Showing papers by "Paul Morris published in 2018"
TL;DR: The augmented infection model more closely resembles the natural situation and establishes the role of resident environmental microflora in the initiation of disease by an invading pathogen.
Abstract: All bacterial infections occur within a polymicrobial environment, from which a pathogen population emerges to establish disease within a host. Emphasis has been placed on prevention of pathogen dominance by competing microflora acting as probiotics1. Here we show that the virulence of the human pathogen Staphylococcus aureus is augmented by native, polymicrobial, commensal skin flora and individual species acting as 'proinfectious agents'. The outcome is pathogen proliferation, but not commensal. Pathogenesis augmentation can be mediated by particulate cell wall peptidoglycan, reducing the S. aureus infectious dose by over 1,000-fold. This phenomenon occurs using a range of S. aureus strains and infection models and is not mediated by established receptor-mediated pathways including Nod1, Nod2, Myd88 and the NLPR3 inflammasome. During mouse sepsis, augmentation depends on liver-resident macrophages (Kupffer cells) that capture and internalize both the pathogen and the proinfectious agent, leading to reduced production of reactive oxygen species, pathogen survival and subsequent multiple liver abscess formation. The augmented infection model more closely resembles the natural situation and establishes the role of resident environmental microflora in the initiation of disease by an invading pathogen. As the human microflora is ubiquitous2, its role in increasing susceptibility to infection by S. aureus highlights potential strategies for disease prevention.
76 citations
TL;DR: To perform detailed analysis of stent expansion, vessel wall stress, hemodynamics, re‐endothelialization, restenosis, and repeat PCI in the simultaneous kissing stents (SKS) technique of bifurcation left main stem (LMS) stenting.
Abstract: OBJECTIVES: To perform detailed analysis of stent expansion, vessel wall stress, hemodynamics, re-endothelialization, restenosis, and repeat PCI in the simultaneous kissing stents (SKS) technique of bifurcation left main stem (LMS) stenting. BACKGROUND: The SKS technique is useful to treat patients with true bifurcation disease of the LMS but remains controversial. METHODS AND RESULTS: Computational structural analysis of SKS expansion demonstrated undistorted and evenly expanded stents. Computational fluid dynamics modelling revealed largely undisturbed blood flow. 239 PCI procedures were performed on 217 patients with unprotected bifurcation LMS disease with SKS using DES (2004-2017). We electively studied 13 stable patients from baseline to 10 years post-SKS with repeat angiography and optical coherence tomography, and demonstrated tissue coverage of the stent struts at the carina, with no evidence of lacunae behind the stents. We studied all patients with symptomatic recurrence. Target lesion revascularization rate was 3.2% at 1 year and 4.6% at 2 years. Of all 20 patients with restenosis, the site was the LMS-Cx stent in 7, the LMS-LAD stent in 2 and both in 11. Two-year recurrence rate was 7/32 (5.3%) for first, and 4/108 (3.7%) for second generation DES. Treatment with repeat kissing techniques was undertaken in 19/20, with sustained clinical results with re-SKS. CONCLUSION: The SKS technique for treating unprotected LMS bifurcation disease does not distort the stents, is associated with favorable hemodynamics, tissue coverage of the exposed struts, and a low restenosis rate when performed with contemporary stents. Re-PCI with repeat SKS appears feasible, safe, and durable.
28 citations
TL;DR: It is found that most mutations that occur during nasopharyngeal carriage are transient indels within repetitive tracts of putative phase-variable loci associated with host-microbe interactions and iron acquisition, and suggests that phase variable genes are often mutated during carriage-associated microevolution.
Abstract: Neisseria lactamica is a harmless coloniser of the infant respiratory tract, and has a mutually-excluding relationship with the pathogen Neisseria meningitidis. Here we report controlled human infection with genomically-defined N. lactamica and subsequent bacterial microevolution during 26 weeks of colonisation. We find that most mutations that occur during nasopharyngeal carriage are transient indels within repetitive tracts of putative phase-variable loci associated with host-microbe interactions (pgl and lgt) and iron acquisition (fetA promotor and hpuA). Recurrent polymorphisms occurred in genes associated with energy metabolism (nuoN, rssA) and the CRISPR-associated cas1. A gene encoding a large hypothetical protein was often mutated in 27% of the subjects. In volunteers who were naturally co-colonised with meningococci, recombination altered allelic identity in N. lactamica to resemble meningococcal alleles, including loci associated with metabolism, outer membrane proteins and immune response activators. Our results suggest that phase variable genes are often mutated during carriage-associated microevolution.
