Sensory integration therapy for children with autism and sensory processing difficulties: the SenITA RCT.

BACKGROUND: Carers report unmet need for occupational therapy services addressing sensory difficulties in autism, yet insufficient evidence exists to recommend a therapeutic approach. OBJECTIVES: Our aim was to determine the clinical effectiveness and cost-effectiveness of sensory integration therapy for children with autism and sensory difficulties across behavioural, functional and quality-of-life outcomes. DESIGN: We carried out a parallel-group randomised controlled trial, incorporating an internal pilot and a process evaluation. Randomisation utilised random permuted blocks. SETTING AND PARTICIPANTS: Children were recruited via services and self-referral in Wales and England. Inclusion criteria were having an autism diagnosis, being in mainstream primary education and having definite/probable sensory processing difficulties. Exclusion criteria were having current/previous sensory integration therapy and current applied behaviour analysis therapy. INTERVENTION: The intervention was manualised sensory integration therapy delivered over 26 weeks and the comparator was usual care. OUTCOMES: The primary outcome was problem behaviours (determined using the Aberrant Behavior Checklist), including irritability/agitation, at 6 months. Secondary outcomes were adaptive behaviour, functioning and socialisation (using the Vineland Adaptive Behavior Scales); carer stress (measured using the Autism Parenting Stress Index); quality of life (measured using the EuroQol-5 Dimensions and Carer Quality of Life); functional change (according to the Canadian Occupational Performance Measure); sensory processing (determined using the Sensory Processing Measure™ at screening and at 6 months to examine mediation effects); and cost-effectiveness (assessed using the Client Service Receipt Inventory). Every effort was made to ensure that outcome assessors were blind to allocation. RESULTS: A total of 138 participants were randomised (n = 69 per group). Usual care was significantly different from the intervention, which was delivered with good fidelity and adherence and minimal contamination, and was associated with no adverse effects. Trial procedures and outcome measures were acceptable. Carers and therapists reported improvement in daily functioning. The primary analysis included 106 participants. There were no significant main effects of the intervention at 6 or 12 months. The adjusted mean difference between groups on the Aberrant Behavior Checklist - irritability at 6 months post randomisation was 0.40 (95% confidence interval -2.33 to 3.14; p = 0.77). Subgroup differences in irritability/agitation at 6 months were observed for sex of child (intervention × female = 6.42, 95% confidence interval 0.00 to 12.85; p = 0.050) and attention deficit hyperactivity disorder (intervention × attention deficit hyperactivity disorder = -6.77, 95% confidence interval -13.55 to -0.01; p = 0.050). There was an effect on carer stress at 6 months by region (intervention × South England = 7.01, 95% confidence interval 0.45 to 13.56; p = 0.04) and other neurodevelopmental/genetic conditions (intervention × neurodevelopmental/genetic condition = -9.53, 95% confidence interval -18.08 to -0.98; p = 0.030). Carer-rated goal performance and satisfaction increased across sessions (p < 0.001), with a mean change of 2.75 (95% confidence interval 2.14 to 3.37) for performance and a mean change of 3.34 (95% confidence interval 2.63 to 4.40) for satisfaction. Health economic evaluation suggests that sensory integration therapy is not cost-effective compared with usual care alone. LIMITATIONS: Limitations included variability of the intervention setting (i.e. NHS vs. private), delay for some receiving therapy, an error in administration of Vineland Adaptive Behavior Scales and no measurement of comparator arm goal performance. CONCLUSIONS: The intervention did not demonstrate clinical benefit above standard care. Subgroup effects are hypothesis-generating only. The intervention is likely to be effective for individualised performance goals, although it is unclear whether effects were in addition to standard care or were maintained. FUTURE WORK: Further investigation of subgroup effects is needed. TRIAL REGISTRATION: This trial is registered as ISRCTN14716440. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 26, No. 29. See the NIHR Journals Library website for further project information.

