Between-centre differences and treatment effects in randomized controlled trials: A case study in traumatic brain injury

BACKGROUND: In Traumatic Brain Injury (TBI), large between-centre differences in outcome exist and many clinicians believe that such differences influence estimation of the treatment effect in randomized controlled trial (RCTs). The aim of this study was to assess the influence of between-centre differences in outcome on the estimated treatment effect in a large RCT in TBI. METHODS: We used data from the MRC CRASH trial on the efficacy of corticosteroid infusion in patients with TBI. We analyzed the effect of the treatment on 14 day mortality with fixed effect logistic regression. Next we used random effects logistic regression with a random intercept to estimate the treatment effect taking into account between-centre differences in outcome. Between-centre differences in outcome were expressed with a 95% range of odds ratios (OR) for centres compared to the average, based on the variance of the random effects (tau2). A random effects logistic regression model with random slopes was used to allow the treatment effect to vary by centre. The variation in treatment effect between the centres was expressed in a 95% range of the estimated treatment ORs. RESULTS: In 9978 patients from 237 centres, 14-day mortality was 19.5%. Mortality was higher in the treatment group (OR = 1.22, p = 0.00010). Using a random effects model showed large between-centre differences in outcome (95% range of centre effects: 0.27- 3.71), but did not substantially change the estimated treatment effect (OR = 1.24, p = 0.00003). There was limited, although statistically significant, between-centre variation in the treatment effect (OR = 1.22, 95% treatment OR range: 1.17-1.26). CONCLUSION: Large between-centre differences in outcome do not necessarily affect the estimated treatment effect in RCTs, in contrast to current beliefs in the clinical area of TBI

The Generation of Successive Unmarked Mutations and Chromosomal Insertion of Heterologous Genes in Actinobacillus pleuropneumoniae Using Natural Transformation

We have developed a simple method of generating scarless, unmarked mutations in Actinobacillus pleuropneumoniae by exploiting the ability of this bacterium to undergo natural transformation, and with no need to introduce plasmids encoding recombinases or resolvases. This method involves two successive rounds of natural transformation using linear DNA: the first introduces a cassette carrying cat (which allows selection by chloramphenicol) and sacB (which allows counter-selection using sucrose) flanked by sequences to either side of the target gene; the second transformation utilises the flanking sequences ligated directly to each other in order to remove the cat-sacB cassette. In order to ensure efficient uptake of the target DNA during transformation, A. pleuropneumoniae uptake sequences are added into the constructs used in both rounds of transformation. This method can be used to generate multiple successive deletions and can also be used to introduce targeted point mutations or insertions of heterologous genes into the A. pleuropneumoniae chromosome for development of live attenuated vaccine strains. So far, we have applied this method to highly transformable isolates of serovars 8 (MIDG2331), which is the most prevalent in the UK, and 15 (HS143). By screening clinical isolates of other serovars, it should be possible to identify other amenable strains

Development of a novel risk prediction and risk stratification score for polycystic ovary syndrome (PCOS)

ObjectiveThe aim of this study was to develop a simple phenotypic algorithm that can capture the underlying clinical and hormonal abnormalities to help in the diagnosis and risk stratification of polycystic ovary syndrome (PCOS).MethodsThe study consisted of 111 women with PCOS fulfilling the Rotterdam diagnostic criteria and 67 women without PCOS. A Firth's penalized logistic regression model was used for independent variable section. Model optimism, discrimination and calibration were assessed using bootstrapping, area under the curve (AUC) and Hosmer‐Lemeshow statistics, respectively. The prognostic index (PI) and risk score for developing PCOS were calculated using independent variables from the regression model.ResultsFirth penalized logistic regression model with backward selection identified four independent predictors of PCOS namely free androgen index [β 0.30 (0.12), P = 0.008], 17‐OHP [β = 0.20 (0.01), P = 0.026], anti‐mullerian hormone [AMH; β = 0.04 (0.01) P < 0.0001] and waist circumference [β = 0.08 (0.02), P < 0.0001]. The model estimates indicated high internal validity (minimal optimism on 1000‐fold bootstrapping), good discrimination ability (bias corrected c‐statistic = 0.90) and good calibration (Hosmer‐Lemeshow χ2 = 3.7865). PCOS women with a high‐risk score (q1 + q2 + q3 vs q4) presented with a worse metabolic profile characterized by a higher 2‐hour glucose (P = 0.01), insulin (P = 0.0003), triglycerides (P = 0.0005), C‐reactive protein (P < 0.0001) and low HDL‐cholesterol (P = 0.02) as compared to those with lower risk score for PCOS.ConclusionsWe propose a simple four‐variable model, which captures the underlying clinical and hormonal abnormalities in PCOS and can be used for diagnosis and metabolic risk stratification in women with PCOS

