Is mitochondrial dysfunction a driving mechanism linking COPD to nonsmall cell lung carcinoma?

© ERS 2017. Chronic obstructive pulmonary disease (COPD) patients are at increased risk of developing nonsmall cell lung carcinoma, irrespective of their smoking history. Although the mechanisms behind this observation are not clear, established drivers of carcinogenesis in COPD include oxidative stress and sustained chronic inflammation. Mitochondria are critical in these two processes and recent evidence links increased oxidative stress in COPD patients to mitochondrial damage. We therefore postulate that mitochondrial damage in COPD patients leads to increased oxidative stress and chronic inflammation, thereby increasing the risk of carcinogenesis. The functional state of the mitochondrion is dependent on the balance between its biogenesis and degradation (mitophagy). Dysfunctional mitochondria are a source of oxidative stress and inflammasome activation. In COPD, there is impaired translocation of the ubiquitin-related degradation molecule Parkin following activation of the Pink1 mitophagy pathway, resulting in excessive dysfunctional mitochondria. We hypothesise that deranged pathways in mitochondrial biogenesis and mitophagy in COPD can account for the increased risk in carcinogenesis. To test this hypothesis, animal models exposed to cigarette smoke and developing emphysema and lung cancer should be developed. In the future, the use of mitochondria-based antioxidants should be studied as an adjunct with the aim of reducing the risk of COPD-associated cancer

Climate Dynamics: A Network-Based Approach for the Analysis of Global Precipitation

Precipitation is one of the most important meteorological variables for defining the climate dynamics, but the spatial patterns of precipitation have not been fully investigated yet. The complex network theory, which provides a robust tool to investigate the statistical interdependence of many interacting elements, is used here to analyze the spatial dynamics of annual precipitation over seventy years (1941-2010). The precipitation network is built associating a node to a geographical region, which has a temporal distribution of precipitation, and identifying possible links among nodes through the correlation function. The precipitation network reveals significant spatial variability with barely connected regions, as Eastern China and Japan, and highly connected regions, such as the African Sahel, Eastern Australia and, to a lesser extent, Northern Europe. Sahel and Eastern Australia are remarkably dry regions, where low amounts of rainfall are uniformly distributed on continental scales and small-scale extreme events are rare. As a consequence, the precipitation gradient is low, making these regions well connected on a large spatial scale. On the contrary, the Asiatic South-East is often reached by extreme events such as monsoons, tropical cyclones and heat waves, which can all contribute to reduce the correlation to the short-range scale only. Some patterns emerging between mid-latitude and tropical regions suggest a possible impact of the propagation of planetary waves on precipitation at a global scale. Other links can be qualitatively associated to the atmospheric and oceanic circulation. To analyze the sensitivity of the network to the physical closeness of the nodes, short-term connections are broken. The African Sahel, Eastern Australia and Northern Europe regions again appear as the supernodes of the network, confirming furthermore their long-range connection structure. Almost all North-American and Asian nodes vanish, revealing that extreme events can enhance high precipitation gradients, leading to a systematic absence of long-range patterns

Assessing Graphical Robot Aids for Interactive Co-working

The shift towards more collaborative working between humans and robots increases the need for improved interfaces. Alongside robust measures to ensure safety and task performance, humans need to gain the confidence in robot co-operators to enable true collaboration. This research investigates how graphical signage can support human–robot co-working, with the intention of increased productivity. Participants are required to co-work with a KUKA iiwa lightweight manipulator on a manufacturing task. The three conditions in the experiment differ in the signage presented to the participants – signage relevant to the task, irrelevant to the task, or no signage. A change between three conditions is expected in anxiety and negative attitudes towards robots; error rate; response time; and participants’ complacency, suggested by facial expressions. In addition to understanding how graphical languages can support human–robot co-working, this study provides a basis for further collaborative research to explore human–robot co-working in more detail

“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

Illustrating risk difference and number needed to treat from a randomized controlled trial of spinal manipulation for cervicogenic headache

<p>Abstract</p> <p>Background</p> <p>The number needed to treat (NNT) for one participant to benefit is considered a useful, clinically meaningful way of reporting binary outcomes from randomized trials. Analysis of continuous data from our randomized controlled trial has previously demonstrated a significant and clinically important difference favoring spinal manipulation over a light massage control.</p> <p>Methods</p> <p>Eighty participants were randomized to receive spinal manipulation or a light massage control (n = 40/group). Improvements in cervicogenic headache pain (primary outcome), disability, and number in prior four weeks were dichotomized into binary outcomes at two thresholds: 30% representing minimal clinically important change and 50% representing clinical success. Groups were compared at 12 and 24-week follow-up using binomial regression (generalized linear models) to compute the adjusted risk difference (RD) between groups and number needed to treat (NNT) after adjusting for baseline differences between groups. Results were compared to logistic regression results.</p> <p>Results</p> <p>For headache pain, clinically important improvement (30% or 50%) was more likely for spinal manipulation: adjusted RD = 17% to 27% and NNT = 3.8 to 5.8 (p = .005 to .028). Some statistically significant results favoring manipulation were found for headache disability and number.</p> <p>Conclusion</p> <p>Spinal manipulation demonstrated a benefit in terms of a clinically important improvement of cervicogenic headache pain. The use of adjusted NNT is recommended; however, adjusted RD may be easier to interpret than NNT. The study demonstrated how results may depend on the threshold for dichotomizing variables into binary outcomes.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov NLM identifier NCT00246350.</p

Reporting on covariate adjustment in randomised controlled trials before and after revision of the 2001 CONSORT statement: a literature review

