Bridging Time Scales in Cellular Decision Making with a Stochastic Bistable Switch

Cellular transformations which involve a significant phenotypical change of the cell's state use bistable biochemical switches as underlying decision systems. In this work, we aim at linking cellular decisions taking place on a time scale of years to decades with the biochemical dynamics in signal transduction and gene regulation, occuring on a time scale of minutes to hours. We show that a stochastic bistable switch forms a viable biochemical mechanism to implement decision processes on long time scales. As a case study, the mechanism is applied to model the initiation of follicle growth in mammalian ovaries, where the physiological time scale of follicle pool depletion is on the order of the organism's lifespan. We construct a simple mathematical model for this process based on experimental evidence for the involved genetic mechanisms. Despite the underlying stochasticity, the proposed mechanism turns out to yield reliable behavior in large populations of cells subject to the considered decision process. Our model explains how the physiological time constant may emerge from the intrinsic stochasticity of the underlying gene regulatory network. Apart from ovarian follicles, the proposed mechanism may also be of relevance for other physiological systems where cells take binary decisions over a long time scale.Comment: 14 pages, 4 figure

Cost effectiveness of stapled haemorrhoidopexy and traditional excisional surgery for the treatment of haemorrhoidal disease

Objective Our objective was to compare the cost effectiveness of stapled haemorrhoidopexy (SH) and traditional haemorrhoidectomy (TH) in the treatment of grade II–IV haemorrhoidal disease from the perspective of the UK national health service. Methods An economic evaluation was conducted alongside an open, two-arm, parallel-group, pragmatic, multicentre, randomised controlled trial conducted in several hospitals in the UK. Patients were randomised into either SH or TH surgery between January 2011 and August 2014 and were followed up for 24 months. Intervention and subsequent resource use data were collected using case review forms and questionnaires. Benefits were collected using the EQ-5D-3L (EuroQoL—five dimensions—three levels) instrument. The primary economic outcome was incremental cost measured in pounds (£), year 2016 values, relative to the incremental benefit, which was estimated using quality-adjusted life-years (QALYs). Cost and benefits accrued in the second year were discounted at 3.5%. The base-case analysis was based on imputed data. Uncertainty was explored using univariate sensitivity analyses. Results Participants (n = 777) were randomised to SH (n = 389) or TH (n = 388). The mean cost of SH was £337 (95% confidence interval [CI] 251–423) higher than that of TH and the mean QALYs were −0.070 (95% CI −0.127 to −0.011) lower than for TH. The base-case cost-utility analysis indicated that SH has zero probability of being cost effective at both the £20,000 and the £30,000 threshold. Results from the sensitivity analyses were similar to those from the base-case analysis. Conclusions The evidence suggests that, on average, the total mean costs over the 24-month follow-up period were significantly higher for the SH arm than for the TH arm. The QALYs were also, on average, significantly lower for the SH arm. These results were supported by the sensitivity analyses. Therefore, in terms of cost effectiveness, TH is a superior surgical treatment for the management of grade II–IV haemorrhoids when compared with SH

Superior canal dehiscence in a patient with three failed stapedectomy operations for otosclerosis: a case report

<p>Abstract</p> <p>Introduction</p> <p>This case illustrates that superior semicircular canal dehiscence syndrome can be associated with a "pseudo"-conductive hearing loss, a symptom that overlaps with the clinical appearance of otosclerosis.</p> <p>Case presentation</p> <p>We present the case of a 48-year-old German Caucasian woman presenting with hearing loss on the left side and vertigo. She had undergone three previous stapedectomies for hearing improvement. Reformatted high-resolution computed tomographic scanning and the patient's history confirmed the diagnosis of concurrent canal dehiscence syndrome.</p> <p>Conclusion</p> <p>Failure of hearing improvement after otosclerosis surgery may indicate an alternative underlying diagnosis which should be explored by further appropriate evaluation.</p

Pharmacoeconomic analysis of adjuvant oral capecitabine vs intravenous 5-FU/LV in Dukes' C colon cancer: the X-ACT trial

Oral capecitabine (Xeloda&lt;sup&gt;&#174;&lt;/sup&gt;) is an effective drug with favourable safety in adjuvant and metastatic colorectal cancer. Oxaliplatin-based therapy is becoming standard for Dukes' C colon cancer in patients suitable for combination therapy, but is not yet approved by the UK National Institute for Health and Clinical Excellence (NICE) in the adjuvant setting. Adjuvant capecitabine is at least as effective as 5-fluorouracil/leucovorin (5-FU/LV), with significant superiority in relapse-free survival and a trend towards improved disease-free and overall survival. We assessed the cost-effectiveness of adjuvant capecitabine from payer (UK National Health Service (NHS)) and societal perspectives. We used clinical trial data and published sources to estimate incremental direct and societal costs and gains in quality-adjusted life months (QALMs). Acquisition costs were higher for capecitabine than 5-FU/LV, but higher 5-FU/LV administration costs resulted in 57% lower chemotherapy costs for capecitabine. Capecitabine vs 5-FU/LV-associated adverse events required fewer medications and hospitalisations (cost savings £3653). Societal costs, including patient travel/time costs, were reduced by &gt;75% with capecitabine vs 5-FU/LV (cost savings £1318), with lifetime gain in QALMs of 9 months. Medical resource utilisation is significantly decreased with capecitabine vs 5-FU/LV, with cost savings to the NHS and society. Capecitabine is also projected to increase life expectancy vs 5-FU/LV. Cost savings and better outcomes make capecitabine a preferred adjuvant therapy for Dukes' C colon cancer. This pharmacoeconomic analysis strongly supports replacing 5-FU/LV with capecitabine in the adjuvant treatment of colon cancer in the UK

