Broadening the Spectrum of SLC22A5 Phenotype: Primary Carnitine Deficiency Presenting with Focal Myoclonus.

Primary carnitine deficiency (PCD) is caused by pathogenic variants of the SLC22A5 gene, which encodes a transmembrane protein that functions as a high affinity carnitine transporter. Carnitine is essential for the transport of acyl-CoA, produced from fatty acids, into the mitochondria where they are oxidised to produce energy. We present the case history of an 8-year-old boy who presented with fever, lethargy, focal rhythmic (3 Hz) left wrist twitching, and severe encephalopathy. MRI brain showed basal ganglia involvement. Metabolic investigations revealed low serum carnitine; whole genome sequencing confirmed compound heterozygous SLC22A5 mutations. With carnitine replacement, intensive care support, and neurorehabilitation, he made a remarkable recovery, regaining independent breathing, speech, mobility, and hand use. Seizure presentation in PCD is rare and presentation with sustained focal myoclonus has not been previously reported. This case expands the known phenotype of PCD. Prompt carnitine replacement is imperative.

Evaluation of the Training in Early Detection for Early Intervention (TEDEI) e-learning course using Kirkpatrick's method.

BACKGROUND: Early intervention in cerebral palsy could improve motor outcome but is only possible following early identification of those affected. There is a need for training of healthcare professionals (HCPs) in early detection of atypical motor development. We developed a video-based e-learning course - Training in Early Detection for Early Intervention (TEDEI) - to address this need. We evaluated whether participation in the course improved knowledge and changed behaviour of HCPs. METHODS: Participants were 332 HCPs (38% physiotherapists, 35.8% occupational therapists), predominantly UK-based (83.7%). Analysis of training effects used mixed methods and followed Kirkpatrick's model, first assessing "Reaction" through a feedback questionnaire involving Likert scale and free text responses (n = 141). "Learning" was assessed through multiple choice questions (MCQs): all 332 HCPs completed a pre-course quiz of 6 MCQs followed by the course, then a 16 item post-course quiz including the 6 pre-course questions. "Behaviour" was assessed through in-depth qualitative interviewing of 23 participants. RESULTS: "Reaction": TEDEI was found to be effective, engaging and well structured. "Learning": Scores improved significantly between the pre-course and post-course quiz, median improvement 1/6 (z = 5.30, p < 0.001). HCPs also reported a perceived improvement in their knowledge, confidence and ability. "Behaviour": HCPs could see how TEDEI would improve their clinical practice through having an assessment framework, ways of working better with parents, and developing observational skills useful for tele-health assessments. CONCLUSION: Our brief e-learning course on early detection for early intervention was viewed positively, improved knowledge and showed potential for positive changes in practice. Kirkpatrick's model provided a useful framework for undertaking this evaluation.

Can wrist-worn devices and a smartphone application influence arm activity in children with unilateral cerebral palsy? A proof-of-concept study.

Aim: To determine whether a wrist-worn triaxial accelerometer-based device and software (including smartphone application), incorporating feedback, is feasible, acceptable, and can lead to increased affected upper limb use during everyday activities in children with unilateral cerebral palsy (UCP). Methods: Study design: Mixed methods proof of concept study. Participants: Children aged 8-18 years with UCP; age-matched typically developing controls ("Buddies"), therapists. Intervention: Baseline (2 weeks): devices recorded arm activity. Active feedback (6 weeks): devices also gave vibratory prompts if affected arm activity fell below pre-set personalised thresholds (UCP group only; control group continued as per Baseline). Final 2 weeks: as baseline. Both groups accessed a smartphone application providing feedback on relative arm motion throughout the study. Assessment and analysis: ABILHAND-Kids questionnaires and MACS classifications captured baseline participant characteristics (UCP group). Accelerometer data was used to calculate relative arm activity (signal vector magnitude) corrected for time worn/day, and trends in relative arm activity examined using single case experimental design (both groups). In-depth interviews with families, "Buddies" and therapists assessed feasibility and acceptability of implementation. A framework approach was used for qualitative data analysis. Results: We recruited 19 participants with UCP; 19 buddies; and 7 therapists. Five participants (two with UCP) did not complete the study. Baseline mean (stdev) ABILHAND-Kids score of children with UCP who completed the study was 65.7 (16.2); modal MACS score was II.Qualitative analysis demonstrated acceptability and feasibility of the approach. Active therapist input for this group was minimal. Therapists appreciated the potential for summary patient data to inform management. Arm activity in children with UCP increased in the hour following a prompt (mean effect size z = 0.261) for the non-dominant hand, and the dominant hand (z = 0.247). However, a significant increase in affected arm activity between baseline and intervention periods was not demonstrated. Discussion: Children with UCP were prepared to wear the wristband devices for prolonged periods. Whilst arm activity increased bilaterally in the hour following a prompt, increases were not sustained. Delivery of the study during the COVID-19 pandemic may have negatively influenced findings. Technological challenges occurred but could be overcome. Future testing should incorporate structured therapy input.

