Considerations for a combined index for limited cutaneous systemic sclerosis to support drug development and improve outcomes

Systemic sclerosis (systemic scleroderma) is characterized by a heterogeneous range of clinical manifestations. Systemic sclerosis is classified into limited cutaneous systemic sclerosis and diffuse cutaneous systemic sclerosis subgroups based on the extent of skin involvement. Randomized controlled trials in scleroderma have mainly focused on diffuse cutaneous systemic sclerosis partly because the measurement of skin involvement, critical for evaluating a therapeutic intervention, is more dynamic in this subset. Nonetheless, limited cutaneous systemic sclerosis, the most common cutaneous subset (about two-third), is also associated with significant morbidity and detrimental impact on health-related quality of life. The lack of interventional studies in limited cutaneous systemic sclerosis is partly due to a lack of relevant outcome measures to evaluate this subgroup. Combining several clinically meaningful outcomes selected specifically for limited cutaneous systemic sclerosis may improve representativeness in clinical trials and responsiveness of outcomes measured in randomized controlled trials. A composite index dedicated to limited cutaneous systemic sclerosis combining such relevant outcomes could advance clinical trial development for limited cutaneous systemic sclerosis by providing the opportunity to test and select among candidate drugs that could act as disease-modifying treatments for this neglected subgroup of systemic sclerosis. This proposed index would include items selected by expert physicians and patients with limited cutaneous systemic sclerosis across domains grounded in the lived experience of limited cutaneous systemic sclerosis. This article reviews the reasons behind the relative neglect of limited cutaneous systemic sclerosis, discusses the current state of outcome measures for limited cutaneous systemic sclerosis, identifies challenges, and proposes a roadmap for a combined limited cutaneous systemic sclerosis-specific treatment response index

“Excellence R Us”: university research and the fetishisation of excellence

The rhetoric of “excellence” is pervasive across the academy. It is used to refer to research outputs as well as researchers, theory and education, individuals and organisations, from art history to zoology. But does “excellence” actually mean anything? Does this pervasive narrative of “excellence” do any good? Drawing on a range of sources we interrogate “excellence” as a concept and find that it has no intrinsic meaning in academia. Rather it functions as a linguistic interchange mechanism. To investigate whether this linguistic function is useful we examine how the rhetoric of excellence combines with narratives of scarcity and competition to show that the hypercompetition that arises from the performance of “excellence” is completely at odds with the qualities of good research. We trace the roots of issues in reproducibility, fraud, and homophily to this rhetoric. But we also show that this rhetoric is an internal, and not primarily an external, imposition. We conclude by proposing an alternative rhetoric based on soundness and capacity-building. In the final analysis, it turns out that that “excellence” is not excellent. Used in its current unqualified form it is a pernicious and dangerous rhetoric that undermines the very foundations of good research and scholarship

Direct Visualization of Protease Action on Collagen Triple Helical Structure

Enzymatic processing of extracellular matrix (ECM) macromolecules by matrix metalloproteases (MMPs) is crucial in mediating physiological and pathological cell processes. However, the molecular mechanisms leading to effective physiological enzyme-ECM interactions remain elusive. Only scant information is available on the mode by which matrix proteases degrade ECM substrates. An example is the enzymatic degradation of triple helical collagen II fragments, generated by the collagenase MMP-8 cleavage, during the course of acute inflammatory conditions by gelatinase B/MMP-9. As is the case for many other matrix proteases, it is not clear how MMP-9 recognizes, binds and digests collagen in this important physiological process. We used single molecule imaging to directly visualize this protease during its interaction with collagen fragments. We show that the initial binding is mediated by the diffusion of the protease along the ordered helix on the collagen ¾ fragment, with preferential binding of the collagen tail. As the reaction progressed and prior to collagen degradation, gelatin-like morphologies resulting from the denaturation of the triple helical collagen were observed. Remarkably, this activity was independent of enzyme proteolysis and was accompanied by significant conformational changes of the working protease. Here we provide the first direct visualization of highly complex mechanisms of macromolecular interactions governing the enzymatic processing of ECM substrates by physiological protease

Linear-in-the-parameters oblique least squares (LOLS) provides more accurate estimates of density-dependent survival

Survival is a fundamental demographic component and the importance of its accurate estimation goes beyond the traditional estimation of life expectancy. The evolutionary stability of isomorphic biphasic life-cycles and the occurrence of its different ploidy phases at uneven abundances are hypothesized to be driven by differences in survival rates between haploids and diploids. We monitored Gracilaria chilensis, a commercially exploited red alga with an isomorphic biphasic life-cycle, having found density-dependent survival with competition and Allee effects. While estimating the linear-in-the-parameters survival function, all model I regression methods (i.e, vertical least squares) provided biased line-fits rendering them inappropriate for studies about ecology, evolution or population management. Hence, we developed an iterative two-step non-linear model II regression (i.e, oblique least squares), which provided improved line-fits and estimates of survival function parameters, while robust to the data aspects that usually turn the regression methods numerically unstable