Absence of Age‐Related Trends in Stable Oxygen Isotope Ratios From Oak Tree Rings

The potential for age‐related trends in the stable oxygen isotope ratios of latewood alpha cellulose was investigated in samples of living oak trees and historic building timbers from the UK. When the series are examined individually, it is clear that the strongest trends in individual trees and timbers reflect concurrent trends in climate. Nonclimatic trends are very small and represent random noise that can be removed by averaging. If the same data are analyzed using the more conventional approach of aligning the series by ring number and fitting a regression line, so that the magnitude of the age trend is based on the slope of the mean and the statistical significance on the correlation coefficient, the results are very different. We demonstrate that this conventional approach regularly produces spurious age trends with grossly inflated probabilities, because of offsets in the mean values of series of different length. We conclude that there is no need to detrend stable oxygen isotope series from individual trees or timbers of oak from the UK and that to do so would remove important climatic information. Long isotope chronologies can safely be constructed by combining data from multiple individual trees, or by pooling material from trees prior to chemical treatment and isotopic measurement. Age‐related trends may occur in other species or in other regions, but where they have been identified using the conventional “slope of the mean” approach they should be reassessed using the “mean of the slope” approach.</p

Consolidated health economic evaluation reporting standards (CHEERS) statement

&lt;p&gt;Economic evaluations of health interventions pose a particular challenge for reporting. There is also a need to consolidate and update existing guidelines and promote their use in a user friendly manner. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement is an attempt to consolidate and update previous health economic evaluation guidelines efforts into one current, useful reporting guidance. The primary audiences for the CHEERS statement are researchers reporting economic evaluations and the editors and peer reviewers assessing them for publication.&lt;/p&gt; &lt;p&gt;The need for new reporting guidance was identified by a survey of medical editors. A list of possible items based on a systematic review was created. A two round, modified Delphi panel consisting of representatives from academia, clinical practice, industry, government, and the editorial community was conducted. Out of 44 candidate items, 24 items and accompanying recommendations were developed. The recommendations are contained in a user friendly, 24 item checklist. A copy of the statement, accompanying checklist, and this report can be found on the ISPOR Health Economic Evaluations Publication Guidelines Task Force website (www.ispor.org/TaskForces/EconomicPubGuidelines.asp).&lt;/p&gt; &lt;p&gt;We hope CHEERS will lead to better reporting, and ultimately, better health decisions. To facilitate dissemination and uptake, the CHEERS statement is being co-published across 10 health economics and medical journals. We encourage other journals and groups, to endorse CHEERS. The author team plans to review the checklist for an update in five years.&lt;/p&gt

Short-lived juvenile effects observed in stable carbon and oxygen isotopes of UK oak trees and historic building timbers

Stable carbon (δ13C) and oxygen (δ18O) isotope ratios were measured on the latewood α-cellulose of individual oak (Quercus robur L, Q. petraea Liebl.) samples from living trees and historic building timbers. This represents the type of material available to produce long tree-ring chronologies for north-western Europe including the UK and Ireland. Results from the juvenile rings, those located closest to the pith, were compared with results from equivalent sections (representing the same calendar years) from independent master isotope chronologies that do not contain any juvenile wood, allowing any juvenile offsets and trends to be separated from those caused by environmental change. Oak timbers from archaeological sources are often relatively short (<100 years). Therefore, removing the first 50 rings, as is typical for Pinus sp., would severely constrain the material available for chronology construction. The aim of this study was to determine the magnitude and duration of juvenile effects, including the detection of trends, offsets and their influence upon signal strength. The results show clearly that juvenile effects for oak from central England are very small and short-lived and that removing merely the first five rings closest to the pith is sufficient to avoid them. This result greatly increases the potential for building long and well-replicated stable isotope chronologies using archived oak samples from historic building timbers, allowing high-resolution climate reconstructions to be produced for the highly-populated regions, where oak is abundant and which are currently under-represented in regional palaeoclimate reconstructions

A hypothetico-deductive approach to assessing the social function of chemical signalling in a non-territorial solitary carnivore

The function of chemical signalling in non-territorial solitary carnivores is still relatively unclear. Studies on territorial solitary and social carnivores have highlighted odour capability and utility, however the social function of chemical signalling in wild carnivore populations operating dominance hierarchy social systems has received little attention. We monitored scent marking and investigatory behaviour of wild brown bears Ursus arctos, to test multiple hypotheses relating to the social function of chemical signalling. Camera traps were stationed facing bear ‘marking trees’ to document behaviour by different age sex classes in different seasons. We found evidence to support the hypothesis that adult males utilise chemical signalling to communicate dominance to other males throughout the non-denning period. Adult females did not appear to utilise marking trees to advertise oestrous state during the breeding season. The function of marking by subadult bears is somewhat unclear, but may be related to the behaviour of adult males. Subadults investigated trees more often than they scent marked during the breeding season, which could be a result of an increased risk from adult males. Females with young showed an increase in marking and investigation of trees outside of the breeding season. We propose the hypothesis that females engage their dependent young with marking trees from a young age, at a relatively ‘safe’ time of year. Memory, experience, and learning at a young age, may all contribute towards odour capabilities in adult bears