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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
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.
INTRODUCTION: There 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 ANALYSIS: We 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 DISSEMINATION: This 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 NUMBER: ClinicalTrials.gov: NCT05746260, registered on 27 February 2023.
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.
Effects of 28-day simvastatin administration on emotional processing, reward learning, working memory, and salivary cortisol in healthy participants at-risk for depression: OxSTEP, an online experimental medicine trial.
BACKGROUND: Statins are among the most prescribed medications worldwide. Both beneficial (e.g. antidepressant and pro-cognitive) and adverse (e.g. depressogenic and cognitive-impairing) mental health outcomes have been described in clinical studies. The underlying neuropsychological mechanisms, whether positive or negative, are, however, not established. Clarifying such activities has implications for the safe prescribing and repurposing potential of these drugs, especially in people with depression. METHODS: In this double-blind, randomized, placebo-controlled experimental medicine study, we investigated the effects of simvastatin on emotional processing, reward learning, working memory, and waking salivary cortisol (WSC) in 101 people at-risk for depression due to reported high loneliness scores (mean 7.3 ± 1.2 on the UCLA scale). This trial was largely conducted during periods of social distancing due to the COVID-19 pandemic (July 2021-February 2023), and we employed a fully remote design within a UK-wide sample. RESULTS: High retention rates, minimal outlier data, and typical main effects of task condition (e.g. emotion) were seen in all cognitive tasks, indicating this approach was comparable to in-person testing. After 28 days, we found no statistically significant differences (F's 0.20) for any of the measures of emotional processing, reward learning, working memory, and WSC. CONCLUSIONS: Study results do not substantiate concerns regarding adverse neuropsychiatric events due to statins and support the safety of their prescribing in at-risk populations. Although other unmeasured cognitive processes may be involved, our null findings are also in line with more recent clinical evidence suggesting statins do not show antidepressant or pro-cognitive efficacy.
Pain management in preterm infants with necrotizing enterocolitis: an international expert consensus statement
Abstract Necrotizing enterocolitis (NEC) is probably the most painful intestinal disease affecting infants born preterm. NEC is known to cause highly severe and prolonged pain that has been associated with adverse short- and long-term effects. However, research on pain management in infants with NEC is scarce. This is likely due to its low incidence and very acute occurrence. As a result, the optimal pain management for these vulnerable infants remains unknown, and analgesic therapy practices are highly variable. Therefore, we aimed to establish expert-based consensus recommendations on pain management for NEC. Experts of the European Society for Paediatric Research (ESPR) Special Interest Groups on Neonatal pain and NEC were invited to participate in two consensus meetings. Prior to the first hybrid consensus meeting, an online survey provided input for potential recommendations. During the consensus meetings, experts shared clinical expertise and voted on recommendations. An expert consensus statement, comprising nine recommendations on optimal pain assessment and pain treatment in infants with NEC, was developed. Expert recommendations included regular pain assessments with a neonatal pain scale with additional assessments on indication and pre-emptive administration of analgesic therapy (e.g., paracetamol and an opioid) in infants with NEC stage ≥ II. Conclusion: This expert consensus statement provides clinical recommendations essential for any healthcare professional caring for premature infants with NEC. The recommended guidance this statement provides on pain management strategies is key to preventing and reducing pain in this vulnerable population. What is Known: • Necrotizing enterocolitis (NEC) is a very painful disease, making effective pain management essential.• Current pain management practices for infants with NEC are highly variable. What is New: • This expert consensus statement provides recommendations on optimal pain assessment and pain treatment in infants with NEC.• These clinical recommendations may help better prevent pain in these vulnerable infants.
Human decisions about when to act originate within a basal forebrain-nigral circuit.
Decisions about when to act are critical for survival in humans as in animals, but how a desire is translated into the decision that an action is worth taking at any particular point in time is incompletely understood. Here we show that a simple model developed to explain when animals decide it is worth taking an action also explains a significant portion of the variance in timing observed when humans take voluntary actions. The model focuses on the current environment's potential for reward, the timing of the individual's own recent actions, and the outcomes of those actions. We show, by using ultrahigh-field MRI scanning, that in addition to anterior cingulate cortex within medial frontal cortex, a group of subcortical structures including striatum, substantia nigra, basal forebrain (BF), pedunculopontine nucleus (PPN), and habenula (HB) encode trial-by-trial variation in action time. Further analysis of the activity patterns found in each area together with psychophysiological interaction analysis and structural equation modeling suggested a model in which BF integrates contextual information that will influence the decision about when to act and communicates this information, in parallel with PPN and HB influences, to nigrostriatal circuits. It is then in the nigrostriatal circuit that action initiation per se begins.
