When the heart rules the head: ischaemic stroke and intracerebral haemorrhage complicating infective endocarditis

Sir William Osler meticulously described the clinical manifestations of infective endocarditis in 1885, concluding that: 'few diseases present greater difficulties in the way of diagnosis … which in many cases are practically insurmountable'. Even with modern investigation techniques, diagnosing infective endocarditis can be hugely challenging, yet is critically important in patients presenting with stroke (both cerebral infarction and intracranial haemorrhage), its commonest neurological complication. In ischaemic stroke, intravenous thrombolysis carries an unacceptably high risk of intracranial haemorrhage, while in intracerebral haemorrhage, mycotic aneurysms require urgent treatment to avoid rebleeding, and in all cases, prompt treatment with antibiotics and valve surgery may be life-saving. Here, we describe typical presentations of ischaemic stroke and intracerebral haemorrhage caused by infective endocarditis. We review the diagnostic challenges, the importance of rapid diagnosis, treatment options and controversies

The potential impact of moxidectin on onchocerciasis elimination in Africa: an economic evaluation based on the Phase II clinical trial data

BACKGROUND: Spurred by success in several foci, onchocerciasis control policy in Africa has shifted from morbidity control to elimination of infection. Clinical trials have demonstrated that moxidectin is substantially more efficacious than ivermectin in effecting sustained reductions in skin microfilarial load and, therefore, may accelerate progress towards elimination. We compare the potential cost-effectiveness of annual moxidectin with annual and biannual ivermectin treatment. METHODS: Data from the first clinical study of moxidectin were used to parameterise the onchocerciasis transmission model EPIONCHO to investigate, for different epidemiological and programmatic scenarios in African savannah settings, the number of years and in-country costs necessary to reach the operational thresholds for cessation of treatment, comparing annual and biannual ivermectin with annual moxidectin treatment. RESULTS: Annual moxidectin and biannual ivermectin treatment would achieve similar reductions in programme duration relative to annual ivermectin treatment. Unlike biannual ivermectin treatment, annual moxidectin treatment would not incur a considerable increase in programmatic costs and, therefore, would generate sizeable in-country cost savings (assuming the drug is donated). Furthermore, the impact of moxidectin, unlike ivermectin, was not substantively influenced by the timing of treatment relative to seasonal patterns of transmission. CONCLUSIONS: Moxidectin is a promising new drug for the control and elimination of onchocerciasis. It has high programmatic value particularly when resource limitation prevents a biannual treatment strategy, or optimal timing of treatment relative to peak transmission season is not feasible. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13071-015-0779-4) contains supplementary material, which is available to authorized users

Skyrmion fluctuations at a first-order phase transition boundary

Magnetic skyrmions are topologically protected spin textures with promising prospects for applications in data storage. They can form a lattice state due to competing magnetic interactions and are commonly found in a small region of the temperature - magnetic field phase diagram. Recent work has demonstrated that these magnetic quasi-particles fluctuate at the μeV energy scale. Here, we use a coherent x-ray correlation method at an x-ray free-electron laser to investigate these fluctuations in a magnetic phase coexistence region near a first-order transition boundary where fluctuations are not expected to play a major role. Surprisingly, we find that the relaxation of the intermediate scattering function at this transition differs significantly compared to that deep in the skyrmion lattice phase. The observation of a compressed exponential behavior suggests solid-like dynamics, often associated with jamming. We assign this behavior to disorder and the phase coexistence observed in a narrow field-window near the transition, which can cause fluctuations that lead to glassy behavior

The Ontology of Intentional Agency in Light of Neurobiological Determinism: Philosophy Meets Folk Psychology

