Anti-tumour necrosis factor therapy for Dupuytren's Disease: a randomised dose response proof of concept phase 2a clinical trial

Background Dupuytren's disease is a common fibrotic condition of the hand that causes irreversible flexion contractures of the fingers, with no approved therapy for early stage disease. Our previous analysis of surgically-excised tissue defined tumour necrosis factor (TNF) as a potential therapeutic target. Here we assessed the efficacy of injecting nodules of Dupuytren's disease with a TNF inhibitor. Methods Patients were randomised to receive adalimumab on one occasion in dose cohorts of 15 mg in 0.3 ml, 35 mg in 0.7 ml, or 40 mg in 0.4 ml, or an equivalent volume of placebo in a 3:1 ratio. Two weeks later the injected tissue was surgically excised and analysed. The primary outcome measure was levels of mRNA expression for α-smooth muscle actin (ACTA2). Secondary outcomes included levels of α-SMA and collagen proteins. The trial was registered with ClinicalTrial.gov (NCT03180957) and the EudraCT (2015-001780-40). Findings We recruited 28 patients, 8 assigned to the 15 mg, 12 to the 35 mg and 8 to the 40 mg adalimumab cohorts. There was no change in mRNA levels for ACTA2, COL1A1, COL3A1 and CDH11. Levels of α-SMA protein expression in patients treated with 40 mg adalimumab (1.09 ± 0.09 ng per μg of total protein) were significantly lower (p = 0.006) compared to placebo treated patients (1.51 ± 0.09 ng/μg). The levels of procollagen type I protein expression were also significantly lower (p < 0.019) in the sub group treated with 40 mg adalimumab (474 ± 84 pg/μg total protein) compared with placebo (817 ± 78 pg/μg). There were two serious adverse events, both considered unrelated to the study drug. Interpretation In this dose-ranging study, injection of 40 mg of adalimumab in 0.4 ml resulted in down regulation of the myofibroblast phenotype as evidenced by reduction in expression of α-SMA and type I procollagen proteins at 2 weeks. These data form the basis of an ongoing phase 2b clinical trial assessing the efficacy of intranodular injection of 40 mg adalimumab in 0.4 ml compared to an equivalent volume of placebo in patients with early stage Dupuytren's disease

Y Kids Academy Program Increases Knowledge of Healthy Living in Young Adolescents

OBJECTIVES It is well established that physical activity levels decline during adolescence. To address this problem, a program called the Y Kids Academy was developed to improve young adolescents’ knowledge of healthy lifestyles. The primary goal was to evaluate whether the program would attract participants with both high and low levels of physical literacy and to evaluate whether baseline knowledge scores were associated with physical literacy knowledge. The secondary goals were to determine whether baseline knowledge scores would increase after Y Kids Academy participation or were associated with a standardized assessment of physical literacy knowledge. METHODS Parent perceptions of their adolescent’s healthy living behaviours were measured to assess the impact of Y Kids Academy participation on the family. The Canadian Assessment of Physical Literacy (CAPL) was completed pre-Academy to measure participants’ physical literacy. Participants and parents also completed questionnaires pre- and post-Academy to assess change in healthy living knowledge and perception of the child’s healthy living behaviours, respectively. 163 children (mean age of 11.1 ± 0.8) consented to participate (73 female, 45%). RESULTS The mean total CAPL score of participants was not significantly different (p=.07) from the mean total CAPL score measured among 3000 Canadian children. The largest proportion of participants (53.3%) were categorized as progressing, similar to the Canadian population (53.2%). Knowledge scores for the Y Kids Academy evaluation were significantly associated with physical literacy knowledge (r = 0.40, p < 0.001). Mean knowledge scores increased significantly (p<0.001) from pre-Academy (10.4 ± 5.4) to post-academy (12.7±6.5). There was no change in parent reported healthy living behaviours (p=0.41). CONCLUSIONS The Y Kids Academy program was successful at attracting youth with lower physical literacy in a proportion similar to the Canadian population. These findings support the suitability of the Y Kids Academy for improving and evaluating knowledge of healthy living in young adolescents

Impaired perception of facial motion in autism spectrum disorder

Copyright: © 2014 O’Brien et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article has been made available through the Brunel Open Access Publishing Fund.Facial motion is a special type of biological motion that transmits cues for socio-emotional communication and enables the discrimination of properties such as gender and identity. We used animated average faces to examine the ability of adults with autism spectrum disorders (ASD) to perceive facial motion. Participants completed increasingly difficult tasks involving the discrimination of (1) sequences of facial motion, (2) the identity of individuals based on their facial motion and (3) the gender of individuals. Stimuli were presented in both upright and upside-down orientations to test for the difference in inversion effects often found when comparing ASD with controls in face perception. The ASD group’s performance was impaired relative to the control group in all three tasks and unlike the control group, the individuals with ASD failed to show an inversion effect. These results point to a deficit in facial biological motion processing in people with autism, which we suggest is linked to deficits in lower level motion processing we have previously reported

