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The Oxford BRC is delighted to announce the appointment of seven new Senior Research Fellows.
Comparative Analysis of the Net Clinical Benefit of Direct Oral Anticoagulants in Atrial Fibrillation: Systematic Review and Network Meta-analysis of Randomised Controlled Trials.
BACKGROUND: Direct oral anticoagulants (DOACs) are the standard treatment for stroke prevention in AF. However, high-quality head-to-head comparisons of DOACs are lacking. This study compared oral anticoagulants in patients with AF. METHODS: Data were retrieved from eligible randomised controlled trials (RCTs). Interventions were ranked using the surface under the cumulative ranking curve (SUCRA) and the frequentist random effects model was applied. Efficacy outcomes included stroke, systemic embolism, MI, and all-cause mortality; the safety outcome was major bleeding. A composite outcome of efficacy and net clinical benefit was also evaluated. RESULTS: From 23,152 records, 11 eligible RCTs were identified and included in the study. Rivaroxaban was superior to vitamin K antagonists (VKA) in net clinical benefit (RR 0.75; 95% CI [0.59-0.94]; p=0.0133), but there were no significant differences between other DOACs and VKA or among the DOACs themselves. Rivaroxaban reduced the risk of the composite outcome of efficacy compared with dabigatran (RR 0.85; 95% CI [0.75-0.98]; p=0.02) and edoxaban (RR 0.84; 95% CI [0.75-0.95]; p=0.0051), but not apixaban (RR 0.89; 95% CI [0.89-1.02]; p=0.087). All DOACs showed superiority over VKA in efficacy, without an increased risk of major bleeding. Based on the SUCRA, rivaroxaban showed a favourable risk-benefit profile compared with the other anticoagulants. CONCLUSION: This study showed that DOACs are superior to VKA in efficacy without increasing major bleeding risk, with rivaroxaban demonstrating the most balanced risk-benefit profile. Well-designed RCTs are needed to validate these findings.
Iron Deficiency in Intensive Care
This chapter discusses iron deficiency in the intensive care unit, highlighting the underlying mechanisms and the challenges in interpreting tests of iron status in the context of inflammation. It also covers the clinical implications of iron deficiency and anaemia and currently available treatment strategies.
Sleep regularity index as a novel indicator of sleep disturbance in stroke survivors: a secondary data analysis
Abstract Sleep disturbance is common but often overlooked after stroke. Regular sleep is increasingly recognised as important for overall health, yet little is known about how sleep regularity changes after stroke. This study examined differences in the Sleep Regularity Index (SRI) between stroke survivors and healthy controls using actigraphy data from an existing dataset (~ 1 week per participant). Data were analysed for 162 stroke survivors (mean age 61 ± 14 years, 5 ± 5 years post-stroke, 89 males) and 60 controls (mean age 57 ± 17 years, 32 males). Stroke survivors had significantly lower SRI scores than controls (p = 0.001), indicating less regular sleep. In the stroke group, higher SRI correlated with longer total sleep time (p = 0.003) and better self-reported sleep quality (p = 0.001) but not with other sleep metrics. Lower SRI was associated with worse depressive symptoms (p = 0.006) and lower quality of life (p = 0.001) but not with disability (p = 0.886) or time since stroke (p = 0.646). These findings suggest that sleep regularity is disrupted post-stroke and may influence well-being. Future research should explore interventions to improve sleep regularity and related health outcomes in stroke survivors.
Nurse-delivered sleep restriction therapy in primary care for adults with insomnia disorder: a mixed-methods process evaluation
BackgroundSleep restriction therapy (SRT) is a behavioural therapy for insomnia.AimTo conduct a process evaluation of a randomised controlled trial comparing SRT delivered by primary care nurses plus a sleep hygiene booklet with the sleep hygiene booklet only for adults with insomnia disorder.Design and settingA mixed-methods process evaluation in a general practice setting.MethodSemi-structured interviews were conducted in a purposive sample of patients receiving SRT, the practice nurses who delivered the therapy, and also GPs or practice managers at the participating practices. Qualitative data were explored using framework analysis, and integrated with nurse comments and quantitative data, including baseline Insomnia Severity Index score and serial sleep efficiency outcomes to investigate the relationships between these.ResultsIn total, 16 patients, 13 nurses, six practice managers, and one GP were interviewed. Patients had no previous experience of behavioural therapy, needed flexible appointment times, and preferred face-to-face consultations; nurses felt prepared to deliver SRT, accommodating patient concerns, tailoring therapy, and negotiating sleep timings despite treatment complexity and delays between training and intervention delivery. How the intervention produced change was explored, including patient and nurse interactions and patient responses to SRT. Difficulties maintaining SRT, negative attitudes towards treatment, and low self-efficacy were highlighted. Contextual factors, including freeing GP time, time constraints, and conflicting priorities for nurses, with suggestions for alternative delivery options, were raised. Participants who found SRT a positive process showed improvements in sleep efficiency, whereas those who struggled did not.ConclusionSRT was successfully delivered by practice nurses and was generally well received by patients, despite some difficulties delivering and applying the intervention in practice.
