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Background: Cancer diagnostics and surgery have been disrupted by the response of health care services to the coronavirus disease 2019 (COVID-19) pandemic. Progression of cancers during delay will impact on patients' long-term survival., Patients and Methods: We generated per-day hazard ratios of cancer progression from observational studies and applied these to age-specific, stage-specific cancer survival for England 2013-2017. We modelled per-patient delay of 3 and 6 months and periods of disruption of 1 and 2 years. Using health care resource costing, we contextualise attributable lives saved and life-years gained (LYGs) from cancer surgery to equivalent volumes of COVID-19 hospitalisations., Results: Per year, 94 912 resections for major cancers result in 80 406 long-term survivors and 1 717 051 LYGs. Per-patient delay of 3/6 months would cause attributable death of 4755/10 760 of these individuals with loss of 92 214/208 275 life-years, respectively. For cancer surgery, average LYGs per patient are 18.1 under standard conditions and 17.1/15.9 with a delay of 3/6 months (an average loss of 0.97/2.19 LYGs per patient), respectively. Taking into account health care resource units (HCRUs), surgery results on average per patient in 2.25 resource-adjusted life-years gained (RALYGs) under standard conditions and 2.12/1.97 RALYGs following delay of 3/6 months. For 94 912 hospital COVID-19 admissions, there are 482 022 LYGs requiring 1 052 949 HCRUs. Hospitalisation of community-acquired COVID-19 patients yields on average per patient 5.08 LYG and 0.46 RALYGs., Conclusions: Modest delays in surgery for cancer incur significant impact on survival. Delay of 3/6 months in surgery for incident cancers would mitigate 19%/43% of LYGs, respectively, by hospitalisation of an equivalent volume of admissions for community-acquired COVID-19. This rises to 26%/59%, respectively, when considering RALYGs. To avoid a downstream public health crisis of avoidable cancer deaths, cancer diagnostic and surgical pathways must be maintained at normal throughput, with rapid attention to any backlog already accrued., Competing Interests: Disclosure The authors have declared no conflicts of interest., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Microvesicles are cell-derived signaling particles emerging as important mediators and biomarkers of systemic inflammation, but their production in severe burn injury patients has not been described. In this pilot investigation, we measured circulating microvesicle levels following severe burns, with severe sepsis patients as a comparator group. We hypothesized that levels of circulating vascular cell-derived microvesicles are elevated acutely following burns injury, mirroring clinical severity due to the early onset and prevalence of systemic inflammatory response syndrome (SIRS) in these patients. Blood samples were obtained from patients with moderate to severe thermal injury burns, with severe sepsis, and from healthy volunteers. Circulating microvesicles derived from total leukocytes, granulocytes, monocytes, and endothelial cells were quantified in plasma by flow cytometry. All circulating microvesicle subpopulations were elevated in burns patients on day of admission (day 0) compared to healthy volunteers (leukocyte-microvesicles: 3.5-fold, p = 0.005; granulocyte-microvesicles: 12.8-fold, p<0.0001; monocyte-microvesicles: 20.4-fold, p<0.0001; endothelial- microvesicles: 9.6-fold, p = 0.01), but decreased significantly by day 2. Microvesicle levels were increased with severe sepsis, but less consistently between patients. Leukocyte- and granulocyte-derived microvesicles on day 0 correlated with clinical assessment scores and were higher in burns ICU non-survivors compared to survivors (leukocyte MVs 4.6 fold, p = 0.002; granulocyte MVs 4.8 fold, p = 0.003). Mortality prediction analysis of area under receiver operating characteristic curve was 0.92 (p = 0.01) for total leukocyte microvesicles and 0.85 (p = 0.04) for granulocyte microvesicles. These findings demonstrate, for the first time, acute increases in circulating microvesicles following burns injury in patients and point to their potential role in propagation of sterile SIRS-related pathophysiology., Competing Interests: The authors have declared that no competing interests exist.