24 citations
TL;DR: The concept that aquatic strains are an efficient source of compounds that inhibit pathogens is supported, and a strategy is outlined to identify other strains that express unique compounds that may be useful biocontrol agents.
Abstract: Seedling root rot of soybeans caused by the host-specific pathogen Phytophthora sojae, and a large number of Pythium species, is an economically important disease across the Midwest United States that negatively impacts soybean yields. Research on biocontrol strategies for crop pathogens has focused on compounds produced by microbes from soil, however, recent studies suggest that aquatic bacteria express distinct compounds that efficiently inhibit a wide range of pathogens. Based on these observations, we hypothesized that freshwater strains of pseudomonads might be producing novel antagonistic compounds that inhibit the growth of oomycetes. To test this prediction, we utilized a collection of 330 Pseudomonas strains isolated from soil and freshwater habitats, and determined their activity against a panel of five oomycetes: Phytophthora sojae, Pythium heterothalicum, Pythium irregulare, Pythium sylvaticum, and Pythium ultimum, all of which are pathogenic on soybeans. Among the bacterial strains, 118 exhibited antagonistic activity against at least one oomycete species, and 16 strains were inhibitory to all pathogens. Antagonistic activity toward oomycetes was significantly more common for aquatic isolates than for soil isolates. One water-derived strain, 06C 126, was predicted to express a siderophore and exhibited diverse antagonistic profiles when tested on nutrient rich and iron depleted media suggesting that more than one compound was produced that effectively inhibited oomycetes. These results support the concept that aquatic strains are an efficient source of compounds that inhibit pathogens. We outline a strategy to identify other strains that express unique compounds that may be useful biocontrol agents.
21 citations
15 Aug 2018
TL;DR: The ability of a fully convolutional neural network to classify molecules from their Simplified Molecular-Input Line-Entry System (SMILES) strings for binding affinity to HIV proteins is demonstrated.
Abstract: Computational techniques for binding-affinity prediction and molecular docking have long been considered in terms of their utility for drug discovery. With the advent of deep learning, new supervised learning techniques have emerged which can utilize the wealth of experimental binding data already available. Here we demonstrate the ability of a fully convolutional neural network to classify molecules from their Simplified Molecular-Input Line-Entry System (SMILES) strings for binding affinity to HIV proteins. The network is evaluated on two tasks to distinguish a set of molecules which are experimentally verified to bind and inhibit HIV-1 Protease and HIV-1 Reverse Transcriptase from a random sample of drug-like molecules. We report 98% and 93% classification accuracy on the respective tasks using a computationally efficient model which outperforms traditional machine learning baselines. Our model is suitable for virtually screening a large set of drug-like molecules for binding to HIV or other protein targets.
6 citations
TL;DR: It is demonstrated that judgments of how ‘threatening’ a person is can be used to accurately index trait aggression at a distance, with strong evidence that the average judgments of the threat posed by the approaching targets accurately reflected the targets’ trait aggression.
Abstract: When in a vulnerable situation (such as walking alone at night), an approaching person may be seen as 'threatening'. Here, we are interested in how well participants' judgments of threat reflected the trait aggression of approaching target people. We use two similar experiments to demonstrate and replicate the relationship between judgments of threat and target aggression. In both studies participants judged how threatening they found 22 approaching people (presented in videos). In Study One, participants judged the targets whilst sitting at a computer. In Study Two, participants were standing and were either oriented facing the videos, or oriented away from the videos so they had to look over their shoulder. This was to emulate a potentially threatening person approaching from behind. Across both studies, there was strong evidence that the average judgments of the threat posed by the approaching targets accurately reflected the targets' trait aggression. It was also found that there was noteworthy variability in individual participants' ability to detect aggression, with a few participants even having an inverse relationship between threat and the target's aggression. This research demonstrates that judgments of how 'threatening' a person is can be used to accurately index trait aggression at a distance.
5 citations
TL;DR: The first in silico estimation of renal artery haemodynamics from CT angiography in patients with RAS is described, showing it is feasible and diagnostically accurate.
