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Objective To evaluate the clinical efficacy of an established programme of occupational therapy in maintaining functional activity and reducing further health risks from inactivity in care home residents living with stroke sequelae.Design Pragmatic, parallel group, cluster randomised controlled trial.Setting 228 care homes (>10 beds each), both with and without the provision of nursing care, local to 11 trial administrative centres across the United Kingdom.Participants 1042 care home residents with a history of stroke or transient ischaemic attack, including those with language and cognitive impairments, not receiving end of life care. 114 homes (n=568 residents, 64% from homes providing nursing care) were allocated to the intervention arm and 114 homes (n=474 residents, 65% from homes providing nursing care) to standard care (control arm). Participating care homes were randomised between May 2010 and March 2012.Intervention Targeted three month programme of occupational therapy, delivered by qualified occupational therapists and assistants, involving patient centred goal setting, education of care home staff, and adaptations to the environment.Main outcome measures Primary outcome at the participant level: scores on the Barthel index of activities of daily living at three months post-randomisation. Secondary outcome measures at the participant level: Barthel index scores at six and 12 months post-randomisation, and scores on the Rivermead mobility index, geriatric depression scale-15, and EuroQol EQ-5D-3L questionnaire, at all time points.Results 64% of the participants were women and 93% were white, with a mean age of 82.9 years. Baseline characteristics were similar between groups for all measures, personal characteristics, and diagnostic tests. Overall, 2538 occupational therapy visits were made to 498 participants in the intervention arm (mean 5.1 visits per participant). No adverse events attributable to the intervention were recorded. 162 (11%) died before the primary outcome time point, and 313 (30%) died over the 12 months of the trial. The primary outcome measure did not differ significantly between the treatment arms. The adjusted mean difference in Barthel index score at three months was 0.19 points higher in the intervention arm (95% confidence interval −0.33 to 0.70, P=0.48). Secondary outcome measures also showed no significant differences at all time points.Conclusions This large phase III study provided no evidence of benefit for the provision of a routine occupational therapy service, including staff training, for care home residents living with stroke related disabilities. The established three month individualised course of occupational therapy targeting stroke related disabilities did not have an impact on measures of functional activity, mobility, mood, or health related quality of life, at all observational time points. Providing and targeting ameliorative care in this clinically complex population requires alternative strategies.Trial registration Current Controlled Trials ISRCTN00757750.

Key points • There are strong policy drivers in the UK to involve patients not only as participants in research, but also as members of the research team. • Patient and public involvement (PPI) can have significant benefits to the patient as well as to the research project. • Many research funders require PPI explicitly described and evaluated in research proposals. • Researchers need increased awareness of PPI, guidance, and a framework of how best to implement PPI within their research strategies. • There is a risk of ‘tokenistic’ involvement of service users. • There is the potential for a power struggle between the PPI representative with personal experience and the lead researcher with academic knowledge of the condition studied. • There is a need to formally evaluate the impact of PPI on the effectiveness of research to bring new treatments to patients.

Co-chair of a national research project into Aboriginal and Torres Strait Islander Suicide Prevention, Professor Sue Dudgeon, says Drumbeat works for young people because it's fun.

The allegations are quite serious. What has come to hand today: the ABC understands that there was a meeting of senior operational police, possibly last year, possibly early this year, who met to talk about the investigation into Mrs [Kamitsis]' case. And at that meeting, it's said that the commissioner at the time, Mr [John McRoberts], advocated for civil rather than criminal charges to be laid against the travel agent. He also apparently quashed a search warrant that was to be executed against her. Another piece of information that's come to hand today is that text messages were discovered on Mrs Kamitsis' phone, her mobile phone, when she was arrested in November last year. And there are text messages on her phone, apparently, to and from Mr McRoberts over quite a period of time, which seems to confirm that there was an ongoing personal relationship. [Kate Wilde]: The fallout at this stage is that the Police Association is saying that it's quite a blow to the morale of the police force. It presents quite a challenge to the NT Police Force to sort of continue with their work without clear leadership and they have called on the NT Government to be swift in reappointing, in appointing a new commissioner and appointing a deputy commissioner.

