Low-dose computed tomography for lung cancer screening in high risk populations: a systematic review and economic evaluation

This is the final version. Available from NIHR Journals Library via the DOI in this record.The dataset associated with this article is located in ORE at: https://doi.org/10.24378/exe.564Background Diagnosis of lung cancer frequently occurs in its later stages. Low-dose computed tomography (LDCT) could detect lung cancer early. Objectives To estimate the effectiveness and cost-effectiveness of LDCT lung cancer screening in high risk populations. Methods Clinical effectiveness A systematic review of randomised controlled trials (RCTs) comparing LDCT screening programmes with usual care (no screening) or other imaging screening programme (such as chest X-ray (CXR)) was conducted. Bibliographic sources included MEDLINE, Embase, Web of Science and the Cochrane Library. Meta-analyses, including network meta-analyses, were performed. Cost-effectiveness An independent economic model employing discrete event simulation and using a natural history model calibrated to results from a large RCT was developed. There were twelve different population eligibility criteria and four intervention frequencies (single screen, triple screen, annual screening and biennial screening) and a no screening control arm. Results Clinical effectiveness Twelve RCTs were included, four of which currently contribute evidence on mortality. Meta-analysis of these demonstrated that LDCT with up to 9.80 years of follow-up was associated with a non-statistically significant decrease in lung cancer mortality (pooled RR 0.94, 95% CI 0.74 to 1.19). The findings also showed that LDCT screening demonstrated a non-statistically significant increasein all-cause mortality. Given the considerable heterogeneity detected between studies for both outcomes, the results should be treated with caution. Network meta-analysis including six RCTs was performed to assess the relative effectiveness of LDCT, CXR and usual care. The results showed that LDCT was ranked as the best screening strategy in terms of lung cancer mortality reduction. CXR had a 99.7% probability of being the worst intervention with usual care intermediate. Cost-effectiveness Screening programmes are predicted to be more effective than no screening, reduce lung cancer mortality and result in more lung cancer diagnoses. Screening programmes also increase costs. Screening for lung cancer is unlikely to be cost-effective at a threshold of £20,000/QALY, but may be cost-effective at a threshold of £30,000/QALY. The incremental cost-effectiveness ratio for a single screen in smokers aged 60–75 years with at least a 3% risk of lung cancer is £28,169 per QALY. Sensitivity and scenario analyses were conducted. Screening was only cost-effective at a threshold of £20,000/QALY in a minority of analyses. Limitations Clinical effectiveness The largest of the included RCTs compared LDCT with CXR screening rather than no screening. Cost-effectiveness A representative cost to the NHS of lung cancer has not been recently estimated according to key variables such as stage at diagnosis. Certain costs associated with running a screening programme have not been included. Conclusions LDCT screening may be clinically effective in reducing lung cancer mortality but there is considerable uncertainty. There is evidence that a single round of screening could be considered cost-effective at conventional thresholds, but there is significant uncertainty about the effect on costs and the magnitude of benefits. Future work Effectiveness and cost-effectiveness estimates should be updated with the anticipated results from several ongoing RCTs (particularly NELSON).This report was commissioned by the NIHR Health Technology Assessment Programme as project number 14/151/0

Alterations in endo-lysosomal function induce similar hepatic lipid profiles in rodent models of drug-induced phospholipidosis and Sandhoff disease

Drug-induced phospholipidosis (DIPL) is characterized by an increase in the phospholipid content of the cell and the accumulation of drugs and lipids inside the lysosomes of affected tissues, including in the liver. Although of uncertain pathological significance for patients, the condition remains a major impediment for the clinical development of new drugs. Human Sandhoff disease (SD) is caused by inherited defects of the β subunit of lysosomal β-hexosaminidases (Hex) A and B, leading to a large array of symptoms, including neurodegeneration and ultimately death by the age of 4 in its most common form. The substrates of Hex A and B, gangliosides GM2 and GA2, accumulate inside the lysosomes of the CNS and in peripheral organs. Given that both DIPL and SD are associated with lysosomes and lipid metabolism in general, we measured the hepatic lipid profiles in rodent models of these two conditions using untargeted LC/MS to examine potential commonalities. Both model systems shared a number of perturbed lipid pathways, notably those involving metabolism of cholesteryl esters, lysophosphatidylcholines, bis(monoacylglycero)phosphates, and ceramides. We report here profound alterations in lipid metabolism in the SD liver. In addition, DIPL induced a wide range of lipid changes not previously observed in the liver, highlighting similarities with those detected in the model of SD and raising concerns that these lipid changes may be associated with underlying pathology associated with lysosomal storage disorders.This work was funded by a Medical Research Council Integrative Toxicology Training Partnership grant with financial support from GlaxoSmithKline. The work on Sandhoff mice was supported by SPARKS, The Children’s Medical Research Charity. JLG’s laboratory is supported by the Wellcome Trust (Equipment grant 093,148/Z/10/Z)) and the Medical Research Council (G0801841 & UD99999906)