Evaluation of Functional Erythropoietin Receptor Status in Skeletal Muscle In Vivo: Acute and Prolonged Studies in Healthy Human Subjects

BACKGROUND: Erythropoietin receptors have been identified in human skeletal muscle tissue, but downstream signal transduction has not been investigated. We therefore studied in vivo effects of systemic erythropoietin exposure in human skeletal muscle. METHODOLOGY/PRINCIPAL FINDINGS: The protocols involved 1) acute effects of a single bolus injection of erythropoietin followed by consecutive muscle biopsies for 1-10 hours, and 2) a separate study with prolonged administration for 16 days with biopsies obtained before and after. The presence of erythropoietin receptors in muscle tissue as well as activation of Epo signalling pathways (STAT5, MAPK, Akt, IKK) were analysed by western blotting. Changes in muscle protein profiles after prolonged erythropoietin treatment were evaluated by 2D gel-electrophoresis and mass spectrometry. The presence of the erythropoietin receptor in skeletal muscle was confirmed, by the M20 but not the C20 antibody. However, no significant changes in phosphorylation of the Epo-R, STAT5, MAPK, Akt, Lyn, IKK, and p70S6K after erythropoietin administration were detected. The level of 8 protein spots were significantly altered after 16 days of rHuEpo treatment; one isoform of myosin light chain 3 and one of desmin/actin were decreased, while three isoforms of creatine kinase and two of glyceraldehyd-3-phosphate dehydrogenase were increased. CONCLUSIONS/SIGNIFICANCE: Acute exposure to recombinant human erythropoietin is not associated by detectable activation of the Epo-R or downstream signalling targets in human skeletal muscle in the resting situation, whereas more prolonged exposure induces significant changes in the skeletal muscle proteome. The absence of functional Epo receptor activity in human skeletal muscle indicates that the long-term effects are indirect and probably related to an increased oxidative capacity in this tissue

International travel and the risk of hospitalization with non-typhoidal Salmonella bacteremia. A Danish population-based cohort study, 1999-2008

<p>Abstract</p> <p>Background</p> <p>Information is sparse regarding the association between international travel and hospitalization with non-typhoidal <it>Salmonella </it>bacteremia. The aim of this study was to determine the proportion, risk factors and outcomes of travel-related non-typhoidal <it>Salmonella </it>bacteremia.</p> <p>Methods</p> <p>We conducted a 10-year population-based cohort study of all patients hospitalized with non-typhoidal <it>Salmonella </it>bacteremia in three Danish counties (population 1.6 million). We used denominator data on Danish travellers to assess the risk per 100,000 travellers according to age and travel destination. We used patients contemporaneously diagnosed with travel-related <it>Salmonella </it>gastroenteritis as reference patients to estimate the relative risk of presenting with travel-related bacteremia as compared with gastroenteritis. To evaluate clinical outcomes, we compared patients with travel-related bacteremia and patients with domestically acquired bacteremia in terms of length of hospital stay, number of extraintestinal focal infections and mortality after 30 and 90 days.</p> <p>Results</p> <p>We identified 311 patients hospitalized with non-typhoidal <it>Salmonella </it>bacteremia of whom 76 (24.4%) had a history of international travel. The risk of travel-related bacteremia per traveller was highest in the age groups 15-24 years (0.8/100,000 travellers) and 65 years and above (1.2/100,000 travellers). The sex- and age-adjusted relative risk of presenting with bacteremia was associated with travel to Sub-Saharan Africa (odds ratio 18.4; 95% confidence interval [6.9-49.5]), the Middle East (10.6; [2.1-53.2]) and South East Asia (4.0; [2.2-7.5]). We found high-risk countries in the same three regions when estimating the risk per traveller according to travel destination. Patients hospitalized with travel-related bacteremia had better clinical outcomes than patients with domestically acquired bacteremia, they had a shorter length of hospital stay (8 vs. 11 days), less extraintestinal focal infections (5 vs. 31 patients) and a lower risk of death within both 30 days (relative risk 0.2; [0.1-0.7]) and 90 days (0.3; [0.1-0.7]). A healthy traveller effect was a plausible explanation for the observed differences in outcomes.</p> <p>Conclusions</p> <p>International travel is a notable risk factor for being hospitalized with non-typhoidal <it>Salmonella </it>bacteremia and the risk differs between age groups and travel destinations. Healthy travellers hospitalized with bacteremia are less likely to have poor outcomes than patients with domestically acquired bacteremia.</p