Search results
Found 23795 matches for
MAIT and other innate-like T cells integrate adaptive immune responses to modulate interval-dependent reactogenicity to mRNA vaccines
Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2 + γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.
Best Oculomotor Endpoints for Clinical Trials in Hereditary Ataxias: A Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital‑Motor Biomarkers.
Oculomotor deficits are common in hereditary cerebellar ataxias (HCAs) and their quantitative assessment offers a sensitive and reliable manner to capture disease-severity and progression. As a group of experts of the Ataxia Global Initiative to support trial readiness, we previously established harmonized methodology for quantitative oculomotor assessments in HCAs. Here, we aimed to identify to most promising oculomotor/vestibular outcomes as endpoints for future trials. Through a systematic MEDLINE search we identified 130 articles reporting oculomotor/vestibular recordings in patients with HCAs. A total of 2,018 subjects were included: 1,776 with genetically-confirmed and 242 with clinically-defined HCAs. Studied diseases included spinocerebellar ataxias (SCA) 1/2/3/6/7/27B, episodic ataxia type 2, Friedreich ataxia, RFC1-related ataxia, fragile X-associated tremor/ataxia syndrome, cerebrotendinous xanthomatosis, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1&2, and Niemann-Pick disease type C. We identified up to four oculomotor/vestibular outcomes per diagnostic entity, based on their ability to robustly discriminate patients from controls, correlate with disease-severity, detect longitudinal change, and represent different disease stages. For each parameter we provide recommendations for recordings. While the implementation of quantitative assessments into clinical trials offers a unique opportunity to track dysfunction of oculomotor/vestibular networks and to assess the impact of interventions, in some HCAs, endpoint qualification of available outcomes requires further validation to characterize their reliability, sensitivity to change, and minimally important change to patients. For all HCAs for which quantitative data are scarce or lacking, there is an urgent need for prospective studies covering a broader range of oculomotor/vestibular domains as approaching new treatments require harmonized and reliable endpoints.
International Consensus on Global Surgery Learning Objectives and Competencies.
ObjectiveThis project aimed to achieve international consensus on core learning objectives for global surgery education.BackgroundAs global surgery emerges as an academic field, there is a growing need for consensus-driven learning objectives to guide education and training. Existing curricula vary widely and lack multidisciplinary input.MethodsA modified Delphi consensus was conducted with an international panel of global surgery experts. A scoping review informed an initial list of learning objectives, categorized into 14 domains based on the Consortium of Universities for Global Health framework. Panelists rated objectives over three iterative survey rounds, with consensus defined as ≥80% agreement within ±1 Likert point of the median.ResultsSixty-one experts from 26 countries across all World Health Organization (WHO) regions participated, representing surgery (40.1%), anesthesia (14.8%), obstetrics and gynecology (14.8%), general practitioners with and without enhanced surgical skills (16.4%), and allied health fields (6.6%). The majority (57.4%) had over 10 years of experience in global surgery. Across three Delphi rounds, 120 learning objectives reached consensus, covering key domains such as the global burden of surgical disease, surgical system strengthening, ethics and equity, health policy, and sustainable development. A total of 25 (20.8%) objectives were designated for introductory learners, 55 (45.8%) for advanced learners, and 40 (33.3%) for both levels.ConclusionThis Delphi consensus provides a structured, globally relevant framework for global surgery education, supporting curriculum development and competency-based training. These findings underscore the importance of aligning global surgery education with evolving healthcare priorities while ensuring adaptability across diverse surgical contexts.
Successful alemtuzumab retreatment in multiple sclerosis following previous diffuse alveolar haemorrhage.
Alemtuzumab-induced diffuse alveolar haemorrhage (DAH) is a rare but serious complication in people with relapsing-remitting multiple sclerosis (RRMS). Evidence supporting retreatment despite adverse events remains limited. We report a 29-year-old female who developed DAH during the first alemtuzumab cycle and was subsequently retreated 1 year later following interdisciplinary advice from respiratory. There was no recurrence of DAH. This case report provides evidence towards retreatment feasibility with regular monitoring and low thresholds for laboratory and radiological investigations.
