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Shannon O Armstrong,1 Richard A Little2,31The Medicines Company, Health Economics and Outcomes Research, Parsippany, NJ, USA; 2Consultant Health Economist, Cambridge, UK; 3London School of Hygiene and Tropical Medicines, London, UKIntroduction: Cardiovascular disease (CVD) is the leading cause of death in the United States, and high cholesterol is a leading risk factor for CVD. While statins are effective at reducing cholesterol, they are frequently underused in patients at highest risk of CVD. The objective of this study was to identify interventions which may improve adherence to statins and to assess their cost effectiveness within the US Medicare population.Methods: A literature review was undertaken to identify interventions to improve adherence in patients with CVD at highest risk of a recurrent event and to quantify non-adherence and the consequences of non-adherence to statins in this population. A Markov cost-utility model was developed to assess the cost effectiveness of these interventions.Results: Ten adherence interventions were identified in the literature, with 6 demonstrating statistically significant improvement in adherence. The six interventions were disease management, interactive voice response, nurse counselling, discharge letter, nurse/dietician counselling and electronic pill bottle with feedback. The model found the cost effectiveness of an intervention was highly dependent on its effectiveness and costs. Incremental cost effectiveness ratios ranged from $27,545/QALY for discharge letter with large adherence gain to $130,399/QALY for disease management program with small adherence gain.Conclusion: Some interventions to improve adherence have been shown to be effective, but little attention has been paid to the costs. Further studies on adherence interventions should include economic evaluations.Keywords: cost-effectiveness, adherence, statins, cardiovascular disease

A patient with spontaneous periodic hypothermia who had both a lipoma and agenesis of the corpus callosum is described. Spontaneous periodic hypothermia associated with corpus callosum abnormalities is a distinct entity and although the mechanism underlying the hypothermic episodes is unexplained, the term “diencephalic autonomic epilepsy” does not seem appropriate. [ABSTRACT FROM PUBLISHER]

Abstract Background ADAM33 has been identified as an asthma-associated gene in an out-bred population. Genetic studies suggested that the functional role of this metalloprotease was in airway remodeling. However, the mechanistic roles of the disease-associated SNPs have yet to be elucidated especially in the context of the pathophysiology of asthma. One disease-associated SNP, BC+1, which resides in intron BC toward the 5' end of ADAM33, is highly associated with the disease. Methods The region surrounding this genetic variant was cloned into a model system to determine if there is a regulatory element within this intron that influences transcription. Results The BC+1 protective allele did not impose any affect on the transcription of the reporter gene. However, the at-risk allele enforced such a repressive affect on the promoter that no protein product from the reporter gene was detected. These results indicated that there exists within intron BC a regulatory element that acts as a repressor for gene expression. Moreover, since SNP BC+1 is a common genetic variant, this region may interact with other undefined regulatory elements within ADAM33 to provide a rheostat effect, which modulates pre-mRNA processing. Thus, SNP BC+1 may have an important role in the modulation of ADAM33 gene expression. Conclusion These data provide for the first time a functional role for a disease-associated SNP in ADAM33 and begin to shed light on the deregulation of this gene in the pathophysiology of asthma.

Oxygen-enhanced MRI (OE-MRI) has shown promise for quantifying and spatially mapping tumor hypoxia, either alone or in combination with perfusion imaging. Previous studies have validated the technique in mouse models and in patients with cancer. Here, we report the first evidence that OE-MRI can track change in tumor oxygenation induced by two drugs designed to modify hypoxia. Mechanism of action of banoxantrone and atovaquone were confirmed using in vitro experiments. Next, in vivo OE-MRI studies were performed in Calu6 and U87 xenograft tumor models, alongside fluorine-18-fluoroazomycin arabinoside PET and immunohistochemistry assays of hypoxia. Neither drug altered tumor size. Banoxantrone reduced OE-MRI hypoxic fraction in Calu6 tumors by 52.5% ± 12.0% (P = 0.008) and in U87 tumors by 29.0% ± 15.8% (P = 0.004) after 3 days treatment. Atovaquone reduced OE-MRI hypoxic fraction in Calu6 tumors by 53.4% ± 15.3% (P = 0.002) after 7 days therapy. PET and immunohistochemistry provided independent validation of the MRI findings. Finally, combined OE-MRI and perfusion imaging showed that hypoxic tissue was converted into necrotic tissue when treated by the hypoxia-activated cytotoxic prodrug banoxantrone, whereas hypoxic tissue became normoxic when treated by atovaquone, an inhibitor of mitochondrial complex III of the electron transport chain. OE-MRI detected and quantified hypoxia reduction induced by two hypoxia-modifying therapies and could distinguish between their differential mechanisms of action. These data support clinical translation of OE-MRI biomarkers in clinical trials of hypoxia-modifying agents to identify patients demonstrating biological response and to optimize treatment timing and scheduling. Significance: For the first time, we show that hypoxic fraction measured by oxygen-enhanced MRI (OE-MRI) detected changes in tumor oxygenation induced by two drugs designed specifically to modify hypoxia. Furthermore, when combined with perfusion imaging, OE-MRI hypoxic volume distinguished the two drug mechanisms of action. This imaging technology has potential to facilitate drug development, enrich clinical trial design, and accelerate clinical translation of novel therapeutics into clinical use., (©2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: Hypoxia mediates treatment resistance in solid tumors. We evaluated if oxygen-enhanced (OE)-MRI-derived hypoxic volume (HVMRI) is repeatable and can detect radiotherapy-induced hypoxia modification in HPV-associated oropharyngeal head and neck squamous cell cancer (HNSCC)., Experimental Design: 27 patients were recruited prospectively between March 2021 and January 2024. HVMRI was measured in primary and nodal tumors prior to standard-of-care (chemo)radiotherapy then at weeks 2 and 4 (W2, W4) into therapy. Two pre-treatment scans assessed biomarker within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment response was measured using mixed-effects modelling. Responding lesions were identified by comparing HVMRI change to RC limits of agreement (LOA)., Results: OE-MRI identified hypoxia in all lesions. HVMRI wCV was 24.6% and RC LOA were -45.7% to 84.1%. Cohort median pre-treatment HVMRI of 11.3 cm3 reduced to 6.9 cm3 at W2 and 5.9 cm3 at W4 (both p < 0.001). HVMRI was reduced in 54.5% of individual lesions by W2 and in 88.2% by W4. All lesions with W2 hypoxia reduction showed persistent modification at W4. HVMRI reduced in some lesions that showed no overall volume change. Hypoxia modification was discordant between primary and nodal tumors in 50.0% of patients., Conclusions: Radiation-induced hypoxia modification can occur as early as W2, but onset varies between patients and was not necessarily associated with overall size change. Half of all patients had discordant changes in primary and nodal tumors. These findings have implications for patient selection and timing of dose de-escalation strategies in HPV-associated oropharyngeal carcinoma.

