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Neurophysiological effects of high-frequency spinal cord stimulation on cortico-sensory areas in large ovine animal model.
Spinal Cord Stimulation (SCS) has been a cornerstone in managing chronic pain since the late 1960s. However, traditional SCS is often associated with variable efficacy and side effects, driving the development of advanced techniques like high-frequency SCS (hSCS). Previous studies have demonstrated that the power of high-frequency cerebral oscillations increases as a function of stimulus intensity and plays a critical role in local neural processing of peripheral sensory stimuli. Extending from the current body of literature, we hypothesized that hSCS could selectively influence stimulus-triggered neural oscillations involved in sensory processing and perception. Using electrocorticography (ECoG) in sheep (n = 4), we investigated the effects of 8.2 KHz hSCS on low-frequency (4-30 Hz) and high-frequency (70-150 Hz) oscillations in ovine somatosensory and association cortices. Neural signals were recorded before, and after hSCS application to assess frequency-specific modulation of cortical activity. Our findings reveal that hSCS induces broad suppression of high-frequency oscillations across both cortical regions. In contrast, low-frequency oscillations were selectively suppressed or enhanced in both cortices. Furthermore, a linear mixed model analysis revealed that low-frequency oscillations better predict high-frequency modulation in the association than the somatosensory cortex, highlighting a reciprocal low-/high-frequency relationship between cortices. These distinct effects on cortical oscillations suggest potential supraspinal mechanisms through which hSCS may exert its analgesic effects. Our findings provide new insights for optimizing neuromodulation strategies in pain management, emphasizing the role of frequency-specific modulation in sensory and cognitive pain processing. PERSPECTIVE: This study demonstrates that high-frequency spinal cord stimulation modulates cortical oscillations in a frequency- and region-specific manner, suggesting a supraspinal mechanism of pain. These findings advance our understanding of how neuromodulation influences sensory components of pain, with implications for optimizing stimulation protocols in chronic pain management.
Therapeutic strategies targeting inflammation and immunity in atherosclerosis: how to proceed?
Atherosclerosis is a chronic inflammatory disease of the arterial wall, characterized by the formation of plaques containing lipid, connective tissue and immune cells in the intima of large and medium-sized arteries. Over the past three decades, a substantial reduction in cardiovascular mortality has been achieved largely through LDL-cholesterol-lowering regimes and therapies targeting other traditional risk factors for cardiovascular disease, such as hypertension, smoking, diabetes mellitus and obesity. However, the overall benefits of targeting these risk factors have stagnated, and a huge global burden of cardiovascular disease remains. The indispensable role of immunological components in the establishment and chronicity of atherosclerosis has come to the forefront as a clinical target, with proof-of-principle studies demonstrating the benefit and challenges of targeting inflammation and the immune system in cardiovascular disease. In this Review, we provide an overview of the role of the immune system in atherosclerosis by discussing findings from preclinical research and clinical trials. We also identify important challenges that need to be addressed to advance the field and for successful clinical translation, including patient selection, identification of responders and non-responders to immunotherapies, implementation of patient immunophenotyping and potential surrogate end points for vascular inflammation. Finally, we provide strategic guidance for the translation of novel targets of immunotherapy into improvements in patient outcomes.
Neutrophils and emergency granulopoiesis drive immune suppression and an extreme response endotype during sepsis.
Sepsis arises from diverse and incompletely understood dysregulated host response processes following infection that leads to life-threatening organ dysfunction. Here we showed that neutrophils and emergency granulopoiesis drove a maladaptive response during sepsis. We generated a whole-blood single-cell multiomic atlas (272,993 cells, n = 39 individuals) of the sepsis immune response that identified populations of immunosuppressive mature and immature neutrophils. In co-culture, CD66b+ sepsis neutrophils inhibited proliferation and activation of CD4+ T cells. Single-cell multiomic mapping of circulating hematopoietic stem and progenitor cells (HSPCs) (29,366 cells, n = 27) indicated altered granulopoiesis in patients with sepsis. These features were enriched in a patient subset with poor outcome and a specific sepsis response signature that displayed higher frequencies of IL1R2+ immature neutrophils, epigenetic and transcriptomic signatures of emergency granulopoiesis in HSPCs and STAT3-mediated gene regulation across different infectious etiologies and syndromes. Our findings offer potential therapeutic targets and opportunities for stratified medicine in severe infection.
