Spastin mutation screening in Chinese patients with pure hereditary spastic paraplegia

BackgroundHereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative diseases. Mutations in the spastin (SPAST) gene are the most common cause of pure HSP. However, few data are available regarding the clinical and genetic spectrum of HSP among Chinese patients.MethodsClinical data were collected at diagnosis and follow-up of 42 Chinese patients with pure HSP. All seventeen exons of the SPAST gene were directly sequenced. Additionally, we used a multiplex ligation dependent probe amplification (MLPA) assay targeting the SPAST gene to evaluate large exon deletion or insertion mutations in patients without SPAST point mutations.ResultsThe age of disease onset of our patients was 19.6 ± 14.4 years. Six novel variations were found, including three missense mutations (p. L363P, p. D441V, and p. S595R), one insertion (c.1511dupT (p. Y505Ifs*7)), and two larger deletions (exons 5–17 and exons 10–17). Four previously reported mutations, including p. S399L, c.1215_c.1219delTATAA (p. N405Kfs*36), exon 1 deletion, and exon 16 deletion, were detected. The SPAST mutation rate was 40% (4/10) in Chinese familial patients and 33.33% (7/21) in Chinese sporadic pure HSP patients. The frequency of large deletions was high in both AD-HSP (20%, 2/10) and sporadic HSP (14.28%, 3/21).ConclusionSPAST mutations are common in Chinese patients with pure HSP. Large exon deletions are an important cause of AD-HSP and sporadic pure HSP in Chinese patients. Large fragment tests should be performed to explore large SPAST mutations in familial and sporadic HSP patients without SPAST point mutations.     

A diagnostic ceiling for exome sequencing in cerebellar ataxia and related neurological disorders

Genetic ataxias are associated with mutations in hundreds of genes with high phenotypic overlap complicating the clinical diagnosis. Whole‐exome sequencing (WES) has increased the overall diagnostic rate considerably. However, the upper limit of this method remains ill‐defined, hindering efforts to address the remaining diagnostic gap. To further assess the role of rare coding variation in ataxic disorders, we reanalyzed our previously published exome cohort of 76 predominantly adult and sporadic‐onset patients, expanded the total number of cases to 260, and introduced analyses for copy number variation and repeat expansion in a representative subset. For new cases (n = 184), our resulting clinically relevant detection rate remained stable at 47% with 24% classified as pathogenic. Reanalysis of the previously sequenced 76 patients modestly improved the pathogenic rate by 7%. For the combined cohort (n = 260), the total observed clinical detection rate was 52% with 25% classified as pathogenic. Published studies of similar neurological phenotypes report comparable rates. This consistency across multiple cohorts suggests that, despite continued technical and analytical advancements, an approximately 50% diagnostic rate marks a relative ceiling for current WES‐based methods and a more comprehensive genome‐wide assessment is needed to identify the missing causative genetic etiologies for cerebellar ataxia and related neurodegenerative diseases.     

Prospective controlled cohort study to evaluate changes of function,activity and participation in patients with bilateral spastic cerebral palsy after Robot-enhanced repetitive treadmill therapy

BackgroundRobot-enhanced therapies are increasingly being used to improve gross motor performance in patients with cerebral palsy.AimTo evaluate gross motor function, activity and participation in patients with bilateral spastic cerebral palsy (BS-CP) after Robot-enhanced repetitive treadmill therapy (ROBERT) in a prospective, controlled cohort study.MethodsParticipants trained for 30–60 min in each of 12 sessions within a three-week-period. Changes in Gross Motor Function Measure (GMFM 66) scores, standardized walking distance, self-selected and maximum walking speed (ICF domain “Activity”), and Canadian Occupational Performance Measure (COPM; “Participation”) were measured. Outcome measures were assessed three weeks in advance (V1), the day before (V2) as well as the day after, and 8 weeks after ROBERT (V3 + V4).Results18 patients with BS-CP participated; age 11.5 (mean, range: 5.0–21.8) years, body weight 36.4 (15.0–72.0) kg. GMFCS levels I–IV were: n = 4; 5; 8; 1. There was no significant difference comparing V1 and V2. GMFM 66 (total +2.5 points, Dimension D +3.8 and E +3.2) and COPM (Performance +2.1 points, Satisfaction +1.8 points) showed statistically significant improvements for V3 or V4 compared to V1 or V2 representing clinically meaningful effect sizes. Age, GMFCS level, and repeated ROBERT blocks correlated negatively with GMFM improvement, but not with COPM improvement.InterpretationFollowing ROBERT, this prospective controlled cohort study showed significant and clinically meaningful improvements of function in ICF domains of “activity” and “participation” in patients with BS-CP. Further assessment in a larger cohort is necessary to allow more specific definition of factors that influence responsiveness to ROBERT program.     