Objectives: To measure dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) biomarker repeatability in patients with non-small cell lung cancer (NSCLC). To use these statistics to identify which individual target lesions show early biological response., Materials and Methods: A single-centre, prospective DCE-MRI study was performed between September 2015 and April 2017. Patients with NSCLC were scanned before standard-of-care radiotherapy to evaluate biomarker repeatability and two weeks into therapy to evaluate biological response. Volume transfer constant (K trans ), extravascular extracellular space volume fraction (v e ) and plasma volume fraction (v p ) were measured at each timepoint along with tumour volume. Repeatability was assessed using a within-subject coefficient of variation (wCV) and repeatability coefficient (RC). Cohort treatment effects on biomarkers were estimated using mixed-effects models. RC limits of agreement revealed which individual target lesions changed beyond that expected with biomarker daily variation., Results: Fourteen patients (mean age, 67 years +/- 12, 8 men) had 22 evaluable lesions (12 primary tumours, 8 nodal metastases, 2 distant metastases). The wCV (in 8/14 patients) was between 9.16% to 17.02% for all biomarkers except for v p , which was 42.44%. Cohort-level changes were significant for K trans and v e (p < 0.001) and tumour volume (p = 0.002). K trans and tumour volume consistently showed the greatest number of individual lesions showing biological response. In distinction, no individual lesions had a real change in v e despite the cohort-level change., Conclusion: Identifying individual early biological responders provided additional information to that derived from conventional cohort cohort-level statistics, helping to prioritise which parameters would be best taken forward into future studies., Clinical Relevance Statement: Dynamic contrast-enhanced magnetic resonance imaging biomarkers K trans and tumour volume are repeatable and detect early treatment-induced changes at both cohort and individual lesion levels, supporting their use in further evaluation of radiotherapy and targeted therapeutics., Key Points: Few literature studies report quantitative imaging biomarker precision, by measuring repeatability or reproducibility. Several DCE-MRI biomarkers of lung cancer tumour microenvironment were highly repeatable. Repeatability coefficient measurements enabled lesion-specific evaluation of early biological response to therapy, improving conventional assessment., (© 2024. The Author(s).)

Background and Purpose: Tumour hypoxia is prognostic in head and neck cancer (HNC), associated with poor loco-regional control, poor survival and treatment resistance. The advent of hybrid MRI - radiotherapy linear accelerator or 'MR Linac' systems - could permit imaging for treatment adaptation based on hypoxic status. We sought to develop oxygen-enhanced MRI (OE-MRI) in HNC and translate the technique onto an MR Linac system., Materials and Methods: MRI sequences were developed in phantoms and 15 healthy participants. Next, 14 HNC patients (with 21 primary or local nodal tumours) were evaluated. Baseline tissue longitudinal relaxation time (T 1 ) was measured alongside the change in 1/T 1 (termed ΔR 1 ) between air and oxygen gas breathing phases. We compared results from 1.5 T diagnostic MR and MR Linac systems., Results: Baseline T 1 had excellent repeatability in phantoms, healthy participants and patients on both systems. Cohort nasal concha oxygen-induced ΔR 1 significantly increased (p < 0.0001) in healthy participants demonstrating OE-MRI feasibility. ΔR 1 repeatability coefficients (RC) were 0.023-0.040 s -1 across both MR systems. The tumour ΔR 1 RC was 0.013 s -1 and the within-subject coefficient of variation (wCV) was 25% on the diagnostic MR. Tumour ΔR 1 RC was 0.020 s -1 and wCV was 33% on the MR Linac. ΔR 1 magnitude and time-course trends were similar on both systems., Conclusion: We demonstrate first-in-human translation of volumetric, dynamic OE-MRI onto an MR Linac system, yielding repeatable hypoxia biomarkers. Data were equivalent on the diagnostic MR and MR Linac systems. OE-MRI has potential to guide future clinical trials of biology guided adaptive radiotherapy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This overview of the current landscape of quantitative magnetic resonance imaging biomarkers (qMR IBs) aims to support the standardisation of academic IBs to assist their translation to clinical practice., Methods: We used three complementary approaches to investigate qMR IB use and quality management practices within the UK: 1) a literature search of qMR and quality management terms during 2011-2015 and 2016-2020; 2) a database search for clinical research studies using qMR IBs during 2016-2020; and 3) a survey to ascertain the current availability and quality management practices for clinical MRI scanners and associated equipment at research institutions across the UK., Results: The analysis showed increased use of all qMR methods between the periods 2011-2015 and 2016-2020 and diffusion-tensor MRI and volumetry to be popular methods. However, the "translation ratio" of journal articles to clinical research studies was higher for qMR methods that have evidence of clinical translation via a commercial route, such as fat fraction and T 2 mapping. The number of journal articles citing quality management terms doubled between the periods 2011-2015 and 2016-2020; although, its proportion relative to all journal articles only increased by 3.0%. The survey suggested that quality assurance (QA) and quality control (QC) of data acquisition procedures are under-reported in the literature and that QA/QC of acquired data/data analysis are under-developed and lack consistency between institutions., Conclusions: We summarise current attempts to standardise and translate qMR IBs, and conclude by outlining the ideal quality management practices and providing a gap analysis between current practice and a metrological standard., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Associazione Italiana di Fisica Medica e Sanitaria. Published by Elsevier Ltd. All rights reserved.)

Imaging biomarkers are used in therapy development to identify and quantify therapeutic response. In oncology, use of MRI, PET and other imaging methods can be complicated by spatially complex and heterogeneous tumor micro-environments, non-Gaussian data and small sample sizes. Linear Poisson Modelling (LPM) enables analysis of complex data that is quantitative and can operate in small data domains. We performed experiments in 5 mouse models to evaluate the ability of LPM to identify responding tumor habitats across a range of radiation and targeted drug therapies. We tested if LPM could identify differential biological response rates. We calculated the theoretical sample size constraints for applying LPM to new data. We then performed a co-clinical trial using small data to test if LPM could detect multiple therapeutics with both improved power and reduced animal numbers compared to conventional t -test approaches. Our data showed that LPM greatly increased the amount of information extracted from diffusion-weighted imaging, compared to cohort t -tests. LPM distinguished biological response rates between Calu6 tumors treated with 3 different therapies and between Calu6 tumors and 4 other xenograft models treated with radiotherapy. A simulated co-clinical trial using real data detected high precision per-tumor treatment effects in as few as 3 mice per cohort, with p -values as low as 1 in 10,000. These findings provide a route to simultaneously improve the information derived from preclinical imaging while reducing and refining the use of animals in cancer research.

Perianal Crohn's Disease (pCD) is a common manifestation of Crohn's Disease. Absence of reliable disease measures makes disease monitoring unreliable. Qualitative MRI has been increasingly used for diagnosing and monitoring pCD and has shown potential for assessing response to treatment. Quantitative MRI sequences, such as diffusion-weighted imaging (DWI), dynamic contrast enhancement (DCE) and magnetisation transfer (MT), along with T2 relaxometry, offer opportunities to improve diagnostic capability. Quantitative MRI sequences (DWI, DCE, MT and T2) were used in a cohort of 25 pCD patients before and 12 weeks after biological therapy at two different field strengths (1.5 and 3 T). Disease activity was measured with the Perianal Crohn's Disease Activity index (PDAI) and serum C-reactive protein (CRP). Diseased tissue areas on MRI were defined by a radiologist. A baseline model to predict outcome at 12 weeks was developed. No differences were seen in the quantitative MR measured in the diseased tissue regions from baseline to 12 weeks; however, PDAI and CRP decreased. Baseline PDAI, CRP, T2 relaxometry and surgical history were found to have a moderate ability to predict response after 12 weeks of biological treatment. Validation in larger cohorts with MRI and clinical measures are needed in order to further develop the model.

