Hannah Buckley

Deletion of the BDNF truncated receptor TrkB.T1 delays disease onset in a mouse model of amyotrophic lateral sclerosis.

Brain Derived Neurotrophic Factor (BDNF) exerts strong pro-survival effects on developing and injured motoneurons. However, in clinical trials, BDNF has failed to benefit patients with amyotrophic lateral sclerosis (ALS). To date, the cause of this failure remains unclear. Motoneurons express the TrkB kinase receptor but also high levels of the truncated TrkB.T1 receptor isoform. Thus, we investigated whether the presence of this receptor may affect the response of diseased motoneurons to endogenous BDNF. We deleted TrkB.T1 in the hSOD1G93A ALS mouse model and evaluated the impact of this mutation on motoneuron death, muscle weakness and disease progression. We found that TrkB.T1 deletion significantly slowed the onset of motor neuron degeneration. Moreover, it delayed the development of muscle weakness by 33 days. Although the life span of the animals was not affected we observed an overall improvement in the neurological score at the late stage of the disease. To investigate the effectiveness of strategies aimed at bypassing the TrkB.T1 limit to BDNF signaling we treated SOD1 mutant mice with the adenosine A2A receptor agonist CGS21680, which can activate motoneuron TrkB receptor signaling independent of neurotrophins. We found that CGS21680 treatment slowed the onset of motor neuron degeneration and muscle weakness similarly to TrkB.T1 removal. Together, our data provide evidence that endogenous TrkB.T1 limits motoneuron responsiveness to BDNF in vivo and suggest that new strategies such as Trk receptor transactivation may be used for therapeutic intervention in ALS or other neurodegenerative disorders.

Point prevalence of complex wounds in a defined United Kingdom population

Complex wounds (superficial‐, partial‐, or full‐thickness skin loss wounds healing by secondary intention) are common; however, there is a lack of high‐quality, contemporary epidemiological data. This paper presents point prevalence estimates for complex wounds overall as well as for individual types. A multiservice, cross‐sectional survey was undertaken across a United Kingdom city (Leeds, population 751,485) during 2 weeks in spring of 2011. The mean age of people with complex wounds was approximately 70 years, standard deviation 19.41. The point prevalence of complex wounds was 1.47 per 1,000 of the population, 95% confidence interval 1.38 to 1.56. While pressure ulcers and leg ulcers were the most frequent, one in five people in the sample population had a less common wound type. Surveys confined to people with specific types of wound would underestimate the overall impact of complex wounds on the population and health care resources.

Can patient involvement improve patient safety? A cluster randomised control trial of the Patient Reporting and Action for a Safe Environment (PRASE) intervention

Objective To evaluate the efficacy of the Patient Reporting and Action for a Safe Environment intervention. Design A multicentre cluster randomised controlled trial. Setting Clusters were 33 hospital wards within five hospitals in the UK. Participants All patients able to give informed consent were eligible to take part. Wards were allocated to the intervention or control condition. Intervention The ward-level intervention comprised two tools: (1) a questionnaire that asked patients about factors contributing to safety (patient measure of safety (PMOS)) and (2) a proforma for patients to report both safety concerns and positive experiences (patient incident reporting tool). Feedback was considered in multidisciplinary action planning meetings. Measurements Primary outcomes were routinely collected ward-level harm-free care (HFC) scores and patient-level feedback on safety (PMOS). Results Intervention uptake and retention of wards was 100% and patient participation was high (86%). We found no significant effect of the intervention on any outcomes at 6 or 12 months. However, for new harms (ie, those for which the wards were directly accountable) intervention wards did show greater, though non-significant, improvement compared with control wards. Analyses also indicated that improvements were largest for wards that showed the greatest compliance with the intervention. Limitations Adherence to the intervention, particularly the implementation of action plans, was poor. Patient safety outcomes may represent too blunt a measure. Conclusions Patients are willing to provide feedback about the safety of their care. However, we were unable to demonstrate any overall effect of this intervention on either measure of patient safety and therefore cannot recommend this intervention for wider uptake. Findings indicate promise for increasing HFC where wards implement ≥75% of the intervention components. Trial registration number ISRCTN07689702; pre-results.