Urinary P75: a promising biomarker for amyotrophic lateral sclerosis.
BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a progressive and fatal disease. The urinary neurotrophin receptor p75 extracellular domain (p75ECD) has previously been reported as a potential disease biomarker for diagnosis, severity assessment and monitoring therapeutic response. METHODS: This study measured urinary p75ECD using an enzyme-linked immunoassay and normalised the results against urinary creatinine. Participants were recruited via A Multicentre Biomarker Resource Strategy in ALS (AMBroSIA) programme. Study participants included 97 ALS patients, 24 of whom were studied longitudinally, and 27 healthy controls. The study focused on urinary p75ECD and its potential association with different subtypes of ALS, change over time, disease progression, severity of symptoms and survival from symptom onset. RESULTS: Confirming previous findings, urinary p75ECD levels were significantly higher in patients with ALS (median 6.78 ng/mg, 95% CI (5.12 to 9.23)) compared with controls (4.57 ng/mg, 95% CI (3.35 to 5.89)) at first study visit. There was a significant negative correlation between absolute change in the Revised ALS Functional Rating Scale score and p75ECD levels (Spearman's rho=-0.371, p≤0.0004, 95% CI (-0.543 to -0.169)), indicating that an increase in the severity of motor neuron injury correlated with an increase in p75ECD levels. There was a significant increase in p75ECD between first and second samples in the same participants, indicating an increase in the level of this biomarker longitudinally during the disease course (moderate effect size of -0.3). CONCLUSIONS: Urinary p75ECD is a promising candidate as a biomarker, which increases with disease progression and has the potential to serve as a pharmacodynamic biomarker.
TDP-43 pathology is associated with divergent protein profiles in ALS brain and spinal cord
Abstract 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.
SLC45A4 is a pain gene encoding a neuronal polyamine transporter
Abstract Polyamines are regulatory metabolites with key roles in transcription, translation, cell signalling and autophagy1. They are implicated in multiple neurological disorders, including stroke, epilepsy and neurodegeneration, and can regulate neuronal excitability through interactions with ion channels2. Polyamines have been linked to pain, showing altered levels in human persistent pain states and modulation of pain behaviour in animal models3. However, the systems governing polyamine transport within the nervous system remain unclear. Here, undertaking a genome-wide association study (GWAS) of chronic pain intensity in the UK Biobank (UKB), we found a significant association between pain intensity and variants mapping to the SLC45A4 gene locus. In the mouse nervous system, Slc45a4 expression is enriched in all sensory neuron subtypes within the dorsal root ganglion, including nociceptors. Cell-based assays show that SLC45A4 is a selective plasma membrane polyamine transporter, and the cryo-electron microscopy (cryo-EM) structure reveals a regulatory domain and basis for polyamine recognition. Mice lacking SLC45A4 show normal mechanosensitivity but reduced sensitivity to noxious heat- and algogen-induced tonic pain that is associated with reduced excitability of C-polymodal nociceptors. Our findings therefore establish a role for neuronal polyamine transport in pain perception and identify a target for therapeutic intervention in pain treatment.
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.
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
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.
Teaching humanities in UK medical schools: towards community-building and coherence
Abstract Medical humanities teaching in UK medical schools has lacked cohesion, having developed opportunistically in different locations. Cohesion is necessary to develop an identifiable community of practice, but within that community there can be multiple readings of what ‘medical humanities’ are and how they may develop. This article details discussions held by medical humanities scholars teaching in UK medical schools at a workshop in January 2025 at the University of Oxford covering five key areas: the role of humanities scholars in medical schools, patients as partners in medical education, core curriculum teaching, intercalated teaching, and assessment. Our discussion highlights opportunities and challenges facing humanities teaching in UK medical schools today and calls for the creation of a community of medical humanities scholars working in UK medical education embracing diversity of opinion and practices. The article is specifically written as a synopsis of a brainstorming symposium.