Children with autism often experience problems with processing sensory information (e.g. noise, touch, movement, taste and sight), and this can lead to problems in daily life. This study was designed to see if sensory integration therapy can help children with these difficulties. Sensory integration therapy is a type of face-to-face play-based treatment that is delivered by occupational therapists. We compared sensory integration therapy with the type of treatment normally offered to children with autism (i.e. 'usual care'). We recruited children and their carers from Wales and England. Children could take part in the study if they had an autism diagnosis, had sensory processing difficulties and were in mainstream primary education. The children taking part in the study were randomly split into two groups. Sixty-nine children were given sensory integration therapy and 69 children carried on with their usual care. The sensory integration therapy involved 24 face-to-face sessions in an occupational therapy clinic, followed by two telephone calls with the carer. The sensory integration therapy lasted for 26 weeks. We collected information on the type of care being given to children in the usual-care group. Carers of each child were asked questions about their child's behaviour 6 and 12 months after starting the study. Some carers also completed an interview to talk about what it was like taking part in the study. Therapists delivered the sensory integration therapy well. Carers and therapists said that they saw some improvements. However, sensory integration therapy was not significantly better than the usual care and is a more expensive option. We cannot say that sensory integration therapy is helpful for all children with autism and different sensory processing difficulties; however, it might be helpful for some children to focus on specific problems. Future work could focus on which children and problems it would help the most.

Genome-wide mapping of Vibrio cholerae VpsT binding identifies a mechanism for c-di-GMP homeostasis.

Many bacteria use cyclic dimeric guanosine monophosphate (c-di-GMP) to control changes in lifestyle. The molecule, synthesized by proteins having diguanylate cyclase activity, is often a signal to transition from motile to sedentary behaviour. In Vibrio cholerae, c-di-GMP can exert its effects via the transcription factors VpsT and VpsR. Together, these proteins activate genes needed for V. cholerae to form biofilms. In this work, we have mapped the genome-wide distribution of VpsT in a search for further regulatory roles. We show that VpsT binds 23 loci and recognises a degenerate DNA palindrome having the consensus 5'-W-5R-4[CG]-3Y-2W-1W+1R+2[GC]+3Y+4W+5-3'. Most genes targeted by VpsT encode functions related to motility, biofilm formation, or c-di-GMP metabolism. Most notably, VpsT activates expression of the vpvABC operon that encodes a diguanylate cyclase. This creates a positive feedback loop needed to maintain intracellular levels of c-di-GMP. Mutation of the key VpsT binding site, upstream of vpvABC, severs the loop and c-di-GMP levels fall accordingly. Hence, as well as relaying the c-di-GMP signal, VpsT impacts c-di-GMP homeostasis.

The quorum sensing transcription factor AphA directly regulates natural competence in Vibrio cholerae.

Many bacteria use population density to control gene expression via quorum sensing. In Vibrio cholerae, quorum sensing coordinates virulence, biofilm formation, and DNA uptake by natural competence. The transcription factors AphA and HapR, expressed at low and high cell density respectively, play a key role. In particular, AphA triggers the entire virulence cascade upon host colonisation. In this work we have mapped genome-wide DNA binding by AphA. We show that AphA is versatile, exhibiting distinct modes of DNA binding and promoter regulation. Unexpectedly, whilst HapR is known to induce natural competence, we demonstrate that AphA also intervenes. Most notably, AphA is a direct repressor of tfoX, the master activator of competence. Hence, production of AphA markedly suppressed DNA uptake; an effect largely circumvented by ectopic expression of tfoX. Our observations suggest dual regulation of competence. At low cell density AphA is a master repressor whilst HapR activates the process at high cell density. Thus, we provide deep mechanistic insight into the role of AphA and highlight how V. cholerae utilises this regulator for diverse purposes.

Sensory integration therapy versus usual care for sensory processing difficulties in autism spectrum disorder in children: study protocol for a pragmatic randomised controlled trial.

