Search results
Found 6389 matches for
Unpacking the relationship between exercise and amyotrophic lateral sclerosis
This scientific commentary refers to ‘Extreme exercise in males is linked to mTOR signalling and onset of amyotrophic lateral sclerosis’ by O’Brien et al. (https://doi.org/10.1093/brain/awaf235).
Evaluation of 1st WHO anti-malaria reference reagent for competition ELISA harmonisation and development of ADAMSEL analytical platform.
This study focuses on harmonising the competition ELISA (cELISA) assay for Plasmodium falciparum (P. falciparum), using the 1st WHO reference reagent for anti-malaria (P. falciparum) human reference serum (10/198). Antibody-mediated immune responses against the Apical Membrane Antigen 1 (AMA1) play a significant role in protection against malaria. However, the sequence diversity of AMA1 and cross-reactivity among variants pose challenges in assessing antibody responses. To address this, the cELISA assay was selected to examine cross-reactive antibody responses against different variants. The harmonisation process for cELISA was performed in three laboratories. The 10/198 served as an internal standard for the calculation of IgG concentrations in the cELISA using ADAMSEL software. Additionally, a novel semi-automated analytical tool was developed in the R-statistics environment. This tool is freely available for download and streamlines generating results while minimising human error. This study demonstrated the effectiveness of the 1st WHO reference reagent as a standard for cELISA. Additionally, the ADAMSEL software and R-platform tool provide a user-friendly and accessible tool for the analysis of cELISA data. Its automation capabilities improve efficiency and ensure global accessibility at no cost, benefitting laboratories with limited resources.
The role of link workers in weight management for people with severe mental illness: a qualitative study.
BACKGROUND: People with severe mental illness (SMI) have an increased risk of cardiovascular disease, partly due to factors such as overweight and obesity. Weight management programmes can potentially reduce this risk, but people with SMI face barriers to access and engagement. AIM: To explore the acceptability of using link workers to address barriers to accessing and engaging with weight management programmes for people with SMI. DESIGN AND SETTING: A qualitative study conducted with people with SMI, link workers, and health promotion workers in primary care. The study was co-designed and co-delivered with a person with lived experience of SMI. METHOD: Five online focus groups and dyad interviews were run with 13 participants, including seven people with SMI and six health professionals (three link workers and three health promotion workers), between 25 July 2023 and 31 March 2024. Discussions were audio-recorded, transcribed verbatim, and analysed using a codebook thematic analysis in NVivo software. RESULTS: We constructed three analytical themes. (1) The view of link workers: all participants saw link workers as valuable in overcoming emotional and practical barriers to weight management. (2) Expectations of link worker support: support must be personalised, culturally responsive, and focused on building trust. (3) Challenges for link workers: barriers included limited mental health training, undefined roles, and capacity concerns. CONCLUSION: Link workers offer an acceptable, low-intense approach to improving access to weight management programmes for people with SMI. Strengthening coordination between link workers and weight management services in primary care, as well as defining their role and level of support, could improve outcomes for this underserved group. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12875-025-02929-4.
Real-world waitlist randomised controlled trial of gameChange VR to treat severe agoraphobic avoidance in patients with psychosis: a study protocol.
