Understanding the pathogenesis of myotonic dystrophy type 1

To identify the full range of targets and the pathogenic consequences, we sought to mimic the pathogenesis of myotonic dystrophy type 1 with temporal and spatial control: temporal to reproduce the developmental pathogenesis of the congenital form, and spatial to isolate tissue specific pathology. To do this, we attempted to use the Cre-lox system for the conditional expression of an EGFP reporter-linked expanded CUG repeat RNA in the mouse. Expression of the transgene was controlled by Cre excision of a transcriptional stop, placed upstream of the EGFP-expanded repeat open reading frame. The transgenes were constructed and tested successfully, and a normal length repeat transgenic line was established. Unfortunately generation of the expanded repeat line was not successful. The constructs were used to generate cell-culture models of DM1, in both human and murine cells, which mimicked the nuclear foci formation and MBNL1 co-localisation seen in patient cells. Expression of exogenous MBNL1/GFP fusion protein in this model resulted in an increase in the size of foci, indicating that MBNL1 protein is limiting within the cell, and may possibly play a protective role. The murine DM1 cell-culture model was used to investigate the effects of expanded CUG repeat expression on splicing within the transcriptome. The differential effect between 5 and 250 repeat RNA expression using Affymetrix whole transcript and exon arrays was compared. Using whole genome arrays, 6 genes were down-regulated and 128 upregulated. With exon arrays, 58 genes showed alternative exon usage. Six genes were selected for further bioinformatics analysis: MtmR4, which has possible neuromuscular involvement; Kcnk4, Narg1, Ttyh1 and Bptf, potentially related to brain development; and Cacna1c, a promising candidate for heart conductance defects and sudden death

Serving High-Risk Youth in Context: Perspectives from Hong Kong

Background: High-risk youth are often defined in occupational therapy terminology as adolescents and young adults who experience personal, contextual, or environmental barriers to effective participation in healthy, age-appropriate occupations. Without assistance for participation, these youth may acquiesce to daily routines of unhealthy risk-taking or isolation, failing to achieve developmental milestones needed for successful transition to adulthood. There are known therapeutic services targeting this population, but occupational therapy involvements have been sparsely documented. Method: Having been affiliated with a community-based occupational therapy program serving high-risk youth for many years in the US, the principal investigator of the study used a sabbatical opportunity to explore services provided to high-risk youth in Hong Kong (HK). This paper reports preliminary findings obtained from an exploratory study of analyzing transcripts of 13 one-on-one interviews with service providers in HK. Results: Two major themes are discussed in this paper: the prevalent behavioral risks among high-risk youth as perceived by the service providers and the intervention approaches used by the service providers with the high-risk youth population in HK. Conclusion: Reflecting on the preliminary outcome of the study, the authors suggest that occupational therapy may contribute to mitigating youths’ risk factors through ecological occupational engagement

Initial Validity and User Experience of a Dynamic Assessment of Occupational Performance for Transitional Age Youth

Background: The Double OT (DOT) assessment is occupation-based and dynamic, designed with a client-centered format requiring skill demonstration. It was developed to support youth transitioning into the workplace. This research intended to analyze initial validity and users’ experience. Method: This study includes qualitative and quantitative analyses of data collected from surveys from 169 client participants (APs) and 30 recipient participants (ARRs) from eight sites in the USA and Europe. AP were 14­ to 25 years of age and engaged in residential, educational, and vocational settings. The ARRs comprised partners who had received DOT assessment summaries about APs with whom they worked. Results: The APs showed high engagement and learning; average ratings for each item fell between 4.24–4.54 on a 5-point Likert scale. The ARRs agreed on the validity and usability of the DOT; average ratings for each item fell between 3.75 and 4.53 on a 5-point Likert scale. Qualitative themes indicated that the DOT is: “fun and engaging,” “vocationally informative and applicable,” and that there is an absence of commonly used assessments informing vocational transitions. Conclusion: The results support initial validity of the DOT. Users find it to be highly engaging, with good usability, and indicate that it facilitates participant learning