Logopenic and nonfluent variants of primary progressive aphasia are differentiated by acoustic measures of speech production

Differentiation of logopenic (lvPPA) and nonfluent/agrammatic (nfvPPA) variants of Primary Progressive Aphasia is important yet remains challenging since it hinges on expert based evaluation of speech and language production. In this study acoustic measures of speech in conjunction with voxel-based morphometry were used to determine the success of the measures as an adjunct to diagnosis and to explore the neural basis of apraxia of speech in nfvPPA. Forty-one patients (21 lvPPA, 20 nfvPPA) were recruited from a consecutive sample with suspected frontotemporal dementia. Patients were diagnosed using the current gold-standard of expert perceptual judgment, based on presence/absence of particular speech features during speaking tasks. Seventeen healthy age-matched adults served as controls. MRI scans were available for 11 control and 37 PPA cases; 23 of the PPA cases underwent amyloid ligand PET imaging. Measures, corresponding to perceptual features of apraxia of speech, were periods of silence during reading and relative vowel duration and intensity in polysyllable word repetition. Discriminant function analyses revealed that a measure of relative vowel duration differentiated nfvPPA cases from both control and lvPPA cases (r2 = 0.47) with 88% agreement with expert judgment of presence of apraxia of speech in nfvPPA cases. VBM analysis showed that relative vowel duration covaried with grey matter intensity in areas critical for speech motor planning and programming: precentral gyrus, supplementary motor area and inferior frontal gyrus bilaterally, only affected in the nfvPPA group. This bilateral involvement of frontal speech networks in nfvPPA potentially affects access to compensatory mechanisms involving right hemisphere homologues. Measures of silences during reading also discriminated the PPA and control groups, but did not increase predictive accuracy. Findings suggest that a measure of relative vowel duration from of a polysyllable word repetition task may be sufficient for detecting most cases of apraxia of speech and distinguishing between nfvPPA and lvPPA

Reexamination of the species assignment of Diacavolinia pteropods using DNA barcoding

© The Author(s), 2013. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS ONE 8 (2013): e53889, doi:10.1371/journal.pone.0053889.Thecosome pteropods (Mollusca, Gastropoda) are an ecologically important, diverse, and ubiquitous group of holoplanktonic animals that are the focus of intense research interest due to their external aragonite shell and vulnerability to ocean acidification. Characterizing the response of these animals to low pH and other environmental stressors has been hampered by continued uncertainty in their taxonomic identification. An example of this confusion in species assignment is found in the genus Diacavolinia. All members of this genus were originally indentified as a single species, Cavolinia longirostris, but over the past fifty years the taxonomy has been revisited multiple times; currently the genus comprises 22 different species. This study examines five species of Diacavolinia, including four sampled in the Northeast Atlantic (78 individuals) and one from the Eastern tropical North Pacific (15 individuals). Diacavolina were identified to species based on morphological characteristics according to the current taxonomy, photographed, and then used to determine the sequence of the “DNA barcoding” region of the cytochrome c oxidase subunit I (COI). Specimens from the Atlantic, despite distinct differences in shell morphology, showed polyphyly and a genetic divergence of <3% (K2P distance) whereas the Pacific and Atlantic samples were more distant (~19%). Comparisons of Diacavolinia spp. with other Cavolinia spp. reveal larger distances (~24%). These results indicate that specimens from the Atlantic comprise a single monophyletic species and suggest possible species-level divergence between Atlantic and Pacific populations. The findings support the maintenance of Diacavolinia as a separate genus, yet emphasize the inadequacy of our current taxonomic understanding of pteropods. They highlight the need for accurate species identifications to support estimates of biodiversity, range extent and natural exposure of these planktonic calcifiers to environmental variability; furthermore, the apparent variation of the pteropods shell may have implications for our understanding of the species’ sensitivity to ocean acidification.This material is based upon work supported by the National Science Foundation under Grant Number OCE-0928801. AEM was funded through the WHOI Postdoctoral Scholarship. Support to LBB was provided by the College of Liberal Arts & Sciences, University of Connecticut; and by the Census of Marine Life/Alfred P. Sloan Foundation