The moot point of the Western philosophical rhetoric about free will consists in examining whether the claim of authorship to intentional, deliberative actions fits into or is undermined by a one-way causal framework of determinism. Philosophers who think that reconciliation between the two is possible are known as metaphysical compatibilists. However, there are philosophers populating the other end of the spectrum, known as the metaphysical libertarians, who maintain that claim to intentional agency cannot be sustained unless it is assumed that indeterministic causal processes pervade the action-implementation apparatus employed by the agent. The metaphysical libertarians differ among themselves on the question of whether the indeterministic causal relation exists between the series of intentional states and processes, both conscious and unconscious, and the action, making claim for what has come to be known as the event-causal view, or between the agent and the action, arguing that a sort of agent causation is at work. In this paper, I have tried to propose that certain features of both event-causal and agent-causal libertarian views need to be combined in order to provide a more defendable compatibilist account accommodating deliberative actions with deterministic causation. The ‘‘agent-executed-eventcausal libertarianism’’, the account of agency I have tried to develop here, integrates certain plausible features of the two competing accounts of libertarianism turning them into a consistent whole. I hope to show in the process that the integration of these two variants of libertarianism does not challenge what some accounts of metaphysical compatibilism propose—that there exists a broader deterministic relation between the web of mental and extra-mental components constituting the agent’s dispositional system—the agent’s beliefs, desires, short-term and long-term goals based on them, the acquired social, cultural and religious beliefs, the general and immediate and situational environment in which the agent is placed, etc. on the one hand and the decisions she makes over her lifetime on the basis of these factors. While in the ‘‘Introduction’’ the philosophically assumed anomaly between deterministic causation and the intentional act of deciding has been briefly surveyed, the second section is devoted to the task of bridging the gap between compatibilism and libertarianism. The next section of the paper turns to an analysis of folk-psychological concepts and intuitions about the effects of neurochemical processes and prior mental events on the freedom of making choices. How philosophical insights can be beneficially informed by taking into consideration folk-psychological intuitions has also been discussed, thus setting up the background for such analysis. It has been suggested in the end that support for the proposed theory of intentional agency can be found in the folk-psychological intuitions, when they are taken in the right perspective

Error-Prone ZW Pairing and No Evidence for Meiotic Sex Chromosome Inactivation in the Chicken Germ Line

In the male mouse the X and Y chromosomes pair and recombine within the small pseudoautosomal region. Genes located on the unsynapsed segments of the X and Y are transcriptionally silenced at pachytene by Meiotic Sex Chromosome Inactivation (MSCI). The degree to which MSCI is conserved in other vertebrates is currently unclear. In the female chicken the ZW bivalent is thought to undergo a transient phase of full synapsis at pachytene, starting from the homologous ends and spreading through the heterologous regions. It has been proposed that the repair of the ZW DNA double-strand breaks (DSBs) is postponed until diplotene and that the ZW bivalent is subject to MSCI, which is independent of its synaptic status. Here we present a distinct model of meiotic pairing and silencing of the ZW pair during chicken oogenesis. We show that, in most oocytes, DNA DSB foci on the ZW are resolved by the end of pachytene and that the ZW desynapses in broad synchrony with the autosomes. We unexpectedly find that ZW pairing is highly error prone, with many oocytes failing to engage in ZW synapsis and crossover formation. Oocytes with unsynapsed Z and W chromosomes nevertheless progress to the diplotene stage, suggesting that a checkpoint does not operate during pachytene in the chicken germ line. Using a combination of epigenetic profiling and RNA–FISH analysis, we find no evidence for MSCI, associated with neither the asynaptic ZW, as described in mammals, nor the synaptic ZW. The lack of conservation of MSCI in the chicken reopens the debate about the evolution of MSCI and its driving forces

The effect of mixing entire male pigs prior to transport to slaughter on behaviour, welfare and carcass lesions

peer-reviewedData set for article is also provided.Research is needed to validate lesions recorded at meat inspection as indicators of pig welfare on farm. The aims were to determine the influence of mixing pigs on carcass lesions and to establish whether such lesions correlate with pig behaviour and lesions scored on farm. Aggressive and mounting behaviour of pigs in three single sex pens was recorded on Day −5, −2, and −1 relative to slaughter (Day 0). On Day 0 pigs were randomly allocated to 3 treatments (n = 20/group) over 5 replicates: males mixed with females (MF), males mixed with males (MM), and males unmixed (MUM). Aggressive and mounting behaviours were recorded on Day 0 at holding on farm and lairage. Skin/tail lesions were scored according to severity at the farm (Day −1), lairage, and on the carcass (Day 0). Effect of treatment and time on behaviour and lesions were analysed by mixed models. Spearman rank correlations between behaviour and lesion scores and between scores recorded at different stages were determined. In general, MM performed more aggressive behaviour (50.4 ± 10.72) than MUM (20.3 ± 9.55, P < 0.05) and more mounting (30.9 ± 9.99) than MF (11.4 ± 3.76) and MUM (9.8 ± 3.74, P < 0.05). Skin lesion scores increased between farm (Day −1) and lairage (P < 0.001), but this tended to be significant only for MF and MM (P = 0.08). There was no effect of treatment on carcass lesions and no associations were found with fighting/mounting. Mixing entire males prior to slaughter stimulated mounting and aggressive behaviour but did not influence carcass lesion scores. Carcass skin/tail lesions scores were correlated with scores recorded on farm (rskin = 0.21 and rtail = 0.18, P < 0.01) suggesting that information recorded at meat inspection could be used as indicators of pig welfare on farm.This study was part of the PIGWELFIND project funded by the Department of Agriculture, Food and the Marine (DAFM), Ireland

