The 'questionableness' of things: opening up the conversation

The authors show, through its structure and form, what it means to open up a collaborative conversation. This chapter developed from a number of conversations that took place at the Fourth International Conference on Value and Virtue in Practice-Based Research, the twin themes of which were 'openness' and 'criticality'. These chance and often fleeting conversations focused on ideas explored in the keynote address that Jon delivered at the conference, but spanned out into a wider discussion of the relevance of those ideas within different areas of professional practice

Prognostic Factors in Patients with Multiple Recurrences of Well-Differentiated Thyroid Carcinoma

Introduction. Patients with multiple recurrences of well-differentiated thyroid carcinoma (WDTC) have markedly reduced overall survival when compared with those who have ≤1 recurrence of their disease. The purpose of this investigation is to identify prognostic factors for mortality in this subgroup. Methods. Patients with multiple recurrences of WDTC were retrospectively identified from the thyroid cancer database at Mount Sinai Hospital, Toronto (1963–2000). Data on patient, tumor, and recurrence characteristics were collected, and each patient was given a MACIS score. Results. A total of 31 patients were identified (11 male, 20 female; 16–83 years). Using univariate analysis, age >45, stage III/IV disease, distant metastasis, vascular invasion, MACIS score >6, and time to recurrence of <12 months were found to be significant predictors for mortality in this subgroup. Conclusions. Patients with multiple recurrences of WDTC follow a distinct clinical course, marked with multiple treatment failures and a substantial risk of mortality

The heterogeneity of systemic inflammation in bronchiectasis

BACKGROUND: Systemic inflammation in bronchiectasis is poorly studied in relation to aetiology and severity. We hypothesized that molecular patterns of inflammation may define particular aetiology and severity groups in bronchiectasis. METHOD: We assayed blood concentrations of 31 proteins from 90 bronchiectasis patients (derivation cohort) and conducted PCA to examine relationships between these markers, disease aetiology and severity. Key results were validated in two separate cohorts of 97 and 79 patients from other centres. RESULTS: There was significant heterogeneity in protein concentrations across the derivation population. Increasing severity of bronchiectasis (BSI) was associated with increasing fibrinogen (rho = 0.34, p = 0.001 -validated in a second cohort), and higher fibrinogen was associated with worse lung function, Pseudomonas colonisation and impaired health-status. There were generally similar patterns of inflammation in patients with idiopathic and post-infectious disease. However, patients with primary immunodeficiency had exaggerated IL-17 responses, validated in a second cohort (n = 79, immunodeficient 12.82 pg/ml versus idiopathic/post-infectious 4.95 pg/ml, p = 0.001), and thus IL-17 discriminated primary immunodeficiency from other aetiologies (AUC 0.769 (95%CI 0.661-0.877)). CONCLUSION: Bronchiectasis is associated with heterogeneity of systemic inflammatory proteins not adequately explained by differences in disease aetiology or severity. More severe disease is associated with enhanced acute-phase responses. Plasma fibrinogen was associated with bronchiectasis severity in two cohorts, Pseudomonas colonisation and health status, and offers potential as a useful biomarker

Mathematical description of bacterial traveling pulses

The Keller-Segel system has been widely proposed as a model for bacterial waves driven by chemotactic processes. Current experiments on {\em E. coli} have shown precise structure of traveling pulses. We present here an alternative mathematical description of traveling pulses at a macroscopic scale. This modeling task is complemented with numerical simulations in accordance with the experimental observations. Our model is derived from an accurate kinetic description of the mesoscopic run-and-tumble process performed by bacteria. This model can account for recent experimental observations with {\em E. coli}. Qualitative agreements include the asymmetry of the pulse and transition in the collective behaviour (clustered motion versus dispersion). In addition we can capture quantitatively the main characteristics of the pulse such as the speed and the relative size of tails. This work opens several experimental and theoretical perspectives. Coefficients at the macroscopic level are derived from considerations at the cellular scale. For instance the stiffness of the signal integration process turns out to have a strong effect on collective motion. Furthermore the bottom-up scaling allows to perform preliminary mathematical analysis and write efficient numerical schemes. This model is intended as a predictive tool for the investigation of bacterial collective motion

