Factors associated with increased radiation exposure in the fixation of proximal femoral fractures.

INTRODUCTION: When using radiation intraoperatively, a surgeon should aim to keep the radiation dose as low as is reasonably achievable to obtain the therapeutic goal. We aimed to investigate factors associated with increased radiation exposure in fixation of proximal femur fractures. METHODS: We assessed 369 neck of femur fractures over a 1-year period in a district general hospital. All hip fracture subtypes that had undergone surgical fixation were included. We assessed the relationship between type of fracture, implants used and surgeon level of experience with the dose-area product (DAP; cGy/cm2) and screening time (dS). We also looked at the quality of reduction and fixation and its effect on the radiation exposure. RESULTS: A total of 184 patients were included in our analysis; 185 patients who were treated with hip arthroplasty were excluded. There was a significant association between higher DAP and fracture subtype (p = 0.001), fracture complexity (p < 0.001), if an additional implant was used (p = 0.001), if fixation was satisfactory (p = 0.002) and operative time (p < 0.001). DAP was higher with a proximal femoral nail than with a dynamic hip screw, especially when a long nail was used. There was some evidence of an association between the surgeon's level of experience and DAP exposure, although this was not statistically significant (p = 0.069). CONCLUSIONS: Increased radiation in proximal femur fractures is seen in the fixation of complex fractures, some subtypes, with certain types of implants used and if an additional implant was required. Surgeon seniority did not result in less radiation exposure, which is in contrast to other published studies.

Coronavirus disease 2019 subphenotypes and differential treatment response to convalescent plasma in critically ill adults: secondary analyses of a randomized clinical trial.

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.

Cross-tissue immune cell analysis reveals tissue-specific features in humans.

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.

Chronic subdural haematoma: the role of peri-operative medicine in a common form of reversible brain injury.

Epidemiological studies project a significant rise in cases of chronic subdural haematoma over the next 20 years. Patients with this condition are frequently older and medically complex, with baseline characteristics that may increase peri-operative risk. The intra-operative period is only a small portion of a patient's total hospital stay, with a majority of patients in the United Kingdom transferred between institutions for their surgical and rehabilitative care. Definitive management remains surgical, but peri-operative challenges exist which resonate with other surgical cohorts where multidisciplinary working has become the gold standard. These include shared decision-making, medical optimisation, the management of peri-operative anticoagulation and the identification of key points of equipoise for examination in the future trials. In this narrative review, we use a stereotyped patient journey to provide context to the recent literature, highlighting where multidisciplinary expertise may be required to optimise patient care and maximise the benefits of surgical management. We discuss the triage, pre-operative optimisation, intra-operative management and immediate postoperative care of patients undergoing surgery for a chronic subdural haematoma. We also discuss where adjunctive medical management may be indicated. In so doing, we present the current and emerging evidence base for the role of an integrated peri-operative medicine team in the care of patients with a chronic subdural haematoma.

A method to isolate and cryopreserve cerebrospinal fluid mononuclear cells from external ventricular drains to investigate immunological processes in acute brain injuries.

The inflammatory response to acute brain injuries is a key contributor to subsequent outcome. The study of local central nervous system inflammatory responses is hindered by raised intracranial pressure precluding cerebrospinal fluid sampling by lumbar puncture. External ventricular drains are sited in some acute brain injury patients to divert cerebrospinal fluid and thus reduce intracranial pressure, and represent a potential route to safely gather large volumes of cerebrospinal fluid for immunological studies. In this manuscript we show that mononuclear cells can be isolated from cerebrospinal fluid collected from external ventricular drains, and that the large volumes of cerebrospinal fluid available yield sufficient mononuclear cells to allow cryopreservation. Prolonged storage of cerebrospinal fluid in the external ventricular drain collection bag can alter the phenotype of cells recovered, but the predicted effect of this can be estimated for a given flow cytometry panel by assessing the changes in peripheral blood mononuclear cells exposed to the same conditions. The described method will allow clinical studies of acute brain injuries to investigate the immunological processes occurring within the central nervous system compartment, rather than relying on changes in the peripheral circulation.

Reorganisation of Brain Hubs across Altered States of Consciousness.