INTRODUCTION: Many people with psychosis find the world very frightening. It can be difficult for them to do everyday things-for example, walking down a busy street, travelling on a bus or going to the shops. Sometimes, the fears are so great that individuals rarely leave their homes. gameChange virtual reality therapy is designed to reduce this agoraphobic avoidance. In gameChange, users practise going into computerised immersive versions of ordinary situations. A virtual therapist guides users through the programme. A mental health worker also supports people. People normally do six sessions of gameChange, but now they can do more as headsets can be left with many people. We originally tested gameChange with 346 patients with psychosis. People saw a significant reduction in their fears. People with the most severe problems made the biggest improvements. This led to gameChange receiving National Institute for Health and Care Excellence (NICE) Early Value Assessment (EVA) approval for its use with patients with psychosis who have severe agoraphobic avoidance. NICE EVA approval is conditional on further evidence generation. We aim to carry out a real-world trial of gameChange used in the NHS. The overall aim is to gather evidence on the four essential areas (clinical benefits on agoraphobia, level of engagement and adherence, healthcare resource use, adverse effects) and the two further supporting areas (health-related quality of life, generalisability) identified in the NICE evidence generation plan for gameChange. METHODS AND ANALYSIS: 200 patients with psychosis and severe agoraphobic avoidance will be randomised (1:1) to receive gameChange in addition to treatment as usual (TAU) or to a waitlist control group receiving TAU. Assessments will be conducted blind to group allocation at baseline, 8 weeks (end of treatment) and 26 weeks (follow-up). The trial will be embedded in services in at least seven National Health Service (NHS) trusts across England. The primary outcome is agoraphobic avoidance at 26 weeks assessed with the Oxford Agoraphobic Avoidance Scale. The secondary clinical outcomes are agoraphobic distress, paranoia and social contacts. There will be tests of moderation of the main clinical outcome. Treatment acceptability, adverse effects and cost-effectiveness will also be assessed. The target estimand is the treatment policy estimand and all primary and secondary analyses will be carried out incorporating data from all participants including those who do not complete treatment. ETHICS AND DISSEMINATION: The trial has received ethical approval from the NHS Health Research Authority and Health and Care Research Wales (25/WA/0081). A key output will be the evidence needed for a NICE guidance update on gameChange and a clear recommendation concerning future routine use in the NHS. TRIAL REGISTRATION NUMBER: ISRCTN79060696.
Lucid Dreaming: Not Just Awareness, but Agency.
During lucid dreaming (LD), dreamers are aware that they are dreaming and may be able to influence the oneiric content. There has been recent debate about the relative importance of the ability to influence the dream and having agency over the pure awareness of dreaming. To underline this, we examined the associations of lucid dreams without agency (LD-Ag) and lucid dreams with agency (LD + Ag) to sleep and mental health problems and long COVID during the pandemic. We collected data in 16 countries on four continents from May to December 2021 on 10,715 subjects. Logistic regression was performed to predict LD-Ag and LD + Ag, with a sample of 8133 participants. We found that 30% of the participants frequently knew they were dreaming during the pandemic. About half of those (17%) reported that they could influence their dreams. Female gender and anxiety symptoms were negatively associated with LD + Ag. Dream recall, nightmares, insomnia, dream enactment behaviour (DEB), sleep vocalisation, short and long COVID and PTSD were positively associated with LD + Ag. Old age, dream recall, nightmares and anxiety symptoms were positively associated with LD-Ag, while short sleep length, being an evening type, and short COVID were negatively associated with LD-Ag. The different associations for LD-Ag and LD + Ag suggest that they may be distinct sleep states. This is also the first study to show that both COVID-19 and long COVID are associated with LD.
Auditory Salience Detection Across Wake and Sleep States: Mismatch Negativity and Event-Related Spectral Perturbation in the Rat Superior Colliculus.
Understanding the detection of salient auditory stimuli by the deep layer of the superior colliculus (dSC) during REM and NREM sleep offers valuable insights into the neurophysiological mechanisms of state-dependent auditory information processing. We recorded local field potentials (LFP) from dSC, electrocorticogram (ECoG) from frontal/parietal cortical regions, and neck electromyogram (EMG) in freely moving rats during sleep and awake states under oddball paradigm auditory stimulations. Our analysis focused on mismatch negativity (MMN) responses and event-related spectral perturbation (ERSP) in slow gamma (30-60 Hz) activity (SGA) and medium gamma (60-95 Hz) activity (MGA) frequency bands in wakefulness, REM and NREM sleep using three different intensities (35-, 55-, 80-dB) of stimulation. Data were analysed using repeated-measure two-way ANOVA and Linear Mixed Model. We found that the dSC exhibited significantly increased MMN responses to salient auditory stimuli across nearly all conditions (p
Heart Rate Profiles During Exercise and Incident Parkinson's Disease.