Sleep and motor learning in stroke (SMiLES): a longitudinal study investigating sleep-dependent consolidation of motor sequence learning in the context of recovery after stroke
IntroductionThere is growing evidence that sleep is disrupted after stroke, with worse sleep relating to poorer motor outcomes. It is also widely acknowledged that consolidation of motor learning, a critical component of poststroke recovery, is sleep-dependent. However, whether the relationship between disrupted sleep and poor outcomes after stroke is related to direct interference of sleep-dependent motor consolidation processes, is currently unknown. Therefore, the aim of the present study is to understand whether measures of motor consolidation mediate the relationship between sleep and clinical motor outcomes post stroke.Methods and analysisWe will conduct a longitudinal observational study of up to 150 participants diagnosed with stroke affecting the upper limb. Participants will be recruited and assessed within 7 days of their stroke and followed up at approximately 1 and 6 months. The primary objective of the study is to determine whether sleep in the subacute phase of recovery explains the variability in upper limb motor outcomes after stroke (over and above predicted recovery potential from the Predict Recovery Potential algorithm) and whether this relationship is dependent on consolidation of motor learning. We will also test whether motor consolidation mediates the relationship between sleep and whole-body clinical motor outcomes, whether motor consolidation is associated with specific electrophysiological sleep signals and sleep alterations during subacute recovery.Ethics and disseminationThis trial has received both Health Research Authority, Health and Care Research Wales and National Research Ethics Service approval (IRAS: 304135; REC: 22/LO/0353). The results of this trial will help to enhance our understanding of the role of sleep in recovery of motor function after stroke and will be disseminated via presentations at scientific conferences, peer-reviewed publication, public engagement events, stakeholder organisations and other forms of media where appropriate.Trial registration numberClinicalTrials.gov:NCT05746260, registered on 27 February 2023.
Nurse-delivered sleep restriction therapy to improve insomnia disorder in primary care: the HABIT RCT
Background Insomnia is a prevalent and distressing sleep disorder. Multicomponent cognitive–behavioural therapy is the recommended first-line treatment, but access remains extremely limited, particularly in primary care where insomnia is managed. One principal component of cognitive–behavioural therapy is a behavioural treatment called sleep restriction therapy, which could potentially be delivered as a brief single-component intervention by generalists in primary care. Objectives The primary objective of the Health-professional Administered Brief Insomnia Therapy trial was to establish whether nurse-delivered sleep restriction therapy in primary care improves insomnia relative to sleep hygiene. Secondary objectives were to establish whether nurse-delivered sleep restriction therapy was cost-effective, and to undertake a process evaluation to understand intervention delivery, fidelity and acceptability. Design Pragmatic, multicentre, individually randomised, parallel-group, superiority trial with embedded process evaluation. Setting National Health Service general practice in three regions of England. Participants Adults aged ≥ 18 years with insomnia disorder were randomised using a validated web-based randomisation programme. Interventions Participants in the intervention group were offered a brief four-session nurse-delivered behavioural treatment involving two in-person sessions and two by phone. Participants were supported to follow a prescribed sleep schedule with the aim of restricting and standardising time in bed. Participants were also provided with a sleep hygiene leaflet. The control group received the same sleep hygiene leaflet by e-mail or post. There was no restriction on usual care. Main outcome measures Outcomes were assessed at 3, 6 and 12 months. Participants were included in the primary analysis if they contributed at least one post-randomisation outcome. The primary end point was self-reported insomnia severity with the Insomnia Severity Index at 6 months. Secondary outcomes were health-related and sleep-related quality of life, depressive symptoms, work productivity and activity impairment, self-reported and actigraphy-defined sleep, and hypnotic medication use. Cost-effectiveness was evaluated using the incremental cost per quality-adjusted life-year. For the process evaluation, semistructured interviews were carried out with participants, nurses and practice managers or general practitioners. Due to the nature of the intervention, both participants and nurses were aware of group allocation. Results We recruited 642 participants (n = 321 for sleep restriction therapy; n = 321 for sleep hygiene) between 29 August 2018 and 23 March 2020. Five hundred