Mutual information rate and bounds for it

The amount of information exchanged per unit of time between two nodes in a dynamical network or between two data sets is a powerful concept for analysing complex systems. This quantity, known as the mutual information rate (MIR), is calculated from the mutual information, which is rigorously defined only for random systems. Moreover, the definition of mutual information is based on probabilities of significant events. This work offers a simple alternative way to calculate the MIR in dynamical (deterministic) networks or between two data sets (not fully deterministic), and to calculate its upper and lower bounds without having to calculate probabilities, but rather in terms of well known and well defined quantities in dynamical systems. As possible applications of our bounds, we study the relationship between synchronisation and the exchange of information in a system of two coupled maps and in experimental networks of coupled oscillators

Green Plants in the Red: A Baseline Global Assessment for the IUCN Sampled Red List Index for Plants

Plants provide fundamental support systems for life on Earth and are the basis for all terrestrial ecosystems; a decline in plant diversity will be detrimental to all other groups of organisms including humans. Decline in plant diversity has been hard to quantify, due to the huge numbers of known and yet to be discovered species and the lack of an adequate baseline assessment of extinction risk against which to track changes. The biodiversity of many remote parts of the world remains poorly known, and the rate of new assessments of extinction risk for individual plant species approximates the rate at which new plant species are described. Thus the question ‘How threatened are plants?’ is still very difficult to answer accurately. While completing assessments for each species of plant remains a distant prospect, by assessing a randomly selected sample of species the Sampled Red List Index for Plants gives, for the first time, an accurate view of how threatened plants are across the world. It represents the first key phase of ongoing efforts to monitor the status of the world’s plants. More than 20% of plant species assessed are threatened with extinction, and the habitat with the most threatened species is overwhelmingly tropical rain forest, where the greatest threat to plants is anthropogenic habitat conversion, for arable and livestock agriculture, and harvesting of natural resources. Gymnosperms (e.g. conifers and cycads) are the most threatened group, while a third of plant species included in this study have yet to receive an assessment or are so poorly known that we cannot yet ascertain whether they are threatened or not. This study provides a baseline assessment from which trends in the status of plant biodiversity can be measured and periodically reassessed

Horizontal DNA transfer mechanisms of bacteria as weapons of intragenomic conflict

Horizontal DNA transfer (HDT) is a pervasive mechanism of diversification in many microbial species, but its primary evolutionary role remains controversial. Much recent research has emphasised the adaptive benefit of acquiring novel DNA, but here we argue instead that intragenomic conflict provides a coherent framework for understanding the evolutionary origins of HDT. To test this hypothesis, we developed a mathematical model of a clonally descended bacterial population undergoing HDT through transmission of mobile genetic elements (MGEs) and genetic transformation. Including the known bias of transformation toward the acquisition of shorter alleles into the model suggested it could be an effective means of counteracting the spread of MGEs. Both constitutive and transient competence for transformation were found to provide an effective defence against parasitic MGEs; transient competence could also be effective at permitting the selective spread of MGEs conferring a benefit on their host bacterium. The coordination of transient competence with cell-cell killing, observed in multiple species, was found to result in synergistic blocking of MGE transmission through releasing genomic DNA for homologous recombination while simultaneously reducing horizontal MGE spread by lowering the local cell density. To evaluate the feasibility of the functions suggested by the modelling analysis, we analysed genomic data from longitudinal sampling of individuals carrying Streptococcus pneumoniae. This revealed the frequent within-host coexistence of clonally descended cells that differed in their MGE infection status, a necessary condition for the proposed mechanism to operate. Additionally, we found multiple examples of MGEs inhibiting transformation through integrative disruption of genes encoding the competence machinery across many species, providing evidence of an ongoing "arms race." Reduced rates of transformation have also been observed in cells infected by MGEs that reduce the concentration of extracellular DNA through secretion of DNases. Simulations predicted that either mechanism of limiting transformation would benefit individual MGEs, but also that this tactic's effectiveness was limited by competition with other MGEs coinfecting the same cell. A further observed behaviour we hypothesised to reduce elimination by transformation was MGE activation when cells become competent. Our model predicted that this response was effective at counteracting transformation independently of competing MGEs. Therefore, this framework is able to explain both common properties of MGEs, and the seemingly paradoxical bacterial behaviours of transformation and cell-cell killing within clonally related populations, as the consequences of intragenomic conflict between self-replicating chromosomes and parasitic MGEs. The antagonistic nature of the different mechanisms of HDT over short timescales means their contribution to bacterial evolution is likely to be substantially greater than previously appreciated