Ultra-high temporal resolution 4D angiography using arterial spin labeling with subspace reconstruction.
PURPOSE: To achieve ultra-high temporal resolution non-contrast 4D angiography with improved spatiotemporal fidelity. METHODS: Continuous data acquisition using 3D golden-angle sampling following an arterial spin labeling preparation allows for flexibly reconstructing 4D dynamic angiograms at arbitrary temporal resolutions. However, k-space data is often temporally "binned" before image reconstruction, negatively affecting spatiotemporal fidelity and limiting temporal resolution. In this work, a subspace was extracted by linearly compressing a dictionary constructed from simulated curves of an angiographic kinetic model. The subspace was used to represent and reconstruct the voxelwise signal timecourse at the same temporal resolution as the data acquisition without temporal binning. Physiological parameters were estimated from the resulting images using a Bayesian fitting approach. A group of eight healthy subjects were scanned and the in vivo results reconstructed by different methods were compared. Because of the difficulty of obtaining ground truth 4D angiograms with ultra-high temporal resolution, the in vivo results were cross-validated with numerical simulations. RESULTS: The proposed method enables 4D time-resolved angiography with much higher temporal resolution (14.7 ms) than previously reported (˜50 ms) while maintaining high spatial resolution (1.1 mm isotropic). Blood flow dynamics were depicted in greater detail, thin vessel visibility was improved, and the estimated physiological parameters also exhibited more realistic spatial patterns with the proposed method. CONCLUSION: Incorporating a subspace compressed kinetic model into the reconstruction of 4D ASL angiograms notably improved the temporal resolution and spatiotemporal fidelity, which was subsequently beneficial for accurate physiological modeling.
Progression and life expectancy in primary lateral sclerosis
Objectives To characterise the clinical characteristics and longitudinal outcomes in primary lateral sclerosis (PLS), including median survival from symptom onset and age at death. Methods The authors retrospectively reviewed electronic health records of patients diagnosed with PLS referred to a specialised motor neuron disorders clinic from 2002 to 2024, analysed longitudinal Revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) assessments using joint models and used Kaplan-Meier methods and life tables to calculate median survival and age at death compared with population-based values. Results Of 52 patients, 34 (65%) were male, 41 (79%) first noted symptoms in the lower limbs and 10 (19%) in corticobulbar function. Median age of symptom onset was 53 years. The mean annual rate of functional decline was -1.92 ALSFRS-R points (95% CI -3.03 to -0.78), with equal highest rates of decline in fine and gross motor subscores. Five patients (10%) received gastrostomy and three (6%) non-invasive ventilation. Median survival from symptom onset was 23.1 years (22.7 to not reached), and median age at death was 79.5 years (77.8 to not reached) compared with a population-based reference mean of 81.9 years (81.1 to 82.8). Discussion PLS may be commensurate with near-normal life expectancy. Significant disability arises from limb motor dysfunction, with a minority of patients requiring nutritional or respiratory support. This has important implications for counselling and trial design.
Quantifying axonal features of human superficial white matter from three-dimensional multibeam serial electron microscopy data assisted by deep learning.
Short-range association fibers located in the superficial white matter play an important role in mediating higher-order cognitive function in humans. Detailed morphological characterization of short-range association fibers at the microscopic level promises to yield important insights into the axonal features driving cortico-cortical connectivity in the human brain yet has been difficult to achieve to date due to the challenges of imaging at nanometer-scale resolution over large tissue volumes. This work presents results from multi-beam scanning electron microscopy (EM) data acquired at 4 × 4 × 33 nm3 resolution in a volume of human superficial white matter measuring 200 × 200 × 112 μm (Braitenberg and Schüz, 2013), leveraging automated analysis methods. Myelin and myelinated axons were automatically segmented using deep convolutional neural networks (CNNs), assisted by transfer learning and dropout regularization techniques. A total of 128,285 myelinated axons were segmented, of which 70,321 and 2,102 were longer than 10 and 100 μm, respectively. Marked local variations in diameter (i.e., beading) and direction (i.e., undulation) were observed along the length of individual axons. Myelinated axons longer than 10 μm had inner diameters around 0.5 µm, outer diameters around 1 µm, and g-ratios around 0.5. This work fills a gap in knowledge of axonal morphometry in the superficial white matter and provides a large 3D human EM dataset and accurate segmentation results for a variety of future studies in different fields.
