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The mini-Oxford cognitive screen (Mini-OCS): A very brief cognitive screen for use in chronic stroke
Introduction: No stroke-specific cognitive screen currently exists for community-dwelling chronic stroke survivors, with primary care and community settings relying on dementia tools which often do not consider specific post-stroke impairments. The Oxford Cognitive Screen (OCS) was developed for use in acute stroke, but its administration time is prohibitive for brief screening. Here, we aimed to develop, standardise and psychometrically validate the Mini-Oxford Cognitive Screen (Mini-OCS), a brief (<8 min) cognitive screen aimed for use in chronic stroke. Method: Existing full OCS data for 464 English participants who were ⩾6 months post-stroke were analysed for the possibility of a short-form. Theoretical choices were made to adapt the short-form to be suitable for use in chronic stroke. The Mini-OCS was then completed by 164 neurologically healthy controls ( M age = 68.66; SD = 12.18, M years of education 15.40; SD = 3.64, 61% female), and 89 chronic stroke survivors ( M age = 69.86; SD = 14.83, M years education = 14.29; SD = 4.01, 44.94% female, M days since stroke = 597.02; SD = 881.12, 78.57% ischaemic, Median NIHSS = 6.5 (IQR = 4–11)). In addition, the original OCS, the Montreal Cognitive Assessment, and an extended neuropsychological battery were administered. Psychometric properties of the Mini-OCS were evaluated via construct validity and retest reliability. Findings: Normative data for the Mini-OCS is provided and known-group discrimination demonstrates increased sensitivity in the memory and executive function domains compared to the OCS. The Mini-OCS further met all appropriate benchmarks for evidence of retest reliability and construct validity. Discussion and conclusion: The Mini-OCS is a short-form standardised cognitive screening tool with initial evidence of good psychometric properties for use in a chronic stroke population.
The Effects of Theta-Gamma Peak Stimulation on Sensorimotor Learning during Speech Production
Abstract Transcranial alternating current stimulation (tACS) is a non-invasive neuromodulatory tool that is thought to entrain intrinsic neural oscillations by supplying low electric currents over the scalp. Recent work has demonstrated the efficacy of theta-gamma phase-amplitude coupled tACS over primary motor cortex to enhance motor skill acquisition and motor recovery after stroke. Here, we wished to assess the efficacy of tACS delivered with 75-Hz gamma coupled to the peak of a 6-Hz theta envelope (theta-gamma peak; TGP) at an intensity of 2 mA peak-to-peak to enhance sensorimotor learning during speech production. Sensorimotor learning was measured by shifting the formant frequency of vowels in real-time as speech is produced and measuring the adaptation to this altered feedback. The study was a between-subjects, single-blind, sham-controlled design. We hypothesised that participants who performed the speech task while receiving TGP tACS over the speech motor cortex (N = 30) would show greater adaptation to altered auditory feedback than those receiving sham stimulation (N = 31). Contrary to this hypothesis, there was no effect of TGP tACS on adaption to the upwards F1 shift in auditory feedback in either the final 30 trials of the learning phase or in the first 15 trials of the after-effect phase. However, a trend emerged in the TGP tACS group for greater retention of the adapted state and slower return to baseline F1 values in the after-effect phase. This finding was not predicted, and highlights the need for further investigation to deepen our understanding of the effects of TGP tACS on speech motor learning.
Autoantibodies in myasthenia gravis.
Autoimmune Myasthenia Gravis (MG) is a disease characterized by fatigable muscle weakness and autoantibodies. It can be divided by the presence of serum autoantibodies into two major categories where Immunoglobulin G (IgG) against either the acetylcholine receptor (AChR), or muscle specific kinase (MuSK) causes fatigable muscle weakness. The clinical relevance of Low-density lipoprotein-receptor related protein-4 IgG (LRP4) is debated. These antibodies disrupt neuromuscular transmission via different mechanisms: AChR antibodies, mostly of IgG1 and IgG3 subclass, can activate complement leading to a simplification of the NMJ architecture, block acetylcholine binding to its receptor to prevent channel opening, and internalize AChR. By contrast, MuSK antibodies, mostly of the IgG4 subclass, impair MuSK-LRP4 interactions, and LRP4 antibodies may interfere with agrin-induced clustering. Once these antibody targets were identified the development of antibody assays began. Patrick and Lindstrom made the landmark discovery that antibodies against soluble AChR caused acute flaccid paralysis in immunized rabbits which kickstarted test development. The first, and until recently, most useful test was the radioimmunoassay (RIA) where AChR radiolabeled with toxin from venomous snakes allowed quantitative measurement of AChR-IgG. Most recently the clustered AChR cell-based assays (CBA) provide a significant improvement in test sensitivity over all other methods. MuSK assays followed a similar but shorter path. The accurate detection of AChR and MuSK antibodies has a crucial role in supporting the clinical diagnosis and management of MG which includes a diverse population of patients with a wide range of clinical manifestations, disease severity and response to standard and new therapies. In this chapter we highlight how distinct target-specific IgG autoantibodies cause neuromuscular transmission defects, and subsequently shape disease manifestations in the different MG antibody subgroups. We review the evolution of diagnostic assays, from early RIA to modern CBA, and addresses interpretative pitfalls, particularly in borderline or "seronegative" cases. Finally, the authors address the significance of accurate autoantibody detection in the diagnosis and management of patients with one of the antibody MG subtypes, as well as in patients with other autoimmune conditions and thymic malignancies.