In the best interests of the deceased: A possible justification for organ removal without consent?

Opt-out systems of postmortem organ procurement are often supposed to be justifiable by presumed consent, but this justification turns out to depend on a mistaken mental state conception of consent. A promising alternative justification appeals to the analogical situation that occurs when an emergency decision has to be made about medical treatment for a patient who is unable to give or withhold his consent. In such cases, the decision should be made in the best interests of the patient. The analogous suggestion to be considered, then, is, if the potential donor has not registered either his willingness or his refusal to donate, the probabilities that he would or would not have preferred the removal of his organs need to be weighed. And in some actual cases the probability of the first alternative may be greater. This article considers whether the analogy to which this argument appeals is cogent, and concludes that there are important differences between the emergency and the organ removal cases, both as regards the nature of the interests involved and the nature of the right not to be treated without one’s consent. Rather, if opt-out systems are to be justified, the needs of patients with organ failure and/or the possibility of tacit consent should be considered

Evaluating the landscape of fear between apex predatory sharks and mobile sea turtles across a large dynamic seascape

The ‘‘landscape of fear’’ model has been proposed as a unifying concept in ecology, describing, in part, how animals behave and move about in their environment. The basic model predicts that as an animal’s landscape changes from low to high risk of predation, prey species will alter their behavior to risk avoidance. However, studies investigating and evaluating the landscape of fear model across large spatial scales (tens to hundreds of thousands of square kilometers) in dynamic, open, aquatic systems involving apex predators and highly mobile prey are lacking. To address this knowledge gap, we investigated predator–prey relationships between tiger sharks (Galeocerdo cuvier) and loggerhead turtles (Caretta caretta) in the North Atlantic Ocean. This included the use of satellite tracking to examine shark and turtle distributions as well as their surfacing behaviors under varying levels of home range overlap. Our findings revealed patterns that deviated from our a priori predictions based on the landscape of fear model. Specifically, turtles did not alter their surfacing behaviors to risk avoidance when overlap in shark–turtle core home range was high. However, in areas of high overlap with turtles, sharks exhibited modified surfacing behaviors that may enhance predation opportunity. We suggest that turtles may be an important factor in determining shark distribution, whereas for turtles, other life history trade-offs may play a larger role in defining their habitat use. We propose that these findings are a result of both biotic and physically driven factors that independently or synergistically affect predator–prey interactions in this system. These results have implications for evolutionary biology, community ecology, and wildlife conservation. Further, given the difficulty in studying highly migratory marine species, our approach and conclusions may be applied to the study of other predator–prey systems.Bald Head Island ConservancyBritish Chelonia GroupNatural Environmental Research CouncilWAVE Foundation/Newport Aquarium CincinnatiPADI project AWARESEATURTLE.ORGWhitener Foundation (NC); an Endangered Species Act Section 6 Cooperative Agreement with NOAA Fisheries and the Grays Reef National Marine Sanctuary (South Carolina and Georgia)Batchelor FoundationDinsey Conservation Fun

Why Are Male Social Relationships Complex in the Doubtful Sound Bottlenose Dolphin Population?

