Decomposition of mutational context signatures using quadratic programming methods [version 1; referees: 1 approved, 1 approved with reservations]

Methods: for inferring signatures of mutational contexts from large cancer sequencing data sets are invaluable for biological research, but impractical for clinical application where we require tools that decompose the context data for an individual into signatures. One such method has recently been published using an iterative linear modelling approach. A natural alternative places the problem within a quadratic programming framework and is presented here, where it is seen to offer advantages of speed and accuracy.AGL was supported in this work by a Cancer Research UK programme grant [C14303/A20406] to Simon Tavaré. AGL acknowledges the support of the University of Cambridge, Cancer Research UK and Hutchison Whampoa Limited. Whole-genome sequencing of oesophageal adenocarcinoma was part of the oesophageal International Cancer Genome Consortium (ICGC) project. The oesophageal ICGC project was funded through a programme and infrastructure grant to Rebecca Fitzgerald as part of the OCCAMS collaboration.This is the final version of the article. It first appeared from F1000Research via http://dx.doi.org/10.12688/f1000research.8918.

Optically trapped bacteria pairs reveal discrete motile response to control aggregation upon cell–cell approach

Aggregation of bacteria plays a key role in the formation of many biofilms. The critical first step is cell–cell approach, and yet the ability of bacteria to control the likelihood of aggregation during this primary phase is unknown. Here, we use optical tweezers to measure the force between isolated Bacillus subtilis cells during approach. As we move the bacteria towards each other, cell motility (bacterial swimming) initiates the generation of repulsive forces at bacterial separations of ~3 μm. Moreover, the motile response displays spatial sensitivity with greater cell–cell repulsion evident as inter-bacterial distances decrease. To examine the environmental influence on the inter-bacterial forces, we perform the experiment with bacteria suspended in Tryptic Soy Broth, NaCl solution and deionised water. Our experiments demonstrate that repulsive forces are strongest in systems that inhibit biofilm formation (Tryptic Soy Broth), while attractive forces are weak and rare, even in systems where biofilms develop (NaCl solution). These results reveal that bacteria are able to control the likelihood of aggregation during the approach phase through a discretely modulated motile response. Clearly, the force-generating motility we observe during approach promotes biofilm prevention, rather than biofilm formation

Impact of Central Line Bundle Care on Reduction of Central Line Associated-Infections: A Scoping Review

Purpose/Background Central venous catheters (CVC) are typical for critically ill patients in the intensive care unit (ICU). Due to the invasiveness of this procedure, there is a high risk for central line-associated bloodstream infection (CLABSI). These infections have been known to increase mortality and morbidity, medical costs, and reduce hospital reimbursements. Evidenced-based interventions were grouped to assemble a central line bundle to decrease the number of CLABSIs and improve patient outcomes. This scoping review will evaluate the literature and examine the association between reduced CLABSI rates and central line bundle care implementation or current use. Methods A literature review was completed of nine critically appraised articles from the years 2010-2021. The association of the use of central line bundles and CLABSI rates was examined. These relationships were investigated to determine if the adherence to a central line bundle directly reduced the number of CLABSI rates in critically ill adult patients. A summary evaluation table was composed to determine the associations related to the implementation or current central line bundle care use. Results Of the study sample (N=9), all but one demonstrated a significant decrease in CLABSI rates when a central line bundle was in place. A trend towards reducing CLABSI was noted in the remaining article, a randomized controlled study, but the results were not significantly different. In all the other studies, a meta-analysis, randomized controlled trial, control trial, cohort or case-control studies, and quality improvement project, there was a significant improvement in CLABSI rates when utilizing a central line bundle. The extensive use of different levels of evidence provided an excellent synopsis that implementing a central line bundle care would directly affect decreasing CLABSI rates. Implications for Nursing Practice Results provided in this scoping review afforded the authors a diverse level of evidence that using a central line bundle has a direct outcome on reducing CLABSI rates. This practice can be implemented within the hospital setting as suggested by the literature review to prevent or reduce CLABSI rates. Implementing a standard central line bundle care hospital-wide helps avoid this hospital-acquired infection

Loneliness, social support and cardiovascular reactivity to laboratory stress

Self-reported or explicit loneliness and social support have been inconsistently associated with cardiovascular reactivity (CVR) to stress. The present study aimed to adapt an implicit measure of loneliness, and use it alongside the measures of explicit loneliness and social support, to investigate their correlations with CVR to laboratory stress. Twenty-five female volunteers aged between 18 and 39 years completed self-reported measures of loneliness and social support, and an Implicit Association Test (IAT) of loneliness. The systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) reactivity indices were measured in response to psychosocial stress induced in the laboratory. Functional support indices of social support were significantly correlated with CVR reactivity to stress. Interestingly, implicit, but not explicit, loneliness was significantly correlated with DBP reactivity after one of the stressors. No associations were found between structural support and CVR indices. Results are discussed in terms of validity of implicit versus explicit measures and possible factors that affect physiological outcomes

Identification and correction of previously unreported spatial phenomena using raw Illumina BeadArray data

<p>Abstract</p> <p>Background</p> <p>A key stage for all microarray analyses is the extraction of feature-intensities from an image. If this step goes wrong, then subsequent preprocessing and processing stages will stand little chance of rectifying the matter. Illumina employ random construction of their BeadArrays, making feature-intensity extraction even more important for the Illumina platform than for other technologies. In this paper we show that using raw Illumina data it is possible to identify, control, and perhaps correct for a range of spatial-related phenomena that affect feature-intensity extraction.</p> <p>Results</p> <p>We note that feature intensities can be unnaturally high when in the proximity of a number of phenomena relating either to the images themselves or to the layout of the beads on an array. Additionally we note that beads neighbour beads of the same type more often than one might expect, which may cause concern in some models of hybridization. We highlight issues in the identification of a bead's location, and in particular how this both affects and is affected by its intensity. Finally we show that beads can be wrongly identified in the image on either a local or array-wide scale, with obvious implications for data quality.</p> <p>Conclusions</p> <p>The image processing issues identified will often pass unnoticed by an analysis of the standard data returned from an experiment. We detail some simple diagnostics that can be implemented to identify problems of this nature, and outline approaches to correcting for such problems. These approaches require access to the raw data from the arrays, not just the summarized data usually returned, making the acquisition of such raw data highly desirable.</p