Ablative therapy for people with localised prostate cancer: a systematic review and economic evaluation

© Queen’s Printer and Controller of HMSO 2015.Background People diagnosed with cancer of the prostate, a sex gland in the pelvis, have a choice of treatment options depending on the severity of disease. For people whose cancer is at medium and low risk of spread, the main options are surgical removal of the prostate, radical prostatectomy (RP), use of external beam radiotherapy (EBRT) to destroy the cancer or delaying treatment until there are signs that the cancer is getting worse [active surveillance (AS)]. RP and radiotherapy are effective at curing the cancer but may also cause long-term urinary incontinence and sexual problems. AS, on the other hand, may be quite difficult for people to cope with as they know that the cancer is still present. Newer treatments aim to target the disease more precisely so that surrounding normal tissues can be preserved, reducing the risk of side effects but still effectively destroying the cancer. These more targeted ablative therapies include cryotherapy, high-intensity focused ultrasound (HIFU), brachytherapy, photodynamic therapy (PDT), radiofrequency interstitial tumour ablation (RITA) and laser therapy, among others. Aims This study aimed to develop clinical care pathways relevant to a UK NHS context review systematically the evidence of the clinical effectiveness and safety of each newer ablative therapy concerning primary and salvage treatment of localised prostate cancer• determine which therapies are most likely to be cost-effective for implementation in the UK NHS identify and prioritise future research needs. Methods Clinical effectiveness review We conducted two discrete systematic reviews: (a) primary ablative treatment of localised prostate cancer compared with AS, RP or EBRT (b) salvage ablative treatment for local prostate cancer relapse after primary EBRT compared with salvage RP. MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, Bioscience Information Service (BIOSIS), Science Citation Index, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and the Health Technology Assessment (HTA) databases were searched to the end of March 2013. Reference lists of all included studies were scanned and experts on our advisory panel were contacted for details of additional reports. Evidence came from randomised controlled trials (RCTs), non-randomised comparative studies (NRCSs) (if no RCT evidence was identified) and single-arm cohort studies (case series) with greater than 10 participants for the ablative procedures only. Conference abstracts or non-English-language reports were excluded. For the primary therapy systematic review, the ablative therapies considered were cryotherapy, HIFU, PDT, RITA, laser ablation and brachytherapy. The comparators were AS, RP and EBRT. For the salvage therapy systematic review, the ablative therapies considered were cryotherapy and HIFU. The comparator was RP. Outcomes were cancer related, adverse effects (functional and procedural) and quality of life. Two reviewers extracted data and carried out quality assessment. For meta-analysis, a Bayesian indirect mixed-treatment comparison was used. Cost-effectiveness The cost-effectiveness of the different treatments and their subsequent care pathways was assessed using a modified Markov individual simulation model, applied to a UK NHS setting. The perspective for the model was a health services perspective. Parameter estimates were derived from the systematic review of clinical effectiveness, a micro-costing exercise, other literature, the expert advisory group and other UK sources. The outputs of the model were costs and quality-adjusted life-years (QALYs) for each procedure, incremental costs and QALYs and incremental cost per QALY over the remaining lifetime. Both costs and QALYs were discounted at 3.5%. An elasticity analysis, together with probabilistic and deterministic sensitivity analyses, were performed to explore the uncertainty surrounding parameter estimates. Results Clinical effectiveness Cryotherapy Data from 3995 patients who received cryotherapy across 19 studies (1 RCT, 4 NRCSs and 14 case series) were included, with most studies considered to be at high risk of bias. In the short term, there was conflicting evidence relating to cancer-specific outcomes when cryotherapy was compared with either EBRT or surgery. The only finding that reached statistical significance was 1-year disease-free survival, which was worse for cryotherapy than for either EBRT or RP. However, none of the other cancer-specific outcomes, such as biochemical failure or overall survival, showed any significant differences between them. The findings in relation to cancer-specific outcomes are best regarded as inconclusive. There was evidence that the rate of urinary incontinence at 1 year was lower for people undergoing cryotherapy than for those undergoing RP [3% vs. 66%; odds ratio (OR) 0.02, 95% credible interval (CrI) < 0.01 to 0.34], but the size of the difference decreased with longer follow-up. There was a general trend for cryotherapy to have fewer procedural complications, apart from urinary retention. The only difference that reached statistical significance was for urethral stricture, which was less frequent after cryotherapy than after RP (1% vs. 8%; OR 0.24, 95% CrI 0.09 to 0.54). High-intensity focused ultrasound Data from 4000 patients who received HIFU across 21 studies (1 NRCS and 20 case series) were included, with all studies considered to be at high risk of bias. There was some evidence that biochemical failure rates were higher at 1 year when using HIFU than when using EBRT, and this was statistically significant. However, the difference was no longer statistically significant at 5 years. Similar findings were observed with regard to disease-free survival at 1 year, with worse outcomes for HIFU than for EBRT, which were statistically significant. The differences were no longer significant at 3 years. The biochemical result was in contrast to overall survival at 4 years, which was higher when using HIFU. There were insufficient data on any urinary incontinence, erectile dysfunction or bowel problems to draw any robust conclusions, although at 1 year HIFU had lower incontinence rates than RP (10% vs. 66%; OR 0.06, 95% CrI 0.01 to 0.48). The safety profile for HIFU was generally good, apart from a potential numerical increase in rates of urinary retention and dysuria. However, HIFU appeared to have a slightly higher incidence of urethral stricture than EBRT, and the difference was statistically significant (8% vs. 1%; OR 5.8, 95% CrI 1.2 to 24.5). Brachytherapy This review considered data from 26,129 patients who received brachytherapy across 40 studies (2 RCTs and 38 NRCSs), with most studies considered to be at high risk of bias. The data for brachytherapy were generally more robust than for other ablative therapies. In the short term, there was some evidence at 5-year follow-up that the rate of biochemical failure was lower for brachytherapy (7%) than for EBRT (13%; OR 0.46, 95% CrI 0.32 to 0.67) or RP (11%; OR 0.35, 95% CrI 0.21 to 0.56). There was also some evidence that disease-free survival was better for brachytherapy at 3-year follow-up. There was evidence that the rate of urinary incontinence up to 5 years after treatment was lower for people undergoing brachytherapy than for RP, but the size of the difference decreased with longer follow-up. There was also a trend towards lower erectile dysfunction rates for brachytherapy than for EBRT or RP and this reached statistical significance at 3 years after treatment (60% vs. 81% for EBRT and 88% for RP). There were insufficient data to draw any conclusions on bowel problems. The findings regarding procedural complications were mixed. Dysuria rates were higher for brachytherapy and this reached statistical significance when compared with RP. Urinary retention was also statistically significantly higher for brachytherapy than for EBRT. Stricture rates for brachytherapy were higher than those for EBRT, but lower than those for RP. The differences for stricture reached statistical significance when compared with RP. For rectal pain, there was evidence that rates were significantly lower for brachytherapy than for EBRT. Acute genitourinary toxicity, though rare, had statistically higher rates for brachytherapy than for EBRT, but acute gastrointestinal toxicity was lower for brachytherapy. Other ablative therapies Only two other ablative therapies were identified in the review: focal laser ablative therapy and PDT. Data were too scarce (a total of 35 participants for these two procedures) for any conclusions. Salvage therapy Data from 400 participants who were treated with salvage therapy following primary EBRT across nine case series were included. Six studies involved salvage RP, two involved salvage cryotherapy and one involved salvage HIFU. In six studies, data were not collected prospectively, and only short-term outcomes were reported. As such, all of the studies were considered as having a high risk of bias. There was no robust evidence that mortality or other cancer-specific outcomes differed between salvage cryotherapy and salvage RP in the short term. There were no data on cancer-specific outcomes for salvage HIFU. In regard to functional and quality of life outcomes, lack of data prevented any conclusions. In terms of adverse event outcomes, salvage cryotherapy had numerically fewer periprocedural complications (especially for bladder neck stenosis) than salvage HIFU or salvage RP, but there was a high level of uncertainty with this observation. Focal ablation Descriptive subgroup assessment within studies reporting the use of focal ablation was limited, but suggested that cancer-specific outcomes were at least comparable with those seen in full-gland therapy