Introduction: Severe burn leads to a state of hypercatabolism, resulting in rapid muscle loss and long-term disability. As survival rates from severe burn are improving, early rehabilitation is essential to facilitate functional recovery. However, there is no way of measuring the degree of disability in the acute stages, and hence, no marker of functional recovery. This hampers both communication and research into interventions to improve functional outcomes. The Chelsea Critical Care Physical Assessment tool (CPAx) is a simple objective measure of function, designed and validated in the general Intensive Care Unit (ICU) cohort. The aim of this study was to test the responsiveness of the CPAx in the burns ICU (BICU) cohort and validate its use., Methods: Observational study of 52 BICU patients admitted for over 48h. All patients were assessed on the CPAx retrospectively for pre-admission, and prospectively at ICU admission, ICU discharge (or final ICU assessment for non-survivors) and hospital discharge. Analysis of variance, post hoc between group differences in median CPAx score, and floor and ceiling effect (i.e. the percentage of patients scoring full marks (50), or zero) for the four time points were completed. Minimal clinically important difference (MCID) was estimated as half of the standard deviation of the CPAx score at ICU discharge., Results: A total of 30 patients were included in the final analysis; mean age was 47.1 years (SD 21.2), 63.3% were male, with a median burn total body surface area (TBSA) of 30% (IQR 11.3-48.8). There was a significant difference in the analysis of variance in median CPAx scores at all four time points (p<.001). In survivors, the differences in CPAx scores post hoc were significant for all time points (p<.05), aside from ICU discharge and hospital discharge. The CPAx MCID for BICU patients was six. Twenty-three (86.7%) patients scored full marks or zero on the CPAx pre-admission. For survivors, no patients scored full marks or zero on the CPAx at ICU and hospital discharge. On ICU admission 66.7% (n=20) scored zero on the CPAx and no patients scored 50., Conclusions: The CPAx score appears to be able to detect improvements in physical function as patients recover from acute severe burn. It has a limited floor and ceiling effect in the acute setting and a change in CPAx score of 6 represents clinically important progress. Further work is required in a larger cohort., (Copyright © 2014 Elsevier Ltd and ISBI. All rights reserved.)

Current guidelines for intra-operative fluid management recommend the use of increments in stroke volume following intravenous fluid bolus administration as a guide to subsequent fluid therapy. To study the physiological premise of this paradigm, we tested the hypothesis that healthy, non-starved volunteers would develop an increment in their stroke volume following a passive leg raise manoeuvre. Subjects were positioned supine and stroke volume was measured by transthoracic echocardiography at baseline, 30 s, 1 min, 3 min and 5 min after passive leg raise manoeuvre to 45°. Stroke volume was measured at end-expiration during quiet breathing, as the mean of three sequential measurements. Seventeen healthy volunteers were recruited; one volunteer in whom it was not possible to obtain Doppler measurements and a further five for reasons of poor Doppler image quality were not included in the study. Mean (SD) percentage difference from baseline to the largest change in stroke volume was 5.7 (9.6)% (p = 0.16). Of the 11 volunteers evaluated, five (45%) had stroke volume increases of greater than 10%. Mean (SD) maximum percentage change in cardiac index was 14.8 (9.7)% (p = 0.004). A wide variation in baseline stroke volume and response to the passive leg raise manoeuvre was seen, suggesting greater heterogeneity in the normal population than current clinical guidelines recognise., (© 2014 The Association of Anaesthetists of Great Britain and Ireland.)

Introduction: Intensive care unit-acquired weakness (ICU-AW) is common in survivors of critical illness, resulting in global weakness and functional deficit. Although ICU-AW is well described subjectively in the literature, the value of objective measures has yet to be established. This project aimed to evaluate the construct validity of the Chelsea Critical Care Physical Assessment tool (CPAx) by analyzing the association between CPAx scores and hospital-discharge location, as a measure of functional outcome., Methods: The CPAx was integrated into practice as a service-improvement initiative in an 11-bed intensive care unit (ICU). For patients admitted for more than 48 hours, between 10 May 2010 and 13 November 2013, the last CPAx score within 24 hours of step down from the ICU or death was recorded (n = 499). At hospital discharge, patients were separated into seven categories, based on continued rehabilitation and care needs. Descriptive statistics were used to explore the association between ICU discharge CPAx score and hospital-discharge location., Results: Of the 499 patients, 171 (34.3%) returned home with no ongoing rehabilitation or care input; 131 (26.2%) required community support; 28 (5.6%) went to inpatient rehabilitation for <6 weeks; and 25 (5.0%) went to inpatient rehabilitation for >6 weeks; 27 (5.4%) required nursing home level of care; 80 (16.0%) died in the ICU, and 37 (7.4%) died in hospital. A significant difference was found in the median CPAx score between groups (P < 0.0001). Four patients (0.8%) scored full marks (50) on the CPAx, all of whom went home with no ongoing needs; 16 patients (3.2%) scored 0 on the CPAx, all of whom died within 24 hours. A 0.8% ceiling effect and a 3.2% floor effect of the CPAx is found in the ICU. Compliance with completion of the CPAx stabilized at 78% of all ICU admissions., Conclusion: The CPAx score at ICU discharge has displayed construct validity by crudely discriminating between groups with different functional needs at hospital discharge. The CPAx has a limited floor and ceiling effect in survivors of critical illness. A significant proportion of patients had a requirement for postdischarge care and rehabilitation.

