The long-term safety and efficacy of bilateral transplantation of human fetal striatal tissue in patients with mild to moderate Huntington's disease.

Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease involving progressive motor, cognitive and behavioural decline, leading to death approximately 20 years after motor onset. The disease is characterised pathologically by an early and progressive striatal neuronal cell loss and atrophy, which has provided the rationale for first clinical trials of neural repair using fetal striatal cell transplantation. Between 2000 and 2003, the 'NEST-UK' consortium carried out bilateral striatal transplants of human fetal striatal tissue in five HD patients. This paper describes the long-term follow up over a 3-10-year postoperative period of the patients, grafted and non-grafted, recruited to this cohort using the 'Core assessment program for intracerebral transplantations-HD' assessment protocol. No significant differences were found over time between the patients, grafted and non-grafted, on any subscore of the Unified Huntington's Disease Rating Scale, nor on the Mini Mental State Examination. There was a trend towards a slowing of progression on some timed motor tasks in four of the five patients with transplants, but overall, the trial showed no significant benefit of striatal allografts in comparison with a reference cohort of patients without grafts. Importantly, no significant adverse or placebo effects were seen. Notably, the raclopride positron emission tomography (PET) signal in individuals with transplants, indicated that there was no obvious surviving striatal graft tissue. This study concludes that fetal striatal allografting in HD is safe. While no sustained functional benefit was seen, we conclude that this may relate to the small amount of tissue that was grafted in this safety study compared with other reports of more successful transplants in patients with HD.

Resting state cortico-thalamic-striatal connectivity predicts pesponse to dorsomedial prefrontal rTMS in major depressive disorder

Despite its high toll on society, there has been little recent improvement in treatment efficacy for Major Depressive Disorder (MDD). The identification of biological markers of successful treatment response may allow for more personalized and effective treatment. Here we investigate whether resting state functional connectivity predicted response to treatment with rapid transcranial magnetic stimulation (rTMS) to dorsomedial prefrontal cortex (dmPFC). Twenty five individuals with treatment-refractory MDD underwent a 4-week course of dmPFC-rTMS. Before and after treatment, subjects received resting state functional MRI scans and assessments of depressive symptoms using the Hamilton Depresssion Rating Scale (HAMD17). We found that higher baseline cortico-cortical connectivity (dmPFC-subgenual cingulate and subgenual cingulate to dorsolateral PFC) and lower cortico-thalamic, cortico-striatal and cortico-limbic connectivity were associated with better treatment outcomes. We also investigated how changes in connectivity over the course of treatment related to improvements in HAMD17 scores. We found that successful treatment was associated with increased dmPFC-thalamic connectivity and decreased sgACC-caudate connectivity, Our findings provide insight into which individuals might respond to rTMS treatment and the mechanisms through which these treatments work.

Cross-sector surveys assessing perceptions of key stakeholders towards barriers, concerns and facilitators to the appropriate use of adaptive designs in confirmatory trials

Background Appropriately conducted adaptive designs (ADs) offer many potential advantages over conventional trials. They make better use of accruing data, potentially saving time, trial participants, and limited resources compared to conventional, fixed sample size designs. However, one can argue that ADs are not implemented as often as they should be, particularly in publicly funded confirmatory trials. This study explored barriers, concerns, and potential facilitators to the appropriate use of ADs in confirmatory trials among key stakeholders. Methods We conducted three cross-sectional, online parallel surveys between November 2014 and January 2015. The surveys were based upon findings drawn from in-depth interviews of key research stakeholders, predominantly in the UK, and targeted Clinical Trials Units (CTUs), public funders, and private sector organisations. Response rates were as follows: 30(55 %) UK CTUs, 17(68 %) private sector, and 86(41 %) public funders. A Rating Scale Model was used to rank barriers and concerns in order of perceived importance for prioritisation. Results Top-ranked barriers included the lack of bridge funding accessible to UK CTUs to support the design of ADs, limited practical implementation knowledge, preference for traditional mainstream designs, difficulties in marketing ADs to key stakeholders, time constraints to support ADs relative to competing priorities, lack of applied training, and insufficient access to case studies of undertaken ADs to facilitate practical learning and successful implementation. Associated practical complexities and inadequate data management infrastructure to support ADs were reported as more pronounced in the private sector. For funders of public research, the inadequate description of the rationale, scope, and decision-making criteria to guide the planned AD in grant proposals by researchers were all viewed as major obstacles. Conclusions There are still persistent and important perceptions of individual and organisational obstacles hampering the use of ADs in confirmatory trials research. Stakeholder perceptions about barriers are largely consistent across sectors, with a few exceptions that reflect differences in organisations’ funding structures, experiences and characterisation of study interventions. Most barriers appear connected to a lack of practical implementation knowledge and applied training, and limited access to case studies to facilitate practical learning. Keywords: Adaptive designs; flexible designs; barriers; surveys; confirmatory trials; Phase 3; clinical trials; early stopping; interim analyses