and eighty participants (90.3%) provided data at a minimum of one follow-up time point; 257 (80.1%) participants in the sleep restriction therapy arm and 291 (90.7%) participants in the sleep hygiene arm provided primary outcome data at 6 months. The estimated adjusted mean difference on the Insomnia Severity Index was −3.05 (95% confidence interval −3.83 to −2.28; p < 0.001, Cohen’s d = −0.74), indicating that participants in the sleep restriction therapy arm [mean (standard deviation) Insomnia Severity Index = 10.9 (5.5)] reported lower insomnia severity compared to sleep hygiene [mean (standard deviation) Insomnia Severity Index = 13.9 (5.2)]. Large treatment effects were also found at 3 (d = –0.95) and 12 months (d = −0.72). Superiority of sleep restriction therapy over sleep hygiene was evident at 3, 6 and 12 months for self-reported sleep, mental health-related quality of life, depressive symptoms, work productivity impairment and sleep-related quality of life. Eight participants in each group experienced serious adverse events but none were judged to be related to the intervention. The incremental cost per quality-adjusted life-year gained was £2075.71, giving a 95.3% probability that the intervention is cost-effective at a cost-effectiveness threshold of £20,000. The process evaluation found that sleep restriction therapy was acceptable to both nurses and patients, and delivered with high fidelity. Limitations While we recruited a clinical sample, 97% were of white ethnic background and 50% had a university degree, which may limit generalisability to the insomnia population in England. Conclusions Brief nurse-delivered sleep restriction therapy in primary care is clinically effective for insomnia disorder, safe, and likely to be cost-effective. Future work Future work should examine the place of sleep restriction therapy in the insomnia treatment pathway, assess generalisability across diverse primary care patients with insomnia, and consider additional methods to enhance patient engagement with treatment. Trial registration This trial is registered as ISRCTN42499563. Funding The award was funded by the National Institute of Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 16/84/01) and is published in full in Health Technology Assessment; Vol. 28, No. 36. See the NIHR Funding and Awards website for further award information.
Neurofeedback modulation of insula activity via MEG-based brain-machine interface: a double-blind randomized controlled crossover trial.
Insula activity has often been linked to pain perception, making it a potential target for therapeutic neuromodulation strategies such as neurofeedback. However, it is not known whether insula activity is under cognitive control and, if so, whether this activity is consequently causally related to pain. Here, we conducted a double-blind randomized controlled crossover trial to test the modulation of insula activity and pain thresholds using neurofeedback training. Nineteen healthy subjects underwent neurofeedback training for upmodulation and downmodulation of right insula activity using our magnetoencephalography (MEG)-based brain-machine interface. We observed significant differences in insula activity between the upmodulation and downmodulation training sessions. Furthermore, resting-state insula activity significantly decreased following downmodulation training compared to following upmodulation training. Compared with upmodulation training, downmodulation training was also associated with increased pain thresholds, albeit with no significant interaction effect. These findings show that humans can cognitively modulate insula activity as a potential route to develop therapeutic MEG neurofeedback systems for clinical testing. However, the present findings do not provide direct evidence of a causal link between modulation of insula activity and changes in pain thresholds.
Alzheimer's disease patient-derived high-molecular-weight tau impairs bursting in hippocampal neurons.
Tau accumulation is closely related to cognitive symptoms in Alzheimer's disease (AD). However, the cellular drivers of tau-dependent decline of memory-based cognition remain elusive. Here, we employed in vivo Neuropixels and patch-clamp recordings in mouse models and demonstrate that tau, independent of β-amyloid, selectively debilitates complex-spike burst firing of CA1 hippocampal neurons, a fundamental cellular mechanism underpinning learning and memory. Impaired bursting was associated with altered hippocampal network activities that are coupled to burst firing patterns (i.e., theta rhythms and high-frequency ripples) and was concurrent with reduced neuronal expression of CaV2.3 calcium channels, which are essential for burst firing in vivo. We subsequently identify soluble high molecular weight (HMW) tau, isolated from human AD brain, as the tau species responsible for suppression of burst firing. These data provide a cellular mechanism for tau-dependent cognitive decline in AD and implicate a rare species of intracellular HMW tau as a therapeutic target.