Improved Adaptive Group Testing Algorithms with Applications to Multiple Access Channels and Dead Sensor Diagnosis

We study group-testing algorithms for resolving broadcast conflicts on a multiple access channel (MAC) and for identifying the dead sensors in a mobile ad hoc wireless network. In group-testing algorithms, we are asked to identify all the defective items in a set of items when we can test arbitrary subsets of items. In the standard group-testing problem, the result of a test is binary--the tested subset either contains defective items or not. In the more generalized versions we study in this paper, the result of each test is non-binary. For example, it may indicate whether the number of defective items contained in the tested subset is zero, one, or at least two. We give adaptive algorithms that are provably more efficient than previous group testing algorithms. We also show how our algorithms can be applied to solve conflict resolution on a MAC and dead sensor diagnosis. Dead sensor diagnosis poses an interesting challenge compared to MAC resolution, because dead sensors are not locally detectable, nor are they themselves active participants.Comment: Expanded version of a paper appearing in ACM Symposium on Parallelism in Algorithms and Architectures (SPAA), and preliminary version of paper appearing in Journal of Combinatorial Optimizatio

Bayesian paternity analysis and mating patterns in a parasitic nematode, Trichostrongylus tenuis

Mating behaviour is a fundamental aspect of the evolutionary ecology of sexually reproducing species, but one that has been under-researched in parasitic nematodes. We analysed mating behaviour in the parasitic nematode Trichostrongylus tenuis by performing a paternity analysis in a population from a single red grouse host. Paternity of the 150 larval offspring of 25 mothers (sampled from one of the two host caeca) was assigned among 294 candidate fathers (sampled from both caeca). Each candidate father's probability of paternity of each offspring was estimated from 10-locus microsatellite genotypes. Seventy-six (51%) offspring were assigned a father with a probability of &gt;0.8, and the estimated number of unsampled males was 136 (95% credible interval (CI) 77-219). The probability of a male from one caecum fathering an offspring in the other caecum was estimated as 0.024 (95% CI 0.003-0.077), indicating that the junction of the caeca is a strong barrier to dispersal. Levels of promiscuity (defined as the probability of two of an adult's offspring sharing only one parent) were high for both sexes. Variance in male reproductive success was moderately high, possibly because of a combination of random mating and high variance in post-copulatory reproductive success. These results provide the first data on individual mating behaviour among parasitic nematodes

Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

Dispelling urban myths about default uncertainty factors in chemical risk assessment - Sufficient protection against mixture effects?

© 2013 Martin et al.; licensee BioMed Central LtdThis article has been made available through the Brunel Open Access Publishing Fund.Assessing the detrimental health effects of chemicals requires the extrapolation of experimental data in animals to human populations. This is achieved by applying a default uncertainty factor of 100 to doses not found to be associated with observable effects in laboratory animals. It is commonly assumed that the toxicokinetic and toxicodynamic sub-components of this default uncertainty factor represent worst-case scenarios and that the multiplication of those components yields conservative estimates of safe levels for humans. It is sometimes claimed that this conservatism also offers adequate protection from mixture effects. By analysing the evolution of uncertainty factors from a historical perspective, we expose that the default factor and its sub-components are intended to represent adequate rather than worst-case scenarios. The intention of using assessment factors for mixture effects was abandoned thirty years ago. It is also often ignored that the conservatism (or otherwise) of uncertainty factors can only be considered in relation to a defined level of protection. A protection equivalent to an effect magnitude of 0.001-0.0001% over background incidence is generally considered acceptable. However, it is impossible to say whether this level of protection is in fact realised with the tolerable doses that are derived by employing uncertainty factors. Accordingly, it is difficult to assess whether uncertainty factors overestimate or underestimate the sensitivity differences in human populations. It is also often not appreciated that the outcome of probabilistic approaches to the multiplication of sub-factors is dependent on the choice of probability distributions. Therefore, the idea that default uncertainty factors are overly conservative worst-case scenarios which can account both for the lack of statistical power in animal experiments and protect against potential mixture effects is ill-founded. We contend that precautionary regulation should provide an incentive to generate better data and recommend adopting a pragmatic, but scientifically better founded approach to mixture risk assessment. © 2013 Martin et al.; licensee BioMed Central Ltd.Oak Foundatio

Diagnostic criteria for idiopathic pulmonary fibrosis: a Fleischner Society White Paper.

This Review provides an updated approach to the diagnosis of idiopathic pulmonary fibrosis (IPF), based on a systematic search of the medical literature and the expert opinion of members of the Fleischner Society. A checklist is provided for the clinical evaluation of patients with suspected usual interstitial pneumonia (UIP). The role of CT is expanded to permit diagnosis of IPF without surgical lung biopsy in select cases when CT shows a probable UIP pattern. Additional investigations, including surgical lung biopsy, should be considered in patients with either clinical or CT findings that are indeterminate for IPF. A multidisciplinary approach is particularly important when deciding to perform additional diagnostic assessments, integrating biopsy results with clinical and CT features, and establishing a working diagnosis of IPF if lung tissue is not available. A working diagnosis of IPF should be reviewed at regular intervals since the diagnosis might change. Criteria are presented to establish confident and working diagnoses of IPF