Early neurological deterioration in patients with minor stroke: A single-center study conducted in Vietnam
A minor ischemic stroke is associated with a higher likelihood of poor clinical outcomes at 90 days when there is early neurological deterioration (END). The objective of this case-control study conducted in a comprehensive stroke facility in Vietnam is to examine the frequency, forecast, and outcomes of patients with END in minor strokes. The study employs a descriptive observational design, longitudinally tracking patients with minor strokes admitted to Bach Mai Hospital’s Stroke Center between December 1, 2023, and August 31, 2024. Hospitalized within 24 hours of symptom onset, minor stroke patients with National Institutes of Health Stroke Scale (NIHSS) scores ≤ 5 and items 1a, 1b, and 1c on the NIHSS scale, each equal to 0, were included in the study. The primary measure of interest is the END rate, defined as a rise of 2 or more points in the NIHSS score during the first 72 hours after admission. We conduct a logistic regression analysis to identify forecasting factors for END. Out of 839 patients, 88 (10.5%) had END. In the END group, we found that most patients had complications within the first 24 hours of stroke, accounting for 43.2%; the 24 – 48-hour window accounted for 35.2%, and the 48 – 72-hour window accounted for 21.6%. END was associated with a higher likelihood of poor outcomes (mRS 2 – 6) at discharge (OR = 22.76; 95% CI 11.22 – 46.20; p < 0.01), 30 days post-stroke(OR = 24.38; 95% CI 14.40 – 41.29; p < 0.01), and 90 days post-stroke (OR = 21.74; 95% CI 12.63 – 37.43; p < 0.01). Some of the prognostic factors for END were admission NIHSS score (OR = 1.24; 95% CI 1.03 – 1.49; p = 0.02), admission systolic blood pressure greater than 150mmHg (OR = 1.70; 95% CI 1.03 – 2.81; p = 0.04), admission blood glucose (OR = 1.07; 95% CI 1.01 – 1.14; p = 0.02), reperfusion therapy (OR = 3.35; 95% CI 1.50 – 7.49; p < 0.01), use of antiplatelet monotherapy (OR = 3.69; 95% CI 2.24 – 6.08; p < 0.01), internal capsule infarction (OR = 2.54; 95% CI 1.37 – 4.71; p < 0.01), hemorrhagic transformation (OR = 5.72; 95% CI 1.07 – 30.45; p = 0.04), corresponding extracranial carotid artery occlusion (OR = 4.84; 95% CI 1.26 – 18.65; p = 0.02), and middle cerebral artery occlusion OR = 3.06; 95% CI 1.29 – 7.30; p = 0.01). END in minor stroke patients accounts for 10.5% and is a risk factor for poor neurological outcomes. Admission NIHSS score, higher systolic blood pressure, admission blood glucose, reperfusion therapy, use of antiplatelet monotherapy, internal capsule infarction, hemorrhagic transformation, corresponding extracranial carotid artery occlusion, and middle cerebral artery occlusion were some of the prognostic factors for END in our observational study.
Mapping of validated apathy scales onto the apathy diagnostic criteria for neurocognitive disorders.
BACKGROUND: Diagnostic criteria for apathy in neurocognitive disorders (DCA-NCD) have recently been updated. OBJECTIVES: We investigated whether validated scales measuring apathy severity capture the three dimensions of the DCA-NCD (diminished initiative, diminished interest, diminished emotional expression). MEASUREMENTS: Degree of mapping ("not at all", "weakly", or "strongly") between items on two commonly used apathy scales, the Neuropsychiatric Inventory-Clinician (NPI-C) apathy and Apathy Evaluation Scale (AES), with the DCA-NCD overall and its 3 dimensions was evaluated by survey. DESIGN: Survey participants, either experts (n = 12, DCA-NCD authors) or scientific community members (n = 19), rated mapping for each item and mean scores were calculated. Interrater reliability between expert and scientific community members was assessed using Cohen's kappa. RESULTS: According to experts, 9 of 11 (81.8%) NPI-C apathy items and 6 of 18 (33.3%) AES items mapped strongly onto the DCA-NCD overall. For the scientific community group, 10 of 11 (90.9%) NPI-C apathy items and 7 of 18 (38.8%) AES items mapped strongly onto the DCA-NCD overall. The overall mean mapping scores were higher for the NPI-C apathy compared to the AES for both expert (t (11) = 3.13, p = .01) and scientific community (t (17) = 3.77, p = .002) groups. There was moderate agreement between the two groups on overall mapping for the NPI-C apathy (kappa= 0.74 (0.57, 1.00)) and AES (kappa= 0.63 (0.35, 1.00)). CONCLUSIONS: More NPI-C apathy than AES items mapped strongly and uniquely onto the DCA-NCD and its dimensions. The NPI-C apathy may better capture the DCA-NCD and its dimensions compared with the AES.
