of blinding

This article is commented on by Day on page 159 of this issue

Development of a Novel Ceramic Support Layer for Planar Solid Oxide Cells

OBJECTIVE: To determine safety of intramuscular botulinum toxin A (BoNT-A) injections to reduce spasticity and improve care and comfort of nonambulatory children with cerebral palsy (CP)

Evaluation of the effects of botulinum toxin A injections when used to improve ease of care and comfort in children with cerebral palsy whom are non-ambulant: a double blind randomized controlled trial

Abstract Background Children with cerebral palsy (CP) whom are non-ambulant are at risk of reduced quality of life and poor health status. Severe spasticity leads to discomfort and pain. Carer burden for families is significant. This study aims to determine whether intramuscular injections of botulinum toxin A (BoNT-A) combined with a regime of standard therapy has a positive effect on care and comfort for children with CP whom are non-ambulant (GMFCS IV/V), compared with standard therapy alone (cycle I), and whether repeated injections with the same regime of adjunctive therapy results in greater benefits compared with a single injecting episode (cycle II). The regime of therapy will include serial casting, splinting and/or provision of orthoses, as indicated, combined with four sessions of goal directed occupational therapy or physiotherapy. Method/design This study is a double blind randomized controlled trial. Forty participants will be recruited. In cycle I, participants will be randomized to either a treatment group who will receive BoNT-A injections into selected upper and/or lower limb muscles, or a control group who will undergo sham injections. Both groups will receive occupational therapy and /or physiotherapy following injections. Groups will be assessed at baseline then compared at 4 and 16 weeks following injections or sham control. Parents, treating clinicians and assessors will be masked to group allocation. In cycle II, all participants will undergo intramuscular BoNT-A injections to selected upper and/or lower limb muscles, followed by therapy. The primary outcome measure will be change in parent ratings in identified areas of concern for their child’s care and comfort, using the Canadian Occupational Performance Measure (COPM). Secondary measures will include the Care and Comfort Hypertonicity Scale (ease of care), the Cerebral Palsy Quality of Life Questionnaire (CP QoL–Child) (quality of life), the Caregiver Priorities and Child Health Index of Life with Disabilities Questionnaire (CPCHILD©) (health status) and the Paediatric Pain Profile (PPP) (pain). Adverse events will be carefully monitored by a clinician masked to group allocation. Discussion This paper outlines the theoretical basis, study hypotheses and outcome measures for a trial of BoNT-A injections and therapy for children with non-ambulant CP. Trial registration Australia New Zealand Clinical Trials Registry:N12609000360213</p

Botulinum toxin a for nonambulatory children with cerebral palsy: A double blind randomized controlled trial

Objectives: To examine the efficacy and safety of intramuscular botulinum toxin A (BoNT-A) to reduce spasticity and improve comfort and ease of care in nonambulant children with cerebral palsy (CP). Study design: Nonambulant children with CP (n = 41; Gross Motor Function Classification System level IV = 3, level V = 38; mean age 7.1 years, range 2.3-16 years, 66% male) were randomly allocated to receive either intramuscular BoNT-A injections (n = 23) or sham procedure (n = 18) combined with therapy. The analysis used generalized estimating equations with primary outcome the Canadian Occupational Performance Measure (COPM) at 4 weeks postintervention and retention of effects at 16 weeks. Adverse events (AE) were collected at 2, 4, and 16 weeks by a physician masked to group allocation. Results: There were significant between group differences favoring the BoNT-A-treated group on COPM performance at 4 weeks (estimated mean difference 2.2, 95% CI 0.8, 3.5; P = .002) and for COPM satisfaction (estimated mean difference 2.2, 95% CI 0.5, 3.9; P = .01). These effects were retained at 16 weeks for COPM satisfaction (estimated mean difference 1.8, 95% CI 0.1, 3.5; P = .04). There were more mild AE at 4 weeks for the BoNT-A group (P = .002), however, there were no significant between-group differences in the reporting of moderate and serious AE. Conclusions: In a double-blind randomized sham-controlled trial, intramuscular BoNT-A and therapy were effective for improving ease of care and comfort for nonambulant children with CP. There was no increase in moderate and severe AE in the children who had BoNT-A injections compared with the sham group