Positive behaviour support training for staff for treating challenging behaviour in people with intellectual disabilities: a cluster RCT.

BACKGROUND: Preliminary studies have indicated that training staff in Positive Behaviour Support (PBS) may help to reduce challenging behaviour among people with intellectual disability (ID). OBJECTIVE: To evaluate whether or not such training is clinically effective in reducing challenging behaviour in routine care. The study also included longer-term follow-up (approximately 36 months). DESIGN: A multicentre, single-blind, two-arm, parallel-cluster randomised controlled trial. The unit of randomisation was the community ID service using an independent web-based randomisation system and random permuted blocks on a 1 : 1 allocation stratified by a staff-to-patient ratio for each cluster. SETTING: Community ID services in England. PARTICIPANTS: Adults (aged > 18 years) across the range of ID with challenging behaviour [≥ 15 Aberrant Behaviour Checklist - Community total score (ABC-CT)]. INTERVENTIONS: Manual-assisted face-to-face PBS training to therapists and treatment as usual (TAU) compared with TAU only in the control arm. MAIN OUTCOME MEASURES: Carer-reported changes in challenging behaviour as measured by the ABC-CT over 12 months. Secondary outcomes included psychopathology, community participation, family and paid carer burden, family carer psychopathology, costs of care and quality-adjusted life-years (QALYs). Data on main outcome, service use and health-related quality of life were collected for the 36-month follow-up. RESULTS: A total of 246 participants were recruited from 23 teams, of whom 109 were in the intervention arm (11 teams) and 137 were in the control arm (12 teams). The difference in ABC-CT between the intervention and control arms [mean difference -2.14, 95% confidence interval (CI) -8.79 to 4.51; p = 0.528] was not statistically significant. No treatment effects were found for any of the secondary outcomes. The mean cost per participant in the intervention arm was £1201. Over 12 months, there was a difference in QALYs of 0.076 in favour of the intervention (95% CI 0.011 to 0.140 QALYs) and a 60% chance that the intervention is cost-effective compared with TAU from a health and social care cost perspective at the threshold of £20,000 per QALY gained. Twenty-nine participants experienced 45 serious adverse events (intervention arm, n = 19; control arm, n = 26). PBS plans were available for 33 participants. An independent assessment of the quality of these plans found that all were less than optimal. Forty-six qualitative interviews were conducted with service users, family carers, paid carers and service managers as part of the process evaluation. Service users reported that they had learned to manage difficult situations and had gained new skills, and carers reported a positive relationship with therapists. At 36 months' follow-up (n = 184), the mean ABC-CT difference between arms was not significant (-3.70, 95% CI -9.25 to 1.85; p = 0.191). The initial cost-effectiveness of the intervention dissipated over time. LIMITATIONS: The main limitations were low treatment fidelity and reach of the intervention. CONCLUSIONS: Findings from the main study and the naturalistic follow-up suggest that staff training in PBS as delivered in this study is insufficient to achieve significant clinical gains beyond TAU in community ID services. Although there is an indication that training in PBS is potentially cost-effective, this is not maintained in the longer term. There is increased scope to develop new approaches to challenging behaviour as well as optimising the delivery of PBS in routine clinical practice. TRIAL REGISTRATION: This study is registered as NCT01680276. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 15. See the NIHR Journals Library website for further project information.

Adverse effects of exposure to armed conflict on pregnancy: a systematic review.

INTRODUCTION: Exposure to armed conflict has manifold implications for both military and civilian populations. Prenatal stress has detrimental effects on both obstetric outcomes, fetal development and the development of an individual later in life. As well as causing stress to the mother, armed conflicts can decimate local infrastructures making it increasingly difficult to access antenatal and general healthcare. The present review is particularly salient in light of the many ongoing current conflicts. It examines the impacts of exposure to armed conflicts on the pregnancy outcomes. METHODS: A thorough literature search was carried out on three databases using MeSH and truncation terms. 13 studies were included in the final analysis relating to mothers exposed to armed conflicts since 1990. RESULTS: The studies include data from 1 172 151 patients: mothers from Libya, Bosnia, Herzegovina, Israel, Palestine, Kosovo, Yugoslavia, Nepal, Somalia, Iraq, Kuwait and Afghanistan. There is evidence of an increased risk of mothers giving birth to babies of low birth weight as reported in nine included studies. All have a degree of bias, with four at lower and five at higher risk of bias, either not adjusting for confounders or not employing robust measures of exposure to conflict. Further evidence suggested an increase in the incidence of miscarriage, stillbirth, prematurity, congenital abnormalities, miscarriage and premature rupture of membranes among mothers exposed to armed conflict. CONCLUSION: Despite the varying degrees of bias which must be considered for the available evidence, the data with the lowest risk of bias suggest a relationship between exposure to armed conflict and low birth weight. In light of the current level of displacement experienced by such populations, the identification of pregnancies at risk could improve the efficacy of antenatal care. Clinicians should consider additional ultrasound scanning where appropriate to monitor for restricted growth in such pregnancies.

