Outcome-sensitive multiple imputation: a simulation study.

BACKGROUND: Multiple imputation is frequently used to deal with missing data in healthcare research. Although it is known that the outcome should be included in the imputation model when imputing missing covariate values, it is not known whether it should be imputed. Similarly no clear recommendations exist on: the utility of incorporating a secondary outcome, if available, in the imputation model; the level of protection offered when data are missing not-at-random; the implications of the dataset size and missingness levels. METHODS: We used realistic assumptions to generate thousands of datasets across a broad spectrum of contexts: three mechanisms of missingness (completely at random; at random; not at random); varying extents of missingness (20-80% missing data); and different sample sizes (1,000 or 10,000 cases). For each context we quantified the performance of a complete case analysis and seven multiple imputation methods which deleted cases with missing outcome before imputation, after imputation or not at all; included or did not include the outcome in the imputation models; and included or did not include a secondary outcome in the imputation models. Methods were compared on mean absolute error, bias, coverage and power over 1,000 datasets for each scenario. RESULTS: Overall, there was very little to separate multiple imputation methods which included the outcome in the imputation model. Even when missingness was quite extensive, all multiple imputation approaches performed well. Incorporating a secondary outcome, moderately correlated with the outcome of interest, made very little difference. The dataset size and the extent of missingness affected performance, as expected. Multiple imputation methods protected less well against missingness not at random, but did offer some protection. CONCLUSIONS: As long as the outcome is included in the imputation model, there are very small performance differences between the possible multiple imputation approaches: no outcome imputation, imputation or imputation and deletion. All informative covariates, even with very high levels of missingness, should be included in the multiple imputation model. Multiple imputation offers some protection against a simple missing not at random mechanism

Performance of formulae based estimates of glomerular filtration rate for carboplatin dosing in stage 1 seminoma

<b>Background:</b> Single cycle carboplatin, dosed by glomerular filtration rate (GFR), is standard adjuvant therapy for stage 1 seminoma. Accurate measurement of GFR is essential for correct dosing. Isotopic methods remain the gold standard for the determination of GFR. Formulae to estimate GFR have improved the assessment of renal function in non-oncological settings. We assessed the utility of these formulae for carboplatin dosing.<p></p> <b>Methods:</b> We studied consecutive subjects receiving adjuvant carboplatin for stage 1 seminoma at our institution between 2007 and 2012. Subjects underwent 51Cr-ethylene diamine tetra-acetic acid (EDTA) measurement of GFR with carboplatin dose calculated using the Calvert formula. Theoretical carboplatin doses were calculated from estimated GFR using Chronic Kidney Disease-Epidemiology (CKD-EPI), Management of Diet in Renal Disease (MDRD) and Cockcroft–Gault (CG) formulae with additional correction for actual body surface area (BSA). Carboplatin doses calculated by formulae were compared with dose calculated by isotopic GFR; a difference <10% was considered acceptable.<p></p> <b>Results:</b> 115 patients were identified. Mean isotopic GFR was 96.9 ml/min/1.73 m2. CG and CKD-EPI tended to overestimate GFR whereas MDRD tended to underestimate GFR. The CKD-EPI formula had greatest accuracy. The CKD-EPI formula, corrected for actual BSA, performed best; 45.9% of patients received within 10% of correct carboplatin dose. Patients predicted as underdosed (13.5%) by CKD-EPI were more likely to be obese (p = 0.013); there were no predictors of the 40.5% receiving an excess dose.<p></p> <b>Conclusions:</b> Our data support further evaluation of the CKD-EPI formula in this patient population but clinically significant variances in carboplatin dosing occur using non-isotopic methods of GFR estimation. Isotopic determination of GFR should remain the recommended standard for carboplatin dosing when accuracy is essential.<p></p&gt

