Risk of cancer in patients with thyroid disease and venous thromboembolism

Diana H Christensen,1 Katalin Veres,1 Anne G Ording,1 Jens Otto L Jørgensen,2 Suzanne C Cannegieter,3 Reimar W Thomsen,1 Henrik T Sørensen1 1Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark; 3Department of Clinical Epidemiology, Leiden University Medical Centre, Leiden, the Netherlands Objective: Risk of venous thromboembolism (VTE) is increased in patients with hypo/hyperthyroidism. It is unknown whether VTE may be a presenting symptom of occult cancer in these patients. Design: Nationwide population-based cohort study based on Danish medical registry data. Methods: We identified all patients diagnosed with VTE during 1978–2013 who had a previous or concurrent diagnosis of hypothyroidism (N=1481) or hyperthyroidism (N=1788). We followed them until a first-time cancer diagnosis, death, emigration, or study end, whichever came first. We calculated 1-year absolute cancer risk and standardized incidence ratios (SIRs) for cancer incidence in the study population compared with national cancer incidence in the general population. Results: During the first year after a VTE diagnosis, the 1-year absolute cancer risk was 3.0% among patients with hypothyroidism and 3.9% among those with hyperthyroidism. During the first year of follow-up, SIRs for cancer in the study population compared with the general population were 1.96 (95% CI: 1.42–2.64) among patients with hypothyroidism and 2.67 (95% CI: 2.07–3.39) among those with hyperthyroidism. SIRs declined substantially after 1 year but remained increased during the remainder of the follow-up period (up to 36 years) (SIR for hypothyroidism=1.16 [95% CI: 0.97–1.39]; SIR for hyperthyroidism=1.26 [95% CI: 1.08–1.46]). Conclusion: VTE may be a marker of underlying occult cancer in patients with hypothyroidism or hyperthyroidism. Keywords: hyperthyroidism, hypothyroidism, venous thromboembolism, cancer, cohort stud

Effectiveness of stratified treatment for back pain in Danish primary care: A randomized controlled trial

Background A randomized controlled trial (RCT) of stratified care demonstrated superior clinical outcomes and cost-effectiveness for low back pain (LBP) patients in UK primary care. This is the first study in Europe, outside of the original UK study, to investigate the clinical efficacy and cost-effectiveness of stratified care compared with current practice for patients with non-specific LBP. Methods The study was a two-armed RCT. Danish primary care patients with LBP were randomized to stratified care (n = 169) or current practice (n = 164). Primary outcomes at 3- and 12-months' follow-up were Roland Morris Disability Questionnaire (RDMQ), patient-reported global change and time off work. Secondary outcomes included pain intensity, patient satisfaction, healthcare resource utilization and quality-adjusted life years. Results Intention-to-treat analyses found no between-group difference in RMDQ scores at 3 months (0.5, 95% CI −1.8 to 0.9) or 12 months (0.4, −2.1 to 1.3). No overall differences were found between the arms at 3 and 12 months with respect to time off work or secondary outcomes. Stratified care intervention resulted in significantly fewer treatment sessions (3.5 [SD 3.1] vs. 4.5 [3.5]) and significantly lower total healthcare costs (€) (13.4 [529] vs. 228 [830], p = .002). There was no difference in cost-effectiveness (0.09, 0.05 to 0.13 vs. 0.10, 0.07–0.14, p = .70). Conclusions There was no significant difference in clinical outcomes between patients with non-specific LBP receiving stratified care and those receiving current practice. However, stratified care may reduce total healthcare costs if implemented in Danish primary care. Significance Stratified care for low back pain based on risk profile is recommended by recent evidence based clinical guidelines. This study is the first broad replication of the STarT Back Trial in Europe. Therefore, the study adds to the body of knowledge evaluating the effectiveness of stratified care for low back pain in primary care, and provides insight into the effects of stratification on clinical practice

Development of the Prevent for Work questionnaire (P4Wq) for assessment of musculoskeletal risk in the workplace: part 1-literature review and domains selection