Patients as teachers: a randomised controlled trial on the use of personal stories of harm to raise awareness of patient safety for doctors in training

Background Patient safety training often provides learners with a health professionals perspective rather than the patients. Personal narratives of health-related harm allow patients to share their stories with health professionals to influence clinical behaviour by rousing emotions and improving attitudes to safety. Aim This study measured the impact of patient narratives used to train junior doctors in patient safety. Methods An open, multi-centre, two-arm, parallel design randomised controlled trial was conducted in the North Yorkshire East Coast Foundation School (NYECFS). The intervention consisted of 1-h-long patient narratives followed by discussion. The control arm received conventional faculty-delivered teaching. The Attitude to Patient Safety Questionnaire (APSQ) and the Positive and Negative Affect Schedule (PANAS) were used to measure the impact of the intervention. Results 142 trainees received the intervention; 141 the control teaching. There was no evidence of a difference in post-intervention APSQ scores between the groups. There was a statistically significant difference in the underlying distribution of both post PA (positive affect) and post NA (negative affect) scores between the groups on the PANAS (p<0.001) with indications of both higher PA and NA scores in the intervention group. Conclusions Involving patients with experiences of safety incidents in training has an ideological appeal and seems an obvious choice in designing safety interventions. On the basis of our primary outcome measure, we were unable to demonstrate effectiveness of the intervention in changing general attitudes to safety compared to control. While the intervention may impact on emotional engagement and learning about communication, we remain uncertain whether this will translate into improved behaviours in the clinical context or indeed if there are any negative effects. Trial registration number Grant reference no. RP-PG-0108-10049.

Acupuncture for irritable bowel syndrome: 2-year follow-up of a randomised controlled trial

Background A recent randomised controlled trial (RCT) of acupuncture as a treatment for irritable bowel syndrome (IBS) demonstrated sustained benefits over a period of 12 months post-randomisation. Aim To extend the trial follow-up to evaluate the effects of acupuncture at 24 months post-randomisation. Methods Patients in primary care with ongoing IBS were recruited to a two-arm pragmatic RCT of acupuncture for IBS. Participants were randomised to the offer of up to 10 weekly sessions of acupuncture plus usual care (n=116 patients) or to continue with usual care alone (n=117). The primary outcome was the self-reported IBS symptom severity score (IBS SSS) measured at 24 months post-randomisation. Analysis was by intention-to-treat using an unstructured multivariate linear model incorporating all repeated measures. Results The overall response rate was 61%. The adjusted difference in mean IBS SSS at 24 months was −18.28 (95% CI −40.95 to 4.40) in favour of the acupuncture arm. Differences at earlier time points estimated from the multivariate model were: −27.27 (−47.69 to −6.86) at 3 months; −23.69 (−45.17 to −2.21) at 6 months; −24.09 (−45.59 to −2.59) at 9 months; and −23.06 (−44.52 to −1.59) at 12 months. Conclusions There were no statistically significant differences between the acupuncture and usual care groups in IBS SSS at 24 months post-randomisation, and the point estimate for the mean difference was approximately 80% of the size of the statistically significant results seen at 6, 9 and 12 months. Trial registration number ISRCTN08827905.

Aspirin for Venous Ulcers: Randomised Trial (AVURT): study protocol for a randomised controlled trial