Genetic variants associated with subjective well-being, depressive symptoms, and neuroticism identified through genome-wide analyses

Very few genetic variants have been associated with depression and neuroticism, likely because of limitations on sample size in previous studies. Subjective well-being, a phenotype that is genetically correlated with both of these traits, has not yet been studied with genome-wide data. We conducted genome-wide association studies of three phenotypes: subjective well-being (n = 298,420), depressive symptoms (n = 161,460), and neuroticism (n = 170,911). We identify 3 variants associated with subjective well-being, 2 variants associated with depressive symptoms, and 11 variants associated with neuroticism, including 2 inversion polymorphisms. The two loci associated with depressive symptoms replicate in an independent depression sample. Joint analyses that exploit the high genetic correlations between the phenotypes (|ρ^| ≈ 0.8) strengthen the overall credibility of the findings and allow us to identify additional variants. Across our phenotypes, loci regulating expression in central nervous system and adrenal or pancreas tissues are strongly enriched for association.</p

The association between treatment adherence to nicotine patches and smoking cessation in pregnancy: a secondary analysis of a randomised controlled trial

IntroductionIn non-pregnant ‘quitters’, adherence to nicotine replacement therapy (NRT) increases smoking cessation. We investigated relationships between adherence to placebo or NRT patches and cessation in pregnancy, including an assessment of reverse causation and whether any adherence: cessation relationship is moderated when using nicotine or placebo patches. MethodsUsing data from 1050 pregnant trial participants, regression models investigated associations between maternal characteristics, adherence and smoking cessation. ResultsAdherence during the first month was associated with lower baseline cotinine concentrations (beta -0.08, 95%CI -0.15 to -0.01) and randomisation to NRT (beta 2.59, 95%CI 1.50 to 3.68). Adherence during both treatment months was associated with being randomised to NRT (beta 0.51, 95%CI 0.29 to 0.72) and inversely associated with higher nicotine dependence. Adherence with either NRT or placebo was associated with cessation at one month (OR 1.11, 95%CI 1.08 to 1.13) and delivery (OR 1.06, 95%CI 1.03 to 1.09), but no such association was observed in the subgroup where reverse causation was not possible. Amongst all women, greater adherence to nicotine patches was associated with increased cessation (OR 2.47, 95%CI 1.32 to 4.63) but greater adherence to placebo was not (OR 0.98, 95%CI: 0.44 to 2.18). ConclusionWomen who were more adherent to NRT were more likely to achieve abstinence; more nicotine dependent women probably showed lower adherence to NRT because they relapsed to smoking more quickly. The interaction between nicotine-containing patches and adherence for cessation suggests that the association between adherence with nicotine patches and cessation may be partly causal

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

A comparison of hazard perception and responding in car drivers and motorcyclists