<i>ESR1</i> Mutations and Overall Survival on Fulvestrant versus Exemestane in Advanced Hormone Receptor-Positive Breast Cancer: A Combined Analysis of the Phase III SoFEA and EFECT Trials.

Purpose ESR1 mutations are acquired frequently in hormone receptor-positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane.Experimental design The phase III EFECT and SoFEA trials randomized patients with hormone receptor-positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies.Results ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0-2.6] on exemestane and 3.9 months (95% CI, 3.0-6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39-0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7-6.2) on exemestane and 4.1 months (95% CI, 3.6-5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81-1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%-75%) on exemestane and 80% (95% CI, 68%-87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%-85%) on exemestane and 81% (95% CI, 74%-87%) on fulvestrant (P = 0.69).Conclusions Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant

Export of functional Streptomyces coelicolor alditol oxidase to the periplasm or cell surface of Escherichia coli and its application in whole-cell biocatalysis

Streptomyces coelicolor A3(2) alditol oxidase (AldO) is a soluble monomeric flavoprotein in which the flavin cofactor is covalently linked to the polypeptide chain. AldO displays high reactivity towards different polyols such as xylitol and sorbitol. These characteristics make AldO industrially relevant, but full biotechnological exploitation of this enzyme is at present restricted by laborious and costly purification steps. To eliminate the need for enzyme purification, this study describes a whole-cell AldO biocatalyst system. To this end, we have directed AldO to the periplasm or cell surface of Escherichia coli. For periplasmic export, AldO was fused to endogenous E. coli signal sequences known to direct their passenger proteins into the SecB, signal recognition particle (SRP), or Twin-arginine translocation (Tat) pathway. In addition, AldO was fused to an ice nucleation protein (INP)-based anchoring motif for surface display. The results show that Tat-exported AldO and INP-surface-displayed AldO are active. The Tat-based system was successfully employed in converting xylitol by whole cells, whereas the use of the INP-based system was most likely restricted by lipopolysaccharide LPS in wild-type cells. It is anticipated that these whole-cell systems will be a valuable tool for further biological and industrial exploitation of AldO and other cofactor-containing enzymes.

What is the effect of a low literacy talking book on patient knowledge, anxiety and communication before radiation therapy starts? A pilot study

Introduction: Radiation therapy is a common cancer treatment, requiring timely information to help patients prepare for treatment. We pilot tested a low literacy, psycho-educational talking book (written booklet, with accompanying audio recording) to examine (i) the effect of the tool on knowledge, anxiety and communication; (ii) acceptability, and (iii) how it was used in appointments. Methods: A pre-post design was employed. Patients scheduled to receive radiation therapy for any cancer were recruited from two hospitals in Sydney, Australia. Participants were sent the talking book before treatment planning and completed baseline and follow-up surveys, before and after the intervention. Results: Forty participants were recruited, and 39 completed all study assessments. Overall, knowledge increased after receiving the talking book by 3.8 points from 13.9 to 17.7/20 (95% confidence interval (CI) 2.7, 4.8, P < 0.001). Anxiety and concerns were significantly lower after receiving the talking book (P = 0.015 and P = 0.004, respectively). Nearly half of participants (s = 17, 48%) reported using the book during appointments. Most reported finding it easier to communicate (n = 31, 89%) and to ask more questions (n = 21, 62%). Conclusion: The talking book shows promise in improving knowledge, reducing anxiety and enhancing communication. Strategies to support the implementation of the talking book are required. Further studies to translate the book into different languages are also planned