Despite their crucial role in health and disease, our knowledge of immune cells within human tissues remains limited. We surveyed the immune compartment of 16 tissues from 12 adult donors by ...single-cell RNA sequencing and VDJ sequencing generating a dataset of ~360,000 cells. To systematically resolve immune cell heterogeneity across tissues, we developed CellTypist, a machine learning tool for rapid and precise cell type annotation. Using this approach, combined with detailed curation, we determined the tissue distribution of finely phenotyped immune cell types, revealing hitherto unappreciated tissue-specific features and clonal architecture of T and B cells. Our multitissue approach lays the foundation for identifying highly resolved immune cell types by leveraging a common reference dataset, tissue-integrated expression analysis, and antigen receptor sequencing.
Introduction
Pressure-reactivity index (PRx) is a useful tool in brain monitoring of trauma patients, but the question remains about its critical values. Using our TBI database, we identified the ...thresholds for PRx and other monitored parameters that maximize the statistical difference between death/survival and favorable/unfavorable outcomes. We also investigated how these thresholds depend on clinical factors such as age, gender and initial GCS
.
Methods
A total of 459 patients from our database were eligible. Tables of 2 × 2 format were created grouping patients according to survival/death or favorable/unfavorable outcomes and varying thresholds for PRx, ICP and CPP. Pearson’s chi square was calculated, and the thresholds returning the highest score were assumed to have the best discriminative value. The same procedure was repeated after division according to clinical factors.
Results
In all patients, we found that PRx had different thresholds for survival (0.25) and for favorable outcome (0.05). Thresholds of 70 mmHg for CPP and 22 mmHg for ICP were identified for both survival and favorable outcomes. The ICP threshold for favorable outcome was lower (18 mmHg) in females and patients older than 55 years. In logistic regression models, independent variables associating with mortality and unfavorable outcome were age, GCS, ICP and PRx.
Conclusion
The prognostic role of PRx is confirmed but with a lower threshold of 0.05 for favorable outcome than for survival (0.25). Results for ICP are in line with current guidelines. However, the lower value in elderly and in females suggests increased vulnerability to intracranial hypertension in these groups.
Initially described as task-induced deactivations during goal-directed paradigms of high attentional load, the unresolved functionality of default mode regions has long been assumed to interfere with ...task performance. However, recent evidence suggests a potential default mode network involvement in fulfilling cognitive demands. We tested this hypothesis in a finger opposition paradigm with task and fixation periods which we compared with an independent resting state scan using functional magnetic resonance imaging and a comprehensive analysis pipeline including activation, functional connectivity, behavioural and graph theoretical assessments. The results indicate task specific changes in the default mode network topography. Behaviourally, we show that increased connectivity of the posterior cingulate cortex with the left superior frontal gyrus predicts faster reaction times. Moreover, interactive and dynamic reconfiguration of the default mode network regions' functional connections illustrates their involvement with the task at hand with higher-level global parallel processing power, yet preserved small-world architecture in comparison with rest. These findings demonstrate that the default mode network does not disengage during this paradigm, but instead may be involved in task relevant processing.
•Default mode network (DMN) processes do not disengage during task execution.•DMN actively contributes to mental processing in a finger opposition paradigm.•Task-induced changes in DMN connectivity correlate with faster reaction times.•DMN interactions show high efficiency and preserved small-world architecture.•Baseline fixation conditions in cognitive tasks cannot be regarded as true rest.
Traumatic brain injury (TBI) is the leading cause of death and disability in young adults in the developed world. The accuracy of early outcome-prediction remains poor even when all known prognostic ...factors are considered, suggesting important currently unidentified variables. In addition, whilst survival and neurological outcomes have improved markedly with the utilisation of therapies that optimise physiology, no treatments specifically modulate the underlying pathophysiology. The immunological response to TBI represents both a potential contributor to outcome heterogeneity and a therapeutically tractable component of the acute disease process. Furthermore, chronic inflammation has been linked with neurodegeneration, and may mark a bridge between acute brain injury and the subsequent neurodegenerative process seen in a proportion of patients following TBI. Given the complexity of the immune response and its varying functions ranging from repair of injury to bystander damage of healthy tissue, attempts at immunomodulatory intervention must necessarily be highly targeted towards the maladaptive facets of the inflammatory process. In this review we aim to provide an integrated description of the immunological processes triggered by TBI in both humans and animal models, in particular considering the interplay between the innate immune system, danger-associated molecular patterns and loss of self-tolerance leading to adaptive autoimmunity.