OBJECTIVE: To determine whether established heart rate parameters of exercise, related to cardiac autonomic function, are associated with incident Parkinson's disease, independent of both clinical and autonomic prodromal features. METHODS: A study of UK Biobank participants who performed a standardized bicycle exercise test (2009-2013), followed until November 2022, and analyzed in January 2024, was carried out. Heart rate increase from rest to exercise, and heart rate decrease from peak exercise to recovery were associated with incident Parkinson's disease. Multivariable adjustment was performed both for clinical characteristics and for prodromal non-cardiac autonomic features. RESULTS: A total of 69,288 eligible participants (men 48%, mean age 56.8 years [SD 8.2 years]) were followed for 12.5 years: among the 319 (0.5%) who developed Parkinson's disease, recognized prodromal markers (constipation, bladder dysfunction) were more common at baseline. The median lag time to diagnosis was 9.3 years (interquartile range 4.4). Both heart rate increase (37.5 [SD 11.5] vs 40.8 [SD 12.4] b.p.m., p
HNF1A and A1CF coordinate a beta cell transcription-splicing axis that is disrupted in type 2 diabetes
Type 2 diabetes (T2D) is a devastating chronic disease marked by pancreatic β cell dysfunction and insulin resistance, whose pathophysiology remains poorly understood. HNF1A, which encodes transcription factor hepatocyte nuclear factor-1 alpha, is the most commonly mutated gene in Mendelian diabetes. HNF1A also carries loss- or gain-of-function coding variants that respectively predispose to or protect against polygenic T2D. The mechanisms underlying HNF1A-deficient diabetes, however, are still unclear. We now demonstrate that diabetes arises from β cell-autonomous defects and identify direct β cell genomic targets of HNF1A. This uncovered a regulatory axis where HNF1A controls transcription of A1CF, which orchestrates an RNA splicing program encompassing genes that regulate β cell function. This HNF1A-A1CF transcription-splicing axis is suppressed in β cells from T2D individuals, while genetic variants reducing pancreatic islet A1CF are associated with increased glycemia and T2D susceptibility. Our findings, therefore, identify a linear hierarchy that coordinates β cell-specific transcription and splicing programs and link this pathway to T2D pathogenesis.
TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord.
Neuronal and glial cytoplasmic inclusions positive for TAR DNA-binding protein 43 (TDP-43) are the defining pathological hallmark of 97% of amyotrophic lateral sclerosis (ALS) and 50% of frontotemporal dementia (FTD). The ALS-FTD clinicopathological spectrum variably involves cortical and spinal anterior horn cell pathology. The broader protein composition of these inclusions is of major importance to understanding pathogenesis, clinical heterogeneity and biomarker development. This study examined the proteome associated with TDP-43 inclusions in ALS, using mass spectrometry-based proteomic analysis of spinal cord and cerebral cortex from donors with phosphoTDP-43 positive ALS (n = 16), alpha-synuclein positive Parkinson's disease (PD, n = 8), phosphotau and beta-amyloid positive Alzheimer's disease (AD, n = 8) and age matched non-neurological controls (n = 8), comparing ALS with non-ALS conditions, spinal cord with cerebral cortex samples, and detergent-soluble with -insoluble fractions. Increased abundance of TDP-43 in the detergent-insoluble fraction of ALS cortex and spinal cord tissue confirmed disease-specific protein enrichment by serial fractionation. The most striking alterations between ALS and other conditions were found in the detergent-insoluble fraction of spinal cord, with predominant enrichment of endosomal and extracellular vesicle pathways. In the cortex mitochondrial membrane/envelope and ion transmembrane transport pathways were enriched in the detergent-insoluble fraction. RNA/DNA metabolic processes (in spinal cord) versus mitochondrial and synaptic protein pathways (in cortex) were upregulated in the detergent-soluble fraction of ALS cases and downregulated in the insoluble protein fraction. Whilst motor cortex and spinal cord may not optimally reflect disease-specific pathways in AD, in PD a significant enrichment of alpha-synuclein in the detergent-insoluble fraction of spinal cord was found. Among proteins concordantly elevated in the detergent-insoluble fractions of spinal cord and cortex, there was greater representation of proteins encoded by ALS-associated genes, specifically Cu/Zn superoxide dismutase 1, valosin containing protein and TDP-43 (odds ratio 16.34, p = 0.002). No significant increase in TDP-43 interacting proteins was observed in either detergent-soluble or -insoluble fractions. Together, this study shows a divergence in the composition of proteins associated with TDP-43 positive detergent-insoluble inclusions between spinal cord and cerebral cortex. A common upregulation of proteins encoded by ALS-causing genes implicates their role in the pathogenesis of the ALS-FTD spectrum of diseases beyond TDP-43. Data are available via ProteomeXchange with identifier PXD067060.