Purpose: We introduce a novel, generalized tracer kinetic model selection framework to quantify microvascular characteristics of liver and tumor tissue in gadoxetate-enhanced dynamic contrast-enhanced MRI (DCE-MRI)., Methods: Our framework includes a hierarchy of nested models, from which physiological parameters are derived in 2 regimes, corresponding to the active transport and free diffusion of gadoxetate. We use simulations to show the sensitivity of model selection and parameter estimation to temporal resolution, time-series duration, and noise. We apply the framework in 8 healthy volunteers (time-series duration up to 24 minutes) and 10 patients with hepatocellular carcinoma (6 minutes)., Results: The active transport regime is preferred in 98.6% of voxels in volunteers, 82.1% of patients' non-tumorous liver, and 32.2% of tumor voxels. Interpatient variations correspond to known co-morbidities. Simulations suggest both datasets have sufficient temporal resolution and signal-to-noise ratio, while patient data would be improved by using a time-series duration of at least 12 minutes., Conclusions: In patient data, gadoxetate exhibits different kinetics: (a) between liver and tumor regions and (b) within regions due to liver disease and/or tumor heterogeneity. Our generalized framework selects a physiological interpretation at each voxel, without preselecting a model for each region or duplicating time-consuming optimizations for models with identical functional forms., (© 2021 The Authors. Magnetic Resonance in Medicine published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Patients with metastatic colorectal cancer are treated with cytotoxic chemotherapy supplemented by molecularly targeted therapies. There is a critical need to define biomarkers that can optimise the use of these therapies to maximise efficacy and avoid unnecessary toxicity. However, it is important to first define the changes in potential biomarkers following cytotoxic chemotherapy alone. This study reports the impact of standard cytotoxic chemotherapy across a range of circulating and imaging biomarkers., Methods: A single-centre, prospective, biomarker-driven study. Eligible patients included those diagnosed with colorectal cancer with liver metastases that were planned to receive first line oxaliplatin plus 5-fluorouracil or capecitabine. Patients underwent paired blood sampling and magnetic resonance imaging (MRI), and biomarkers were associated with progression-free survival (PFS) and overall survival (OS)., Results: Twenty patients were recruited to the study. Data showed that chemotherapy significantly reduced the number of circulating tumour cells as well as the circulating concentrations of Ang1, Ang2, VEGF-A, VEGF-C and VEGF-D from pre-treatment to cycle 2 day 2. The changes in circulating concentrations were not associated with PFS or OS. On average, the MRI perfusion/permeability parameter, K trans , increased in response to cytotoxic chemotherapy from pre-treatment to cycle 2 day 2 and this increase was associated with worse OS (HR 1.099, 95%CI 1.01-1.20, p = 0.025)., Conclusions: In patients diagnosed with colorectal cancer with liver metastases, treatment with standard chemotherapy changes cell- and protein-based biomarkers, although these changes are not associated with survival outcomes. In contrast, the imaging biomarker, K trans , offers promise to direct molecularly targeted therapies such as anti-angiogenic agents.

Imaging biomarkers require technical, biological, and clinical validation to be translated into robust tools in research or clinical settings. This study contributes to the technical validation of radiomic features from magnetic resonance imaging (MRI) by evaluating the repeatability of features from four MR sequences: pre-contrast T1- and T2-weighted images, pre-contrast quantitative T1 maps (qT1), and contrast-enhanced T1-weighted images. Fifty-one patients with colorectal cancer liver metastases were scanned twice, up to 7 days apart. Repeatability was quantified using the intraclass correlation coefficient (ICC) and repeatability coefficient (RC), and the impact of non-Gaussian feature distributions and image normalisation was evaluated. Most radiomic features had non-Gaussian distributions, but Box-Cox transformations enabled ICCs and RCs to be calculated appropriately for an average of 97% of features across sequences. ICCs ranged from 0.30 to 0.99, with volume and other shape features tending to be most repeatable; volume ICC > 0.98 for all sequences. 19% of features from non-normalised images exhibited significantly different ICCs in pair-wise sequence comparisons. Normalisation tended to increase ICCs for pre-contrast T1- and T2-weighted images, and decrease ICCs for qT1 maps. RCs tended to vary more between sequences than ICCs, showing that evaluations of feature performance depend on the chosen metric. This work suggests that feature-specific repeatability, from specific combinations of MR sequence and pre-processing steps, should be evaluated to select robust radiomic features as biomarkers in specific studies. In addition, as different repeatability metrics can provide different insights into a specific feature, consideration of the appropriate metric should be taken in a study-specific context.

Purpose: Hypoxia is associated with poor prognosis and is predictive of poor response to cancer treatments, including radiotherapy. Developing noninvasive biomarkers that both detect hypoxia prior to treatment and track change in tumor hypoxia following treatment is required urgently., Experimental Design: We evaluated the ability of oxygen-enhanced MRI (OE-MRI) to map and quantify therapy-induced changes in tumor hypoxia by measuring oxygen-refractory signals in perfused tissue (perfused Oxy-R). Clinical first-in-human study in patients with non-small cell lung cancer (NSCLC) was performed alongside preclinical experiments in two xenograft tumors (Calu6 NSCLC model and U87 glioma model)., Results: MRI perfused Oxy-R tumor fraction measurement of hypoxia was validated with ex vivo tissue pathology in both xenograft models. Calu6 and U87 experiments showed that MRI perfused Oxy-R tumor volume was reduced relative to control following single fraction 10-Gy radiation and fractionated chemoradiotherapy ( P < 0.001) due to both improved perfusion and reduced oxygen consumption rate. Next, evaluation of 23 patients with NSCLC showed that OE-MRI was clinically feasible and that tumor perfused Oxy-R volume is repeatable [interclass correlation coefficient: 0.961 (95% CI, 0.858-0.990); coefficient of variation: 25.880%]. Group-wise perfused Oxy-R volume was reduced at 14 days following start of radiotherapy ( P = 0.015). OE-MRI detected between-subject variation in hypoxia modification in both xenograft and patient tumors., Conclusions: These findings support applying OE-MRI biomarkers to monitor hypoxia modification, to stratify patients in clinical trials of hypoxia-modifying therapies, to identify patients with hypoxic tumors that may fail treatment with immunotherapy, and to guide adaptive radiotherapy by mapping regional hypoxia., (©2019 American Association for Cancer Research.)

Bovine tuberculosis (bTB) is an epidemiologically, politically, and socially complex disease. Across multiple international contexts, policy makers have struggled to balance the competing demands of wildlife and agricultural interests in their efforts to create workable and effective disease management strategies. This paper draws comparative lessons between the cases of Michigan in the USA and the UK to exemplify some of the challenges of developing an effective strategy for the long-term control of endemic disease, particularly reflecting on efforts to "responsibilise" cattle producers and engage them in proactive activities to mitigate transmission risks on their own farms. Using qualitative data derived from 22 stakeholder interviews, it is argued that the management of bTB in Michigan has important lessons for the UK on the role of human dimensions in influencing the direction of disease control. The management of endemic bTB relies on the actions of individuals to minimise risk and, in contrast to the predominantly voluntary approach pursued in the UK, Michigan has shifted the emphasis towards obtaining producer support for wildlife risk mitigation and biosecurity via a mix of regulatory, fiscal, and social interventions. Whilst the scale of the bTB challenge differs between these two contexts, analysis of the different ideological bases for selecting management approaches offers interesting insights on the role of negotiated outcomes in attempts to adaptively manage a disease that is characterised by complexity and uncertainty.

Oncological use of anti-angiogenic VEGF inhibitors has been limited by the lack of informative biomarkers. Previously we reported circulating Tie2 as a vascular response biomarker for bevacizumab-treated ovarian cancer patients. Using advanced MRI and circulating biomarkers we have extended these findings in metastatic colorectal cancer (n = 70). Bevacizumab (10 mg/kg) was administered to elicit a biomarker response, followed by FOLFOX6-bevacizumab until disease progression. Bevacizumab induced a correlation between Tie2 and the tumor vascular imaging biomarker, K trans (R:-0.21 to 0.47) implying that Tie2 originated from the tumor vasculature. Tie2 trajectories were independently associated with pre-treatment tumor vascular characteristics, tumor response, progression free survival (HR for progression = 3.01, p = 0.00014; median PFS 248 vs. 348 days p = 0.0008) and the modeling of progressive disease (p < 0.0001), suggesting that Tie2 should be monitored clinically to optimize VEGF inhibitor use. A vascular response is defined as a 30% reduction in Tie2; vascular progression as a 40% increase in Tie2 above the nadir. Tie2 is the first, validated, tumor vascular response biomarker for VEGFi.