Objective This study aims to define appropriate domains and items for the development of a self-administered questionnaire to assess the risk of developing work-related musculoskeletal disorder (WMSD) and the risk of its progression to chronicity. Design Literature review and survey study. Setting and participants A literature review and a two-round interview with 15 experts in musculoskeletal pain were performed to identify the available domains for WMSD assessment. Interventions and outcome To ensure quality, only validated questionnaires were included for the Delphi process. A three-round Delphi method, with three round steps, was used to select the most pertinent and relevant domains and items. Results Nine questionnaires were identified through the expert discussion and literature review, comprising 38 candidate domains and 504 items. In the first round of the Delphi group, 17 domains reached more than 70% agreement and were selected. In the second round, 10 domains were rejected, while 11 were selected to complete the pool of domains. In the third and final round, 89 items belonging to 28 domains were defined as significant to develop a WMSDs risk assessment questionnaire. Conclusions No specific risk assessment questionnaires for WMSDs were identified from the literature. WMSD risk of presence and chronicity can be defined by an assessment tool based on the biopsychosocial model and the fear-avoidance components of chronic pain. The present study provides the formulation and operationalisation of the constructs in domains and items needed for developing and validating the questionnaire

Extended self-knowledge

We aim to move the externalism and self-knowledge debate forward by exploring two novel sceptical challenges to the prospects of self-knowledge of a paradigmatic sort, both of which result from ways in which our thought content, cognitive processes and cognitive successes depend crucially on our external environments. In particular, it is shown how arguments from extended cognition (e.g., Clark A, Chalmers D. Analysis 58:7–19 (1998); Clark A. Supersizing the mind: Embodiment, action, and cognitive extension. Oxford: Oxford University Press (2008)) and situationism (e.g., Alfano M. The Philosophical Quarterly 62:223–249 (2012), Alfano M. Expanding the situationist challenge to reliabilism about inference. In Fairweather A (ed) Virtue epistemology naturalized, Springer, Dordrecht, pp 103–122 (2014); Doris JM. Noûs 32:504–530 (1998), Doris JM. Lack of character: Personality and moral behavior. Cambridge University Press, Cambridge (2002); Harman G. Proceedings of the Aristotelian Society. 99:315–331 (1999), Harman G. Proceedings of the Aristotelian Society 100:223–226 (2000)) pose hitherto unexplored challenges to the prospects of self-knowledge as it is traditionally conceived. It is shown, however, that, suitably understood, these apparent challenges in fact only demonstrate two ways in which our cognitive lives can be dependent on our environment. As such, rather than undermining our prospects for attaining self-knowledge, they instead illustrate how self-knowledge can be extended and expanded

Sphingosine 1-phosphate modulates antigen capture by murine langerhans cells via the S1P2 receptor subtype

Dendritic cells (DCs) play a pivotal role in the development of cutaneous contact hypersensitivity (CHS) and atopic dermatitis as they capture and process antigen and present it to T lymphocytes in the lymphoid organs. Recently, it has been indicated that a topical application of the sphingolipid sphingosine 1-phosphate (S1P) prevents the inflammatory response in CHS, but the molecular mechanism is not fully elucidated. Here we indicate that treatment of mice with S1P is connected with an impaired antigen uptake by Langerhans cells (LCs), the initial step of CHS. Most of the known actions of S1P are mediated by a family of five specific G protein-coupled receptors. Our results indicate that S1P inhibits macropinocytosis of the murine LC line XS52 via S1P2 receptor stimulation followed by a reduced phosphatidylinositol 3-kinase (PI3K) activity. As down-regulation of S1P2 not only diminished S1P-mediated action but also enhanced the basal activity of LCs on antigen capture, an autocrine action of S1P has been assumed. Actually, S1P is continuously produced by LCs and secreted via the ATP binding cassette transporter ABCC1 to the extracellular environment. Consequently, inhibition of ABCC1, which decreased extracellular S1P levels, markedly increased the antigen uptake by LCs. Moreover, stimulation of sphingosine kinase activity, the crucial enzyme for S1P formation, is connected not only with enhanced S1P levels but also with diminished antigen capture. These results indicate that S1P is essential in LC homeostasis and influences skin immunity. This is of importance as previous reports suggested an alteration of S1P levels in atopic skin lesions

Predicting consumer biomass, size-structure, production, catch potential, responses to fishing and associated uncertainties in the world's marine ecosystems