Draft Genome of the Filarial Nematode Parasite \u3ci\u3eBrugia malayi\u3c/i\u3e

Parasitic nematodes that cause elephantiasis and river blindness threaten hundreds of millions of people in the developing world. We have sequenced the ∼90 megabase (Mb) genome of the human filarial parasite Brugia malayi and predict ∼11,500 protein coding genes in 71 Mb of robustly assembled sequence. Comparative analysis with the free-living, model nematode Caenorhabditis elegans revealed that, despite these genes having maintained little conservation of local synteny during ∼350 million years of evolution, they largely remain in linkage on chromosomal units. More than 100 conserved operons were identified. Analysis of the predicted proteome provides evidence for adaptations of B. malayi to niches in its human and vector hosts and insights into the molecular basis of a mutualistic relationship with its Wolbachia endosymbiont. These findings offer a foundation for rational drug design

Natriuretic peptide-based inclusion criteria in a heart failure clinical trial: insights from COMMANDER HF

Objectives: This study investigated the effects of a mid-trial protocol amendment requiring elevated natriuretic peptides for inclusion in the COMMANDER-HF (A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants with Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure) trial. Background: Heart failure (HF) trials that select patients based on history of HF hospitalization alone are susceptible to regional variations in event rates. Elevated plasma concentrations of natriuretic peptides (NPs) as selection criteria may help HF ascertainment and risk enrichment. In the COMMANDER-HF trial, B-type natriuretic peptide greater than or equal to 200 ng/l or N-terminal pro–B-type natriuretic peptide greater than or equal to 800 ng/l were added to inclusion criteria as a mid-trial protocol amendment, providing a unique case-study of NP-based inclusion criteria. Methods: We compared the baseline characteristics, event rates, and treatment effects for patients enrolled before and after the NP protocol amendment. The primary endpoint was all-cause death, myocardial infarction, or stroke. Secondary endpoints included HF rehospitalization and cardiovascular death. Results: A total of 5,022 patients with left ventricular ejection fraction less than or equal to 40% and coronary artery disease were included. Compared to patients enrolled before the NP protocol amendment, those enrolled post-amendment (n = 3,867, 77%) were older, more often had diabetes, and had lower values for body mass index, left ventricular ejection fraction, and estimated glomerular filtration rate, higher heart rate, and higher event rates: primary endpoint (hazard ratio [HR]: 1.32; 95% confidence interval [CI]: 1.16 to 1.50), cardiovascular death (HR: 1.29; 95% CI: 1.11 to 1.50), HF rehospitalization (HR: 1.31; 95% CI: 1.15 to 1.49), and major bleeding (HR: 1.71; 95% CI: 1.11 to 2.65). Differences between pre- and post-amendment rates were confined to and driven by Eastern Europe. This protocol amendment did not modify the neutral effect of rivaroxaban on the primary endpoint (p interaction = 0.36) or secondary endpoints. Conclusions: In a global event-driven trial of rivaroxaban in HF, requiring elevated NPs for inclusion increased event rates allowing earlier completion of the trial but did not modify treatment effect. These data inform future HF trials regarding the expected impact of NP-based inclusion criteria on patient characteristics and event rates. (COMMANDER HF [A Study to Assess the Effectiveness and Safety of Rivaroxaban in Reducing the Risk of Death, Myocardial Infarction, or Stroke in Participants With Heart Failure and Coronary Artery Disease Following an Episode of Decompensated Heart Failure] NCT01877915

The Evolutionary Genetics and Emergence of Avian Influenza Viruses in Wild Birds

We surveyed the genetic diversity among avian influenza virus (AIV) in wild birds, comprising 167 complete viral genomes from 14 bird species sampled in four locations across the United States. These isolates represented 29 type A influenza virus hemagglutinin (HA) and neuraminidase (NA) subtype combinations, with up to 26% of isolates showing evidence of mixed subtype infection. Through a phylogenetic analysis of the largest data set of AIV genomes compiled to date, we were able to document a remarkably high rate of genome reassortment, with no clear pattern of gene segment association and occasional inter-hemisphere gene segment migration and reassortment. From this, we propose that AIV in wild birds forms transient “genome constellations,” continually reshuffled by reassortment, in contrast to the spread of a limited number of stable genome constellations that characterizes the evolution of mammalian-adapted influenza A viruses

Economic Analysis of Knowledge: The History of Thought and the Central Themes

Following the development of knowledge economies, there has been a rapid expansion of economic analysis of knowledge, both in the context of technological knowledge in particular and the decision theory in general. This paper surveys this literature by identifying the main themes and contributions and outlines the future prospects of the discipline. The wide scope of knowledge related questions in terms of applicability and alternative approaches has led to the fragmentation of research. Nevertheless, one can identify a continuing tradition which analyses various aspects of the generation, dissemination and use of knowledge in the economy