ZFP36-family RNA-binding proteins in regulatory T cells reinforce immune homeostasis
RNA binding proteins (RBP) of the ZFP36 family limit the differentiation and effector functions of CD4 and CD8 T cells, but little is known of their expression or function in regulatory T (Treg) cells. By using Treg cell-restricted deletion of Zfp36 family members we identify the role of Zfp36l1 and Zfp36l2 in Treg cells to maintain immune homeostasis. Mice with Treg cells deficient in these RBP display an inflammatory phenotype with an expansion in the numbers of type-2 conventional dendritic cells, T effector cells, T follicular helper and germinal center B cells and elevated serum cytokines and immunoglobulins. In the absence of Zfp36l1 and Zfp36l2, the pool of cycling CTLA-4 in naïve Treg cells is reduced, Treg cells are less sensitive to IL-2 and IL-7 but are more sensitive to IFNγ. In mice lacking both RBP in Treg cells, the deletion of a single allele of Ifng is sufficient to ameliorate the pathology. Our results indicate that ZFP36L1 and ZFP36L2 regulate the availability of IFNγ and are required for the maintenance of Treg cell stability. Thus, ZFP36L1 and ZFP36L2 regulate multiple pathways that enable Treg cells to enforce immune homeostasis.
Low-Rank Conjugate Gradient-Net for Accelerated Cardiac MR Imaging
Cardiovascular diseases (CVDs) remain the leading cause of mortality and morbidity worldwide. Both diagnosis and prognosis of these diseases benefit from high-quality imaging, which cardiac magnetic resonance imaging provides. CMR imaging requires lengthy acquisition times and multiple breath-holds for a complete exam, which can lead to patient discomfort and frequently results in image artifacts. In this work, we present a Low-rank tensor U-Net method (LowRank-CGNet) that rapidly reconstructs highly undersampled data with a variety of anatomy, contrast, and undersampling artifacts. The model uses conjugate gradient data consistency to solve for the spatial and temporal bases and employs a U-Net to further regularize the basis vectors. Currently, model performance is superior to a standard U-Net, but inferior to conventional compressed sensing methods. In the future, we aim to further improve model performance by increasing the U-Net size, extending the training duration, and dynamically updating the tensor rank for different anatomies.
Smartphone-based Monitoring and cognition Modification Against Recurrence of Depression (SMARD): An RCT of Memory Bias Modification Training vs. Cognitive Control Training vs. Attention Bias Modification Training in remitted recurrently depressed patients with 1.5 year follow-up.
BACKGROUND: Major Depressive Disorder (MDD) has a 50-80% recurrence rate highlighting the urgent need for more efficient recurrence prevention programs. Currently, recurrences are often identified too late, while existing preventive strategies may not sufficiently address ethio-patho-physiological mechanisms for recurrence. Negative memory bias (the tendency to better remember negative than positive events), negative attention bias (selective attention favoring mood-congruent information), and cognitive control deficits are important factors involved in the onset, maintenance, and recurrence of depressive episodes. METHODS: Here we describe the protocol for the Smartphone-based Monitoring and cognition Modification Against Recurrence of Depression (SMARD) study, aiming to investigate different forms of cognitive training programs administered via smartphones, in order to develop a second-generation recurrence prevention program. In addition, we will gather Experience Sampling Method (ESM) assessments during a 6-day period, and during the follow-up period we will obtain behavioral data on (social) activities with BEHAPP, a smartphone-based Mobile Passive Monitoring application for remote behavioral monitoring to identify behavioral changes indicative of an imminent depressive episode. In a randomized controlled trial, SMARD will compare the effects of a smartphone-based Memory Bias Modification Training (MBT), Cognitive Control Training (CCT), and Attention Bias Modification Training (ABT) versus cognitive domain-specific (active-) sham trainings in 120 remitted MDD-patients with recurrent-MDD. Over the course of three weeks, participants receive multiple daily training sessions. Thereafter, participants will be followed up for 1.5 years with 3-monthly interviews to assess recurrences. DISCUSSION: The SMARD study aims to 1. assess the effects of the cognitive training programs versus their training-specific (active-) sham conditions on changes in memory, cognitive control dysfunction and attention; 2. relate training effects to neural networks previously identified in (recurrence of) MDD (therefore we obtain functional Magnetic Resonance Imaging ((f)MRI) scans before and after the training in a subset of participants); 3. link baseline and change in memory, cognitive control, attention and neural functioning, and ESM data to prospective recurrences; 4. examine whether passive smartphone-use monitoring can be used for prediction of recurrences. TRIAL REGISTRATION: NL-OMON26184 and NL-OMON27513. Registered 12 August 2021-Retrospectively registered, https://onderzoekmetmensen.nl/en/trial/26184 en https://onderzoekmetmensen.nl/en/trial/27513 .