Purpose To cross-validate T1-weighted oxygen-enhanced (OE) MRI measurements of tumor hypoxia with intrinsic susceptibility MRI measurements and to demonstrate the feasibility of translation of the technique for patients. Materials and Methods Preclinical studies in nine 786-0-R renal cell carcinoma (RCC) xenografts and prospective clinical studies in eight patients with RCC were performed. Longitudinal relaxation rate changes (∆R1) after 100% oxygen inhalation were quantified, reflecting the paramagnetic effect on tissue protons because of the presence of molecular oxygen. Native transverse relaxation rate (R2*) and oxygen-induced R2* change (∆R2*) were measured, reflecting presence of deoxygenated hemoglobin molecules. Median and voxel-wise values of ∆R1 were compared with values of R2* and ∆R2*. Tumor regions with dynamic contrast agent-enhanced MRI perfusion, refractory to signal change at OE MRI (referred to as perfused Oxy-R), were distinguished from perfused oxygen-enhancing (perfused Oxy-E) and nonperfused regions. R2* and ∆R2* values in each tumor subregion were compared by using one-way analysis of variance. Results Tumor-wise and voxel-wise ∆R1 and ∆R2* comparisons did not show correlative relationships. In xenografts, parcellation analysis revealed that perfused Oxy-R regions had faster native R2* (102.4 sec -1 vs 81.7 sec -1 ) and greater negative ∆R2* (-22.9 sec -1 vs -5.4 sec -1 ), compared with perfused Oxy-E and nonperfused subregions (all P < .001), respectively. Similar findings were present in human tumors (P < .001). Further, perfused Oxy-R helped identify tumor hypoxia, measured at pathologic analysis, in both xenografts (P = .002) and human tumors (P = .003). Conclusion Intrinsic susceptibility biomarkers provide cross validation of the OE MRI biomarker perfused Oxy-R. Consistent relationship to pathologic analyses was found in xenografts and human tumors, demonstrating biomarker translation. Published under a CC BY 4.0 license. Online supplemental material is available for this article.

Motivation: Imaging demonstrates that preclinical and human tumors are heterogeneous, i.e. a single tumor can exhibit multiple regions that behave differently during both development and also in response to treatment. The large variations observed in control group, tumors can obscure detection of significant therapeutic effects due to the ambiguity in attributing causes of change. This can hinder development of effective therapies due to limitations in experimental design rather than due to therapeutic failure. An improved method to model biological variation and heterogeneity in imaging signals is described. Specifically, linear Poisson modeling (LPM) evaluates changes in apparent diffusion co-efficient between baseline and 72 h after radiotherapy, in two xenograft models of colorectal cancer. The statistical significance of measured changes is compared to those attainable using a conventional t-test analysis on basic apparent diffusion co-efficient distribution parameters., Results: When LPMs were applied to treated tumors, the LPMs detected highly significant changes. The analyses were significant for all tumors, equating to a gain in power of 4-fold (i.e. equivalent to having a sample size 16 times larger), compared with the conventional approach. In contrast, highly significant changes are only detected at a cohort level using t-tests, restricting their potential use within personalized medicine and increasing the number of animals required during testing. Furthermore, LPM enabled the relative volumes of responding and non-responding tissue to be estimated for each xenograft model. Leave-one-out analysis of the treated xenografts provided quality control and identified potential outliers, raising confidence in LPM data at clinically relevant sample sizes., Availability and Implementation: TINA Vision open source software is available from www.tina-vision.net., Supplementary Information: Supplementary data are available at Bioinformatics online.

Purpose: Previous work has shown that combining dynamic contrast-enhanced (DCE)-MRI and oxygen-enhanced (OE)-MRI binary enhancement maps can identify tumor hypoxia. The current work proposes a novel, data-driven method for mapping tissue oxygenation and perfusion heterogeneity, based on clustering DCE/OE-MRI data., Methods: DCE-MRI and OE-MRI were performed on nine U87 (glioblastoma) and seven Calu6 (non-small cell lung cancer) murine xenograft tumors. Area under the curve and principal component analysis features were calculated and clustered separately using Gaussian mixture modelling. Evaluation metrics were calculated to determine the optimum feature set and cluster number. Outputs were quantitatively compared with a previous non data-driven approach., Results: The optimum method located six robustly identifiable clusters in the data, yielding tumor region maps with spatially contiguous regions in a rim-core structure, suggesting a biological basis. Mean within-cluster enhancement curves showed physiologically distinct, intuitive kinetics of enhancement. Regions of DCE/OE-MRI enhancement mismatch were located, and voxel categorization agreed well with the previous non data-driven approach (Cohen's kappa = 0.61, proportional agreement = 0.75)., Conclusion: The proposed method locates similar regions to the previous published method of binarization of DCE/OE-MRI enhancement, but renders a finer segmentation of intra-tumoral oxygenation and perfusion. This could aid in understanding the tumor microenvironment and its heterogeneity. Magn Reson Med 79:2236-2245, 2018. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., (© 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine.)

Background: Solid tumours exhibit enhanced vessel permeability and fenestrated endothelium to varying degree, but it is unknown how this varies in patients between and within tumour types. Dynamic contrast-enhanced (DCE) MRI provides a measure of perfusion and permeability, the transfer constant K trans , which could be employed for such comparisons in patients., Aim: To test the hypothesis that different tumour types exhibit systematically different K trans ., Materials and Methods: DCE-MRI data were retrieved from 342 solid tumours in 230 patients. These data were from 18 previous studies, each of which had had a different analysis protocol. All data were reanalysed using a standardised workflow using an extended Tofts model. A model of the posterior density of median K trans was built assuming a log-normal distribution and fitting a simple Bayesian hierarchical model., Results: 12 histological tumour types were included. In glioma, median K trans was 0.016min -1 and for non-glioma tumours, median K trans ranged from 0.10 (cervical) to 0.21min -1 (prostate metastatic to bone). The geometric mean (95% CI) across all the non-glioma tumours was 0.15 (0.05, 0.45)min -1 . There was insufficient separation between the posterior densities to be able to predict the K trans value of a tumour given the tumour type, except that the median K trans for gliomas was below 0.05min -1 with 80% probability, and median K trans measurements for the remaining tumour types were between 0.05 and 0.4min -1 with 80% probability., Conclusion: With the exception of glioma, our hypothesis that different tumour types exhibit different K trans was not supported. Studies in which tumour permeability is believed to affect outcome should not simply seek tumour types thought to exhibit high permeability. Instead, K trans is an idiopathic parameter, and, where permeability is important, K trans should be measured in each tumour to personalise that treatment., (Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To determine whether using figure-of-eight modules affects the rate of lower incisor alignment compared with conventionally tied modules., Design: Prospective randomised controlled trial., Setting: Orthodontic department at Queen's Hospital, Burton upon Trent, UK., Methods: One hundred and twenty participants were randomly allocated to conventional module or figure-of-eight module groups, stratified for extraction or non-extraction lower arch treatment. Eligibility criteria included patients who were 12-15 years of age at the start of treatment, in the permanent dentition, and had mandibular incisor irregularity of 5-10 mm (clinical observation). The primary outcome was the rate of lower incisor alignment during the first 12 weeks of orthodontic treatment. The secondary outcome was bracket failure rate. Lower labial segment alignment was measured on study models using the Little's Irregularity Index at the start (T0) of treatment, at 6 weeks (T1) and 12 weeks (T2). Case records were analysed to assess the number of bracket failures., Results: The four groups were well matched at baseline with respect to gender, age and irregularity. All patients completed the trial and data were analysed on an intention to treat basis. In both ligation groups, the lower teeth aligned significantly faster when the treatment involved extractions, for the time periods T0-T1 and T0-T2 (p < 0.05). There were no statistically significant differences between conventional module and figure-of-eight module ligation on the rate of alignment (per month) for all three-time periods. The bracket failure rate was also similar in both test groups; 4.08% for conventional and 3.21% for figure-of-eight ligation., Conclusions: Ligation with figure-of-eight modules has no clinically significant effect on the rate of lower incisor alignment; it does not seem to hinder or quicken the alignment of teeth. There were no differences in the mean number of bracket failures per person.