Patterns of functional interactions across distributed brain regions are suggested to provide a scaffold for the conscious processing of information, with marked topological alterations observed in loss of consciousness. However, establishing a firm link between macro-scale brain network organisation and conscious cognition requires direct investigations into neuropsychologically-relevant architectural modifications across systematic reductions in consciousness. Here we assessed both global and regional disturbances to brain graphs in a group of healthy participants across baseline resting state fMRI as well as two distinct levels of propofol-induced sedation. We found a persistent modular architecture, yet significant reorganisation of brain hubs that formed parts of a wider rich-club collective. Furthermore, the reduction in the strength of rich-club connectivity was significantly associated with the participants' performance in a semantic judgment task, indicating the importance of this higher-order topological feature for conscious cognition. These results highlight a remarkable interplay between global and regional properties of brain functional interactions in supporting conscious cognition that is relevant to our understanding of clinical disorders of consciousness.

The immunological response to traumatic brain injury.

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.

Brain network disintegration during sedation is mediated by the complexity of sparsely connected regions.

The precise mechanism of anaesthetic action on a neural level remains unclear. Recent approaches suggest that anaesthetics attenuate the complexity of interactions (connectivity) however evidence remains insufficient. We used tools from network and information theory to show that, during propofol-induced sedation, a collection of brain regions displayed decreased complexity in their connectivity patterns, especially so if they were sparsely connected. Strikingly, we found that, despite their low connectivity strengths, these regions exhibited an inordinate role in network integration. Their location and connectivity complexity delineated a specific pattern of sparse interactions mainly involving default mode regions while their connectivity complexity during the awake state also correlated with reaction times during sedation signifying its importance as a reliable indicator of the effects of sedation on individuals. Contrary to established views suggesting sedation affects only richly connected brain regions, we propose that suppressed complexity of sparsely connected regions should be considered a critical feature of any candidate mechanistic description for loss of consciousness.

Pressure Reactivity-Based Optimal Cerebral Perfusion Pressure in a Traumatic Brain Injury Cohort.

OBJECTIVES: Retrospective data from patients with severe traumatic brain injury (TBI) indicate that deviation from the continuously calculated pressure reactivity-based "optimal" cerebral perfusion pressure (CPPopt) is associated with worse patient outcome. The objective of this study was to assess the relationship between prospectively collected CPPopt data and patient outcome after TBI. METHODS: We prospectively collected intracranial pressure (ICP) monitoring data from 231 patients with severe TBI at Addenbrooke's Hospital, UK. Uncleaned arterial blood pressure and ICP signals were recording using ICM+® software on dedicated bedside computers. CPPopt was determined using an automatic curve fitting procedure of the relationship between pressure reactivity index (PRx) and CPP using a 4-h window, as previously described. The difference between an instantaneous CPP value and its corresponding CPPopt value was denoted every minute as ΔCPPopt. A negative ΔCPPopt that was associated with impaired PRx (>+0.15) was denoted as being below the lower limit of reactivity (LLR). Glasgow Outcome Scale (GOS) score was assessed at 6 months post-ictus. RESULTS: When ΔCPPopt was plotted against PRx and stratified by GOS groupings, data belonging to patients with a more unfavourable outcome had a U-shaped curve that shifted upwards. More time spent with a ΔCPPopt value below the LLR was positively associated with mortality (area under the receiver operating characteristic curve = 0.76 [0.68-0.84]). CONCLUSIONS: In a recent cohort of patients with severe TBI, the time spent with a CPP below the CPPopt-derived LLR is related to mortality. Despite aggressive CPP- and ICP-oriented therapies, TBI patients with a fatal outcome spend a significant amount of time with a CPP below their individualised CPPopt, indicating a possible therapeutic target.

Moving to human trials for argon neuroprotection in neurological injury: a narrative review.

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.

ICP Versus Laser Doppler Cerebrovascular Reactivity Indices to Assess Brain Autoregulatory Capacity.