Existing estimates of fish and consumer biomass in the world’s oceans are disparate. This creates uncertainty about the roles of fish and other consumers in biogeochemical cycles and ecosystem processes, the extent of human and environmental impacts and fishery potential. We develop and use a size-based macroecological model to assess the effects of parameter uncertainty on predicted consumer biomass, production and distribution. Resulting uncertainty is large (e.g. median global biomass 4.9 billion tonnes for consumers weighing 1 g to 1000 kg; 50% uncertainty intervals of 2 to 10.4 billion tonnes; 90% uncertainty intervals of 0.3 to 26.1 billion tonnes) and driven primarily by uncertainty in trophic transfer efficiency and its relationship with predator-prey body mass ratios. Even the upper uncertainty intervals for global predictions of consumer biomass demonstrate the remarkable scarcity of marine consumers, with less than one part in 30 million by volume of the global oceans comprising tissue of macroscopic animals. Thus the apparently high densities of marine life seen in surface and coastal waters and frequently visited abundance hotspots will likely give many in society a false impression of the abundance of marine animals. Unexploited baseline biomass predictions from the simple macroecological model were used to calibrate a more complex size- and trait-based model to estimate fisheries yield and impacts. Yields are highly dependent on baseline biomass and fisheries selectivity. Predicted global sustainable fisheries yield increases ≈4 fold when smaller individuals (< 20 cm from species of maximum mass < 1kg) are targeted in all oceans, but the predicted yields would rarely be accessible in practice and this fishing strategy leads to the collapse of larger species if fishing mortality rates on different size classes cannot be decoupled. Our analyses show that models with minimal parameter demands that are based on a few established ecological principles can support equitable analysis and comparison of diverse ecosystems. The analyses provide insights into the effects of parameter uncertainty on global biomass and production estimates, which have yet to be achieved with complex models, and will therefore help to highlight priorities for future research and data collection. However, the focus on simple model structures and global processes means that non-phytoplankton primary production and several groups, structures and processes of ecological and conservation interest are not represented. Consequently, our simple models become increasingly less useful than more complex alternatives when addressing questions about food web structure and function, biodiversity, resilience and human impacts at smaller scales and for areas closer to coasts

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

B cells and monocytes from patients with active multiple sclerosis exhibit increased surface expression of both HERV-H Env and HERV-W Env, accompanied by increased seroreactivity

<p>Abstract</p> <p>Background</p> <p>The etiology of the neurogenerative disease multiple sclerosis (MS) is unknown. The leading hypotheses suggest that MS is the result of exposure of genetically susceptible individuals to certain environmental factor(s). Herpesviruses and human endogenous retroviruses (HERVs) represent potentially important factors in MS development. Herpesviruses can activate HERVs, and HERVs are activated in MS patients.</p> <p>Results</p> <p>Using flow cytometry, we have analyzed HERV-H Env and HERV-W Env epitope expression on the surface of PBMCs from MS patients with active and stable disease, and from control individuals. We have also analyzed serum antibody levels to the expressed HERV-H and HERV-W Env epitopes. We found a significantly higher expression of HERV-H and HERV-W Env epitopes on B cells and monocytes from patients with active MS compared with patients with stable MS or control individuals. Furthermore, patients with active disease had relatively higher numbers of B cells in the PBMC population, and higher antibody reactivities towards HERV-H Env and HERV-W Env epitopes. The higher antibody reactivities in sera from patients with active MS correlate with the higher levels of HERV-H Env and HERV-W Env expression on B cells and monocytes. We did not find such correlations for stable MS patients or for controls.</p> <p>Conclusion</p> <p>These findings indicate that both HERV-H Env and HERV-W Env are expressed in higher quantities on the surface of B cells and monocytes in patients with active MS, and that the expression of these proteins may be associated with exacerbation of the disease.</p

Varicella zoster virus infection of highly pure terminally differentiated human neurons

In vitro analyses of varicella zoster virus (VZV) reactivation from latency in human ganglia have been hampered by the inability to isolate virus by explantation or cocultivation techniques. Furthermore, attempts to study interaction of VZV with neurons in experimentally infected ganglion cells in vitro have been impaired by the presence of nonneuronal cells, which become productively infected and destroy the cultures. We have developed an in vitro model of VZV infection in which highly pure (>95 %) terminally differentiated human neurons derived from pluripotent stem cells were infected with VZV. At 2 weeks post-infection, infected neurons appeared healthy compared to VZV-infected human fetal lung fibroblasts (HFLs), which developed a cytopathic effect (CPE) within 1 week. Tissue culture medium from VZV-infected neurons did not produce a CPE in uninfected HFLs and did not contain PCR-amplifiable VZV DNA, but cocultivation of infected neurons with uninfected HFLs did produce a CPE. The nonproductively infected neurons contained multiple regions of the VZV genome, as well as transcripts and proteins corresponding to VZV immediate-early, early, and late genes. No markers of the apoptotic caspase cascade were detected in healthy-appearing VZV-infected neurons. VZV infection of highly pure terminally differentiated human neurons provides a unique in vitro system to study the VZV-neuronal relationship and the potential to investigate mechanisms of VZV reactivation