Psychometric properties of the parent-infant caregiving touch scale

Recent work in animals suggests that the extent of early tactile stimulation by parents of offspring is an important element in early caregiving. We evaluate the psychometric properties of a new parent-report measure designed to assess frequency of tactile stimulation across multiple caregiving domains in infancy. We describe the full item set of the Parent-Infant Caregiving Touch Scale (PICTS) and, using data from a UK longitudinal Child Health and Development Study, the response frequencies and factor structure and whether it was invariant over two time points in early development (5 and 9 weeks). When their infant was 9 weeks old, 838 mothers responded on the PICTS while a stratified subsample of 268 mothers completed PICTS at an earlier 5 week old assessment (229 responded on both occasions). Three PICTS factors were identified reflecting stroking, holding and affective communication. These were moderately to strongly correlated at each of the two time points of interest and were unrelated to, and therefore distinct from, a traditional measure of maternal sensitivity at 7-months. A wholly stable psychometry over 5 and 9-week assessments was not identified which suggests that behavior profiles differ slightly for younger and older infants. Tests of measurement invariance demonstrated that all three factors are characterized by full configural and metric invariance, as well as a moderate degree of evidence of scalar invariance for the stroking factor. We propose the PICTS as a valuable new measure of important aspects of caregiving in infancy.

The relationship between diffuse spectral reflectance of the soil and its cation exchange capacity is scale-dependent

Diffuse reflectance spectroscopy (DRS) is increasingly being used to predict numerous soil physical, chemical and biochemical properties. However, soil properties and processes vary at different scales and, as a result, relationships between soil properties often depend on scale. In this paper we report on how the relationship between one such property, cation exchange capacity (CEC), and the DRS of the soil depends on spatial scale. We show this by means of a nested analysis of covariance of soils sampled on a balanced nested design in a 16 km × 16 km area in eastern England. We used principal components analysis on the DRS to obtain a reduced number of variables while retaining key variation. The first principal component accounted for 99.8% of the total variance, the second for 0.14%. Nested analysis of the variation in the CEC and the two principal components showed that the substantial variance components are at the > 2000-m scale. This is probably the result of differences in soil composition due to parent material. We then developed a model to predict CEC from the DRS and used partial least squares (PLS) regression do to so. Leave-one-out cross-validation results suggested a reasonable predictive capability (R2 = 0.71 and RMSE = 0.048 molc kg− 1). However, the results from the independent validation were not as good, with R2 = 0.27, RMSE = 0.056 molc kg− 1 and an overall correlation of 0.52. This would indicate that DRS may not be useful for predictions of CEC. When we applied the analysis of covariance between predicted and observed we found significant scale-dependent correlations at scales of 50 and 500 m (0.82 and 0.73 respectively). DRS measurements can therefore be useful to predict CEC if predictions are required, for example, at the field scale (50 m). This study illustrates that the relationship between DRS and soil properties is scale-dependent and that this scale dependency has important consequences for prediction of soil properties from DRS data

Self-, parent-report and interview measures of obsessive-compulsive disorder in children and adolescents