BACKGROUND: To explore the relationship between various autoregulatory indices in order to determine which approximate small vessel/microvascular (MV) autoregulatory capacity most accurately. METHODS: Utilizing a retrospective cohort of traumatic brain injury patients (N = 41) with: transcranial Doppler (TCD), intracranial pressure (ICP) and cortical laser Doppler flowmetry (LDF), we calculated various continuous indices of autoregulation and cerebrovascular responsiveness: A. ICP derived [pressure reactivity index (PRx)-correlation between ICP and mean arterial pressure (MAP), PAx-correlation between pulse amplitude of ICP (AMP) and MAP, RAC-correlation between AMP and cerebral perfusion pressure (CPP)], B. TCD derived (Mx-correlation between mean flow velocity (FVm) and CPP, Mx_a-correlation between FVm and MAP, Sx-correlation between systolic flow velocity (FVs) and CPP, Sx_a-correlation between FVs and MAP, Dx-correlation between diastolic flow index (FVd) and CPP, Dx_a-correlation between FVd and MAP], and LDF derived (Lx-correlation between LDF cerebral blood flow [CBF] and CPP, Lx_a-correlation between LDF-CBF and MAP). We assessed the relationship between these indices via Pearson correlation, Friedman test, principal component analysis (PCA), agglomerative hierarchal clustering (AHC), and k-means cluster analysis (KMCA). RESULTS: LDF-based autoregulatory index (Lx) was most associated with TCD-based Mx/Mx_a and Dx/Dx_a across Pearson correlation, PCA, AHC, and KMCA. Lx was only remotely associated with ICP-based indices (PRx, PAx, RAC). TCD-based Sx/Sx_a was more closely associated with ICP-derived PRx, PAx and RAC. This indicates that vascular-derived indices of autoregulatory capacity (i.e., TCD and LDF based) covary, with Sx/Sx_a being the exception, whereas indices of cerebrovascular reactivity derived from pulsatile CBV (i.e., ICP indices) appear to not be closely related to those of vascular origin. CONCLUSIONS: Transcranial Doppler Mx is the most closely associated with LDF-based Lx/Lx_a. Both Sx/Sx-a and the ICP-derived indices appear to be dissociated with LDF-based cerebrovascular reactivity, leaving Mx/Mx-a as a better surrogate for the assessment of cortical small vessel/MV cerebrovascular reactivity. Sx/Sx_a cocluster/covary with ICP-derived indices, as seen in our previous work.

Critical care management of traumatic brain injury.

Traumatic brain injury (TBI) is a growing global problem, which is responsible for a substantial burden of disability and death, and which generates substantial healthcare costs. High-quality intensive care can save lives and improve the quality of outcome. TBI is extremely heterogeneous in terms of clinical presentation, pathophysiology, and outcome. Current approaches to the critical care management of TBI are not underpinned by high-quality evidence, and many of the current therapies in use have not shown benefit in randomized control trials. However, observational studies have informed the development of authoritative international guidelines, and the use of multimodality monitoring may facilitate rational approaches to optimizing acute physiology, allowing clinicians to optimize the balance between benefit and risk from these interventions in individual patients. Such approaches, along with the emerging impact of advanced neuroimaging, genomics, and protein biomarkers, could lead to the development of precision medicine approaches to the intensive care management of TBI.

Angular default mode network connectivity across working memory load.

Initially identified during no-task, baseline conditions, it has now been suggested that the default mode network (DMN) engages during a variety of working memory paradigms through its flexible interactions with other large-scale brain networks. Nevertheless, its contribution to whole-brain connectivity dynamics across increasing working memory load has not been explicitly assessed. The aim of our study was to determine which DMN hubs relate to working memory task performance during an fMRI-based n-back paradigm with parametric increases in difficulty. Using a voxel-wise metric, termed the intrinsic connectivity contrast (ICC), we found that the bilateral angular gyri (core DMN hubs) displayed the greatest change in global connectivity across three levels of n-back task load. Subsequent seed-based functional connectivity analysis revealed that the angular DMN regions robustly interact with other large-scale brain networks, suggesting a potential involvement in the global integration of information. Further support for this hypothesis comes from the significant correlations we found between angular gyri connectivity and reaction times to correct responses. The implication from our study is that the DMN is actively involved during the n-back task and thus plays an important role related to working memory, with its core angular regions contributing to the changes in global brain connectivity in response to increasing environmental demands. Hum Brain Mapp 38:41-52, 2017. © 2016 Wiley Periodicals, Inc.

An evaluation of the clinical and cost-effectiveness of alternative care locations for critically ill adult patients with acute traumatic brain injury.

