Promoting activity, independence and stability in early dementia and milk cognitive impairment (PrAISED): randomised controlled trial

Objective To determine the effectiveness of an exercise and functional activity therapy intervention in adults with early dementia or mild cognitive impairment compared with usual care. Design Randomised controlled trial. Setting Participants’ homes and communities at five sites in the United Kingdom. Participants 365 adults with early dementia or mild cognitive impairment who were living at home, and family members or carers. Intervention The intervention, Promoting activity, Independence, and Stability in Early Dementia and mild cognitive impairment (PrAISED), was a specially designed, dementia specific, rehabilitation programme focusing on strength, balance, physical activity, and performance of activities of daily living, which was tailored and progressive and addressed risk and the psychological needs of people with dementia. Up to 50 therapy sessions were provided over 12 months. The control group received usual care plus a falls risk assessment. Procedures were adapted during the covid-19 pandemic. Main outcome measures The primary outcome was score on the carer (informant) reported disability assessment for dementia scale 12 months after randomisation. Secondary outcomes were self-reported activities of daily living, physical activity, quality of life, balance, functional mobility, fear of falling, frailty, cognition, mood, carer strain, service use at 12 months, and falls between months 4 and 15. Results 365 patient participants were randomised, 183 to intervention and 182 to control. The median age of participants was 80 years (range 65-95), median Montreal cognitive assessment score was 20 out of 30 (range 13-26), and 58% (n=210) were men. Intervention participants received a median of 31 therapy sessions (interquartile range 22-40) and reported completing a mean 121 minutes of PrAISED exercise each week. Primary outcome data were available for 149 intervention and 141 control participants. Scores on the disability assessment for dementia scale did not differ between groups: adjusted mean difference −1.3, 95% confidence interval −5.2 to 2.6; Cohen’s d effect size −0.06, 95% confidence interval −0.26 to 0.15; P=0.51). Upper 95% confidence intervals excluded small to moderate effects on any of the range of outcome measures. Between months 4 and 15 the intervention group experienced 79 falls and the control group 200 falls (adjusted incidence rate ratio 0.78, 95% confidence interval 0.5 to 1.3; P=0.3). Conclusion The intensive PrAISED programme of exercise and functional activity training did not improve activities of daily living, physical activity, or quality of life; reduce falls; or improve any other secondary health status outcomes, despite good uptake. Future research should consider alternative approaches to maintaining ability and wellbeing in people with dementia

Promoting Activity, Independence and Stability in early dementia and mild cognitive impairment (PrAISED): A randomised controlled trial

Background Dementia is associated with frailty leading to increased risks of falls and hospitalisations. Interventions are required to maintain functional ability, strength and balance.Design Multi-centre parallel group randomised controlled trial, with embedded process evaluation. Procedures were adapted during the COVID-19 pandemic.Participants People with mild dementia or mild cognitive impairment (MCI), living at home, and a family member or carer.Objectives To determine the effectiveness of an exercise and functional activity therapy intervention compared to usual care.Intervention A specially-designed dementia-specific rehabilitation programme focussing on strength, balance, physical activity and performance of ADL, which was tailored, progressive, addressed risk and the psychological and learning needs of people with dementia, providing up to 50 therapy sessions over 12 months. The control group received usual care plus a falls risk assessment.Main outcome measure The primary outcome was the informant-reported Disability Assessment for Dementia (DAD) 12 months after randomisation. Secondary outcomes were: self-reported ADL, cognition, physical activity, quality of life, frailty, balance, functional mobility, fear of falling, mood, carer strain and service use (at 12 months) and falls (between months 4 and 15).Results 365 people were randomised, 183 to intervention and 182 to control. Median age of participants was 80 years (range 65-95), median Montreal Cognitive Assessment score 20/30 (range 13-26), 58% were men. Participants received a median of 31 (IQR = 22-40) therapy sessions out of a possible maximum of 50. Participants reported completing a mean 121 minutes/week of PrAISED activity outside of supervised sessions. Primary outcome data were available for 149 (intervention) and 141 (control) participants. There was no difference in DAD scores between groups: adjusted mean difference -1.3/100, 95% Confidence Interval (−5.2 to +2.6); Cohen’s d effect size -0.06 (−0.26 to +0.15); p=0.5. Upper 95% confidence intervals excluded small to moderate effects on any of the range of secondary outcome measures. Between months 4 and 15 there were 79 falls in the intervention group and 200 falls in the control group, adjusted incidence rate ratio 0.78 (0.5 to 1.3); p= 0.3.Conclusion The intensive PrAISED programme of exercise and functional activity training did not improve ADLs, physical activity, quality of life, reduce falls or improve any other secondary health status outcomes even though uptake was good. Future research should consider alternative approaches to risk reduction and ability maintenance