Aim: To assess the changes in interviewees' and interviewers' perceptions and experiences of national recruitment and a multi-station interview (MSI) for the selection of Orthodontic Specialty Registrars to UK training programmes from 2012 to 2014., Design: Questionnaire-based longitudinal survey., Setting: Interviews for selection of Orthodontic Specialty Registrars (StRs) held at London Deanery, London, UK., Methods: Interviewees and interviewers completed an anonymous questionnaire comprising of 17 and 26 questions, respectively., Results: Interviewees: The number, age (p = 0.29) and time since qualification (p = 0.90) increased slightly over the 3 years but these changes were not statistically significant. The proportion of females (p = 0.32) and those with a UK primary dental qualification (p = 0.52) varied slightly but the variation was not statistically significant. The proportion that had experience of the MSI format increased significantly over the 3 years (p < 0.01). More than 75% were positive about the organization, experience and fairness of the MSI interview format. Interviewers: The age (p = 0.54), time since being a consultant (p = 0.90), proportion of females (p = 0.43) and those favouring the MSI format (p = 0.29) varied slightly but this was not statistically significant. More than 75% were positive about the organization, experience and fairness of the MSI format. More than 90% of interviewers thought that the process selected the best candidates, was fair and that more than one assessor was required at each station., Conclusions: Interviewees were consistently very positive about the organization and fairness of the MSI format. Interviewers were consistently very positive about the selection of candidates, fairness and conduct of the MSIs.

There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic., (©2015 American Association for Cancer Research.)

This article illustrates three case reports which describe a very simple appliance that is used to correct both class II and class III buccal segments. A class I molar relationship is achieved within 2-6 months. Hundreds of cases have been treated with these appliances over a number of years at Queen's Hospital, Burton upon Trent with great success.

Severe haemorrhage leads to a reflex bradycardia and hypotension. This is thought to be protective, but is attenuated by both concomitant musculoskeletal injury and exogenous morphine. The aim of this study was to determine whether the injury-induced attenuation of the response to severe haemorrhage could be blocked by naloxone. Male Wistar rats, terminally anaesthetized with alphadolone/alphaxalone (19-20 mg kg(-1) h(-1)I.V.), were randomly allocated to one of four groups. In groups I and IV, haemorrhage was simple [40% of estimated total blood volume (BV)], while in groups II and III it was initiated 10 min after the onset of bilateral hindlimb ischaemia (a model of musculoskeletal injury). Groups I and II received 20 microl of 0.9% saline intracerebroventricularly (I.C.V.) immediately before haemorrhage, while groups III and IV received 20 microg of naloxone I.C.V., in the same volume. In group I, the bradycardia reached its peak after the loss of 32.8 +/- 0.3% BV (mean +/- S.E.M.). Blood pressure did not fall significantly until the loss of 15.0 +/- 3.0% BV. The response in group IV was not significantly different from group I. By contrast, the bradycardia was absent after similar blood losses in groups II and III, while hypotension was attenuated. These results indicate that naloxone, at a dose known to be effective in blocking mu-opioid receptors and preventing other aspects of the response to injury, does not prevent the injury-induced attenuation of the response to severe haemorrhage. Thus the attenuation of the response to blood loss by injury is unlikely to be mediated via the mu-opioid receptors.

Objective: Evaluation of selective decontamination of the digestive tract (SDD) on late mortality in ventilated trauma patients in an intensive care unit (ICU)., Methods: A multicenter, randomized controlled trial was undertaken in 401 trauma patients with Hospital Trauma Index-Injury Severity Score of 16 or higher. Patients were randomized to control (n=200) or SDD (n=201), using polymyxin E, tobramycin, and amphotericin B in throat and gut throughout ICU treatment combined with cefotaxime for 4 days. Primary endpoint was late mortality excluding early death from hemorrhage or craniocerebral injury. Secondary endpoints were infection and organ dysfunction., Results: Mortality was 20.9% with SDD and 22.0% in controls. Overall late mortality was 15.3% (57/372) as 29 patients died from cerebral injury, 16 SDD and 13 control. The odds ratio (95% confidence intervals) of late mortality for SDD relative to control was 0.75 (0.40-1.37), corresponding to estimates of 13.4% SDD and 17.2% control. The overall infection rate was reduced in the test group (48.8% vs. 61.0%). SDD reduced lower airway infections (30.9% vs. 50.0%) and bloodstream infections due to aerobic Gram-negative bacilli (2.5% vs. 7.5%). No difference in organ dysfunction was found., Conclusion: This study demonstrates that SDD significantly reduces infection in multiple trauma, although this RCT in 401 patients was underpowered to detect a mortality benefit.

Bacterial translocation and intestinal mucosal damage have been reported as potentially clinically important sequelae of injury. Evidence that endogenous interleukin-6 (IL-6) is able to protect against infection, and that orally administered IL-6 could prevent bacterial translocation and mucosal damage following haemorrhage, led us to evaluate the impact of injury on the intestinal mucosa and the role of endogenous IL-6. Normal and IL-6-deficient (IL-6-/-) mice were subjected to haemorrhage of increasing severity, hind limb ischaemia, or both. Mucosal integrity and bacterial translocation to the liver, spleen and mesenteric lymph nodes (MLN) were examined after 16 h. Bacterial translocation to each of these tissues was observed in unoperated animals. The more severe haemorrhage procedures, and hind limb ischaemia, increased bacterial translocation to the liver significantly in most experiments with normal mice. The IL-6-/- mice survived the most severe haemorrhage procedure less well (p = 0.0015), although increased bacterial translocation was not seen. There was no clear evidence of mucosal damage, or bacterial translocation to spleen and mesenteric lymph nodes, in either normal or IL-6-/- mice. Intestinal IgA concentrations were the same in IL-6-/- mice and controls. These data demonstrate that increased bacterial translocation can be observed following severe injury, but that neither bacterial translocation nor severe injury are inevitably associated with morphological damage to the intestinal mucosa, and endogenous IL-6 is more likely to promote bacterial translocation than protect the gut.