Self-report measures of obsessive-compulsive disorder (OCD) in children and adolescents are needed for practical evaluation of severity and treatment response. We compared the self- and parent-report Obsessional Compulsive Inventory Revised (CHOCI-R) to the interview-based Child Yale-Brown Obsessive-Compulsive Scale (CY-BOCS) in a clinical sample of 285 children and adolescents with OCD. Classical test theory and item-response theory were applied to compare the instruments. The self- and parent-report CHOCI-R had good internal consistency and were strongly related to each other. The self- and parent-report CHOCI-R severity scores correlated with the CY-BOCS (Pearson's r 0.55 and 0.45 respectively). The CY-BOCS discriminated better at the severe end of the spectrum. The CHOCI-R provided better discrimination in the mild to moderate range. The time-efficient self- and parent-report alternatives will enable routine measurement of OCD severity in clinical practice. Estimates of equivalent summed scores are provided to facilitate comparison. (c) 2007 Elsevier Ltd. All rights reserved.

Borg's rating of perceived exertion scales: do the verbal anchors mean the same for different clinical groups?

Objective: To examine the interpretation of the verbal anchors used in the Borg rating of perceived exertion (RPE) scales in different clinical groups and a healthy control group. Design: Prospective experimental study. Setting: Rehabilitation center. Participants: Nineteen subjects with brain injury, 16 with chronic low back pain (CLBP), and 20 healthy controls. Interventions: Not applicable. Main Outcome Measures: Subjects used a visual analog scale (VAS) to rate their interpretation of the verbal anchors from the Borg RPE 6-20 and the newer 10-point category ratio scale. Results: All groups placed the verbal anchors in the order that they occur on the scales. There were significant within-group differences (P > .05) between VAS scores for 4 verbal anchors in the control group, 8 in the CLBP group, and 2 in the brain injury group. There was no significant difference in rating of each verbal anchor between the groups (P > .05). Conclusions: All subjects rated the verbal anchors in the order they occur on the scales, but there was less agreement in rating of each verbal anchor among subjects in the brain injury group. Clinicians should consider the possibility of small discrepancies in the meaning of the verbal anchors to subjects, particularly those recovering from brain injury, when they evaluate exercise perceptions.

Working together? Parent and local authority views on the process of obtaining appropriate educational provision for children with autism spectrum disorders

Background: There is general agreement across all interested parties that a process of working together is the best way to determine which school or educational setting is right for an individual child with autism spectrum disorder. In the UK, families and local authorities both desire a constructive working relationship and see this as the best means by which to reach an agreement to determine where a child should be educated. It has been shown in published works 1 1. Batten and colleagues (Make schools make sense. Autism and education: the reality for families today; London: The National Autistic Society, 2006). View all notes that a constructive working relationship is not always achieved. Purpose: This small-scale study aims to explore the views of both parents and local authorities, focussing on how both parties perceive and experience the process of determining educational provision for children with autism spectrum disorders (ASD) within an English context. Sample, design and method: Parental opinion was gathered through the use of a questionnaire with closed and open responses. The questionnaire was distributed to two national charities, two local charities and 16 specialist schools, which offered the questionnaire to parents of children with ASD, resulting in an opportunity sample of 738 returned surveys. The views of local authority personnel from five local authorities were gathered through the use of semi-structured interviews. Data analyses included quantitative analysis of the closed response questionnaire items, and theme-based qualitative analysis of the open responses and interviews with local authority personnel. Results: In the majority of cases, parents in the survey obtained their first choice placement for their child. Despite this positive outcome, survey data indicated that parents found the process bureaucratic, stressful and time consuming. Parents tended to perceive alternative placement suggestions as financially motivated rather than in the best interests of the child. Interviews with local authority personnel showed an awareness of these concerns and the complex considerations involved in determining what is best for an individual child. Conclusions: This small-scale study highlights the need for more effective communication between parents of children with ASDs and local authority personnel at all stages of the process

Intrinsic chess rating

This paper develops and tests formulas for representing playing strength at chess by the quality of moves played, rather than by the results of games. Intrinsic quality is estimated via evaluations given by computer chess programs run to high depth, ideally so that their playing strength is sufficiently far ahead of the best human players as to be a `relatively omniscient' guide. Several formulas, each having intrinsic skill parameters s for `sensitivity' and c for `consistency', are argued theoretically and tested by regression on large sets of tournament games played by humans of varying strength as measured by the internationally standard Elo rating system. This establishes a correspondence between Elo rating and the parameters. A smooth correspondence is shown between statistical results and the century points on the Elo scale, and ratings are shown to have stayed quite constant over time. That is, there has been little or no `rating inflation'. The theory and empirical results are transferable to other rational-choice settings in which the alternatives have well-defined utilities, but in which complexity and bounded information constrain the perception of the utility values.