BackgroundVenous leg ulcers (VLUs) are the commonest cause of leg ulceration, affecting 1 in 100 adults. There is a significant health burden associated with VLUs – it is estimated that the cost of treatment for 1 ulcer is up to £1300 per year in the NHS. The mainstay of treatment is with graduated compression bandaging; however, treatment is often prolonged and up to one quarter of venous leg ulcers do not heal despite standard care. Two previous trials have suggested that low-dose aspirin, as an adjunct to standard care, may hasten healing, but these trials were small and of poor quality. Aspirin is an inexpensive, widely used medication but its safety and efficacy in the treatment of VLUs remains to be established.Methods/DesignAVURT is a phase II randomised double blind, parallel-group, placebo-controlled efficacy trial. The primary objective is to examine whether aspirin, in addition to standard care, is effective in patients with chronic VLUs (i.e. over 6 weeks in duration or a history of VLU). Secondary objectives include feasibility and safety of aspirin in this population. A target of 100 participants, identified from community leg ulcer clinics and hospital clinics, will be randomised to receive either 300 mg of aspirin once daily or placebo. All participants will receive standard care with compression therapy. The primary outcome will be time to healing of the reference ulcer. Follow-up will occur for a maximum of 27 weeks. The primary analysis will use a Cox proportional hazards model to compare time to healing using the principles of intention-to-treat. Secondary outcomes will include ulcer size, pain evaluation, compliance and adverse events.DiscussionThe AVURT trial will investigate the efficacy and safety of aspirin as a treatment for VLU and will inform on the feasibility of proceeding to a larger phase III study. This study will address the paucity of information currently available regarding aspirin therapy to treat VLU.Trial registrationThe study is registered on a public database with clinicaltrials.gov (NCT02333123; registered on 5 November 2014).

Pilot feasibility randomized clinical trial of negative-pressure wound therapy versus usual care in patients with surgical wounds healing by secondary intention: Feasibility study of negative-pressure wound therapy

Surgical wounds healing by secondary intention (SWHSI) are increasingly being treated with negative‐pressure wound therapy (NPWT) despite a lack of high‐quality research evidence regarding its clinical and cost‐effectiveness. This pilot feasibility RCT aimed to assess the methods for and feasibility of conducting a future definitive RCT of NPWT for the treatment of SWHSI.

Experience of, awareness of and help-seeking for potential cancer symptoms in smokers and non-smokers: a cross-sectional study

Background Presenting to primary care with potential cancer symptoms is contingent on one’s ability to recognize potentially serious symptoms. We investigated differences between smokers and non-smokers in symptoms experienced, awareness and consulting of potential respiratory, head and neck cancer symptoms. Methods Smokers and non-smokers aged over 50 from Yorkshire general practice lists were sent a postal questionnaire asking about symptoms, consulting and awareness of cancer symptoms. Data were analysed using STATA14. Results Response rate after one reminder was 30.5% (1205/3954). Smoking status was associated with experience of cough (p<0.001), breathlessness (p = 0.002) and tiredness (p = 0.004) with smokers (25.8% of population) more likely than never-smokers (53.6% of population) to experience all three symptoms (cough OR = 2.56;95%CI[1.75–3.75], breathlessness OR = 2.39;95%CI[1.43–4.00], tiredness OR = 1.57;95%CI[1.12–2.19]). Smoking status was associated with awareness of breathlessness as a potential cancer symptom (p = 0.035) and consulting for cough (p = 0.011) with smokers less likely to consult than never-smokers (OR = 0.37;95% CI[0.17–0.80]). Conclusion Our findings suggest that current smokers are more likely to experience cough, breathlessness and tiredness, but are less likely to consult for cough than never-smokers. To increase cancer awareness and promote consulting among smokers, innovative interventions improving symptom recognition and empowering smokers to seek help are required.

Outcomes to measure patient safety: the patient reporting and action for a safe environment (PRASE) trial.

The Patient Reporting and Action for a Safe Environment (PRASE) study, evaluated a ward-level intervention using ward-specific patient feedback to improve patient safety. We discuss choice of outcomes for patient safety trials.

Post-it notes to improve questionnaire response rates in RCTs - findings from a randomised sub-study

Methods A two-arm RCT was embedded into the follow-up of older adults as part of the UK Casper Plus trial and Casper Cohort. At 4 months follow-up, participants were randomised to receive either a questionnaire or a questionnaire + post-it note requesting completion. Logistic regression and time-to-event analyses were used to assess attrition. Results were combined with those of a previous embedded RCT (ATLAS) in a meta-analysis.