BACKGROUND: Autism spectrum disorder (ASD) is a common lifelong condition affecting 1 in 100 people. ASD affects how a person relates to others and the world around them. Difficulty responding to sensory information (noise, touch, movement, taste, sight) is common, and might include feeling overwhelmed or distressed by loud or constant low-level noise (e.g. in the classroom). Affected children may also show little or no response to these sensory cues. These 'sensory processing difficulties' are associated with behaviour and socialisation problems, and affect education, relationships, and participation in daily life. Sensory integration therapy (SIT) is a face-to-face therapy or treatment provided by trained occupational therapists who use play-based sensory-motor activities and the just-right challenge to influence the way the child responds to sensation, reducing distress, and improving motor skills, adaptive responses, concentration, and interaction with others. With limited research into SIT, this protocol describes in detail how the intervention will be defined and evaluated. METHODS: This is a two-arm pragmatic individually 1:1 randomised controlled trial with an internal pilot of SIT versus usual care for primary school aged children (aged 4 to 11 years) with ASD and sensory processing difficulties; 216 children will be recruited from multiple sources. Therapy will be delivered in clinics meeting full fidelity criteria for manualised SIT over 26 weeks (face-to-face sessions: two per week for 10 weeks, two per month for 2 months; telephone call: one per month for 2 months). Follow-up assessments will be completed at 6 and 12 months post-randomisation. Prior to recruitment, therapists will be invited to participate in focus groups/interviews to explore what is delivered as usual care in trial regions; carers will be invited to complete an online survey to map out their experience of services. Following recruitment, carers will be given diaries to record their contact with services. Following intervention, carer and therapist interviews will be completed. DISCUSSION: Results of this trial will provide high-quality evidence on the clinical and cost effectiveness of SIT aimed at improving behavioural, functional, social, educational, and well-being outcomes for children and well-being outcomes for carers and families. TRIAL REGISTRATION: ISRCTN14716440 . Registered on 8 November 2016.

Moving and handling: reducing risk through assessment.

Manual handling injuries can occur almost anywhere in a healthcare environment, and most staff perform a variety of moving and handling tasks every day. Heavy lifting, awkward posture, and previous or existing injury can increase the risk of musculoskeletal disorders. A healthcare professional's involvement in moving and handling is more widespread than it might appear, and their actions and understanding of techniques, legislation and guidelines have a direct effect on patient care. Every situation that involves the handling, or partial handling, of a person presents varying levels of risk to the patient and the carer. Maintaining a good level of patient mobility and independence is an essential part of care delivery and can reduce the risk of long-term physical and psychological effects. Delivery of care should focus on the individual's capacity, not their incapacity, to ensure that they are treated with dignity and respect.

Are Angelman and Prader-Willi syndromes more similar than we thought? Food-related behavior problems in Angelman, Cornelia de Lange, fragile X, Prader-Willi and 1p36 deletion syndromes.

Food-related behavior problems are well documented in Prader-Willi syndrome (PWS), with impaired satiety, preoccupation with food and negative food-related behaviors (such as taking and storing food) frequently reported as part of the behavioral phenotype of older children and adults. Food-related behavior problems in other genetic neurodevelopmental syndromes remain less well studied, including those seen in Angelman Syndrome (AS), the 'sister imprinted disorder' of PWS. Food-related behavior problems were assessed in 152 participants each with one of five genetic neurodevelopmental syndromes ­ PWS, AS, 1p36 deletion, Cornelia de Lange, and fragile X. Predictably, levels of food-related behavior problems reported in participants with PWS significantly exceeded those of at least one other groups in most areas (impaired satiety; preoccupation with food; taking and storing food; composite negative behavior). However, in some areas people with AS were reported to display food-related problems at least as severe as those with PWS, with the AS group reported to display significantly more food-related behavior problems than at least one comparison group on measures of taking and storing food, composite negative behaviors, impaired satiety and preoccupation with food. Over 50% of participants in the AS group scored above the median point of the distribution of PWS scores on a measure of taking and storing food. These findings indicate further investigation of eating problems in AS are warranted and have implications for current theoretical interpretations of the behavioral differences between AS and PWS.

An environment-dependent structural switch underlies the regulation of carnitine palmitoyltransferase 1A.