Abstract: Background: Measuring the extent to which renal artery stenosis (RAS) alters renal haemodynamics may permit precision medicine by physiologically guided revascularization. This currently requires invasive intra-arterial pressure measurement with associated risks and is rarely performed. The present proof-of-concept study investigates an in silico approach that uses computational fluid dynamic (CFD) modeling to non-invasively estimate renal artery haemodynamics from routine anatomical computed tomography (CT) imaging of RAS.
Methods: We evaluated 10 patients with RAS by CT angiography. Intra-arterial renal haemodynamics were invasively measured by a transducing catheter under resting and hyperaemic conditions, calculating the translesional ratio of distal to proximal pressure (Pd/Pa). The diagnostic and quantitative accuracy of the CFD-derived virtual Pd/Pa ratio (vPd/Pa) was evaluated against the invasively measured Pd/Pa ratio (mPd/Pa).
Results: Hyperaemic haemodynamics was infeasible and CT angiography in 4 patients had insufficient image resolution. Resting flow data is thus reported for 7 stenosed arteries from 6 patients (one patient had bilateral RAS). The comparison showed a mean difference of 0.015 (95% confidence intervals of ± 0.08), mean absolute error of 0.064, and a Pearson correlation coefficient of 0.6, with diagnostic accuracy for a physiologically significant Pd/Pa of ≤ 0.9 at 86%.
Conclusion: We describe the first in silico estimation of renal artery haemodynamics from CT angiography in patients with RAS, showing it is feasible and diagnostically accurate. This provides a methodological framework for larger prospective studies to ultimately develop non-invasive precision medicine approaches for studies and interventions of RAS and resistant hypertension.
5 citations
TL;DR: For the first time clinicians can perform a patient-specific assessment prior to making treatment decisions, which could be advantageous in patients with complex disease patterns where the optimal treatment strategy is not clear.
Abstract: Computational modeling has been used routinely in the pre-clinical development of
medical devices such as coronary artery stents. The ability to simulate and predict
physiological and structural parameters such as flow disturbance, wall shear-stress,
and mechanical strain patterns is beneficial to stent manufacturers. These methods
are now emerging as useful clinical tools, used by physicians in the assessment and
management of patients. Computational models, which can predict the physiological
response to intervention, offer clinicians the ability to evaluate a number of different
treatment strategies in silico prior to treating the patient in the cardiac catheter
laboratory. For the first time clinicians can perform a patient-specific assessment prior
to making treatment decisions. This could be advantageous in patients with complex
disease patterns where the optimal treatment strategy is not clear. This article reviews
the key advances and the potential barriers to clinical adoption and translation of these
virtual treatment planning models.
4 citations
18 May 2018
TL;DR: The TDWG Data Quality Interest Group (TG2) as mentioned in this paper provides a standard suite of tests and resulting assertions that can assist with filtering occurrence records for as many applications as possible.
Abstract: Task Group 2 of the TDWG Data Quality Interest Group aims to provide a standard suite of tests and resulting assertions that can assist with filtering occurrence records for as many applications as possible. Currently ‘data aggregators’ such as the Global Biodiversity Information Facility (GBIF), the Atlas of Living Australia (ALA) and iDigBio run their own suite of tests over records received and report the results of these tests (the assertions): there is, however, no standard reporting mechanisms. We reasoned that the availability of an internationally agreed set of tests would encourage implementations by the aggregators, and at the data sources (museums, herbaria and others) so that issues could be detected and corrected early in the process. All the tests are limited to Darwin Core terms. The ~95 tests refined from over 250 in use around the world, were classified into four output types: validations, notifications, amendments and measures. Validations test one of more Darwin Core terms, for example, that dwc:decimalLatitude is in a valid range (i.e. between -90 and +90 inclusive). Notifications report a status that a user of the record should know about, for example, if there is a user-annotation associated with the record. Amendments are made to one or more Darwin Core terms when the information across the record can be improved, for ‡ § | ¶ # ¤ © Belbin L et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. example, if there is no value for dwc:scientificName, it can be filled in from a valid dwc:taxonID. Measures report values that may be useful for assessing the overall quality of a record, for example, the number of validation tests passed. Evaluation of the tests was complex and time-consuming, but the important parameters of each test have been consistently documented. Each test has a globally unique identifier, a label, an output type, a resource type, the Darwin Core terms used, a description, a dimension (from the Framework on Data Quality from TG1), an example, references, implementations (if any), test-prerequisites and notes. For each test, generic code is being written that should be easy for institutions to implement – be they aggregators or data custodians. A valuable product of the work of TG2 has been a set of general principles. One example is “Darwin Core terms are either: 1. literal verbatim (e.g., dwc:verbatimLocality) and cannot be assumed capable of validation, 2. open-ended (e.g., dwc:behavior) and cannot be assumed capable of validation, or 3. bounded by an agreed vocabulary or extents, and therefore capable of validation (e.g., dwc:countryCode)”. Another is “criteria for including tests is that they are informative, relatively simple to implement, mandatory for amendments and have power in that they will not likely result in 0% or 100% of all record hits.” A third: “Do not ascribe precision where it is unknown.” GBIF, the ALA and iDigBio have committed to implementing the tests once they have been finalized. We are confident that many museums and herbaria will also implement the tests over time. We anticipate that demonstration code and a test dataset that will validate the code will be available on project completion.