Follicular dendritic cells (FDCs) and complement receptor (Cr)1 and complement receptor (Cr)2 are important for the generation of humoral immunity. Cr1/2 expression on B cells and FDCs was shown to provide a secondary signal for B cell activation, to facilitate transport of Ag in immune follicles, and to enhance retention of immune complexes by FDCs. We show in this study that murine B cells predominantly express the Cr2 product from the Cr2 gene, whereas FDCs almost exclusively express the Cr1 isoform generated from the Cr2 gene. To define the specific role of Cr1, we created an animal that maintains normal cell-restricted expression of Cr2 but does not express Cr1. Cr1-deficient (Cr1KO) mice develop normal B1 and B2 immature and mature B cell subsets and have normal levels of naive serum Abs but altered levels of natural Abs. Immunization of the Cr1KO animal demonstrates deficient Ab responses to T-dependent, but not T-independent, Ags. Germinal centers from the immunized Cr1KO animal possess a deficiency in activated B cells, similar to that seen for animals lacking both Cr1 and Cr2 or C3. Finally, animals lacking only Cr1 respond similarly to wild-type animals to infections with Streptococcus pneumoniae, a pathogen to which animals lacking C3 or both Cr1 and Cr2 are particularly sensitive. Altogether, these data suggest that the production of Cr1, primarily by FDCs, is critical in the generation of appropriately activated B cells of the germinal center and the generation of mature Ab responses.

Tumor necrosis factor α-converting enzyme (TACE) is responsible for the shedding of cell surface TNF. Studies suggest that reactive oxygen species (ROS) mediate up-regulation of TACE activity by direct oxidization or modification of the protein. However, these investigations have been largely based upon nonphysiological stimulation of promonocytic cell lines which may respond and process TACE differently from primary cells. Furthermore, investigators have relied upon TACE substrate shedding as a surrogate for activity quantification. We addressed these concerns, employing a direct, cell-based fluorometric assay to investigate the regulation of TACE catalytic activity on freshly isolated primary human monocytes during LPS stimulation. We hypothesized that ROS mediate up-regulation of TACE activity indirectly, by activation of intracellular signaling pathways. LPS up-regulated TACE activity rapidly (within 30 min) without changing cell surface TACE expression. Scavenging of ROS or inhibiting their production by flavoprotein oxidoreductases significantly attenuated LPS-induced TACE activity up-regulation. Exogenous ROS (H(2)O(2)) also up-regulated TACE activity with similar kinetics and magnitude as LPS. H(2)O(2)- and LPS-induced TACE activity up-regulation were effectively abolished by a variety of selective p38 MAPK inhibitors. Activation of p38 was redox-sensitive as H(2)O(2) caused p38 phosphorylation, and ROS scavenging significantly reduced LPS-induced phospho-p38 expression. Inhibition of the p38 substrate, MAPK-activated protein kinase 2, completely attenuated TACE activity up-regulation, whereas inhibition of ERK had little effect. Lastly, inhibition of cell surface oxidoreductases prevented TACE activity up-regulation distal to p38 activation. In conclusion, our data indicate that in primary human monocytes, ROS mediate LPS-induced up-regulation of TACE activity indirectly through activation of the p38 signaling pathway.

Reduced HLA-DR expression on monocytes has been suggested as a predictive marker of immunosuppression following very high risk surgery, but there are few reports in lower risk surgery. In 32 patients undergoing low to intermediate risk surgery, blood samples were analysed by flow cytometry for HLA-DR expression and numbers in both CD14(high) and CD14(low)CD16+ monocyte subsets. The numbers of CD14(high) monocytes increased at 24 h (mean (SD), 5.0 (2.2) vs 7.6 (3.9) x 10(5) cells.ml(-1); p < 0.01) while CD14(low)CD16+ monocytes decreased (0.68 (0.36) vs 0.44 (0.36) x 10(5) cells.ml(-1); p < 0.01). HLA-DR expression was significantly reduced in both subsets by 24 h (mean (SD) fluorescent intensity 440 (310) vs 160 (130) for CD14(high) and 1000 (410) vs 560 (380) for CD14(low)CD16+ subsets; p < 0.01). This reduction of monocyte HLA-DR expression 24 h following lower risk surgery raises questions about the purported clinical utility of this biomarker as an early predictor of postoperative complications. Our results also suggest that surgery induces significant trafficking (i.e. mobilisation, margination and extravasation) of monocyte subsets, and that monocyte HLA-DR depression is the result of a down-regulatory phenomenon (decreased protein expression on each cell) rather than the differential trafficking of monocyte subsets.

The advent of balanced solutions for i.v. fluid resuscitation and replacement is imminent and will affect any specialty involved in fluid management. Part of the background to their introduction has focused on the non-physiological nature of 'normal' saline solution and the developing science about the potential problems of hyperchloraemic acidosis. This review assesses the physiological significance of hyperchloraemic acidosis and of acidosis in general. It aims to differentiate the effects of the causes of acidosis from the physiological consequences of acidosis. It is intended to provide an assessment of the importance of hyperchloraemic acidosis and thereby the likely benefits of balanced solutions.