KIF1A‐related disorders in children: A wide spectrum of central and peripheral nervous system involvement

KIF1A‐related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood‐onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case‐notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent—but sometimes progressive—changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits.     

仿生训练对痉挛型脑瘫患儿粗大运动功能的影响

目的：探讨仿生训练对痉挛型脑性瘫痪患儿粗大运动功能的影响。方法：选取痉挛型脑性瘫痪患儿40例,随机分为观察组和对照组各20例。2组患儿均进行常规康复训练,观察组在常规康复训练的基础上增加仿生训练(兔子跳跃、蜥蜴行走、猴子攀爬)。在训练前后分别对2组患儿用粗大运动功能评估量表（GMFM）、Peabody粗大运动发育量表(PDMS-GM)进行评估,并利用关节量角器对其内收肌角、足背屈角进行测量。观察训练前后2组痉挛型脑性瘫痪患儿GMFM、PDMS-GM原始分差异及患儿内收肌角、足背屈角差异。结果：治疗12周后,2组GMFM及PDMS-GM评分均较治疗前显著提高（均P＜0.05）,且观察组均高于对照组(均P＜0.05);2组患儿内收肌角及足背屈角均大于治疗前(均P＜0.05),且观察组均大于对照组(均P＜0.05)。结论：仿生训练可改善痉挛型脑瘫患儿的粗大运动功能。     

Stakeholder involvement in the systematic optimisation of two school-based relationships and sex education interventions,Project Respect and Positive Choices

Background

There is increasing emphasis on involving intended beneficiaries and other stakeholders in the development of public health interventions to maximise acceptability and remove barriers to adoption, implementation, and maintenance before costly implementation. Yet the processes whereby key actors are engaged in intervention development are rarely reported, and frameworks for carrying out such work remain limited. We outline our approach to involving stakeholders in the optimisation of two school-based relationships and sex education programmes (Project Respect and Positive Choices) and reflect on the challenges of co-producing with teachers, students, and other partners.

Maternal and child health workforce profile and density in China since 1949: a systematic review

Background

Routine sources of information on the maternal and child health workforce in China are without clear definition and categorisation. The aim of the study was to systematically review all the evidence on China's maternal and child health workforce profile (ie, level of education, training, qualification, and professional title), and determine the density of the maternal and child health workforce.

Developing a risk prediction model for 30-day unplanned hospitalization in patients receiving outpatient parenteral antimicrobial therapy

ObjectivesOutpatient parenteral antimicrobial therapy (OPAT) is increasingly used to treat a wide range of infections. However, there is risk of hospital readmissions. The study aim was to develop a prediction model for the risk of 30-day unplanned hospitalization in patients receiving OPAT.MethodsUsing a retrospective cohort design, we retrieved data on 1073 patients who received OPAT over 2 years (January 2015 to January 2017) at a large teaching hospital in Sheffield, UK. We developed a multivariable logistic regression model for 30-day unplanned hospitalization, assessed its discrimination and calibration abilities, and internally them validated using bootstrap resampling.ResultsThe 30-day unplanned hospitalization rate was 11% (123/1073). The main indication for hospitalization was worsening or nonresponse of infection (52/123, 42%). The final regression model consisted of age (adjusted odds ratio (aOR), 1.18 per decade; 95% confidence interval (CI), 1.04–1.34), Charlson comorbidity score (aOR, 1.11 per unit increase; 95% CI, 1.00–1.23), prior hospitalizations in past 12 months (aOR, 1.30 per admission; 95% CI, 1.17–1.45), concurrent intravenous antimicrobial therapy (aOR, 1.89; 95% CI, 1.03–3.47) and endovascular infection (aOR, 3.51; 95% CI, 1.49–8.28). Mode of OPAT treatment was retained in the model as a confounder. The model had adequate concordance (c-statistic 0.72; 95% CI 0.67–0.77) and calibration (Hosmer-Lemeshow p 0.546; calibration slope 0.99; 95% CI 0.78–1.21), and low degree of optimism (bootstrap optimism corrected c-statistic, 0.70).ConclusionsWe identified a set of six important predictors of unplanned hospitalization based on readily available data. The prediction model may help improve OPAT outcomes through better identification of high-risk patients and provision of tailored care.