The enzyme carnitine palmitoyltransferase 1 (CPT1), which is anchored in the outer mitochondrial membrane (OMM), controls the rate-limiting step in fatty acid ß-oxidation in mammalian tissues. It is inhibited by malonyl-CoA, the first intermediate of fatty acid synthesis, and it responds to OMM curvature and lipid characteristics, which reflect long term nutrient/hormone availability. Here, we show that the N-terminal regulatory domain (N) of CPT1A can adopt two complex amphiphilic structural states, termed Nα and Nß, that interchange in a switch-like manner in response to offered binding surface curvature. Structure-based site-directed mutageneses of native CPT1A suggest Nα to be inhibitory and Nß to be noninhibitory, with the relative Nα/Nß ratio setting the prevalent malonyl-CoA sensitivity of the enzyme. Based on the amphiphilic nature of N and molecular modeling, we propose malonyl-CoA sensitivity to be coupled to the properties of the OMM by Nα-OMM associations that alter the Nα/Nß ratio. For enzymes residing at the membrane-water interface, this constitutes an integrative regulatory mechanism of exceptional sophistication.

Packing of transmembrane domain 2 of carnitine palmitoyltransferase-1A affects oligomerization and malonyl-CoA sensitivity of the mitochondrial outer membrane protein.

The purpose of this study was to investigate the sequence-dependence of oligomerization of transmembrane domain 2 (TM2) of rat carnitine palmitoyltransferase 1A (rCPT1A), to elucidate the role of this domain in the function of the full-length enzyme. Oligomerization of TM2 was studied qualitatively using complementary genetic assays that facilitate measurement of helix-helix interactions in the Escherichia coli inner membrane, and multiple quantitative biophysical methods. The effects of TM2-mutations on oligomerization and malonyl-CoA inhibition of the full-length enzyme (expressed in the yeast Pichia pastoris) were quantified. Changes designed to disrupt close-packing of the GXXXG(A) motifs reduced the oligomeric state of the corresponding TM2 peptides from hexamer to trimer (or lower), a reduction also observed on mutation of the TM2 sequence in the full-length enzyme. Disruption of these GXXXG(A) motifs had a parallel effect on the malonyl-CoA sensitivity of rCPT1A, reducing the IC(50) from 30.3 ± 5.0 to 3.0 ± 0.6 µM. For all measurements, wild-type rCPT1A was used as a control alongside various appropriate (e.g., molecular mass) standards. Our results suggest that sequence-determined, TM2-mediated oligomerization is likely to be involved in the modulation of malonyl-CoA inhibition of CPT1A in response to short- and long-term changes in protein-protein and protein-lipid interactions that occur in vivo.

Relationship between psychopathy and indirect aggression use in a noncriminal population.

Psychopathy has long been associated with increased use of direct aggression and violence, especially among male inmates. Little research has, of yet, considered the relation between psychopathy and indirect forms of aggression. The current research sought to investigate the relationship between psychopathy and indirect aggression in a noncriminal sample. The results indicated that there was a strong relationship between psychopathic traits and indirect aggression, with strong correlations between indirect aggression and both factor 1 (coldheartedness) and factor 3 (impulsive antisociality). This association remained significant even after the effects of direct aggression had been controlled for. Path analysis indicated that both direct and indirect aggression was underpinned by the same psychopathy factors. This suggests that high psychopathy scorers will utilize direct and indirect aggression equally and, as such, the choice of one type of aggression over the other may be dependant on either situational factors or external moderators.

Contributions of the transmembrane domain and a key acidic motif to assembly and function of the TatA complex.

The twin-arginine translocase (Tat) pathway transports folded proteins across bacterial and thylakoid membranes. In Escherichia coli, a membrane-bound TatA complex, which oligomerizes to form complexes of less than 100 to more than 500 kDa, is considered essential for translocation. We have studied the contributions of various TatA domains to the assembly and function of this heterogeneous TatA complex. The TOXCAT assay was used to analyze the potential contribution of the TatA transmembrane (TM) domain. We observed relatively weak interactions between TatA TM domains, suggesting that the TM domain is not the sole driving force behind oligomerization. A potential hydrogen-bonding role for a TM domain glutamine was also investigated, and it was found that mutation blocks transport at low expression levels, while assembly is unaffected at higher expression levels. Analysis of truncated TatA proteins instead highlighted an acidic motif directly following the TatA amphipathic helix. Mutating these negatively charged residues to apolar uncharged residues completely blocks activity, even at high levels of TatA, and appears to disrupt ordered complex formation.