The effects of river flooding on dioxin and PCBs in beef

In 2008-2010, samples of meat from 40 beef cattle, along with grass, soil and commercial feed, taken from ten matched pairs of flood-prone and control farms, were analysed for PCDD/Fs and PCBs. Concentrations were higher in soil and grass from flood-prone farms. The beef samples from flood-prone farms had total TEQ levels about 20% higher than on control farms. A majority of flood-prone farms (7/10) had higher median levels in beef than on the corresponding control farm. This first controlled investigation into PCDD/F and PCB contamination in beef produced on flood-prone land, presents robust evidence that flooding is a contaminant transfer mechanism to cattle raised on river catchments with a history of urbanisation and industrialisation. PCDD/F and PCB sources in these river systems are likely to be a result of the legacy of contamination from previous industrialisation, as well as more recent combustion activity or pollution events. Crow

Effects of high relative humidity and dry purging on VOCs obtained during breath sampling on common sorbent tubes.

BACKGROUND:Offline breath analysis by GC-MS requires the use of sorbent traps to concentrate and store volatile compounds. The selection of which sorbent to use and best practices for managing water retention are important considerations to allow for reproducible, untargeted, biomarker discovery in water saturated breath samples. OBJECTIVE:To assess three commonly used sorbent materials for their use in breath volatile sampling and determine how the high relative humidity inherent in such samples effects the capture of volatile compounds of interest. METHODS:TenaxGR, TenaxTA/Carbograph1TD and TenaxTA/Carbograph5TD tubes were selected as they are the most commonly used sorbents in the breath sampling literature. The recovery of 29 compounds in a standard mix loaded using high humidity gas was tested for each sorbent and compared to loading in dry gas. Water retention and dry purge rates were determined. Finally, breath samples were sampled simultaneously on to each sorbent type using the ReCIVA and analysed by TD-GC-MS. RESULTS:All three sorbents exhibited acceptable reproducibility when loaded with the standard mix in dry gas. Loading the standard mix in humid gas led to reduced recovery of compounds based on their chemical properties. Dry purging performance for each sorbent material was assessed and was shown to be 1.14, 1.13 and 0.89 mg H2O min-1for TenaxGR, TenaxTA/Carbograph1TD and TenaxTA/Carbograph5TD respectively. A comparison of breath profiles on different sorbents showed differences in background artefacts (sulfur dioxide, cyclopenten-1-one and 3-nonene) and endogenous breath compounds (2-methyl-furan and furfural). CONCLUSIONS:High relative humidity during sampling reduces the ability of sorbent tubes to capture volatile compounds and could impact method detection limits during breath sampling. Sufficient water to impair accurate analysis was retained on all tubes. Minimal differences were observed between sorbent materials when used to sample breath, however, suggestions are provided for sorbent selection for future studies

Pulmonary retention of primed neutrophils: a novel protective host response, which is impaired in the acute respiratory distress syndrome.

RATIONALE: Acute respiratory distress syndrome (ARDS) affects over 200000 people annually in the USA. Despite causing severe, and often refractory, hypoxaemia, the high mortality and long-term morbidity of ARDS results mainly from extra-pulmonary organ failure; however the mechanism for this organ crosstalk has not been determined. METHODS: Using autologous radiolabelled neutrophils we investigated the pulmonary transit of primed and unprimed neutrophils in humans. Flow cytometry of whole blood samples was used to assess transpulmonary neutrophil priming gradients in patients with ARDS, sepsis and perioperative controls. MAIN RESULTS: Unprimed neutrophils passed through the lungs with a transit time of 14.2 s, only 2.3 s slower than erythrocytes, and with <5% first-pass retention. Over 97% of neutrophils primed ex vivo with granulocyte macrophage colony-stimulating factor were retained on first pass, with 48% still remaining in the lungs at 40 min. Neutrophils exposed to platelet-activating factor were initially retained but subsequently released such that only 14% remained in the lungs at 40 min. Significant transpulmonary gradients of neutrophil CD62L cell surface expression were observed in ARDS compared with perioperative controls and patients with sepsis. CONCLUSIONS: We demonstrated minimal delay and retention of unprimed neutrophils transiting the healthy human pulmonary vasculature, but marked retention of primed neutrophils; these latter cells then 'deprime' and are re-released into the systemic circulation. Further, we show that this physiological depriming mechanism may fail in patients with ARDS, resulting in increased numbers of primed neutrophils within the systemic circulation. This identifies a potential mechanism for the remote organ damage observed in patients with ARDS.This work was supported by the Wellcome Trust, MRC (UK), Papworth Hospital R&D, Intensive Care Society and NIHR Cambridge Biomedical Research Centre.This is the final published version, also available from http://thorax.bmj.com/content/early/2014/04/04/thoraxjnl-2013-204742.full