Effects of a high-dose 24-h infusion of tranexamic acid on death and thromboembolic events in patients with acute gastrointestinal bleeding (HALT-IT): an international randomised, double-blind, placebo-controlled trial

Background: Tranexamic acid reduces surgical bleeding and reduces death due to bleeding in patients with trauma. Meta-analyses of small trials show that tranexamic acid might decrease deaths from gastrointestinal bleeding. We aimed to assess the effects of tranexamic acid in patients with gastrointestinal bleeding. Methods: We did an international, multicentre, randomised, placebo-controlled trial in 164 hospitals in 15 countries. Patients were enrolled if the responsible clinician was uncertain whether to use tranexamic acid, were aged above the minimum age considered an adult in their country (either aged 16 years and older or aged 18 years and older), and had significant (defined as at risk of bleeding to death) upper or lower gastrointestinal bleeding. Patients were randomly assigned by selection of a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients received either a loading dose of 1 g tranexamic acid, which was added to 100 mL infusion bag of 0·9% sodium chloride and infused by slow intravenous injection over 10 min, followed by a maintenance dose of 3 g tranexamic acid added to 1 L of any isotonic intravenous solution and infused at 125 mg/h for 24 h, or placebo (sodium chloride 0·9%). Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was death due to bleeding within 5 days of randomisation; analysis excluded patients who received neither dose of the allocated treatment and those for whom outcome data on death were unavailable. This trial was registered with Current Controlled Trials, ISRCTN11225767, and ClinicalTrials.gov, NCT01658124. Findings: Between July 4, 2013, and June 21, 2019, we randomly allocated 12 009 patients to receive tranexamic acid (5994, 49·9%) or matching placebo (6015, 50·1%), of whom 11 952 (99·5%) received the first dose of the allocated treatment. Death due to bleeding within 5 days of randomisation occurred in 222 (4%) of 5956 patients in the tranexamic acid group and in 226 (4%) of 5981 patients in the placebo group (risk ratio [RR] 0·99, 95% CI 0·82–1·18). Arterial thromboembolic events (myocardial infarction or stroke) were similar in the tranexamic acid group and placebo group (42 [0·7%] of 5952 vs 46 [0·8%] of 5977; 0·92; 0·60 to 1·39). Venous thromboembolic events (deep vein thrombosis or pulmonary embolism) were higher in tranexamic acid group than in the placebo group (48 [0·8%] of 5952 vs 26 [0·4%] of 5977; RR 1·85; 95% CI 1·15 to 2·98). Interpretation: We found that tranexamic acid did not reduce death from gastrointestinal bleeding. On the basis of our results, tranexamic acid should not be used for the treatment of gastrointestinal bleeding outside the context of a randomised trial

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Effective Induction Programme for Higher Specialist Trainees: A Quality Improvement Project