3 citations
04 Jun 2018
TL;DR: The findings of a study of individual differences using 13 very carefully trained and selected participants must be treated with great caution; the statistical analysis is also problematic, as interpreting the magnitude of effects from a mixed-effects model is problematic.
Abstract: Examining the relationship between jealous behaviour and the amygdala may be quite informative about the function of the amygdala, but the amygdala may be less helpful in informing us about jealous behaviour. Claims about the potential practical relevance of the results also require that the magnitude of the effects inform the relevant discussion. The dogs used in the study probably share some very important personality characteristics; this too limits the practical implications of Cook et al.’s findings for dogs in general. It is nevertheless a testament to the skill of the experimenters, and the amazing bond between dogs and humans, that such research could be conducted at all. Paul Morris is a psychologist interested in how intentions and emotions are embodied in behaviour. His work includes research on the manifestation and perception of emotions in human infants and non-human animals. Website It is a remarkable feat to have trained 13 dogs to tolerate an fMRI scanner, let alone get them to cooperate in an experiment in such a context. One cannot help but be deeply impressed by the experimental virtuosity of the researchers (Cook et al., 2018). However, I am certainly not the first to be uneasy about the real utility of much neuroscience research: There is something of a backlash against many of the claims of neuroscience (Satel & Lilienfeld, 2013), a backlash so well established that there is a backlash against the backlash (Marcus, 2013). At a broad philosophical level, my concern with the target article is that it is implicit in the title that we can take jealousy in dogs more seriously because of evidence from neuroscience. However, it is an uncomfortable truth for some scientists studying emotion that the primary data for our knowledge about emotions are subjective experience and human judgement. The plural of anecdote in this case is data. Our knowledge of the localisation of affect is ultimately derived from human experience and judgement. We think a particular area of the brain may be associated with a particular emotion because we have induced a particular emotion and then observed what the brain gets up to. We know what emotions are because we are emotional beings. We began investigating jealousy in dogs because our experience with dogs suggested that dogs were jealous. We did not start to investigate jealousy in dogs because of what was going on in their amygdala. Studying brain/behaviour relationships provides a rich source of information concerning brain function, but much less so concerning behaviour. There are several more technical issues that I would like to mention. I am not at all sure that amygdala function can provide really useful information. The amygdala is implicated in just about everything from emotion, to fundamental cognitive processes such as long-term memory, working memory and visual attention (Schaefer & Gray, 2007). The statistical analysis is also problematic, as interpreting the magnitude of effects from a mixed-effects model is by Animal Sentience 2018.132: Morris on Cook et al. on Dog Jealousy 2 no means straightforward. In the discussion, the authors make no mention of the magnitude of the effects, but simply state that there was a positive correlation between aggressive temperament and amygdala activation. The magnitude of any such relationship is crucial to any claims that the information from the study could inform behavioural interventions. My final comment is that regardless of the C-BARQ scores, given what the dogs were required to do, I cannot think that these dogs were anything but highly social, unaggressive and co-operative. These may be special dogs. In any study of individual differences, it is crucial to have sampled the range of the trait of interest. The findings of a study of individual differences using 13 very carefully trained and selected participants must be treated with great caution. My overwhelming feeling having written this commentary is social guilt (which I believe is thought to be localised to the anterior middle cingulate cortex) because being a critic is easy, and I remain amazed that the researchers managed to conduct this study at all.