Prediction of 30-day mortality after hip fracture surgery by the Nottingham Hip Fracture Score and the Surgical Outcome Risk Tool

The care of the elderly with hip fractures and their outcomes might be improved with resources targeted by the accurate calculation of risks of mortality and morbidity. We used a multicentre national dataset to evaluate and recalibrate the Nottingham Hip Fracture Score and Surgical Outcome Risk Tool. We split 9,017 hip fracture cases from the Anaesthesia Sprint Audit of Practice into derivation and validation data sets and used logistic regression to derive new model co-efficients for death at 30 postoperative days. The area (95% CI) under the receiver operator characteristic curve of 0.71 (0.67 0.75) indicated acceptable discrimination by the Nottingham Hip Fracture Score and acceptable calibration fit (Hosmer–Lemeshow test), p = 0.23, with a similar discrimination by the Surgical Outcome Risk Tool, 0.70 (0.66–0.74), which was miscalibrated to the observed data, p = 0.001. We recommend that studies test these scores for patients with hip fractures in other countries. We also recommend these models are compared with case-mix adjustment tools used in the UK

Responsible participation and housing: restoring democratic theory to the scene

Tensions between individual liberty and collective social justice characterise many advanced liberal societies. These tensions are reflected in the challenges posed for representative democracy both by participatory democratic practices and by the current emphasis on (so-called) responsible participation. Based on the example of ‘community’ housing associations in Scotland, this paper explores these tensions. It is argued that the critique of responsibility may have been over-stated – that, in particular, ‘community’ housing associations offer the basis for relatively more inclusive and effective processes of decision-making than council housing, which relies on the traditional processes and institutions of representative local government for its legitimacy

Numerical Study of Magnetoaerodynamic Flow Around a Hemisphere

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83560/1/AIAA-49278-455.pd

Breath and plasma metabolomics to assess inflammation in acute stroke

From Springer Nature via Jisc Publications RouterHistory: received 2021-04-27, accepted 2021-09-27, registration 2021-10-26, pub-electronic 2021-11-09, online 2021-11-09, collection 2021-12Publication status: PublishedFunder: Moulton Charitable TrustFunder: Manchester Biomedical Research Centre; doi: http://dx.doi.org/10.13039/100014653Abstract: Inflammation is strongly implicated in both injury and repair processes occurring after stroke. In this exploratory study we assessed the feasibility of repeated sampling of exhaled volatile organic compounds and performed an untargeted metabolomic analysis of plasma collected at multiple time periods after stroke. Metabolic profiles were compared with the time course of the inflammatory markers C-reactive protein (CRP) and interleukin-6 (IL-6). Serial breath sampling was well-tolerated by all patients and the measurement appears feasible in this group. We found that exhaled decanal tracks CRP and IL-6 levels post-stroke and correlates with several metabolic pathways associated with a post-stroke inflammatory response. This suggests that measurement of breath and blood metabolites could facilitate development of novel therapeutic and diagnostic strategies. Results are discussed in relation to the utility of breath analysis in stroke care, such as in monitoring recovery and complications including stroke associated infection