Poor hazard perception skills have been shown to contribute to novice driver crash involvement. Yet driving and riding differ in terms of hazards, responses and consequences and many novice motorcyclists are experienced drivers. Therefore the extent to which the findings of research into car driver hazard perception and responding are relevant to motorcyclists may be limited. This paper presents results from the first stage of a program of research to develop hazard perception training for motorcyclists. The research began by examining the different theoretical frameworks that have been applied to hazard perception by car drivers. The four-component model of responding to risk (Grayson, Maycock, Groeger, Hammond &amp; Field, 2003) was considered to be the most useful because it includes a response implementation phase, which appears to be more important in motorcycling than in car driving. Analyses of motorcycle crash data from Victoria, Australia were undertaken in an attempt to identify those hazards and situations that pose a crash risk for motorcyclists of different levels of experience. However, road-based hazards were rarely recorded and the differences in crash situations appeared to largely reflect patterns of riding, rather than intrinsic risk. The literature review identified very little research into hazard perception and responding by motorcycle riders. For car drivers, research has shown that experienced drivers are quicker to detect hazards and that slower responses to hazards are associated with higher self-reported crash involvement – but this has not been tested for motorcycle riders. While research has shown that hazard perception training in novice drivers leads to improved performance on hazard perception tests, it is not yet known whether these drivers go on to be safer drivers and have fewer accidents. Training in how to respond appropriately may be more critical for riders than for drivers because failures in responding may result in a failure to avoid the initial hazard or a different type of crash. Most available hazard perception tests do not measure whether the correct response is chosen or implemented – the focus is on the detection of the hazard only. In addition, the tests may not give sufficient emphasis to hazards specific to riding, particularly road surface hazards. This may limit the extent to which such tests are able to predict the crash risk for riders. The methods needed to examine responding by riders may require a higher level of physical fidelity than those required for drivers because riding requires more complex vehicle control skills than driving. These issues question the relevance of the results of car driver hazard perception research for novice motorcyclists and have led to our current research to assess the fundamental differences in hazard perception and responding between drivers and riders and between experienced and inexperienced riders

Crashes of older Australian riders

Motorcyclist fatalities and injuries are increasing in many developed countries, particularly among older riders. Older riders are often grouped into continuing, returned and new riders. There is widespread concern about the safety of returned riders, but little objective data available. While Australian data show higher crash rates for young than for older riders and for newly licensed older riders than full licence holders (continuing and returned riders), the crash involvement of returned and continuing riders is difficult to compare because these groups cannot be separated in the official crash or licensing databases. An Internet survey of motorcycle riders was undertaken in 2005 to compare the crash involvement of the three groups of older riders and identify implications for rider training and other rider safety measures. Paper questionnaires were provided to riders without Internet access. Respondents had ridden in Australia in the last five years and were aged 25 and over. Of the 1,500 completed questionnaires, 930 were from continuing riders, 281 were from new riders, and 262 were from returned riders. The largest proportion of riders was aged 45-54. New riders were generally younger than returned riders. Most respondents rode in both rural and urban areas but about three-quarters rode less than 100 km in an average week. Continuing riders rode further in an average week than new and returned riders. Riders were asked how many motorcycle accidents they had been involved in on Australian roads in the last five years in which someone was hurt, the Police were called, or a vehicle was damaged and had to be taken away. About 30% of riders had been involved in at least one crash. Returned riders had a lower crash risk than continuing riders even after adjusting for the lower distance ridden in an average week by returned riders. While the crash risk of new and continuing riders did not differ significantly in this study, this may have reflected less riding during the previous five years by new riders. Most crashes resulted in slight injuries (cuts and bruises). Injuries to new riders were less severe on average and there was a tendency for continuing riders to be less severely injured than returned riders. Riders aged 55-64 were over-represented in serious injury (admitted to hospital) crashes, possibly because they are more susceptible to injury than younger riders. New riders had relatively more single vehicle (motorcycle only) crashes than continuing or returned riders. They were more likely to report that they were to blame for their crash, nominating not being able to handle the motorcycle well enough, not knowing what to do in the situation, being unfamiliar with the location, going too fast and not braking quickly enough as contributing factors on their part. New riders were more likely to have completed a training course (93%) than continuing (67%) and returned riders (57%). Less than 10% of returned riders had completed a refresher course but almost 30% had completed an advanced course. Riders who had completed a training course were more likely to have been involved in a crash than those who had not. Riders who had completed a training course were more likely to have been involved in a crash. This counter-intuitive finding remained after adjusting for distance ridden

Teaching Old Dogs New Tricks? Training and Older Motorcyclists

Past studies of the effects of motorcycle training on crash involvement have shown mixed results. However, many of the studies were conducted when most trainee riders were aged under 20. Now, many trainees are older and have considerable car driving experience. Training programs have also changed. For these reasons, this paper examines the training history of a sample of older riders and the links to their crash involvement