Background: Global end diastolic volume (GEDV) has a constant and predictable relationship to intrathoracic blood volume (ITBV). The present study assesses the difference between ITBV derived from GEDV and ITBV measured directly in pigs with acute lung injury (ALI) and mild haemorrhage., Methods: We caused ALI in 12 anaesthetized pigs by i.v. injection of oleic acid and removed 10% of estimated blood volume. EVLW, GEDV, ITBV (COLD; Pulsion Medical Systems), Pa(o(2))/Fi(o(2)), lung compliance and haemodynamic variables were measured at baseline (time 0) and at 30 and 120 min. All animals were volume-resuscitated, followed by measurements at 180 min. A linear equation estimated from the 44 pairs of ITBV and GEDV values in 11 animals was applied iteratively to the four GEDV measurements in the 12th animal, enabling 48 comparisons between measured (ITBVm) and derived ITBV (ITBVd) to be made., Results: Increase in extravascular lung water index (EVLWi) was associated with significant pulmonary hypertension, worsening of oxygenation and compliance (repeated measures ANOVA; P<0.05). There was good within-subject correlation and agreement between ITBV(m) and ITBV(d) (r=0.72, mean bias 0.8 ml; sd 32 ml). Mean error in deriving ITBV from GEDV was 4.5%. (sd 4.2%; range 0.05-19%). There were no significant differences in errors in the presence of small (up to 10%) deficits in blood volume (F=1.0; P=0.41)., Conclusions: ITBV estimated by thermodilution alone is comparable to measurements made by the thermo-dye dilution technique in the presence of pulmonary hypertension and mild deficits in total blood volume.

Background: In nine patients with multiple organ failure ultrasound was able to identify muscle wasting despite the presence of oedema (Campbell et al., J Clin Nutr 62 (1995) 533)., Aims: The purpose of the present study was twofold: one was to determine whether this technique was applicable to a much larger ICU population, many of whom were not as ill as the original subjects. The second reason was to determine whether a relationship could be identified between rates of wasting and energy balance., Methods: Serial measurements of both mid-upper arm circumference (MAC) and muscle thickness, using ultrasound, were made at 1-3 day intervals between 5 and 39 (median 7) days in 50 critically ill patients., Results: Muscle thickness decreased in 48 of the 50 patients at a median rate of 1.6%/day with a range of 0.2-5.7%/day. In 33 patients, in whom MAC did not change significantly with time, muscle thickness decreased by between 0.3 and 4.2 (median 1.6)%/day. In three patients MAC increased significantly with time but muscle thickness decreased by between 1.3 and 5.7 (median 2.6)%/day. Twelve patients showed a significant decrease in MAC with time and muscle thickness in this group decreased by between 0.2 and 4.0 (median 1.3)%/day. The percentage decrease in muscle thickness between the groups, in whom MAC decreased or did not change, was not significantly different (P = 0.475)., Conclusion: We have demonstrated that an ultrasound technique devised to identify muscle wasting in the presence of severe fluid retention works in the majority (48/50) of patients when applied to a wider ICU population. Energy balance made no difference to the rate of wasting.

Objective: To determine the effects of reinfusion of shed blood on the regional blood flow changes induced by hemorrhage and hemorrhage plus nociceptive nerve stimulation (injury) with special reference to the gut., Design: Randomized controlled laboratory study., Setting: Medical Research Council laboratory, university medical school., Subjects: Four groups of anesthetized immature female Large-White pigs (15-27 kg): 30% hemorrhage, 30% hemorrhage plus afferent nerve stimulation, nerve stimulation alone, surgical controls., Interventions: In addition to standard invasive hemodynamic monitoring, electromagnetic flow probes were placed around a branch of the superior mesenteric artery and the right femoral artery. Stimulating electrodes were placed on brachial nerves in both axillae. Animals underwent 30% hemorrhage over 30 mins. After a 30-min shock period, the shed blood was reinfused at 2 mL/kg/min., Measurements and Main Results: Measurements/calculations of standard global hemodynamics, gut and femoral blood flows/vascular resistance, metabolism, arterial plasma lactate, portal venous endotoxin, interleukin-6, and tumor necrosis factor-alpha were made before and after hemorrhage, before and after reinfusion, and at 30-min intervals for 3 hrs. Blood and tissue samples were taken for the presence of translocated coliforms. Hemorrhage elicited the expected changes in global hemodynamics, metabolism, and gut and femoral blood flows. There was a partial hemodynamic recovery during the shock period. Nearly all hemodynamic and metabolic variables were rapidly restored by reinfusion. The response to hemorrhage was modified by nerve stimulation: Reductions in systemic hemodynamics and gut flow were greater, and there was no recovery during the shock phase. Cytokine and endotoxin concentrations increased significantly in all groups. There was no bacterial translocation., Conclusions: When hemorrhage occurs in the presence of nerve stimulation (injury), the relative protection of the gut circulation is attenuated and this effect persists after the end of hemorrhage and reinfusion. However, there was no evidence that injury increased the hemorrhage/surgery-induced cytokine and endotoxin responses.

Background: The temporal evolution of lung injury following post-traumatic shock is poorly understood. In the present study we have tested the hypothesis that manifestations of pulmonary vascular dysfunction may be demonstrable within the first hour after the onset of shock., Methods: Twenty-nine anaesthetized pigs (mean weight 27.4 kg; (SD) 3.2) were randomly allocated to three groups: control (C, n=9), shock resuscitated with either NaCl 0.9% (S, n=10), or 4% gelatine (G, n=10). Shock was maintained for 1 h followed by fluid resuscitation with either normal saline or 4% gelatine solution. Cardiac output (CO), mean arterial pressure (MAP), mixed venous saturation (Sv(O(2))), blood lactate concentration, mean pulmonary artery pressure (MPAP), MPAP/MAP, pulmonary vascular resistance (PVR), extravascular lung water index (EVLWi), Pa(O(2))/FI(O(2)), venous admixture (Q(.)(S)/Q(.)(T)), and dynamic lung compliance (C(dyn)) were measured at baseline, beginning of shock phase, end of shock phase, and post-resuscitation., Results: At the end of volume resuscitation CO was restored to control values in both shock groups. MAP remained significantly below control values (95% CI: C=70-95, S=28-52, G=45-69 mm Hg) in both shock groups. MPAP/MAP was significantly greater in both shock groups at the end of the shock phase (95% CI; C=0.15-0.24, S=0.28-0.38, G=0.32-0.42) and at the post-resuscitation phase (95% CI: C=0.12-0.30, S=0.43-0.61, G=0.32-0.49) indicating the presence of relative pulmonary hypertension. This was associated with a significant increase in PVR in Group S (F=3.9; P<0.05). There were no significant changes in Pa(O(2))/FI(O(2)), Q(.)(S)/Q(.)(T), EVLWi, or C(dyn). In a small cohort of animals a measurable increase in EVLWi (>30%) and reduction in C(dyn) (>10%) were observed., Conclusions: Pulmonary vascular injury manifesting as relative pulmonary hypertension and increased PVR may occur within the first hour after the onset of shock. These changes may not be accompanied by overt changes in oxygenation, compliance, or EVLWi. Br J Anaesth 2003; 91: 224-32

The cytokines IL-1 and IL-6 are able to induce prostaglandin (PG)-dependent activation of the hypothalamo-pituitary-adrenal axis (HPAA) and are thought to play key roles in immune-neuroendocrine interactions during inflammation. The present study shows that inflammation induced by im injection of turpentine (TPS) in the hind limb of mice causes an increase in the plasma concentration of IL-6, but not that of IL-1 alpha or IL-1 beta, together with a prolonged (>18-h) activation of the HPAA. IL-6 plays a causal role in the TPS-induced elevation in HPAA activity, because the sustained (8-18 h) increases in 1) plasma corticosterone, 2) plasma ACTH, and 3) induction of c-Fos in the hypothalamic paraventricular nucleus are all markedly blunted in IL-6-deficient (IL-6(-/-)) mice. Peripheral administration of a neutralizing IL-6 antiserum inhibited the plasma corticosterone response of normal (C57BL/6) mice to hind limb inflammation to an extent similar to that seen in IL-6(-/-) mice, suggesting that the IL-6 responsible for the increased HPAA activity is produced, or acts, on the blood side of the blood-brain barrier. We also show that IL-6 in the circulation is induced almost exclusively at the local inflammatory site, where IL-1 beta is produced. Induction of IL-6 and activation of the HPAA are dependent upon prior activation of an IL-1 type I receptor, as both are inhibited in type I IL-1 receptor-deficient mice. Furthermore, hind limb inflammation induced cyclooxygenase-2 protein expression around the cerebrovasculature of normal (IL-6(+/+)), but not IL-6(-/-), mice. Based on these data, we propose that IL-6 is produced at the local inflammatory site under the control of IL-1 beta and is the circulating afferent signal that is in part responsible for elevated HPAA activity, possibly acting via eicosanoid production within the cerebrovasculature.