Constraint-induced movement therapy in children with unilateral cerebral palsy

Background Unilateral cerebral palsy (CP) is a condition that affects muscle control and function on one side of the body. Children with unilateral CP experience difficulties using their hands together secondary to disturbances that occur in the developing fetal or infant brain. Often, the more affected limb is disregarded. Constraint‐induced movement therapy (CIMT) aims to increase use of the more affected upper limb and improve bimanual performance. CIMT is based on two principles: restraining the use of the less affected limb (for example, using a splint, mitt or sling) and intensive therapeutic practice of the more affected limb. Objectives To evaluate the effect of constraint‐induced movement therapy (CIMT) in the treatment of the more affected upper limb in children with unilateral CP. Search methods In March 2018 we searched CENTRAL, MEDLINE, Embase, CINAHL, PEDro, OTseeker, five other databases and three trials registers. We also ran citation searches, checked reference lists, contacted experts, handsearched key journals and searched using Google Scholar. Selection criteria Randomised controlled trials (RCTs), cluster‐RCTs or clinically controlled trials implemented with children with unilateral CP, aged between 0 and 19 years, where CIMT was compared with a different form of CIMT, or a low dose, high‐dose or dose‐matched alternative form of upper‐limb intervention such as bimanual intervention. Primarily, outcomes were bimanual performance, unimanual capacity and manual ability. Secondary outcomes included measures of self‐care, body function, participation and quality of life. Data collection and analysis Two review authors independently screened titles and abstracts to eliminate ineligible studies. Five review authors were paired to extract data and assess risk of bias in each included study. GRADE assessments were undertaken by two review authors. Main results We included 36 trials (1264 participants), published between 2004 and 2018. Sample sizes ranged from 11 to 105 (mean 35). Mean age was 5.96 years (standard deviation (SD) 1.82), range three months to 19.8 years; 53% male and 47% participants had left hemiplegia. Fifty‐seven outcome measures were used across studies. Average length of CIMT programs was four weeks (range one to 10 weeks). Frequency of sessions ranged from twice weekly to seven days per week. Duration of intervention sessions ranged from 0.5 to eight hours per day. The mean total number of hours of CIMT provided was 137 hours (range 20 to 504 hours). The most common constraint devices were a mitt/glove or a sling (11 studies each). We judged the risk of bias as moderate to high across the studies. Key results: Primary outcomes at primary endpoint (immediately after intervention) CIMT versus low‐dose comparison (e.g. occupational therapy) We found low‐quality evidence that CIMT was more effective than a low‐dose comparison for improving bimanual performance (mean difference (MD) 5.44 Assisting Hand Assessment (AHA) units, 95% confidence interval (CI) 2.37 to 8.51). CIMT was more effective than a low‐dose comparison for improving unimanual capacity (Quality of upper extremity skills test (QUEST) ‐ Dissociated movement MD 5.95, 95% CI 2.02 to 9.87; Grasps; MD 7.57, 95% CI 2.10 to 13.05; Weight bearing MD 5.92, 95% CI 2.21 to 9.6; Protective extension MD 12.54, 95% CI 8.60 to 16.47). Three studies reported adverse events, including frustration, constraint refusal and reversible skin irritations from casting. CIMT versus high‐dose comparison (e.g. individualised occupational therapy, bimanual therapy) When compared with a high‐dose comparison, CIMT was not more effective for improving bimanual performance (MD −0.39 AHA Units, 95% CI −3.14 to 2.36). There was no evidence that CIMT was more effective than a high‐dose comparison for improving unimanual capacity in a single study using QUEST (Dissociated movement MD 0.49, 95% CI −10.71 to 11.69; Grasp MD −0.20, 95% CI −11.84 to 11.44). Two studies reported that some children experienced frustration participating in CIMT. CIMT versus dose‐matched comparison (e.g. Hand Arm Bimanual Intensive Therapy, bimanual therapy, occupational therapy) There was no evidence of differences in bimanual performance between groups receiving CIMT or a dose‐matched comparison (MD 0.80 AHA units, 95% CI −0.78 to 2.38). There was no evidence that CIMT was more effective than a dose‐matched comparison for improving unimanual capacity (Box and Blocks Test MD 1.11, 95% CI −0.06 to 2.28; Melbourne Assessment MD 1.48, 95% CI −0.49 to 3.44; QUEST Dissociated movement MD 6.51, 95% CI −0.74 to 13.76; Grasp, MD 6.63, 95% CI −2.38 to 15.65; Weightbearing MD −2.31, 95% CI −8.02 to 3.40) except for the Protective extension domain (MD 6.86, 95% CI 0.14 to 13.58). There was no evidence of differences in manual ability between groups receiving CIMT or a dose‐matched comparison (ABILHAND‐Kids MD 0.74, 95% CI 0.31 to 1.18). From 15 studies, two children did not tolerate CIMT and three experienced difficulty. Authors' conclusions The quality of evidence for all conclusions was low to very low. For children with unilateral CP, there was some evidence that CIMT resulted in improved bimanual performance and unimanual capacity when compared to a low‐dose comparison, but not when compared to a high‐dose or dose‐matched comparison. Based on the evidence available, CIMT appears to be safe for children with CP