•Significant unexplained heterogeneity in outcome after TBI suggests important undiscovered factors.•Activation of both the innate and adaptive immune systems are seen following TBI.•Persistent immune activation can be seen years after injury.•Attempts at immunomodulation must be precisely targeted to avoid compromising beneficial effects.
Angle-resolved photoemission spectroscopy (ARPES) and ab initio band structure calculations have been used to study the detailed valence band structure of molybdenite, MoS2 and MoSe2. The ...experimental band structure obtained from ARPES has been found to be in good agreement with the theoretical calculations performed using the linear augmented plane wave (LAPW) method. In going from MoS2 to MoSe2, the dispersion of the valence bands decreases along both k| and k , revealing the increased two-dimensional character which is attributed to the increasing interlayer distance or c a ratio in these compounds. The width of the valence band and the band gap are also found to decrease, whereas the valence band maxima shift towards the higher binding energy from MoS2 to MoSe2.
Purpose
Benefit from convalescent plasma therapy for coronavirus disease 2019 (COVID-19) has been inconsistent in randomized clinical trials (RCTs) involving critically ill patients. As COVID-19 ...patients are immunologically heterogeneous, we hypothesized that immunologically similar COVID-19 subphenotypes may differ in their treatment responses to convalescent plasma and explain inconsistent findings between RCTs .
Methods
We tested this hypothesis in a substudy involving 1239 patients, by measuring 26 biomarkers (cytokines, chemokines, endothelial biomarkers) within the randomized, embedded, multifactorial, adaptive platform trial for community-acquired pneumonia (REMAP-CAP) that assigned 2097 critically ill COVID-19 patients to either high-titer convalescent plasma or usual care. Primary outcome was organ support free days at 21 days (OSFD-21) .
Results
Unsupervised analyses identified three subphenotypes/endotypes. In contrast to the more homogeneous subphenotype-2 (
N
= 128 patients, 10.3%; with elevated type i and type ii effector immune responses) and subphenotype-3 (
N
= 241, 19.5%; with exaggerated inflammation), the subphenotype-1 had variable biomarker patterns (
N
= 870 patients, 70.2%). Subphenotypes-2, and -3 had worse outcomes, and subphenotype-1 had better outcomes with convalescent plasma therapy compared with usual care (median (IQR). OSFD-21 in convalescent plasma vs usual care was 0 (− 1, 21) vs 10 (− 1, to 21) in subphenotype-2; 1.5 (− 1, 21) vs 12 (− 1, to 21) in suphenotype-3, and 0 (− 1, 21) vs 0 (− 1, to 21) in subphenotype-1 (test for between-subphenotype differences in treatment effects
p
= 0.008).
Conclusions
We reported three COVID-19 subphenotypes, among critically ill adults, with differential treatment effects to ABO-compatible convalescent plasma therapy. Differences in subphenotype prevalence between RCT populations probably explain inconsistent results with COVID-19 immunotherapies.
Despite the global burden of brain injury, neuroprotective agents remain elusive. There are no clinically effective therapies which reduce mortality or improve long-term cognitive outcome. ...Ventilation could be an easily modifiable variable in resuscitation; gases are relatively simple to administer. Xenon is the prototypic agent of a new generation of experimental treatments which show promise. However, use is hindered by its prohibitive cost and anaesthetic properties. Argon is an attractive option, being cheaper, easy to transport, non-sedating, and mechanistically distinct from xenon. In vitro and in vivo models provide evidence of argon reducing brain injury, with improvements in neurocognitive, histological, and biomarker metrics, as well as improved survival. Current data suggest that the effect of argon is mediated via the toll-like receptors 2 and 4, the extracellular signal-regulated kinase 1/2, and phosphatidylinositol 3 kinase (PI-3K)-AKT pathways. Ventilation with argon appears to be safe in pigs and preliminary human trials. Given recent evidence that arterial hyperoxia may be harmful, the supplementation of high-concentration argon may not necessitate changes to clinical practice. Given the logistic benefits, and the evidence for argon neuroprotection summarized in this manuscript, we believe that the time has come to consider developing Phase II clinical trials to assess its benefit in acute neurological injury.