Copyright 2008 Elsevier B.V., All rights reserved.Peer reviewedPublisher PD

The role of TG2 in regulating S100A4-mediated mammary tumour cell migration

The importance of S100A4, a Ca2+-binding protein, in mediating tumour cell migration, both intracellularly and extracellularly, is well documented. Tissue transglutaminase (TG2) a Ca2+-dependent protein crosslinking enzyme, has also been shown to enhance cell migration. Here by using the well characterised non-metastatic rat mammary R37 cells (transfected with empty vector) and highly metastatic KP1 cells (R37 cells transfected with S100A4), we demonstrate that inhibition of TG2 either by TG2 inhibitors or transfection of cells with TG2 shRNA block S100A4-accelerated cell migration in the KP1cells and in R37 cells treated with exogenous S100A4. Cell migration was also blocked by the treatment with the non-cell permeabilizing TG2 inhibitor R294, in the human breast cancer cell line MDA-MB-231 (Clone 16, which has a high level of TG2 expression). Inhibition was paralleled by a decrease in S100A4 polymer formation. co-immunoprecipitation and Far Western blotting assays and cross-linking assays showed not only the direct interaction between TG2 and S100A4, but also confirmed S100A4 as a substrate for TG2. Using specific functional blocking antibodies, a targeting peptide and a recombinant protein as a competitive treatment, we revealed the involvement of syndecan-4 and a5ß1 integrin co-signalling pathways linked by activation of PKCa in this TG2 and S100A4-mediated cell migration. We propose a mechanism for TG2-regulated S100A4-related mediated cell migration, which is dependent on TG2 crosslinking

Whole Body Mechanics of Stealthy Walking in Cats

The metabolic cost associated with locomotion represents a significant part of an animal's metabolic energy budget. Therefore understanding the ways in which animals manage the energy required for locomotion by controlling muscular effort is critical to understanding limb design and the evolution of locomotor behavior. The assumption that energetic economy is the most important target of natural selection underlies many analyses of steady animal locomotion, leading to the prediction that animals will choose gaits and postures that maximize energetic efficiency. Many quadrupedal animals, particularly those that specialize in long distance steady locomotion, do in fact reduce the muscular contribution required for walking by adopting pendulum-like center of mass movements that facilitate exchange between kinetic energy (KE) and potential energy (PE) [1]–[4]. However, animals that are not specialized for long distance steady locomotion may face a more complex set of requirements, some of which may conflict with the efficient exchange of mechanical energy. For example, the “stealthy” walking style of cats may demand slow movements performed with the center of mass close to the ground. Force plate and video data show that domestic cats (Felis catus, Linnaeus, 1758) have lower mechanical energy recovery than mammals specialized for distance. A strong negative correlation was found between mechanical energy recovery and diagonality in the footfalls and there was also a negative correlation between limb compression and diagonality of footfalls such that more crouched postures tended to have greater diagonality. These data show a previously unrecognized mechanical relationship in which crouched postures are associated with changes in footfall pattern which are in turn related to reduced mechanical energy recovery. Low energy recovery was not associated with decreased vertical oscillations of the center of mass as theoretically predicted, but rather with posture and footfall pattern on the phase relationship between potential and kinetic energy. An important implication of these results is the possibility of a tradeoff between stealthy walking and economy of locomotion. This potential tradeoff highlights the complex and conflicting pressures that may govern the locomotor choices that animals make

Multiple ITS Copies Reveal Extensive Hybridization within Rheum (Polygonaceae), a Genus That Has Undergone Rapid Radiation

During adaptive radiation events, characters can arise multiple times due to parallel evolution, but transfer of traits through hybridization provides an alternative explanation for the same character appearing in apparently non-sister lineages. The signature of hybridization can be detected in incongruence between phylogenies derived from different markers, or from the presence of two divergent versions of a nuclear marker such as ITS within one individual.In this study, we cloned and sequenced ITS regions for 30 species of the genus Rheum, and compared them with a cpDNA phylogeny. Seven species contained two divergent copies of ITS that resolved in different clades from one another in each case, indicating hybridization events too recent for concerted evolution to have homogenised the ITS sequences. Hybridization was also indicated in at least two further species via incongruence in their position between ITS and cpDNA phylogenies. None of the ITS sequences present in these nine species matched those detected in any other species, which provides tentative evidence against recent introgression as an explanation. Rheum globulosum, previously indicated by cpDNA to represent an independent origin of decumbent habit, is indicated by ITS to be part of clade of decumbent species, which acquired cpDNA of another clade via hybridization. However decumbent and glasshouse morphology are confirmed to have arisen three and two times, respectively.These findings suggested that hybridization among QTP species of Rheum has been extensive, and that a role of hybridization in diversification of Rheum requires investigation