Proximity-inducing modalities that co-opt cellular pathways offer new opportunities to regulate oncogenic drivers. Inspired by the success of proximity-based chimeras in both intracellular and extracellular target space, here we describe the development of LY sosome M embrane TA rgeting C himera s (LYMTACs) as a small molecule-based platform that functions intracellularly to modulate the membrane proteome. Conceptually, LYMTACs are heterobifunctional small molecules that co-opt short-lived lysosomal membrane proteins (LMPs) as effectors to deliver targets for lysosomal degradation. We demonstrate that a promiscuous kinase inhibitor-based LYMTAC selectively targets membrane proteins for lysosomal degradation via RNF152, a short-lived LMP. We extend this concept by showing that oncogenic KRAS G12D signaling can be potently inhibited by LYMTACs. Mechanistically, LYMTACs display multi-pharmacology and exert their activity through both target relocalization into the lysosome and degradation. We further generalize LYMTACs across various LMPs and thus offer a platform to access challenging membrane proteins through targeted protein relocalization and degradation. LYMTACs are heterobifunctional small molecules that take advantage of lysosomal membrane proteins to degrade membrane targets via relocalization and lysosomal degradation, offering a modular approach to drug otherwise intractable membrane proteins.

Background Phenotypic studies have identified distinct patterns of autistic characteristics in genetic syndromes associated with intellectual disability (ID), leading to diagnostic uncertainty and compromised access to autism-related support. Previous research has tended to include small samples and diverse measures, which limits the generalisability of findings. In this study, we generated detailed profiles of autistic characteristics in a large sample of > 1500 individuals with rare genetic syndromes. Methods Profiles of autistic characteristics based on the Social Communication Questionnaire (SCQ) scores were generated for thirteen genetic syndrome groups (Angelman n  = 154, Cri du Chat n  = 75, Cornelia de Lange n  = 199, fragile X n  = 297, Prader–Willi n  = 278, Lowe n  = 89, Smith–Magenis n  = 54, Down n  = 135, Sotos n  = 40, Rubinstein–Taybi n  = 102, 1p36 deletion n  = 41, tuberous sclerosis complex n  = 83 and Phelan–McDermid n  = 35 syndromes). It was hypothesised that each syndrome group would evidence a degree of specificity in autistic characteristics. To test this hypothesis, a classification algorithm via support vector machine (SVM) learning was applied to scores from over 1500 individuals diagnosed with one of the thirteen genetic syndromes and autistic individuals who did not have a known genetic syndrome (ASD; n  = 254). Self-help skills were included as an additional predictor. Results Genetic syndromes were associated with different but overlapping autism-related profiles, indicated by the substantial accuracy of the entire, multiclass SVM model (55% correctly classified individuals). Syndrome groups such as Angelman, fragile X, Prader–Willi, Rubinstein–Taybi and Cornelia de Lange showed greater phenotypic specificity than groups such as Cri du Chat, Lowe, Smith–Magenis, tuberous sclerosis complex, Sotos and Phelan-McDermid. The inclusion of the ASD reference group and self-help skills did not change the model accuracy. Limitations The key limitations of our study include a cross-sectional design, reliance on a screening tool which focuses primarily on social communication skills and imbalanced sample size across syndrome groups. Conclusions These findings replicate and extend previous work, demonstrating syndrome-specific profiles of autistic characteristics in people with genetic syndromes compared to autistic individuals without a genetic syndrome. This work calls for greater precision of assessment of autistic characteristics in individuals with genetic syndromes associated with ID.

BackgroundSystematic reviews suggest school-based mindfulness training (SBMT) shows promise in promoting student mental health.ObjectiveThe My Resilience in Adolescence (MYRIAD) Trial evaluated the effectiveness and cost-effectiveness of SBMT compared with teaching-as-usual (TAU).MethodsMYRIAD was a parallel group, cluster-randomised controlled trial. Eighty-five eligible schools consented and were randomised 1:1 to TAU (43 schools, 4232 students) or SBMT (42 schools, 4144 students), stratified by school size, quality, type, deprivation and region. Schools and students (mean (SD); age range=12.2 (0.6); 11–14 years) were broadly UK population-representative. Forty-three schools (n=3678 pupils; 86.9%) delivering SBMT, and 41 schools (n=3572; 86.2%) delivering TAU, provided primary end-point data. SBMT comprised 10 lessons of psychoeducation and mindfulness practices. TAU comprised standard social-emotional teaching. Participant-level risk for depression, social-emotional-behavioural functioning and well-being at 1 year follow-up were the co-primary outcomes. Secondary and economic outcomes were included.FindingsAnalysis of 84 schools (n=8376 participants) found no evidence that SBMT was superior to TAU at 1 year. Standardised mean differences (intervention minus control) were: 0.005 (95% CI −0.05 to 0.06) for risk for depression; 0.02 (−0.02 to 0.07) for social-emotional-behavioural functioning; and 0.02 (−0.03 to 0.07) for well-being. SBMT had a high probability of cost-effectiveness (83%) at a willingness-to-pay threshold of £20 000 per quality-adjusted life year. No intervention-related adverse events were observed.ConclusionsFindings do not support the superiority of SBMT over TAU in promoting mental health in adolescence.Clinical implicationsThere is need to ask what works, for whom and how, as well as considering key contextual and implementation factors.Trial registrationCurrent controlled trials ISRCTN86619085. This research was funded by the Wellcome Trust (WT104908/Z/14/Z and WT107496/Z/15/Z).