Health-related quality of life in Huntington’s Disease patients: a comparison of proxy assessment and patient self-rating using the disease-specific Huntington’s Disease health-related quality of life questionnaire (HDQoL)

Huntington’s disease (HD) is a fatal, neurodegenerative disease for which there is no known cure. Proxy evaluation is relevant for HD as its manifestation might limit the ability of persons to report their health-related quality of life (HrQoL). This study explored patient–proxy ratings of HrQoL of persons at different stages of HD, and examined factors that may affect proxy ratings. A total of 105 patient–proxy pairs completed the Huntington’s disease health-related quality of life questionnaire (HDQoL) and other established HrQoL measures (EQ-5D and SF-12v2). Proxy–patient agreement was assessed in terms of absolute level (mean ratings) and intraclass correlation. Proxies’ ratings were at a similar level to patients’ self-ratings on an overall Summary Score and on most of the six Specific Scales of the HDQoL. On the Specific Hopes and Worries Scale, proxies on average rated HrQoL as better than patients’ self-ratings, while on both the Specific Cognitive Scale and Specific Physical and Functional Scale proxies tended to rate HrQoL more poorly than patients themselves. The patient’s disease stage and mental wellbeing (SF-12 Mental Component scale) were the two factors that primarily affected proxy assessment. Proxy scores were strongly correlated with patients’ self-ratings of HrQoL, on the Summary Scale and all Specific Scales. The patient–proxy correlation was lower for patients at moderate stages of HD compared to patients at early and advanced stages. The proxy report version of the HDQoL is a useful complementary tool to self-assessment, and a promising alternative when individual patients with advanced HD are unable to self-report.

The treatment of child anxiety disorders via guided parent-delivered cognitive-behavioural therapy: a randomised controlled trial

Background Promising evidence has emerged of clinical gains using guided self-help cognitive-behavioural therapy (CBT) for child anxiety and by involving parents in treatment; however, the efficacy of guided parent-delivered CBT has not been systematically evaluated in UK primary and secondary settings. Aims To evaluate the efficacy of low-intensity guided parent-delivered CBT treatments for children with anxiety disorders. Method A total of 194 children presenting with a current anxiety disorder, whose primary carer did not meet criteria for a current anxiety disorder, were randomly allocated to full guided parent-delivered CBT (four face-to-face and four telephone sessions) or brief guided parent-delivered CBT (two face-to-face and two telephone sessions), or a wait-list control group (trial registration: ISRCTN92977593). Presence and severity of child primary anxiety disorder (Anxiety Disorders Interview Schedule for DSM-IV, child/parent versions), improvement in child presentation of anxiety (Clinical Global Impression-Improvement scale), and change in child anxiety symptoms (Spence Children’s Anxiety Scale, child/parent version and Child Anxiety Impact scale, parent version) were assessed at post-treatment and for those in the two active treatment groups, 6 months post-treatment. Results Full guided parent-delivered CBT produced superior diagnostic outcomes compared with wait-list at post-treatment, whereas brief guided parent-delivered CBT did not: at post-treatment, 25 (50%) of those in the full guided CBT group had recovered from their primary diagnosis, compared with 16 (25%) of those on the wait-list (relative risk (RR) 1.85, 95% CI 1.14-2.99); and in the brief guided CBT group, 18 participants (39%) had recovered from their primary diagnosis post-treatment (RR = 1.56, 95% CI 0.89-2.74). Level of therapist training and experience was unrelated to child outcome. Conclusions Full guided parent-delivered CBT is an effective and inexpensive first-line