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.
Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19.
Single cell spatial analysis reveals inflammatory foci of immature neutrophil and CD8 T cells in COVID-19 lungs.
Single cell spatial interrogation of the immune-structural interactions in COVID -19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We provide our pipeline [Spatial Omics Oxford Pipeline (SpOOx)] and visual-analytical tool, Multi-Dimensional Viewer (MDV) software, as a resource for spatial analysis.
Lipid-associated macrophages transition to an inflammatory state in human atherosclerosis increasing the risk of cerebrovascular complications.
The immune system is integral to cardiovascular health and disease. Targeting inflammation ameliorates adverse cardiovascular outcomes. Atherosclerosis, a major underlying cause of cardiovascular disease (CVD), is conceptualised as a lipid-driven inflammation where macrophages play a non-redundant role. However, evidence emerging so far from single cell atlases suggests a dichotomy between lipid associated and inflammatory macrophage states. Here, we present an inclusive reference atlas of human intraplaque immune cell communities. Combining scRNASeq of human surgical carotid endarterectomies in a discovery cohort with bulk RNASeq and immunohistochemistry in a validation cohort (the Carotid Plaque Imaging Project-CPIP), we reveal the existence of PLIN2hi/TREM1hi macrophages as a toll-like receptor-dependent inflammatory lipid-associated macrophage state linked to cerebrovascular events. Our study shifts the current paradigm of lipid-driven inflammation by providing biological evidence for a pathogenic macrophage transition to an inflammatory lipid-associated phenotype and for its targeting as a new treatment strategy for CVD.
Lipoproteins act as vehicles for lipid antigen delivery and activation of invariant natural killer T cells.
Invariant natural killer T (iNKT) cells act at the interface between lipid metabolism and immunity because of their restriction to lipid antigens presented on CD1d by antigen-presenting cells (APCs). How foreign lipid antigens are delivered to APCs remains elusive. Since lipoproteins routinely bind glycosylceramides structurally similar to lipid antigens, we hypothesized that circulating lipoproteins form complexes with foreign lipid antigens. In this study, we used 2-color fluorescence correlation spectroscopy to show, for the first time to our knowledge, stable complex formation of lipid antigens α-galactosylceramide (αGalCer), isoglobotrihexosylceramide, and OCH, a sphingosine-truncated analog of αGalCer, with VLDL and/or LDL in vitro and in vivo. We demonstrate LDL receptor-mediated (LDLR-mediated) uptake of lipoprotein-αGalCer complexes by APCs, leading to potent complex-mediated activation of iNKT cells in vitro and in vivo. Finally, LDLR-mutant PBMCs of patients with familial hypercholesterolemia showed impaired activation and proliferation of iNKT cells upon stimulation, underscoring the relevance of lipoproteins as a lipid antigen delivery system in humans. Taken together, circulating lipoproteins form complexes with lipid antigens to facilitate their transport and uptake by APCs, leading to enhanced iNKT cell activation. This study thereby reveals a potentially novel mechanism of lipid antigen delivery to APCs and provides further insight into the immunological capacities of circulating lipoproteins.
Cell selectivity in succinate receptor SUCNR1/GPR91 signaling in skeletal muscle.