Linking microscopy to diffusion MRI with degenerate biophysical models: an application of the Bayesian EstimatioN of CHange (BENCH) framework
Abstract Biophysical modelling of diffusion MRI (dMRI) is used to non-invasively estimate microstructural features of tissue, particularly in the brain. However, meaningful description of tissue requires many unknown parameters, resulting in a model that is often ill-posed. The Bayesian EstimatioN of CHange (BENCH) framework was specifically designed to circumvent parameter fitting for ill-conditioned models when one is simply interested in interpreting signal changes related to some variable of interest. To understand the biological underpinning of some observed change in MR signal between different conditions, BENCH predicts which model parameter, or combination of parameters, best explains the observed change, without having to invert the model. BENCH has been previously used to identify which biophysical parameters could explain group-wise dMRI signal differences (e.g. patients vs. controls); here, we adapt BENCH to interpret dMRI signal changes related to continuous variables. We investigate how parameters from the dMRI standard model of white matter, with an additional sphere compartment to represent glial cell bodies, relate to tissue microstructure quantified from histology. We validate BENCH using synthetic dMRI data from numerical simulations. We then apply it to ex-vivo macaque brain data with dMRI and microscopy metrics of glial density, axonal density, and axonal dispersion in the same brain. We found that (i) increases in myelin density are primarily associated with an increased intra-axonal volume fraction and (ii) changes in the orientation dispersion derived from myelin microscopy are linked to variations in the orientation dispersion index. Finally, we found that the dMRI signal is sensitive to changes in glial cell load in the brain white matter, though no single parameter in the extended standard model was able to explain this observed signal change.
Defining the genetic determinants of CD8 + T cell receptor repertoire in the context of immune checkpoint blockade
The relationship between genetic variation and CD8 + T cell receptor (TCR) repertoire usage in patients receiving immune checkpoint blockade (ICB) therapy for cancer is unexplored. We have conducted a genome-wide and human leukocyte antigen (HLA)–focused analysis of CD8 + TCR repertoire to identify genetic determinants of variable gene (V-gene) and CDR3 K -nucleotide oligomer usage from samples taken before and after ICB ( n = 250). We identify 11 cis and 10 trans V-gene associations, primarily to the MHC, that meet genome-wide significance. TCR clones containing HLA associated V-genes were less stable across treatment, while, at the single-cell level, genetically associated clones demonstrate subset enrichment and increased tumor reactivity expression profiles. Notably, patients with HLA-matched TCR clones demonstrate improved overall survival. Our work indicates a complex relationship between genotype and TCR repertoire in the context of ICB treatment, with implications for understanding factors relating to therapeutic response and patient outcomes.
Social resource as a critical and overlooked factor for patient safety in low-resource settings.
Clinicians, NGOs, funders and academics (among others) in global health are accustomed to discussion of the "low-resource setting". Commonly, the resources implicit in this term are physical (equipment, drugs) and infrastructural (electricity, water and sanitation) in nature. Human resources are well recognised as scarce in this context too, and the focus in most "workforce" research is on the number, distribution and/or training of healthcare workers. In this article, we make the case for closer examination of "social resource" as necessary to patient safety and distinct from simple enumeration of available/trained personnel. We use the clinical specialty of anaesthesia as a case study, identifying the different ways in which social resource is necessary to enable safe practice for anaesthesia providers, and the potential challenges to accessing social resource relevant in the low- and middle-income context. Finally, we suggest ways in which social resource for anaesthesia professionals in LMICs might be meaningfully investigated, with a view to improving its priority and access for safe anaesthesia care worldwide.
Lesion level and severity acutely influence metabolomic profiles in spinal cord injury.
Changes in the peripheral metabolome, particularly in the blood, may provide biomarkers for assessing lesion severity and predicting outcomes after spinal cord injury (SCI). Using principal component analysis (PCA) and Orthogonal Partial Least Squares Discriminatory Analysis (OPLS-DA), we sought to discover how SCI severity and location acutely affect the nuclear magnetic resonance-acquired metabolome of the blood, spinal cord, and liver at 6 h post-SCI in mice. Unsupervised PCA of the spinal cord metabolome separated mild (30 kdyne) and severe (70 kdyne) contusion injury groups but did not distinguish between lesion level. However, OPLS-DA could discriminate thoracic level T2 from T9 lesions in both blood plasma (accuracy 86 ± 6%) and liver (accuracy 89 ± 5%) samples. These differences were dependent on alterations in energy metabolites (lactate and glucose), lipoproteins, and lipids. Lactate was the most discriminatory between mild and severe injury at T2, whereas overlapping valine/proline resonances were most discriminatory between injury severities at T9. Plasma lactate correlated with blood-spinal cord barrier breakdown and plasma glucose with microglial density. We propose that peripheral biofluid metabolites can serve as biomarkers of SCI severity and associated pathology at the lesion site; their predictive value is most accurate when the injury level is also considered.
Multi-omic integration with human dorsal root ganglia proteomics highlights TNFα signalling as a relevant sexually dimorphic pathway
Abstract The peripheral nervous system (PNS) plays a critical role in pathological conditions, including chronic pain disorders, that manifest differently in men and women. To investigate this sexual dimorphism at the molecular level, we integrated quantitative proteomic profiling of human dorsal root ganglia (hDRG) and peripheral nerve tissue into the expanding omics framework of the PNS. Using data-independent acquisition (DIA) mass spectrometry, we characterized a comprehensive proteomic profile, validating tissue-specific differences between the hDRG and peripheral nerve. Through multi-omic analyses and in vitro functional assays, we identified sex-specific molecular differences, with TNFα signalling emerging as a key sexually dimorphic pathway with higher prominence in men. Genetic evidence from genome-wide association studies further supports the functional relevance of TNFα signalling in the periphery, while clinical trial data and meta-analyses indicate a sex-dependent response to TNFα inhibitors. Collectively, these findings underscore a functionally sexual dimorphism in the PNS, with direct implications for sensory and pain-related clinical translation.