studies. Urinary incontinence rates may be lower following focal ablation, but the evidence is weak in light of the poor quality and quantity of the data. Active surveillance Lack of outcome data prevented comparison of the efficacy of ablative therapies with a programme of AS, apart from the rate of erectile dysfunction at 12 months, where there was no statistically significant difference. Cost-effectiveness Assuming equal recurrence in line with the lack of statistical differences from the effectiveness review, EBRT was the least costly (£19,363 per patient) and least effective (3.63 QALYs), whereas HIFU was more costly (£19,860 per patient) and more effective (3.86 QALYs). HIFU was more effective and less costly than the other newer ablative interventions. The lifetime incremental cost per QALY for HIFU compared with EBRT was £2915. There was a 75% chance that HIFU would be considered cost-effective at a £30,000-per-QALY threshold. In a plausible best-and-worst-case analysis, the probability that HIFU would be considered cost-effective varied between 60% and 70%. Strengths and limitations The main strength of the study was the systematic approach taken to review the literature and the inclusion of a relatively large quantity of studies, giving a high total number of participants. The main limitations were the low quantity and poor quality of the data available on cancer-related outcomes and long-term adverse events of urinary incontinence, sexual and bowel dysfunction, and the changing technology over the review period. Many published studies were poorly reported or lacked sufficient detail. Inconsistency in outcome definition, measurement and reporting was also a significant problem, and much of the information available was unsuitable for meta-analysis. Another major limitation resulted from the majority of comparisons being made using case series, with few head-to-head comparisons of ablative therapies against current practice. The estimates were therefore generated using indirect comparisons. Like all analyses, they require assumptions to be made that may or may not be reasonable. Accordingly, the results should be interpreted with a large degree of caution. Despite the considerable efforts to construct a model and seek the best data available, the lack of effectiveness data had implications for the economic evaluation. The limited data meant that there was insufficient evidence to assume that there was any difference between interventions for a number of parameters, a particular issue for biochemical recurrence, which was a key parameter in the evaluation. The impact of these assumptions was explored in sensitivity analyses. Conclusions Implications for health care For primary ablative therapy, neither cryotherapy nor HIFU had sufficiently robust data to enable any definitive conclusions to be made. The effectiveness data on brachytherapy were more robust and there was some evidence that cancer-specific outcomes in the short term were either better or equivalent to either EBRT or RP, with comparable adverse effect profiles apart from a possible increased risk of dysuria and urinary retention. The findings on focal ablative therapy were mostly derived from data on focal cryotherapy, which suggested that cancer-specific outcomes were at least comparable with those of full-gland cryotherapy, and there was a suggestion that the urinary incontinence outcome may be better following focal cryotherapy than whole-gland cryotherapy. The cost-effectiveness analysis confirmed the uncertainty from the clinical review and that there is no technology which appears superior, on the basis of current evidence, in terms of average cost-effectiveness. The probabilistic sensitivity analyses suggest that a number of ablative techniques are worthy of further research. For salvage ablative therapy following primary EBRT, a lack of reliable and robust data prevented any meaningful conclusions from being made, in comparison with salvage RP. The findings from the review indicate that there is insufficient evidence to help inform recommendations on the use of ablative therapies in the UK NHS. Need for further research The main gaps in the evidence base are the lack of direct comparative studies of ablative therapies; the consequent lack of robust data to inform calculations of cost-effectiveness and the role of focal ablative therapies; and the lack of longer-term data on cancer control, such as overall and cancer-specific mortality. The key research recommendations, in order of importance, are as follows: 1. HIFU and brachytherapy seem the most promising newer interventions but they lack high-quality evaluation. Such evaluation should ideally be by multicentre RCT with long-term follow-up, and would include predefined assessment of cancer-specific, dysfunction and health-related quality-of-life measures. Such studies should incorporate economic evaluations and also inform economic modelling