Succinate is released by skeletal muscle during exercise and activates SUCNR1/GPR91. Signaling of SUCNR1 is involved in metabolite-sensing paracrine communication in skeletal muscle during exercise. However, the specific cell types responding to succinate and the directionality of communication are unclear. We aim to characterize the expression of SUCNR1 in human skeletal muscle. De novo analysis of transcriptomic datasets demonstrated that SUCNR1 mRNA is expressed in immune, adipose, and liver tissues, but scarce in skeletal muscle. In human tissues, SUCNR1 mRNA was associated with macrophage markers. Single-cell RNA sequencing and fluorescent RNAscope demonstrated that in human skeletal muscle, SUCNR1 mRNA is not expressed in muscle fibers but coincided with macrophage populations. Human M2-polarized macrophages exhibit high levels of SUCNR1 mRNA and stimulation with selective agonists of SUCNR1 triggered Gq- and Gi-coupled signaling. Primary human skeletal muscle cells were unresponsive to SUCNR1 agonists. In conclusion, SUCNR1 is not expressed in muscle cells and its role in the adaptive response of skeletal muscle to exercise is most likely mediated via paracrine mechanisms involving M2-like macrophages within the muscle.NEW & NOTEWORTHY Macrophages but not skeletal muscle cells respond to extracellular succinate via SUCNR1/GPR91.
A blood atlas of COVID-19 defines hallmarks of disease severity and specificity
SummaryTreatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete understanding of potentially druggable immune mediators of disease. To advance this, we present a comprehensive multi-omic blood atlas in patients with varying COVID-19 severity and compare with influenza, sepsis and healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity revealed cells, their inflammatory mediators and networks as potential therapeutic targets, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Tensor and matrix decomposition of the overall dataset revealed feature groupings linked with disease severity and specificity. Our systems-based integrative approach and blood atlas will inform future drug development, clinical trial design and personalised medicine approaches for COVID-19.
Evaluation of changes in prediction modelling in biomedicine using systematic reviews.
The number of prediction models proposed in the biomedical literature has been growing year on year. In the last few years there has been an increasing attention to the changes occurring in the prediction modeling landscape. It is suggested that machine learning techniques are becoming more popular to develop prediction models to exploit complex data structures, higher-dimensional predictor spaces, very large number of participants, heterogeneous subgroups, with the ability to capture higher-order interactions. We examine the changes in modelling practices by investigating a selection of systematic reviews on prediction models published in the biomedical literature. We selected systematic reviews published between 2020 and 2022 which included at least 50 prediction models. Information was extracted guided by the CHARMS checklist. Time trends were explored using the models published since 2005. We identified 8 reviews, which included 1448 prediction models published in 887 papers. The average number of study participants and outcome events increased considerably between 2015 and 2019 but remained stable afterwards. The number of candidate and final predictors did not noticeably increase over the study period, with a few recent studies using very large numbers of predictors. Internal validation and reporting of discrimination measures became more common, but assessing calibration and carrying out external validation were less common. Information about missing values was not reported in about half of the papers, however the use of imputation methods increased. There was no sign of an increase in using of machine learning methods. Overall, most of the findings were heterogeneous across reviews. Our findings indicate that changes in the prediction modeling landscape in biomedicine are smaller than expected and that poor reporting is still common; adherence to well established best practice recommendations from the traditional biostatistics literature is still needed. For machine learning best practice recommendations are still missing, whereas such recommendations are available in the traditional biostatistics literature, but adherence is still inadequate.
Is age associated with different vital signs in adults presenting to hospital with bacterial infection? A systematic review and meta-analysis.
BACKGROUND: It has long been suspected that the vital sign abnormalities that accompany bacterial infection are subtle or absent in older adults. This review summarises the evidence for whether older adults present with different vital sign abnormalities to younger adults when hospitalised with bacterial infection. METHODS: MEDLINE, EMBASE and CINAHL EBSCO were searched from inception to 19 December 2024 for English-language research articles of patients hospitalised with bacterial infection reporting age and admission vital signs. We used meta-regression to assess how vital signs vary with age. Where studies reported vital signs in multiple age groups, we undertook a meta-analysis in younger (<65) and older patients (≥65). Evidence quality was assessed using an adapted Quality Assessment of Diagnostic Accuracy Studies-2 tool. RESULTS: Our search yielded 14 487 studies; 132 were included after screening. Older adults were less likely to be tachycardic (RR 0.82, 0.69 to 0.97, I2 = 86.5%) with a mean difference in heart rate of 5 bpm (-7 to -3 bpm, I2 = 88.3%). Older adults were less likely to be febrile (RR 0.89, 0.83 to 0.95, I2 = 85.9%) with a mean difference in temperature of 0.14°C (-0.26 to -0.02°C, I2 = 94.6%). Most (129/132) studies were at high risk of bias. CONCLUSIONS: Whilst differences in absolute values were small, there was consistency in the finding that older adults were less likely than younger adults to be tachycardic or febrile. As vital signs at presentation may prompt suspicion of infection, influencing investigations and treatment, special consideration for the possibility of infection in older patients with normal vital signs may be warranted.