Brain magnetic resonance imaging is a predictor of bimanual performance and executive function in children with unilateral cerebral palsy

Aim To examine the association between brain magnetic resonance imaging (MRI) characteristics and executive function and bimanual performance in children with unilateral cerebral palsy (CP). Method Clinical MRI brain scans were classified as: (1) predominant pathological pattern (normal, white matter injury [WMI]; grey matter injury; focal vascular insults [FVI]; malformations; or miscellaneous); and (2) focal lesions (frontal, basal ganglia, and/or thalamus). Assessments included: (1) bimanual performance; (2) unimanual dexterity; and (3) executive function tasks (information processing, attention control, cognitive flexibility, and goal setting) and behavioural ratings (parent). Results From 131 recruited children, 60 were ineligible for analysis, leaving 71 children (47 males, 24 females) in the final sample (mean age 9y [SD 2y], 6y–12y 8mo). Brain MRIs were WMI (69%) and FVI (31%); and frontal (59%), thalamic (45%), basal ganglia (37%), and basal ganglia plus thalamic (21%). Bimanual performance was lower in FVI versus WMI (p<0.003), and with frontal (p=0.36), basal ganglia (p=0.032), and thalamic/basal ganglia lesions (p=0.013). Other than information processing, executive function tasks were not associated with predominant pattern. Frontal lesions predicted attention control (p=0.049) and cognitive flexibility (p=0.009) but not goal setting, information processing, or behavioural ratings. Interpretation Clinical brain MRI predicts cognitive and motor outcomes when focal lesions and predominate lesion patterns are considered. What this paper adds Early brain magnetic resonance imaging (MRI) predicts bimanual performance and cognitive outcomes. Brain MRI may identify children requiring targeted interventions. Basal ganglia with/without thalamic lesions predicted bimanual performance. Frontal lesions were associated with attention control and cognitive flexibility. Brain MRI predominant patterns predicted motor, not cognitive outcomes, other than information processing

Preschool HABIT-ILE:Study protocol for a randomised controlled trial to determine efficacy of intensive rehabilitation compared with usual care to improve motor skills of children, aged 2-5 years, with bilateral cerebral palsy

Introduction Young children with bilateral cerebral palsy (BCP) often experience difficulties with gross motor function, manual ability and posture, impacting developing independence in daily life activities, participation and quality of life. Hand Arm Bimanual Intensive Training Including Lower Extremity (HABIT-ILE) is a novel intensive motor intervention integrating upper and lower extremity training that has been developed and tested in older school-Aged children with unilateral and BCP. This study aims to compare an adapted preschool version of HABIT-ILE to usual care in a randomised controlled trial. Methods and analysis 60 children with BCP aged 2-5 years, Gross Motor Function Classification System (GMFCS) II-IV will be recruited. Children will be stratified by GMFCS and randomised using concealed allocation to either receive Preschool HABIT-ILE or usual care. Preschool HABIT-ILE will be delivered in groups of four to six children, for 3 hours/day for 10 days (total 30 hours). Children receiving Preschool HABIT-ILE be provided a written home programme with the aim of achieving an additional 10 hours of home practice (total dose 40 hours). Outcomes will be assessed at baseline, immediately following intervention and then retention of effects will be tested at 26 weeks. The primary outcome will be the Peabody Developmental Motors Scales-Second Edition to evaluate gross and fine motor skills. Secondary outcomes will be gross motor function (Gross Motor Function Measure-66), bimanual hand performance (Both Hands Assessment), self-care and mobility (Pediatric Evaluation of Disability Inventory-Computer Adapted Test), goal attainment (Canadian Occupational Performance Measure), global performance of daily activities (ACTIVLIM-CP), cognition and adaptive function (Behavior Rating Inventory of Executive Function-Preschool Version), habitual physical activity (ActiGraph GT3X+) and quality of life (Infant Toddler Quality of Life Questionnaire and Child Health Utility Index-9). Analyses will follow standard principles for RCTs using two-group comparisons on all participants on an intention-To-Treat basis. Comparisons between groups for primary and secondary outcomes will be conducted using regression models. Ethics and dissemination Ethics approval has been granted by the Medical Research Ethics Committee Children's Health Queensland Hospital and Health Service Human Research Ethics Committee (HREC/19/QCHQ/59444) and The University of Queensland (2020000336/HREC/19/QCHQ/59444). Trial registration number ACTRN126200000719.</p