Flash X-ray (FXR) sources for dynamic radiography operate in different electron beam diode geometries depending on the applied voltage and impedance of the pulse power systems driving them. Rod-pinch ...(RP) diode is a suitable candidate for accelerating voltages up to few MeVs. It is desirable to have a small source size (0.5-3 mm) with a higher X-ray dose for a better figure of merit (FoM) "for short pulse" radiographic sources. A 3-D particle-in-cell (PIC) simulation study to optimize the RP source geometry for voltages in the range 0.8-3 MeV is presented here. Single disk and double disk cathodes were studied for the cathode to anode radius ratio of 10 and having a 1 mm anode radius. Comparison has been made with space charge-limited (SCL) model for cylindrical diode and critical current model for both single species electron only, as well as with both electron and ion PIC simulation. The electron current collected at the anode tip for single disk cathode and double disk cathodes has been compared for various accelerating voltages. Double-disk cathode with a 3 mm separation between the disks would provide better FoM as an X-ray source for operating voltages in the range 0.8-3 MV.
To validate risk prediction models for acute traumatic brain injury (TBI) and to use the best model to evaluate the optimum location and comparative costs of neurocritical care in the NHS.
Cohort ...study.
Sixty-seven adult critical care units.
Adult patients admitted to critical care following actual/suspected TBI with a Glasgow Coma Scale (GCS) score of < 15.
Critical care delivered in a dedicated neurocritical care unit, a combined neuro/general critical care unit within a neuroscience centre or a general critical care unit outside a neuroscience centre.
Mortality, Glasgow Outcome Scale - Extended (GOSE) questionnaire and European Quality of Life-5 Dimensions, 3-level version (EQ-5D-3L) questionnaire at 6 months following TBI.
The final Risk Adjustment In Neurocritical care (RAIN) study data set contained 3626 admissions. After exclusions, 3210 patients with acute TBI were included. Overall follow-up rate at 6 months was 81%. Of 3210 patients, 101 (3.1%) had no GCS score recorded and 134 (4.2%) had a last pre-sedation GCS score of 15, resulting in 2975 patients for analysis. The most common causes of TBI were road traffic accidents (RTAs) (33%), falls (47%) and assault (12%). Patients were predominantly young (mean age 45 years overall) and male (76% overall). Six-month mortality was 22% for RTAs, 32% for falls and 17% for assault. Of survivors at 6 months with a known GOSE category, 44% had severe disability, 30% moderate disability and 26% made a good recovery. Overall, 61% of patients with known outcome had an unfavourable outcome (death or severe disability) at 6 months. Between 35% and 70% of survivors reported problems across the five domains of the EQ-5D-3L. Of the 10 risk models selected for validation, the best discrimination overall was from the International Mission for Prognosis and Analysis of Clinical Trials in TBI Lab model (IMPACT) (c-index 0.779 for mortality, 0.713 for unfavourable outcome). The model was well calibrated for 6-month mortality but substantially underpredicted the risk of unfavourable outcome at 6 months. Baseline patient characteristics were similar between dedicated neurocritical care units and combined neuro/general critical care units. In lifetime cost-effectiveness analysis, dedicated neurocritical care units had higher mean lifetime quality-adjusted life-years (QALYs) at small additional mean costs with an incremental cost-effectiveness ratio (ICER) of £14,000 per QALY and incremental net monetary benefit (INB) of £17,000. The cost-effectiveness acceptability curve suggested that the probability that dedicated compared with combined neurocritical care units are cost-effective is around 60%. There were substantial differences in case mix between the 'early' (within 18 hours of presentation) and 'no or late' (after 24 hours) transfer groups. After adjustment, the 'early' transfer group reported higher lifetime QALYs at an additional cost with an ICER of £11,000 and INB of £17,000.
The risk models demonstrated sufficient statistical performance to support their use in research but fell below the level required to guide individual patient decision-making. The results suggest that management in a dedicated neurocritical care unit may be cost-effective compared with a combined neuro/general critical care unit (although there is considerable statistical uncertainty) and support current recommendations that all patients with severe TBI would benefit from transfer to a neurosciences centre, regardless of the need for surgery. We recommend further research to improve risk prediction models; consider alternative approaches for handling unobserved confounding; better understand long-term outcomes and alternative pathways of care; and explore equity of access to postcritical care support for patients following acute TBI.
The National Institute for Health Research Health Technology Assessment programme.
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