A cross-species analysis of neuroanatomical covariance sex differences in humans and mice.
BACKGROUND: Structural covariance within the brain is thought to reflect inter-regional sharing of developmental influences. This hypothesis has proved difficult to test but can be informatively probed by the study of sex differences. Here, we use neuroimaging in humans and mice to study sex-differences in anatomical covariance- asking (1) are there sex differences in structural covariance and (2) do regions that share the same developmental influences, as exhibited by shared sex differences in volume, also show shared sex differences in volume covariance. This study design illuminates both the biology of sex-differences and theoretical models for anatomical covariance- benefitting from tests of inter-species convergence. METHODS: Brain volume correlations for males and females across 255 regions in mice (n = 423) and 378 regions in humans (n = 436) were calculated using volumetric measures obtained from structural MRI. Mean correlations for each sex were compared within species to determine whether covariance sex differences exist. Specific covariances with strong sex differences in each species were identified via permutation tests for statistical significance. Brain maps of regional average structural covariance sex-bias were generated for mice and humans. Regional average structural covariance sex-bias and volumetric sex-bias were correlated to identify whether these features align in their direction of sex-bias. RESULTS: We find that volumetric structural covariance is stronger in adult females than males for both wild-type mice and healthy human subjects: 98% of comparisons with statistically significant covariance sex differences in mice are female-biased, while 76% of such comparisons are female-biased in humans (q
Rhythmic liver drives feeding behavior.
The hepatic vagal nerve mediates the impact of circadian disruption on food intake in mice.
OPTOGENETIC VISION RESTORATION IN THE FACE OF SECONDARY AND TERTIARY REMODELLING IN THE RD1 MOUSE RETINA.
Photoreceptor loss in retinal degeneration is followed by progressive remodelling of the surviving retina, which may present a barrier to vision restoration. To determine the impact of remodelling on the retina's suitability for therapeutic interventions, we track changes in visual code produced by the optogenetic actuator ReaChR expressed in ON-bipolar cells of the rd1 mouse at 3,5,9 and 12 months. Anatomical analyses confirm these ages encompass phase II (photoreceptor degeneration) to phase III (inner retinal thinning, dysmorphia, pigment epithelium infiltration) remodelling. Multi-electrode array recording from retinal ganglion cells reveal that ReaChR-driven responses to a range of visual stimuli are stable across this age range. Response amplitude, sensitivity and reproducibility all increased between 3 and 5 months, remaining consistent thereafter. Receptive field sizes, contrast sensitivity, and temporal frequency tuning showed minor changes with age. The diversity of retinal ganglion cell coding was maintained, reflected by the diversity captured by unsupervised functional clustering with 11 distinct visual channels retained across ages. Our data indicate that remodelling does not significantly impair, and at early stages may even enhance the surviving retina's ability to support visual restoration. Clinical intervention thus remains viable throughout remodelling, suggesting a wide window in disease progression for therapeutic benefit.
Interaction between native and prosthetic visual responses in optogenetic visual restoration.
Degenerative retinal disorders leading to irreversible photoreceptor death are a common cause of blindness. Optogenetic gene therapy aims to restore vision in affected individuals by introducing light sensitive opsins into the surviving neurons of the inner retina. While up until now the main focus of optogenetic therapy has been on terminally blind individuals, treating at stages where residual native vision is present could have several advantages. Yet, it is still unknown how residual native and optogenetic vision would interact if present at the same time. Using transgenic mice expressing the optogenetic tool ReaChR in ON-bipolar cells, we herein examine this interaction through electroretinography (ERG) and visually evoked potentials (VEP). We find that optogenetic responses show a peculiar ERG signature and are enhanced in retinas without photoreceptor loss. Conversely, native responses are dampened in the presence of ReaChR. Moreover, in VEP recordings we find that optogenetic responses reach the cortex asynchronous to the native response. These findings should be taken into consideration when planning future clinical trials and may direct future preclinical research to optimize optogenetic approaches for visual restoration. The identified ERG signatures moreover may serve to track treatment efficiency in clinical trials.