This study was carried out to measure blood volume in interleukin-6 (IL-6) deficient and the wild type mice and to relate any differences to concomitant changes in body composition. Young animals (8-20 weeks of age) were used in this study. The red blood cell (RBC) and plasma volumes were measured by isotope-dilution using Cr(51)-labeled erythrocytes and I(131)-labeled human albumin injected simultaneously in each animal. Red blood cells and plasma volumes and hence total measured blood volume were significantly larger in the IL-6-deficient than in either male or female wild type mice. There were no differences in either whole body hematocrit or Fcells ratio. There were no differences in water, fat, protein and mineral content between the genotypes of either gender. Thus, IL-6-deficient mice at young age have a significantly greater blood volume than the wild type mice without concomitant changes in body composition. We suggest that the changes in blood volume may reflect a role for IL-6 in the regulation of the peripheral circulation.

Type 2 diabetes is associated with biochemical evidence of low-grade inflammation, and experimental studies have suggested that both insulin and glucose affect inflammatory responses. To determine the effect of in vivo changes in glucose availability and plasma insulin concentrations in humans, we administered 20 U/kg Escherichia coli lipopolysaccharide (LPS) or saline (control) to 14 subjects during a euglycemic hyperinsulinemic clamp (n = 6) or an infusion of sterile saline (n = 8). Parallel in vitro studies on human whole blood were undertaken to determine whether there was a direct effect of glucose, insulin, and leptin on proinflammatory cytokine production. Infusion of glucose and insulin significantly amplified and/or prolonged the cardiovascular, plasma interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and counterregulatory hormone responses to LPS, whereas the effects on fever, plasma norepinephrine concentrations, and oxygen consumption were unaffected. In vitro studies showed no modulation of LPS-stimulated IL-6 or TNF-alpha production by glucose, insulin, or leptin at physiologically relevant concentrations. Hyperinsulinemia indirectly enhances key components of the systemic inflammatory and stress responses in this human model of infection.

Objective: To compare the ability of plasma (lactate) and the plasma lactate/pyruvate (L/P) ratio to predict shock-related outcome after injury and also to examine the influence of plasma ethanol on any relationships found., Design: Prospective observational study., Setting: Emergency departments in the UK and the Republic of South Africa., Patients: Blood samples were taken at presentation from 232 adult patients 1-23 hrs (median, 3.5 hrs) after sustaining an injury or injuries deemed sufficiently severe to require inpatient care., Measurements: Plasma concentrations of lactate, pyruvate, and ethanol, anatomical severity of injury, development of multiple organ failure, and 30-day survival were determined., Results: At 90% specificity for predicting subsequent mortality and/or multiple organ failure, plasma lactate >or=3.85 mmol/L was 23% (5% to 41%) more sensitive than an L/P ratio of >or=42.76. At 90% sensitivity for ruling out morbidity, plasma lactate <1.6 mmol/L is 6% (-1% to 13%) more specific than an L/P ratio of <14.08. High L/P ratios were noted to be associated with a detectable plasma alcohol level. A post hoc regression analysis showed that alcohol-positive/-negative status was a much stronger predictor of the L/P ratio than was anatomical severity of injury, shock, or time after injury., Conclusions: Plasma lactate alone is a better predictor than the L/P ratio of shock-related outcome after injury. The interpretation of L/P ratios after injury is confounded in the presence of elevated plasma ethanol.

Tracheal gas insufflation is a technique in which gas is injected intratracheally during positive pressure ventilation. The fresh gas rinses expired gas from the tracheal tube and anatomical dead space, aiding carbon dioxide elimination. This reduces ventilatory volume and pressure, helping to reduce ventilator-induced lung damage. Complications of tracheal gas insufflation include interference with ventilator function, tracheal damage and barotrauma. Expiratory washout is a variation of tracheal gas insufflation. We designed and constructed an original expiratory washout system and evaluated its safety and performance in lung and animal models. We found that expiratory limb and tracheal tube occlusion tests caused the device to disable itself at acceptable intratracheal pressures. We also demonstrated up to 31% reduction in tidal volume compared with conventional ventilation, supporting the possibility of using this device clinically to lessen volutrauma. We concluded that aspects of this design might alleviate many of the safety concerns of using tracheal gas insufflation.

Lower body negative pressure (LBNP) reduces central venous pressure (CVP) and cardiac output. The elderly are reported to have a limited capacity to increase cardiac output by increasing heart rate (HR), are especially dependent on end diastolic volume to maintain stroke volume and therefore should be especially vulnerable to LBNP. The present study compared the effects of LBNP in the young and old. Stroke volume was assessed non-invasively as stroke distance (SD) by aortovelography. Two groups of healthy male volunteers were studied: eight young (29.7 +/- 2.0 years, mean +/- S.E.M.) and nine old (70.1 +/- 0.9 years). LBNP was applied progressively at 17.5, 35 and 50 mmHg in 20 min steps, with measurements taken during each steady state. There were similar, significant, falls in CVP in both groups. SD fell significantly in both groups from respective control values of 24.8 +/- 1.6 and 16.6 +/- 0.9 cm to 12.5 +/- 1.3 and 8.9 +/- 0.4 cm at a LBNP of 50 mmHg. Although SD in the elderly was significantly lower than in the young, the LBNP-induced changes were not different between groups. Both groups produced similar significant increases in vascular resistance, HR, plasma vasopressin (AVP) and noradrenaline. Mean arterial blood pressure (MBP) and plasma adrenaline did not change significantly. Therefore healthy old men respond to LBNP in a similar manner to the young, although MBP and SD are regulated around different baselines in the two groups.

Infection results in a state of insulin resistance, but the pathogenesis is poorly understood. Intravenous administration of bacterial lipopolysaccharide (LPS) has been used to mimic the febrile and systemic inflammatory responses to infection, but it is unclear whether LPS induces insulin resistance in man. To investigate the effects of LPS on insulin sensitivity and substrate utilization, we administered, in paired cross-over studies, either 20 U/kg Escherichia coli endotoxin or saline control to healthy volunteers (n = 6) 120 min after the start of a 10-h euglycemic hyperinsulinemic clamp (insulin infusion rate, 80 mU/m2 x min). LPS induced a fever, tachycardia, and mild arterial hypotension. Glucose utilization increased abruptly 120 min after LPS administration (+64.1+/-12.0%; P < 0.003), but then declined progressively, and insulin resistance was evident by 420 min (+1.9+/-3.5%; P < 0.05). The reduction in glucose utilization, like that observed in sepsis, was related to impaired nonoxidative glucose disposal and not abnormal glucose oxidation. The cortisol and GH responses to LPS were of sufficient duration and magnitude to explain the insulin resistance. LPS administration results in metabolic responses very similar to those observed in sepsis and could provide a useful model for the study of insulin resistance in human critical illness.