Behavioural and cognitive-behavioural interventions for outwardly-directed aggressive behaviour in people with intellectual disabilities.

BACKGROUND: Outwardly-directed aggressive behaviour is a significant part of problem behaviours presented by people with intellectual disabilities. Prevalence rates of up to 50% have been reported in the literature, depending on the population sampled. Such behaviours often run a long-term course and are a major cause of social exclusion. This is an update of a previously published systematic review (see Hassiotis 2004; Hassiotis 2008). OBJECTIVES: To evaluate the efficacy of behavioural and cognitive-behavioural interventions on outwardly-directed aggressive behaviour in people with intellectual disabilities when compared to standard intervention or wait-list controls. SEARCH METHODS: In April 2014 we searched CENTRAL, Ovid MEDLINE, Embase, and eight other databases. We also searched two trials registers, checked reference lists, and handsearched relevant journals to identify any additional trials. SELECTION CRITERIA: We included studies if more than four participants (children or adults) were allocated by random or quasi-random methods to either intervention, standard treatment, or wait-list control groups. DATA COLLECTION AND ANALYSIS: Two review authors independently identified studies and extracted and assessed the quality of the data. MAIN RESULTS: We deemed six studies (309 participants), based on adult populations with intellectual disabilities, suitable for inclusion in the current version of this review. These studies examined a range of cognitive-behavioural therapy (CBT) approaches: anger management (three studies (n = 235); one individual therapy and two group-based); relaxation (one study; n = 12), mindfulness based on meditation (one study; n = 34), problem solving and assertiveness training (one study; n = 28). We were unable to include any studies using behavioural interventions. There were no studies of children.Only one study reported moderate quality of evidence for outcomes of interest as assessed by the Grades of Recommendations, Assessment, Development and Evaluation (GRADE) approach. We judged the evidence for the remaining studies to be of very low to low quality. Most studies were at risk of bias in two or more domains: one study did not randomly allocate participants and in two studies the process of randomisation was unclear; in one study there was no allocation concealment and in three studies this was unclear; blinding of assessors did not occur in three studies; incomplete outcome data were presented in one study and unclear in two studies; there was selective reporting in one study; and other biases were present in one study and unclear in four studies.Three of the six studies showed some benefit of the intervention on improving anger ratings. We did not conduct a meta-analysis, as we considered the studies too heterogeneous to combine (e.g. due to differences in the types of participants, sample size interventions, and outcome measures).Follow-up data for anger ratings for both the treatment and control groups were available for two studies. Only one of these studies (n = 161) had adequate long-term data (10 months), which found some benefit of treatment at follow-up (continued improvement in anger coping skills as rated by key workers; moderate-quality evidence).Two studies (n = 192) reported some evidence that the intervention reduces the number of incidents of aggression and one study (n = 28) reported evidence that the intervention improved mental health symptoms.One study investigated the effects of the intervention on quality of life and cost of health and social care utilisation. This study provided moderate-quality evidence, which suggests that compared to no treatment, behavioural or cognitive-behavioural interventions do not improve quality of life at 16 weeks (n = 129) or at 10 months follow-up (n = 140), or reduce the cost of health service utilisation (n = 133).Only one study (n = 28) assessed adaptive functioning. It reported evidence that assertiveness and problem-solving training improved adaptive behaviour.No studies reported data on adverse events. AUTHORS' CONCLUSIONS: The existing evidence on the effectiveness of behavioural and cognitive-behavioural interventions on outwardly-directed aggression in children and adults with intellectual disabilities is limited. There is a paucity of methodologically sound clinical trials and a lack of long-term follow-up data. Given the impact of such behaviours on the individual and his or her support workers, effective interventions are essential. We recommend that randomised controlled trials of sufficient power are carried out using primary outcomes that include reduction in outward-directed aggressive behaviour, improvement in quality of life, and cost effectiveness.