Precursors to social and communication difficulties in infants at-risk for autism: gaze following and attentional engagement

Whilst joint attention (JA) impairments in autism have been widely studied, little is known about the early development of gaze following, a precursor to establishing JA. We employed eye-tracking to record gaze following longitudinally in infants with and without a family history of autism spectrum disorder (ASD) at 7 and 13 months. No group difference was found between at-risk and low-risk infants in gaze following behaviour at either age. However, despite following gaze successfully at 13 months, at-risk infants with later emerging socio-communication difficulties (both those with ASD and atypical development at 36 months of age) allocated less attention to the congruent object compared to typically developing at-risk siblings and low-risk controls. The findings suggest that the subtle emergence of difficulties in JA in infancy may be related to ASD and other atypical outcomes

Atypical disengagement from faces and its modulation by the control of eye fixation in children with Autism Spectrum Disorder

By using the gap overlap task, we investigated disengagement from faces and objects in children (9–17 years old) with and without autism spectrum disorder (ASD) and its neurophysiological correlates. In typically developing (TD) children, faces elicited larger gap effect, an index of attentional engagement, and larger saccade-related event-related potentials (ERPs), compared to objects. In children with ASD, by contrast, neither gap effect nor ERPs differ between faces and objects. Follow-up experiments demonstrated that instructed fixation on the eyes induces larger gap effect for faces in children with ASD, whereas instructed fixation on the mouth can disrupt larger gap effect in TD children. These results suggest a critical role of eye fixation on attentional engagement to faces in both groups

Measuring the value of social engagement in adults with and without autism

Differences in social communication are commonly reported in autism spectrum condition (ASC). A recent theory attributes this to a reduced motivation to engage with others, that is, deficits in social motivation. However, there are currently few simple, direct, behavioural ways to test this claim. This study uses a new behavioural measure of social motivation to test if preferences for direct gaze and face stimuli are linked to autistic traits or an ASC diagnosis. Our novel choose-a-movie (CAM) paradigm measures the effort participants invest to see particular stimuli. This aspect of social motivation is also known as social seeking. Methods In experiment 1, 80 typical adults completed the CAM task and a measure of autistic traits. In experiment 2, 30 adults with ASC and 24 age/IQ-matched typical adults completed the CAM paradigm. Results The results from study one showed that typical adults prefer social stimuli over non-social, but this preference is weaker in those with higher levels of autistic traits. In study two, adults with ASC showed a significant reduction in their preference for direct gaze but little difference in their preference for faces without direct gaze. Conclusions These data show that social motivation can be measured in a simple, direct, behavioural paradigm. Furthermore, adults with ASC prefer direct gaze less than typical adults but may not avoid faces without direct gaze. This data advance our understanding of how social motivation may differ between those with and without autism

When prototypes are not best: Judgments made by children with autism

The current study used a factorial comparison experimental design to investigate conflicting findings on prototype effects shown by children with autism (Klinger & Dawson, 2001; Molesworth, Bowler, & Hampton, 2005). The aim was to see whether children with high –functioning autism could demonstrate prototype effects via categorization responses and whether failure to do so was related to difficulty understanding ambiguous task demands. Two thirds of the autism group did show an effect. The remainder, a sub-group defined by performance on a control task, did not. The discussion focuses on the influence of heterogeneity within the autism group and the ability to resolve ambiguity on task performance. Finally, an alternative experimental design is recommended for further research into these issues

Do faces capture the attention of individuals with Williams syndrome or Autism? Evidence from tracking eye movements

The neuro-developmental disorders of Williams syndrome (WS) and autism can reveal key components of social cognition. Eye‐tracking techniques were applied in two tasks exploring attention to pictures containing faces. Images were i) scrambled pictures containing faces or ii) pictures of scenes with embedded faces. Compared to individuals who were developing typically, participants with WS and autism showed atypicalities of gaze behaviour. Individuals with WS showed prolonged face gaze across tasks, relating to the typical WS social phenotype. Participants with autism exhibited reduced face gaze, linking to a lack of interest in socially relevant information. The findings are interpreted in terms of wider issues regarding socio‐cognition and attention mechanisms