BACKGROUND: For critically ill adult patients with acute traumatic brain injury (TBI), we assessed the clinical and cost-effectiveness of: (a) Management in dedicated neurocritical care units versus combined neuro/general critical care units within neuroscience centres. (b) 'Early' transfer to a neuroscience centre versus 'no or late' transfer for those who present at a non-neuroscience centre. METHODS: The Risk Adjustment In Neurocritical care (RAIN) Study included prospective admissions following acute TBI to 67 UK adult critical care units during 2009-11. Data were collected on baseline case-mix, mortality, resource use, and at six months, Glasgow Outcome Scale Extended (GOSE), and quality of life (QOL) (EuroQol 5D-3L). We report incremental effectiveness, costs and cost per Quality-Adjusted Life Year (QALY) of the alternative care locations, adjusting for baseline differences with validated risk prediction models. We tested the robustness of results in sensitivity analyses. FINDINGS: Dedicated neurocritical care unit patients (N = 1324) had similar six-month mortality, higher QOL (mean gain 0.048, 95% CI -0.002 to 0.099) and increased average costs compared with those managed in combined neuro/general units (N = 1341), with a lifetime cost per QALY gained of £14,000. 'Early' transfer to a neuroscience centre (N = 584) was associated with lower mortality (odds ratio 0.52, 0.34-0.80), higher QOL for survivors (mean gain 0.13, 0.032-0.225), but positive incremental costs (£15,001, £11,123 to £18,880) compared with 'late or no transfer' (N = 263). The lifetime cost per QALY gained for 'early' transfer was £11,000. CONCLUSIONS: For critically ill adult patients with acute TBI, within neuroscience centres management in dedicated neurocritical care units versus combined neuro/general units led to improved QoL and higher costs, on average, but these differences were not statistically significant. This study finds that 'early' transfer to a neuroscience centre is associated with reduced mortality, improvement in QOL and is cost-effective.

TBI-the most complex disease in the most complex organ: the CENTER-TBI trial-a commentary.

Each year, approximately 2.5 million people experience some form of traumatic brain injury (TBI) in Europe. One million of these are admitted to hospital and 75 000 will die. TBI represents a major cause of death and disability, particularly among those of working age. Substantial investments have been made in an effort to improve diagnosis, management and survival in TBI, but with little success. The Collaborative European Neuro-Trauma Effectiveness Research in TBI (CENTER-TBI) study promises to use the natural variability seen in the management of TBI across Europe with the application of Comparative Effectiveness Research (CER). It will generate repositories of baseline and comprehensive TBI patient data, neuroimaging, neurogenetics and biomarkers, which aim to improve the diagnosis, stratification, management and prognostication of patients with TBI.

Default mode network connectivity during task execution.

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.

Predictors and outcome impact of perioperative serum sodium changes in a high-risk population.

BACKGROUND: The perioperative period may be associated with a marked neurohumoral stress response, significant fluid losses, and varied fluid replacement regimes. Acute changes in serum sodium concentration are therefore common, but predictors and outcomes of these changes have not been investigated in a large surgical population. METHODS: We carried out a retrospective cohort analysis of 27 068 in-patient non-cardiac surgical procedures in a tertiary teaching hospital setting. Data on preoperative conditions, perioperative events, hospital length of stay, and mortality were collected, along with preoperative and postoperative serum sodium measurements up to 7 days after surgery. Logistic regression was used to investigate the association between sodium changes and mortality, and to identify clinical characteristics associated with a deviation from baseline sodium >5 mmol litre(-1). RESULTS: Changes in sodium concentration >5 mmol litre(-1) were associated with increased mortality risk (adjusted odds ratio 1.49 for a decrease, 3.02 for an increase). Factors independently associated with a perioperative decrease in serum sodium concentration >5 mmol litre(-1) included age >60, diabetes mellitus, and the use of patient-controlled opioid analgesia. Factors associated with a similar increase were preoperative oxygen dependency, mechanical ventilation, central nervous system depression, non-elective surgery, and major operative haemorrhage. CONCLUSIONS: Maximum deviation from preoperative serum sodium value is associated with increased hospital mortality in patients undergoing in-patient non-cardiac surgery. Specific preoperative and perioperative factors are associated with significant serum sodium changes.