The parental overprotection scale: associations with child and parental anxiety

Background: Parental overprotection has commonly been implicated in the development and maintenance of childhood anxiety disorders. Overprotection has been assessed using questionnaire and observational methods interchangeably; however, the extent to which these methods access the same construct has received little attention. Edwards, 2008 and Edwards et al., 2010 developed a promising parent-report measure of overprotection (OP) and reported that, with parents of pre-school children, the measure correlated with observational assessments and predicted changes in child anxiety symptoms. We aimed to validate the use of the OP measure with mothers of children in middle childhood, and examine its association with child and parental anxiety. Methods: Mothers of 90 children (60 clinically anxious, 30 non-anxious) aged 7–12 years completed the measure and engaged in a series of mildly stressful tasks with their child. Results: The internal reliability of the measure was good and scores correlated significantly with observations of maternal overprotection in a challenging puzzle task. Contrary to expectations, OP was not significantly associated with child anxiety status or symptoms, but was significantly associated with maternal anxiety symptoms. Limitations: Participants were predominantly from affluent social groups and of non-minority status. Overprotection is a broad construct, the use of specific sub-dimensions of behavioural constructs may be preferable. Conclusions: The findings support the use of the OP measure to assess parental overprotection among 7–12 year-old children; however, they suggest that parental responses may be more closely related to the degree of parental rather than child anxiety.

Randomized controlled trial of parent-enhanced CBT compared with individual CBT for obsessive-compulsive disorder in young people

Objective: Obsessive-compulsive disorder (OCD) in young people can be effectively treated with Cognitive Behavior Therapy (CBT). Practice guidelines in the United Kingdom recommend that CBT be delivered with parental or family involvement; however, there is no evidence from randomized trials that this enhances effectiveness. The aim of this trial was to assess if CBT with high parental involvement was more effective than CBT with low parental involvement (individual CBT) in reducing symptoms of OCD. Method: Fifty young people ages 12–17 years with OCD were randomly allocated to individual CBT or parent-enhanced CBT. In parent-enhanced CBT parents attended all treatment sessions; in individual CBT, parents attended only Sessions 1, 7, and the final session. Participants received up to 14 sessions of CBT. Data were analyzed using intent-to-treat and per-protocol methods. The primary outcome measure was the Children’s Yale-Brown Obsessive Compulsion Scale (Scahill et al., 1997). Results: Both forms of CBT significantly reduced symptoms of OCD and anxiety. Change in OCD symptoms was maintained at 6 months. Per-protocol analysis suggested that parent-enhanced CBT may be associated with significantly larger reductions in anxiety symptoms. Conclusions: High and low parental involvement in CBT for OCD in young people were both effective, and there was no evidence that 1 method of delivery was superior on the primary outcome measure. However, this study was small. Future trials should be adequately powered and examine interactions with the age of the young person and comorbid anxiety disorders.

Development and validation of a parent report measure for detection of cognitive delay in infancy

Aim To develop a brief, parent-completed instrument (‘ERIC’) for detection of cognitive delay in 10-24 month-olds born preterm, or with low birth weight, or with perinatal complications, and to establish its diagnostic properties. Method Scores were collected from parents of 317 children meeting ≥1 inclusion criteria (birth weight <1500g; gestational age <34 completed weeks; 5-minute Apgar <7; presence of hypoxic-ischemic encephalopathy) and meeting no exclusion criteria. Children were assessed for cognitive delay using a criterion score on the Bayley Scales of Infant and Toddler Development Cognitive Scale III1 <80. Items were retained according to their individual associations with delay. Sensitivity, specificity, Positive and Negative Predictive Values were estimated and a truncated ERIC was developed for use <14 months. Results ERIC detected 17 out of 18 delayed children in the sample, with 94.4% sensitivity (95% CI [confidence interval] 83.9-100%), 76.9% specificity (72.1-81.7%), 19.8% positive predictive value (11.4-28.2%); 99.6% negative predictive value (98.7-100%); 4.09 likelihood ratio positive; and 0.07 likelihood ratio negative; the associated Area under the Curve was .909 (.829-.960). Interpretation ERIC has potential value as a quickly-administered diagnostic instrument for the absence of early cognitive delay in preterm or premature infants of 10-24 months, and as a screen for cognitive delay. Further research may be needed before ERIC can be recommended for wide-scale use.