A cross-sectional study examining predictors of visit frequency to local green space and the impact this has on physical activity levels

Background Lack of physical activity (PA) is a growing public health concern. There is a growing body of literature that suggests a positive relationship may exist between the amount of local green space near one?s home and PA levels. For instance, park proximity has been shown to predict PA levels amongst certain populations. However, there is little evidence for the role of relatedness towards nature and perceptions of local green space on this relationship. The aim of this study was to examine, in a National UK sample, whether subjective indices associated with local green space were better predictors of visit frequency to local green space and PA levels compared to objectively measured quantity of local green space. Methods A cross-sectional survey was designed. From a random sample, 2079 working age adults responded to an online survey in September 2011. Demographics, self-reported PA, objective measures of the local environment (including local green space, road coverage, and environmental deprivation), were assessed in conjunction with perceptions of local green space and nature relatedness. Quantity of local green space was assessed by cross-referencing respondents? home postcodes with general land use databases. Regression models were conducted to assess which of our independent variables best predicted visit frequency to local green space and/or meeting PA guidelines. In addition, an ordinal regression was run to examine the relationship between visit frequency to local green space and the likelihood of meeting national PA guidelines. Results Nature relatedness was the strongest predictor for both visit frequency to local green space and meeting PA guidelines. Results show that perceived quality is a better predictor of visit frequency to local green space than objective quantity of local green space. The odds of achieving the recommended amount of PA was over four times greater for people who visited local green space once per week compared to never going (OR 4.151; 95 % CI, 2.40 to 7.17). Conclusions These results suggest that perceptions of local green space and nature relatedness play an important role in the relationship between local green space and PA. Considering the known health benefits of PA, our results are potentially important for public health interventions, policy making and environmental planning

Why pharmacokinetic differences among oral triptans have little clinical importance: a comment

Triptans, selective 5-HT1B/1D receptor agonists, are specific drugs for the acute treatment of migraine that have the same mechanism of action. Here, it is discussed why the differences among kinetic parameters of oral triptans have proved not to be very important in clinical practice. There are three main reasons: (1) the differences among the kinetic parameters of oral triptans are smaller than what appears from their average values; (2) there is a large inter-subject, gender-dependent, and intra-subject (outside/during the attack) variability of kinetic parameters related to the rate and extent of absorption, i.e., those which are considered as critical for the response; (3) no dose-concentration–response curves have been defined and it is, therefore, impossible both to compare the kinetics of triptans, and to verify the objective importance of kinetic differences; (4) the importance of kinetic differences is outweighed by non-kinetic factors of variability of response to triptans. If no oral formulations are found that can allow more predictable pharmacokinetics, the same problems will probably also arise with new classes of drugs for the acute treatment of migraine

Managing Carbon Aspirations: The Influence of Corporate Climate Change Targets on Environmental Performance

Addressing climate change is among the most challenging ethical issues facing contemporary business and society. Unsustainable business activities are causing significant distributional and procedural injustices in areas such as public health and vulnerability to extreme weather events, primarily because of a distinction between primary emitters and those already experiencing the impacts of climate change. Business, as a significant contributor to climate change and beneficiary of externalizing environmental costs, has an obligation to address its environmental impacts. In this paper, we explore the role of firms’ climate change targets in shaping their emissions trends in the context of a large multi-country sample of companies. We contrast two intentions for setting emissions reductions targets: symbolic attempts to manage external stakeholder perceptions via “greenwashing” and substantive commitments to reducing environmental impacts. We argue that the attributes of firms’ climate change targets (their extent, form, and time horizon) are diagnostic of firms’ underlying intentions. Consistent with our hypotheses, while we find no overall effect of setting climate change targets on emissions, we show that targets characterized by a commitment to more ambitious emissions reductions, a longer target time frame, and absolute reductions in emissions are associated with significant reductions in firms’ emissions. Our evidence suggests the need for vigilance among policy-makers and environmental campaigners regarding the underlying intentions that accompany environmental management practices and shows that these can to some extent be diagnosed analytically