<p>Abstract</p> <p>Objectives</p> <p>To evaluate the use and reporting of adjusted analysis in randomised controlled trials (RCTs) and compare the quality of reporting before and after the revision of the CONSORT Statement in 2001.</p> <p>Design</p> <p>Comparison of two cross sectional samples of published articles.</p> <p>Data Sources</p> <p>Journal articles indexed on PubMed in December 2000 and December 2006.</p> <p>Study Selection</p> <p>Parallel group RCTs with a full publication carried out in humans and published in English</p> <p>Main outcome measures</p> <p>Proportion of articles reported adjusted analysis; use of adjusted analysis; the reason for adjustment; the method of adjustment and the reporting of adjusted analysis results in the main text and abstract.</p> <p>Results</p> <p>In both cohorts, 25% of studies reported adjusted analysis (84/355 in 2000 vs 113/422 in 2006). Compared with articles reporting only unadjusted analyses, articles that reported adjusted analyses were more likely to specify primary outcomes, involve multiple centers, perform stratified randomization, be published in general medical journals, and recruit larger sample sizes. In both years a minority of articles explained why and how covariates were selected for adjustment (20% to 30%). Almost all articles specified the statistical methods used for adjustment (99% in 2000 vs 100% in 2006) but only 5% and 10%, respectively, reported both adjusted and unadjusted results as recommended in the CONSORT guidelines.</p> <p>Conclusion</p> <p>There was no evidence of change in the reporting of adjusted analysis results five years after the revision of the CONSORT Statement and only a few articles adhered fully to the CONSORT recommendations.</p

Language-free graphical signage improves human performance and reduces anxiety when working collaboratively with robots

As robots become more ubiquitous, and their capabilities extend, novice users will require intuitive instructional information related to their use. This is particularly important in the manufacturing sector, which is set to be transformed under Industry 4.0 by the deployment of collaborative robots in support of traditionally low-skilled, manual roles. In the first study of its kind, this paper reports how static graphical signage can improve performance and reduce anxiety in participants physically collaborating with a semi-autonomous robot. Three groups of 30 participants collaborated with a robot to perform a manufacturing-type process using graphical information that was relevant to the task, irrelevant, or absent. The results reveal that the group exposed to relevant signage was significantly more accurate in undertaking the task. Furthermore, their anxiety towards robots significantly decreased as a function of increasing accuracy. Finally, participants exposed to graphical signage showed positive emotional valence in response to successful trials. At a time when workers are concerned about the threat posed by robots to jobs, and with advances in technology requiring upskilling of the workforce, it is important to provide intuitive and supportive information to users. Whilst increasingly sophisticated technical solutions are being sought to improve communication and confidence in human-robot co-working, our findings demonstrate how simple signage can still be used as an effective tool to reduce user anxiety and increase task performance

Modulation of the surface proteome through multiple ubiquitylation pathways in African Trypanosomes

Recently we identified multiple suramin-sensitivity genes with a genome wide screen in Trypanosoma brucei that includes the invariant surface glycoprotein ISG75, the adaptin-1 (AP-1) complex and two deubiquitylating enzymes (DUBs) orthologous to ScUbp15/HsHAUSP1 and pVHL-interacting DUB1 (type I), designated TbUsp7 and TbVdu1, respectively. Here we have examined the roles of these genes in trafficking of ISG75, which appears key to suramin uptake. We found that, while AP-1 does not influence ISG75 abundance, knockdown of TbUsp7 or TbVdu1 leads to reduced ISG75 abundance. Silencing TbVdu1 also reduced ISG65 abundance. TbVdu1 is a component of an evolutionarily conserved ubiquitylation switch and responsible for rapid receptor modulation, suggesting similar regulation of ISGs in T. brucei. Unexpectedly, TbUsp7 knockdown also blocked endocytosis. To integrate these observations we analysed the impact of TbUsp7 and TbVdu1 knockdown on the global proteome using SILAC. For TbVdu1, ISG65 and ISG75 are the only significantly modulated proteins, but for TbUsp7 a cohort of integral membrane proteins, including the acid phosphatase MBAP1, that is required for endocytosis, and additional ISG-related proteins are down-regulated. Furthermore, we find increased expression of the ESAG6/7 transferrin receptor and ESAG5, likely resulting from decreased endocytic activity. Therefore, multiple ubiquitylation pathways, with a complex interplay with trafficking pathways, control surface proteome expression in trypanosomes

Pediatric primary intramedullary spinal cord glioblastoma

Spinal cord tumors in pediatric patients are rare, representing less than 1% of all central nervous system tumors. Two cases of pediatric primary intramedullary spinal cord glioblastoma at ages 14 and 8 years are reported. Both patients presented with rapid onset paraparesis and quadraparesis. Magnetic resonance imaging in both showed heterogeneously enhancing solitary mass lesions localized to lower cervical and upper thoracic spinal cord parenchyma. Histopathologic diagnosis was glioblastoma. Case #1 had a small cell component (primitive neuroectodermal tumor-like areas), higher Ki67, and p53 labeling indices, and a relatively stable karyotype with only minimal single copy losses involving regions: Chr8;pter-30480019, Chr16;pter-29754532, Chr16;56160245–88668979, and Chr19;32848902-qter on retrospective comparative genomic hybridization using formalin-fixed, paraffin-embedded samples. Case #2 had relatively bland histomorphology and negligible p53 immunoreactivity. Both underwent multimodal therapy including gross total resection, postoperative radiation and chemotherapy. However, there was no significant improvement in neurological deficits, and overall survival in both cases was 14 months.This report highlights the broad histological spectrum and poor overall survival despite multi modality therapy. The finding of relatively unique genotypic abnormalities resembling pediatric embryonal tumors in one case may highlight the value of genome-wide profiling in development of effective therapy. The differences in management with intracranial and low-grade spinal cord gliomas and current management issues are discussed