Explainable machine learning for predicting ICU mortality in myocardial infarction patients using pseudo-dynamic data.
Myocardial infarction (MI) remains one of the greatest contributors to mortality, and patients admitted to the intensive care unit (ICU) with myocardial infarction are at higher risk of death. In this study, we use two retrospective cohorts extracted from two US-based ICU databases, eICU and MIMIC-IV, to develop an explainable pseudo-dynamic machine learning framework for mortality prediction in the ICU. The method provides accurate prediction for ICU patients up to 24 hours before the event and provides time-resolved interpretability. We compare standard supervised machine learning algorithms with novel tabular deep learning approaches and find that an integrated XGBoost model in our EHR time-series extraction framework (XMI-ICU) performs best. The framework was evaluated on a held-out test set from eICU and externally validated on the MIMIC-IV cohort using the most important features identified by time-resolved Shapley values. XMI-ICU achieved AUROCs of 92.0 (balanced accuracy of 82.3) for a 6-hour prediction of mortality. We demonstrate that XMI-ICU maintains reliable predictive performance across different prediction horizons (6, 12, 18, and 24 hours) during ICU stay while also achieving successful external validation in a separate patient cohort from MIMIC-IV without any previous training on that dataset. We also evaluated the framework for clinical risk analysis by comparing it to the standard APACHE IV system in active use. We show that our framework successfully leverages time-series physiological measurements from ICU health records by translating them into stacked static prediction problems for mortality in heart attack patients and can offer clinical insight from time-resolved interpretability through the use of Shapley values.
Apathy and impulsivity in neurological and psychiatric disorders
Apathy and impulsivity are debilitating syndromes of motivation that are common across neurological and psychiatric disorders. Both are associated with pathology within well described fronto-striatal networks where dopaminergic neurons play an important role in regulating motivated behavior. In this chapter, we investigate whether dopaminergic dysfunction within this network is associated with either apathetic or impulsive behavior. We focus on patients with Parkinson's disease and schizophrenia, investigating a wide range of behavioral and neuroimaging studies. Current findings suggest that both apathy and impulsivity are associated with altered responsiveness to rewards during decision-making and altered function within fronto-striatal networks. While dopaminergic therapy also alters reward sensitivity, there are instances where the effects of apathy and/or impulsivity on this metric are independent of—and extend beyond—dopaminergic tone. This suggests a more nuanced relationship between fronto-striatal dopamine and human motivation syndromes that warrants further investigation.
Altered network efficiency in isolated REM sleep behavior disorder: A multicentric study.
INTRODUCTION: Isolated rapid eye movement (REM) sleep behavior disorder (iRBD), characterized by abnormal movements during REM sleep, is a prodromal stage of dementia with Lewy bodies (DLB) and Parkinson's disease (PD). While iRBD shows emerging brain changes, their impact on structural connectivity and network efficiency, and their predictive value, remain poorly characterized. METHODS: In this international prospective study, 198 polysomnography-confirmed iRBD patients and 174 controls underwent diffusion magnetic resonance imaging and were analyzed. Cutting-edge diffusion tractography and network-based statistics were applied to reconstruct individual connectomes and assess network properties predicting DLB or PD. RESULTS: Structural architecture was already disrupted in iRBD, with both reduced and compensatory increased connections. Global efficiency was decreased. Local efficiency in motor regions was altered and associated with early clinical symptoms. Altered local efficiency in the supramarginal gyrus predicted DLB only. DISCUSSION: Early disruption of brain architecture in iRBD predicts progression to synucleinopathy-related dementia, offering a novel potential prognostic biomarker. HIGHLIGHTS: Isolated rapid eye movement sleep behavior disorder (iRBD) patients show significant alterations in inter-regional structural connectivity. Global efficiency is reduced in iRBD compared to controls. Areas with increased local efficiency contribute to decreased global efficiency. Altered network efficiency is associated with emerging Parkinsonian features. Higher supramarginal efficiency predicts dementia with Lewy bodies in iRBD.