2 citations
TL;DR: Overall, the participants in this study were highly accurate at detecting trait aggression, and there was no difference in average aggression detection between older and young adults but there was in sample agreement.
Abstract: The extant literature has generally demonstrated that young adults can detect the trait aggression of another person with limited information. However, there is little research that investigates the life course persistence of aggression detection accuracy. Here, we aimed to explore the accuracy of older adults at detecting potential aggressors. Thirty-nine older adults (M = 71.49, SD = 7.59) and eighty-seven young adults (M = 20.24, SD = 1.74) made intimidation judgments, via video recordings, for nine people (targets). 'Aggression detection accuracy' was shown in the relationship between the intimidation judgments made by participants and the targets' responses to the Buss-Perry Aggression Questionnaire. Both age groups were highly accurate in their recognition of trait aggression and accuracy was maintained into older age, with no difference in accuracy between the older and young adults. There was, however, more variability in the ratings given by the older adults compared to the young adults, suggesting less consensus in judgment for the older compared to the young group. Overall, the participants in this study were highly accurate at detecting trait aggression. There was no difference in average aggression detection between older and young adults but there was in sample agreement. These results are discussed in the context of age effects on intimidation, as well as research in accurate aggression detection.
TL;DR: A computational protocol to process the recorded pressure signals in a consistent manner and result in significant differences in the classification of physiological lesion significance is developed, providing an objective and repeatable result.
Abstract: AIMS: Fractional flow reserve (FFR), the reference-standard for guiding coronary revascularisation, is most commonly acquired during intravenous adenosine infusion. Results may be sensitive to system- and operator-dependent variability in how pressure data are analysed and interpreted. We developed a computational protocol to process the recorded pressure signals in a consistent manner to objectively quantify FFR. We studied the impact upon lesion (re)classification and compared this with the operator-selected FFR obtained during cardiac catheterisation. METHODS AND RESULTS: The algorithm used a moving average and Fourier transformation to identify the Pd/Pa ratio at its nadir (FFRmin) and during the stable hyperaemic period (FFRstable) in <2s with 100% repeatability, in 163 coronary stenoses (93 patients). The mean operator-selected FFR (FFRCL) was higher than FFRmin and lower than FFRstable (0.779 vs 0.762 vs 0.806, P=<0.01). Compared with FFRmin, FFRstable resulted in 16.5% of all lesions being re-classified, all from significant to non-significant (p<0.01). FFRCL classified lesion significance differently to both FFRstable and FFRmin (11.7% and 6.1% lesions reclassified respectively, p<0.01). CONCLUSIONS: Subtle differences in how pressure data are analysed and interpreted by the operator during adenosine infusion result in significant differences in the classification of physiological lesion significance. An algorithmic analysis may be helpful in standardising FFR analysis providing an objective and repeatable result.
TL;DR: It is shown that the Phytophthora capsici genome contains five putative prolyl 4-hydroxylases, and in mycelia, all P4Hs were downregulated in response to hypoxia, but the expression of PcP4H1 was most affected.
01 Apr 2018
TL;DR: It is remarkable that, 40 years after Andreas Gruntzig’s first PCI, the first double-blind, placebo-controlled trial of PCI in stable angina: the Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stableAngina (ORBITA) trial is only now published.
Abstract: Commentary on : Al-Lamee R, Thompson D, Dehbi HM, et al . Percutaneous coronary intervention in stable angina (ORBITA): a double-blind, randomised controlled trial. Lancet 2017;391:31-40.
More than 500 000 percutaneous coronary intervention (PCI) procedures are performed worldwide each year for stable coronary artery disease (CAD). In addition to medical therapy, physiologically targeted PCI reduces urgent revascularisation in this group1; however, unlike in acute coronary syndromes, evidence supporting a reduction in myocardial infarction and mortality is lacking,2 especially in those with low ischaemic burden.3 Consequently, in stable CAD, PCI is used predominantly for symptomatic relief. It is therefore remarkable that, 40 years after Andreas Gruntzig’s first PCI, we only now have results of the first double-blind, placebo-controlled trial of PCI in stable angina: the Objective Randomised Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina (ORBITA) trial.4
Patients with stable angina and single-vessel …