Sympatric Speciation: When Is It Possible in Bacteria?

This study investigated a potential auditory illusion in duration perception induced by rhythmic temporal contexts. Listeners with or without musical training performed a duration discrimination task for a silent period in a rhythmic auditory sequence. The critical temporal interval was presented either within a perceptual group or between two perceptual groups. We report the just-noticeable difference (difference limen, DL) for temporal intervals and the point of subjective equality (PSE) derived from individual psychometric functions based on performance of a two-alternative forced choice task. In musically untrained individuals, equal temporal intervals were perceived as significantly longer when presented between perceptual groups than within a perceptual group (109.25% versus 102.5% of the standard duration). Only the perceived duration of the between-group interval was significantly longer than its objective duration. Musically trained individuals did not show this effect. However, in both musically trained and untrained individuals, the relative difference limens for discriminating the comparison interval from the standard interval were larger in the between-groups condition than in the within-group condition (7.3% vs. 5.6% of the standard duration). Thus, rhythmic grouping affected sensitivity to duration changes in all listeners, with duration differences being harder to detect at boundaries of rhythm groups than within rhythm groups. Our results show for the first time that temporal Gestalt induces auditory duration illusions in typical listeners, but that musical experts are not susceptible to this effect of rhythmic grouping.Ellison Medical FoundationSwiss National Science Foundation (PA00P1_131448/1

Reach and grasp by people with tetraplegia using a neurally controlled robotic arm

Paralysis following spinal cord injury (SCI), brainstem stroke, amyotrophic lateral sclerosis (ALS) and other disorders can disconnect the brain from the body, eliminating the ability to carry out volitional movements. A neural interface system (NIS)1–5 could restore mobility and independence for people with paralysis by translating neuronal activity directly into control signals for assistive devices. We have previously shown that people with longstanding tetraplegia can use an NIS to move and click a computer cursor and to control physical devices6–8. Able-bodied monkeys have used an NIS to control a robotic arm9, but it is unknown whether people with profound upper extremity paralysis or limb loss could use cortical neuronal ensemble signals to direct useful arm actions. Here, we demonstrate the ability of two people with long-standing tetraplegia to use NIS-based control of a robotic arm to perform three-dimensional reach and grasp movements. Participants controlled the arm over a broad space without explicit training, using signals decoded from a small, local population of motor cortex (MI) neurons recorded from a 96-channel microelectrode array. One of the study participants, implanted with the sensor five years earlier, also used a robotic arm to drink coffee from a bottle. While robotic reach and grasp actions were not as fast or accurate as those of an able-bodied person, our results demonstrate the feasibility for people with tetraplegia, years after CNS injury, to recreate useful multidimensional control of complex devices directly from a small sample of neural signals