Aims To create a safe and effective induction programme for Higher Specialist Trainees (HST) at Nottinghamshire Healthcare NHS Foundation Trust. An effective induction improves trainees' satisfaction, they feel welcomed and valued. It improves patient safety, retention, and recruitment (GMC Report 2020). Methods Based on GMC report, published in 2020, a survey was developed locally and data for 2021 HST induction was collected using digital platform. Initial stakeholder analysis completed, and relevant parties were invited to share the results. Two key deliverables were identified after consultation, one was a dedicated induction programme for HST which was co-produced along with trainees and stakeholders. The other deliverable was updating the induction booklet. The proposed induction plan was implemented in August 2023, the survey was repeated to the new HST cohort following induction via digital platform. Results of the survey were analysed via mixed methods (qualitative & quantitative). Results The surveys conducted in 2021 and 2023 were compared and there was an increase in response rate from 50% to 64%. The domains were devised from GMC standards and assessed by if staff had received everything in the domain within a week of starting their placement and results evaluated using a t-test. Domain A is gaining access to places and system (keys, fobs, security passes, computers, ID badges, mobile phones, IT system). This significantly improved from 27% to 88% with a p-value of < 0.001. Domain B is physical orientation of the setting (staff facilities such as lockers, parking, library, and site layout). This significantly improved from 45% to 88% with a p-value of < 0.018. Domain C is gaining day to day knowledge (HR, rota, annual leave, study leave, pay-roll, mandatory training, e-expenses, and guardian of safe working). There was no significant change between 9% and 19% with a p-value of < 0.48. Domain D is an understanding of expectations (duties and responsibility during working hours, on-call, team introduction). This significantly improved from 9% to 69% with a p-value of < 0.002. HSTs were given the chance to add comments and the responses in 2023 were more positive “excellent induction compared to previous years” compared with 2021 when HSTs felt isolated and devalued “worst ever induction in whole career in NHS”. Conclusion Overall, the results of the 2023 survey showed considerable improvement in all the key areas of induction within one week of starting the placement. Domain C demonstrates a challenge still and needs further work

Evaluating the effects of the novel GLP-1 analogue liraglutide in Alzheimer's disease: Study protocol for a randomised controlled trial (ELAD study)

Background: Liraglutide is a glucagon-like peptide-1 (GLP-1) analogue currently approved for type 2 diabetes and obesity. Preclinical evidence in transgenic models of Alzheimer's disease suggests that liraglutide exerts neuroprotective effects by reducing amyloid oligomers, normalising synaptic plasticity and cerebral glucose uptake, and increasing the proliferation of neuronal progenitor cells. The primary objective of the study is to evaluate the change in cerebral glucose metabolic rate after 12 months of treatment with liraglutide in participants with Alzheimer's disease compared to those who are receiving placebo. Methods/design: ELAD is a 12-month, multi-centre, randomised, double-blind, placebo-controlled, phase IIb trial of liraglutide in participants with mild Alzheimer's dementia. A total of 206 participants will be randomised to receive either liraglutide or placebo as a daily injection for a year. The primary outcome will be the change in cerebral glucose metabolic rate in the cortical regions (hippocampus, medial temporal lobe, and posterior cingulate) from baseline to follow-up in the treatment group compared with the placebo group. The key secondary outcomes are the change from baseline to 12 months in z scores for clinical and cognitive measures (Alzheimer's Disease Assessment Scale - Cognitive Subscale and Executive domain scores of the Neuropsychological Test Battery, Clinical Dementia Rating Sum of Boxes, and Alzheimer's Disease Cooperative Study - Activities of Daily Living) and the incidence and severity of treatment-emergent adverse events or clinically important changes in safety assessments. Other secondary outcomes are 12-month change in magnetic resonance imaging volume, diffusion tensor imaging parameters, reduction in microglial activation in a subgroup of participants, reduction in tau formation and change in amyloid levels in a subgroup of participants measured by tau and amyloid imaging, and changes in composite scores using support machine vector analysis in the treatment group compared with the placebo group. Discussion: Alzheimer's disease is a leading cause of morbidity worldwide. As available treatments are only symptomatic, the search for disease-modifying therapies is a priority. If the ELAD trial is successful, liraglutide and GLP-1 analogues will represent an important class of compounds to be further evaluated in clinical trials for Alzheimer's treatment. Trial registration: ClinicalTrials.gov, NCT01843075. Registration 30 April 2013