Objectives: To assess the feasibility of constructing left ventricular response curves non-invasively during the fluid resuscitation of critically ill patients in the emergency department (ED) using a portable suprasternal Doppler ultrasound (PSSDU) device., Design: Prospective case series., Setting: Emergency department, Catholic University of Leuven, Belgium., Patients: Shocked patients in the ED were diagnosed by predefined criteria. Only those thought to require standardised intravenous colloid challenges were observed i. e., sequential boluses of 3.5 ml/kg/10 min titrated against changes in stroke distance (Doppler surrogate for left ventricular stroke volume)., Results: A total of 50 shocked patients were studied. Stroke distance was measurable in 45 patients. 35 patients were fluid responders in terms of stroke distance. Group mean stroke distance increased during resuscitation (8.6 +/- 4.1 cm to 19.5 +/- 4.6 cm, P < 0.001) and then reached a plateau value (19.6 +/- 4.6 cm, P = 0.488). No response to fluid was seen in nine patients of which eight had severe sepsis. Alternative therapeutic approaches increased stroke distance for all of these patients. Evidence for right ventricular dysfunction was found as a cause for fluid non-response in the majority of patients with sepsis., Conclusions: Previous experimental work has shown that changes in central blood flow can be derived using the PSSDU device. This clinical feasibility study suggests that the PSSDU can help tailor haemodynamic therapy for an individual patient and give an early indication of treatment failure in the ED.

Following severe burns, patients frequently develop a profound resistance to nondepolarizing neuromuscular blockers. Several mechanisms have been proposed to account for this, including upregulation of nicotinic acetylcholine receptors. We investigated the effects of a 30% body surface area (BSA) scald on neuromuscular transmission in slow-twitch soleus (SOL) and fast-twitch extensor digitorum longus (EDL) of rats. Rats were sacrificed 72 h after the injury, a time at which sepsis is unlikely and body weight gain and core temperature have returned to normal. Further groups of rats were sham operated and either pair fed to the scalded rats or freely fed to assess the influence of food restriction. When compared with muscle from pair-fed control rats, scald resulted in an almost 50% increase in miniature endplate potential (mEPP) frequency in both SOL and EDL. However, scald did not increase mean mEPP amplitude in SOL, although it did cause a 10% increase in EDL. Scald injury did produce a significant increase in the size of the evoked endplate potential in SOL (33%) and EDL (37%). These data indicate that a significant increase in the quantal content of evoked transmitter released in SOL (38%) and EDL (30%) occurred by 72 h after scald. Such an increase may contribute to the resistance to nondepolarizing neuromuscular blockers documented in patients following thermal injury., (Copyright 1999 John Wiley & Sons, Inc.)

Objective: To evaluate accuracy and repeatability of blood volume determinations made by the carbon monoxide method, using a ventilator-driven administration system., Design: Prospective within-patient comparison, using simultaneous measurements by two methods to determine accuracy. Prospective laboratory investigation in animals to estimate repeatability., Subjects: For accuracy: Nineteen ventilated critically ill patients in a university hospital intensive care unit. For repeatability: Six anesthetized, mechanically ventilated normovolemic pigs because this is impossible to perform in humans., Interventions: In the accuracy study, a small mass of carbon monoxide was administered via a closed breathing system and arterial blood samples were taken from existing cannulas. In the repeatability study, an intramuscular sedative was given, followed by an inhalational anesthetic induction and mechanical ventilation via a tracheal tube. Left axillary artery and external jugular vein cannulas were sited. Anesthesia was maintained using an intravenous infusion. Five sequential circulating hemoglobin and blood volume estimations were made using the carbon monoxide method., Measurements and Main Results: The small carboxyhemoglobin increase produced by uptake of a small, known mass of carbon monoxide was used to estimate the circulating blood volume. Simultaneous measurement, using 51Cr-labeled red blood cells, was performed. Twenty measurements were made in 19 patients. The bias (mean difference between blood volume measurements by the two methods) was 397 mL (5.53 mL x kg(-1)) +/-415 mL (+/-5.95 mL x kg(-1)); the limits of agreement (mean difference +/-2 SD) were -433 mL and 1227 mL (-6.36 mL x kg(-1) and 17.42 mL x kg(-1)). Therefore, 95% of expected differences will lie between these limits. The mean blood volume was 75.8 mL x kg(-1) in the animals. The coefficient of variation of repeated estimates was 9.49%. Mean circulating hemoglobin mass was 7.31 mmol with a coefficient of variation of 10.18%. The mean hemoglobin concentration, by co-oximetry, was 5.014 mmol x L(-1), coefficient of variation, 2.99%., Conclusion: This arrangement is a potential bedside method of estimating blood volume and circulating hemoglobin mass. We have rendered the technique more acceptable clinically by creating a ventilator-driven administration system.

Background: Tissue injury modifies heart rate and blood pressure responses to hemorrhage. The effect of concomitant injury on the hemorrhage-induced redistribution of cardiac output is much less clear. However, if injury elicits the visceral alerting response of the defense reaction, then a change in this redistribution of peripheral blood flow might be expected. If such a change compromised the gut circulation, then it might explain the deleterious effects of injury on the ability to withstand hemorrhage., Methods: Immature pigs anesthetized with Saffan were bled 30% of blood volume with or without concomitant somatic afferent (brachial) nerve stimulation (to mimic injury). In addition to global cardiovascular and oxygen transport variables, blood flow was measured in the cranial mesenteric (gut) and right femoral (skeletal muscle) arteries after a 60-minute stabilization period after surgery, at the end of the 30-minute hemorrhage, and after a 30-minute shock period., Results: Hemorrhage induced the expected cardiovascular and oxygen transport changes accompanied by a reduction in skeletal muscle blood flow and a 55% increase in skeletal muscle vascular resistance, but gut blood flow and vascular resistance were unchanged. However, in the presence of brachial nerve stimulation, the pattern of response to hemorrhage was modified, such that gut blood flow was now reduced and gut vascular resistance increased., Conclusion: The sparing of the gut circulation after hemorrhage was abolished in the presence of "injury." This finding is consistent with injury eliciting the defense reaction and may help explain the deleterious effects of injury on resistance to hypovolemia.

Background: Glucose utilization in sepsis is impaired but the mechanisms are unclear. This study examined the effect of sepsis on total glucose utilization, oxidation and storage, and the energetic costs of these metabolic processes., Methods: Glucose infusion rate (GIR), glucose oxidation rate (GOR), non-oxidative disposal rate and the energetic cost of glucose storage were studied in 24 patients with abdominal sepsis and in 26 healthy controls, using indirect calorimetry and the euglycaemic hyperinsulinaemic clamp with insulin infusion rates of 40 and 240 mU m-2 min-1., Results: Basal GOR was significantly lower in septic patients than in controls (1.5 versus 2.3 mg per kg fat-free mass (FFM) per min, P < 0.001). Septic patients had a significantly lower GIR at 40 mU m-2 min-1 (4.2 versus 9.1 mg per kg FFM per min) and at 240 mU m-2 min-1 (7.5 versus 11.8 mg per kg FFM per min), relative to controls (P < 0.001). GOR was similar in septic and control subjects at both rates of insulin infusion whereas non-oxidative disposal was significantly lower in septic patients (P < 0.001) and accounted entirely for the reduction in GIR. The energetic cost of glucose disposal was unaffected by sepsis., Conclusion: Sepsis is associated with selective impairment of glucose storage but the energetic cost of non-oxidative disposal is unaffected.