Purpose Integrating genomic sequencing in clinical care requires standardization of variant interpretation practices. The Clinical Genome Resource has established expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology classification framework for specific genes and diseases. The Cardiomyopathy Expert Panel selected MYH7 , a key contributor to inherited cardiomyopathies, as a pilot gene to develop a broadly applicable approach. Methods Expert revisions were tested with 60 variants using a structured double review by pairs of clinical and diagnostic laboratory experts. Final consensus rules were established via iterative discussions. Results Adjustments represented disease-/gene-informed specifications (12) or strength adjustments of existing rules (5). Nine rules were deemed not applicable. Key specifications included quantitative frameworks for minor allele frequency thresholds, the use of segregation data, and a semiquantitative approach to counting multiple independent variant occurrences where fully controlled case-control studies are lacking. Initial inter-expert classification concordance was 93%. Internal data from participating diagnostic laboratories changed the classification of 20% of the variants ( n  = 12), highlighting the critical importance of data sharing. Conclusion These adapted rules provide increased specificity for use in MYH7 -associated disorders in combination with expert review and clinical judgment and serve as a stepping stone for genes and disorders with similar genetic and clinical characteristics.

Patients with single ventricle heart disease are living into adulthood due to medical and surgical advancements but have significant physical comorbidities and an increased risk for psychological comorbidities compared to healthy subjects or those with other CHD diagnoses. This study aimed to systematically review psychological functioning in paediatric single ventricle heart disease. Literature was searched using PubMed, Embase, PsycInfo, CINAHL Complete and Scopus. Peer-reviewed articles that included patients ages 0-25 years with single ventricle heart disease, and quantitative measures of psychological outcomes were included. Meta-analysis using a fixed-effect model was conducted for internalising and externalising t-scores, utilised by the Achenbach Child Behavior Checklist. Twenty-nine records met the criteria for inclusion. 13/24 studies demonstrated increased risk for internalising disorders, such as anxiety/depression; 16/22 studies demonstrated risk for externalising disorders, such as attention or behavioural problems. Meta-analysis of four studies revealed that paediatric single ventricle heart disease patients had no significant difference in internalising and externalising t-scores compared to normative values. The current review demonstrates the need for further studies to better understand psychological functioning in patients with single ventricle heart disease, with a majority of studies showing increased risk for psychological problems despite no difference seen in a small meta-analysis. This summary of the literature underscores the need for regular psychological screening, earlier intervention and integrated mental health therapies in paediatric single ventricle heart disease.

Background A high proportion of hypertensive patients remain above the target threshold for blood pressure, increasing the risk of adverse health outcomes. A digital intervention to facilitate healthcare practitioners (hereafter practitioners) to initiate planned medication escalations when patients’ home readings were raised was found to be effective in lowering blood pressure over 12 months. This mixed-methods process evaluation aimed to develop a detailed understanding of how the intervention was implemented in Primary Care, possible mechanisms of action and contextual factors influencing implementation. Methods One hundred twenty-five practitioners took part in a randomised controlled trial, including GPs, practice nurses, nurse-prescribers, and healthcare assistants. Usage data were collected automatically by the digital intervention and antihypertensive medication changes were recorded from the patients’ medical notes. A sub-sample of 27 practitioners took part in semi-structured qualitative process interviews. The qualitative data were analysed using thematic analysis and the quantitative data using descriptive statistics and correlations to explore factors related to adherence. The two sets of findings were integrated using a triangulation protocol. Results Mean practitioner adherence to escalating medication was moderate (53%), and the qualitative analysis suggested that low trust in home readings and the decision to wait for more evidence influenced implementation for some practitioners. The logic model was partially supported in that self-efficacy was related to adherence to medication escalation, but qualitative findings provided further insight into additional potential mechanisms, including perceived necessity and concerns. Contextual factors influencing implementation included proximity of average readings to the target threshold. Meanwhile, adherence to delivering remote support was mixed, and practitioners described some uncertainty when they received no response from patients. Conclusions This mixed-methods process evaluation provided novel insights into practitioners’ decision-making around escalating medication using a digital algorithm. Implementation strategies were proposed which could benefit digital interventions in addressing clinical inertia, including facilitating tracking of patients’ readings over time to provide stronger evidence for medication escalation, and allowing more flexibility in decision-making whilst discouraging clinical inertia due to borderline readings. Implementation of one-way notification systems could be facilitated by enabling patients to send a brief acknowledgement response. Trial registration ( ISRCTN13790648 ). Registered 14 May 2015.