Ethics, Nanobiosensors and Elite Sport: The Need for a New Governance Framework

Individual athletes, coaches and sports teams seek continuously for ways to improve performance and accomplishment in elite competition. New techniques of performance analysis are a crucial part of the drive for athletic perfection. This paper discusses the ethical importance of one aspect of the future potential of performance analysis in sport, combining the field of biomedicine, sports engineering and nanotechnology in the form of ‘Nanobiosensors’. This innovative technology has the potential to revolutionise sport, enabling real time biological data to be collected from athletes that can be electronically distributed. Enabling precise real time performance analysis is not without ethical problems. Arguments concerning (1) data ownership and privacy; (2) data confidentiality; and (3) athlete welfare are presented alongside a discussion of the use of the Precautionary Principle in making ethical evaluations. We conclude, that although the future potential use of Nanobiosensors in sports analysis offers many potential benefits, there is also a fear that it could be abused at a sporting system level. Hence, it is essential for sporting bodies to consider the development of a robust ethically informed governance framework in advance of their proliferated use

Voltage-gated Na⁺ channel activity increases colon cancertranscriptional activity and invasion via persistent MAPK signaling

© 2015 Macmillan Publishers Limited. All rights reserved. Functional expression of voltage-gated Na+ channels (VGSCs) has been demonstrated in multiple cancer cell types where channel activity induces invasive activity. The signaling mechanisms by which VGSCs promote oncogenesis remain poorly understood. We explored the signal transduction process critical to VGSC-mediated invasion on the basis of reports linking channel activity to gene expression changes in excitable cells. Coincidentally, many genes transcriptionally regulated by the SCN5A isoform in colon cancer have an over-representation of cis-acting sites for transcription factors phosphorylated by ERK1/2 MAPK. We hypothesized that VGSC activity promotes MAPK activation to induce transcriptional changes in invasion-related genes. Using pharmacological inhibitors/activators and siRNA-mediated gene knockdowns, we correlated channel activity with Rap1-dependent persistent MAPK activation in the SW620 human colon cancer cell line. We further demonstrated that VGSC activity induces downstream changes in invasion-related gene expression via a PKA/ERK/c-JUN/ELK-1/ETS-1 transcriptional pathway. This is the first study illustrating a molecular mechanism linking functional activity of VGSCs to transcriptional activation of invasion-related genes

Faecal immunochemical tests (FIT) can help to rule out colorectal cancer in patients presenting in primary care with lower abdominal symptoms:a systematic review conducted to inform new NICE DG30 diagnostic guidance

__Background:__ This study has attempted to assess the effectiveness of quantitative faecal immunochemical tests (FIT) for triage of people presenting with lower abdominal symptoms, where a referral to secondary care for investigation of suspected colorectal cancer (CRC) is being considered, particularly when the 2-week criteria are not met. __Methods:__ We conducted a systematic review following published guidelines for systematic reviews of diagnostic tests. Twenty-one resources were searched up until March 2016. Summary estimates were calculated using a bivariate model or a random-effects logistic regression model. __Results:__ Nine studies are included in this review. One additional study, included in our systematic review, was provided as 'academic in confidence' and cannot be described herein. When FIT was based on a single faecal sample and a cut-off of 10 μg Hb/g faeces, sensitivity estimates indicated that a negative result using either the OC-Sensor or HM-JACKarc may be adequate to rule out nearly all CRC; the summary estimate of sensitivity for the OC-Sensor was 92.1%, based on four studies, and the only study of HM-JACKarc to assess the 10 μg Hb/g faeces cut-off reported a sensitivity of 100%. The corresponding specificity estimates were 85.8% (95% CI 78.3-91.0%) and 76.6%, respectively. When the diagnostic criterion was changed to include lower grades of neoplasia, i.e. the target condition included higher risk adenoma (HRA) as well as CRC, the rule-out performance of both FIT assays was reduced. __Conclusions:__ There is evidence to suggest that triage using FIT at a cut-off around 10 μg Hb/g faeces has the potential to correctly rule out CRC and avoid colonoscopy in 75-80% of symptomatic patients. Systematic review registration: PROSPERO 4201603772