GRACE: protocol for a UK, secondary care, multicentre, assessor-blinded randomised controlled trial with a non-inferiority comparison to evaluate graduated compression stockings as an adjunct to extended duration pharmacological thromboprophylaxis for venous thromboembolism prevention.
INTRODUCTION: Venous thromboembolism (VTE) occurs when a blood clot forms in a vein. It is comprised of deep vein thrombosis (DVT) and pulmonary embolism and can be potentially life-threatening. Patients undergoing surgery are at increased risk of developing VTE within hospital admission and 90 days after hospital discharge are collectively known as hospital-acquired thrombosis (HAT). Without the use of thromboprophylaxis, the untreated risk of VTE is reported to be as high as 40-60% in those undergoing major orthopaedic procedures and around 15-40% in the general surgical population.HAT accounts for around 12 000 deaths per year in the UK. For patients undergoing surgery, there is good evidence for the use of thromboprophylaxis to prevent VTE.Thromboprophylaxis is available in both pharmacological and mechanical forms. While there is a huge body of evidence demonstrating that pharmacological thromboprophylaxis significantly reduces VTE by 30-65%, the benefit of graduated compression stockings (GCS) has been called into question. The GRACE study (Graduated Compression stocking as an adjunct to Extended duration pharmacological thromboprophylaxis for venous thromboembolism prevention) aims to evaluate the adjuvant benefit of GCS in addition to extended duration pharmacological thromboprophylaxis (EDPTP) for elective surgical patients at highest risk of VTE. METHODS AND ANALYSIS: GRACE is a pragmatic, multicentre randomised trial of adults undergoing surgery who are at high risk of VTE. Participants are randomised into a 1:1 ratio to either EDPTP and compression stockings (control arm) or EDPTP (intervention arm). Following randomisation, participants will undergo surgery and be followed up centrally at 7, 21-35 and 90 days after their procedure. All participants will be offered a bilateral full lower limb duplex scan at 21-35 days post procedure to capture any asymptomatic DVT.The trial aims to randomise 8608 participants from around 50 National Health Service (NHS) and non-NHS sites in the UK over a 24-month period. The primary endpoint is any imaging-confirmed incidence of VTE within 90 days of surgery. ETHICS AND DISSEMINATION: On 20 December 2023, GRACE received favourable ethical approval from the Wales Research Ethics Committee 3 Cardiff (23/WA/0350) and the Health Research Authority (IRAS 333539). The results of the study will be disseminated via peer-reviewed publications, presentation at national and international conferences and to study participants via electronic newsletter and social media channels. TRIAL REGISTRATION NUMBER: ISRCTN11667770.
Metabolomics data for 'Glycogen synthase kinase-3 is essential for Treg development and function'
Underlying data for LC-MS experiment in Figure 4.
Regulation of pulmonary plasma cell responses during secondary infection with influenza virus.
During secondary infection with influenza virus, plasma cells (PCs) develop within the lung, providing a local source of antibodies. However, the site and mechanisms that regulate this process are poorly defined. Here, we show that while circulating memory B cells entered the lung during rechallenge and were activated within inducible bronchus-associated lymphoid tissues (iBALTs), resident memory B (BRM) cells responded earlier, and their activation occurred in a different niche: directly near infected alveoli. This process required NK cells but was largely independent of CD4 and CD8 T cells. Innate stimuli induced by virus-like particles containing ssRNA triggered BRM cell differentiation in the absence of cognate antigen, suggesting a low threshold of activation. In contrast, expansion of PCs in iBALTs took longer to develop and was critically dependent on CD4 T cells. Our work demonstrates that spatially distinct mechanisms evolved to support pulmonary secondary PC responses, and it reveals a specialized function for BRM cells as guardians of the alveoli.