A Proteomic and Functional Study of the Schistosoma mansoni Egg

Newly released eggs ofthe parasitic wonn Schistosoma mansoni either pass through the gut wall to escape from the host or are washed away in the host's bloodstream. In the latte~ scenario most eggs become lodged in ihe host's liver, where they become the focus ofa granulomatous response which can have severe pathological consequences. In this study, the S. mansoni soluble egg proteome is described and characterised for the first time. Mature eggs were separated from immature eggs and then fractionated into their morphological components: the miracidia, the hatch fluid (which bathes the miracidia) and the egg-secreted proteins. Each egg preparation was subjected to two-dimensional electrophoresis and tandem mass spectrometry. Developmental proteomic changes were then described in tenns ofthe egg's morphology so insights into the egg's natural history were gained. For example, acquisition of aerobic respiratory enzymes by the miracidium was seen, but nevertheless the miracidium still favours the use of energy-efficient heat shock proteins. Western blotting was used to show that the immature egg adopts the ubiquitin- --proteasome pathway to degrade its nutritive vitelline cells. The hatch fluid contains host proteins but it also has a defensive role, although its most abundant constituent (a large, acidic glycoprotein) is ofunknown function. The egg-secreted proteins consist ofdifferent variants ofjust four proteins, one of which has a pro-protein convertase domain and another of which appears to be a general purpose binding protein. A protocol is devised to pmi[y ea~h variant, so further functional studies into the individual secreted proteins can be carried out in the futur~. The secreted proteins induce a profound proliferative response in lymphocytes from acutely infected mice, indicating that they may work by activating granuloma T cells to secrete pro-proteases that are subsequently activated, enabling the egg to cross the gut wall

Toward a personalized real-time diagnosis in neonatal seizure detection

The problem of creating a personalized seizure detection algorithm for newborns is tackled in this paper. A probabilistic framework for semi-supervised adaptation of a generic patient-independent neonatal seizure detector is proposed. A system that is based on a combination of patient-adaptive (generative) and patient-independent (discriminative) classifiers is designed and evaluated on a large database of unedited continuous multichannel neonatal EEG recordings of over 800 h in duration. It is shown that an improvement in the detection of neonatal seizures over the course of long EEG recordings is achievable with on-the-fly incorporation of patient-specific EEG characteristics. In the clinical setting, the employment of the developed system will maintain a seizure detection rate at 70% while halving the number of false detections per hour, from 0.4 to 0.2 FD/h. This is the first study to propose the use of online adaptation without clinical labels, to build a personalized diagnostic system for the detection of neonatal seizures

New insights from field observations of the Younger giant dyke complex and mafic lamprophyres of the gardar province on Tuttutooq island, South Greenland

LK, RW, RC, LM and AM received funding from the Mining Institute of Scotland, Institute of Materials, Minerals and Mining, the Edinburgh Geological Society, the Augustine Courtauld Trust and the Scott Polar Research Institute. LK received funding from the Society of Economic Geology Hickok-Radford Fund.The Gardar Province of south Greenland is defined by the products of alkaline igneous magmatism during the Mesoproterozoic. The most laterally extensive Gardar intrusions are a series of giant dyke complexes best exposed on the Tuttutooq archipelago. We present new field observations and a geological map of north-east Tuttutooq island that provide fresh insights into the temporal evolution of the Younger giant dyke complex and two associated ultramafic lamprophyres. Our data demonstrate that distinctive crystallisation regimes occurred in different sectors of the dyke complex, leading to the formation of marginal gabbros and ovoid pod-like domains displaying lamination, modal layering and/or more evolved differentiates. We infer that at least two pulses of magma contributed to the formation of the Younger giant dyke complex. In addition, the relative ages of two ultramafic lamprophyre diatremes are constrained and attributed to two distinct phases of rifting in the Gardar Province.Publisher PDFPeer reviewe

Neonatal EEG graded for severity of background abnormalities in hypoxic-ischaemic encephalopathy

This report describes a set of neonatal electroencephalogram (EEG) recordings graded according to the severity of abnormalities in the background pattern. The dataset consists of 169 hours of multichannel EEG from 53 neonates recorded in a neonatal intensive care unit. All neonates received a diagnosis of hypoxic-ischaemic encephalopathy (HIE), the most common cause of brain injury in full term infants. For each neonate, multiple 1-hour epochs of good quality EEG were selected and then graded for background abnormalities. The grading system assesses EEG attributes such as amplitude and frequency, continuity, sleep--wake cycling, symmetry and synchrony, and abnormal waveforms. Background severity was then categorised into 4 grades: normal or mildly abnormal EEG, moderately abnormal EEG, severely abnormal EEG, and inactive EEG. The data can be used as a reference set of multi-channel EEG for neonates with HIE, for EEG training purposes, or for developing and evaluating automated grading algorithms

T cells drive negative feedback mechanisms in Cancer Associated Fibroblasts, promoting expression of co-inhibitory ligands, CD73 and IL-27 in non-small cell lung cancer

The success of immune checkpoint therapy shows tumor-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumor micro-environment (TME). Cancer associated fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localize with T cells in non-small cell lung cancer. We demonstrate the bidirectional nature of CAF/T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bidirectional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells

International consensus on clinical severity scale use in evaluating Niemann–Pick disease Type C in paediatric and adult patients: results from a Delphi Study

Background: Several scales have been developed in the past two decades to evaluate Niemann–Pick disease Type C (NPC) severity in clinical practice and trials. However, a lack of clarity concerning which scale to use in each setting is preventing the use of standardised assessments across the world, resulting in incomparable data sets and clinical trial outcome measures. This study aimed to establish agreed approaches for the use of NPC severity scales in clinical practice and research.Methods: A Delphi method of consensus development was used, comprising three survey rounds. In Round 1, participants were asked nine multiple-choice and open-ended questions to gather opinions on the six severity scales and domains. In Rounds 2 and 3, questions aimed to gain consensus on the opinions revealed in Round 1 using a typical Likert scale.Results: Nineteen experts, active in NPC paediatric and adult research and treatment, participated in this study. Of these, 16/19 completed Rounds 1 and 2 and 19/19 completed Round 3. Consensus (defined as ≥ 70% agreement or neutrality, given the study aim to identify the severity scales that the clinical community would accept for international consistency) was achieved for 66.7% of the multiple-choice questions in Round 2 and 83% of the multiple-choice questions in Round 3. Consensus was almost reached (68%) on the use of the 5-domain NPCCSS scale as the first choice in clinical practice. Consensus was reached (74%) for the 17-domain NPCCSS scale as the first choice in clinical trial settings, but the domains measured in the 5-domain scale should be prioritised as the primary endpoints. Experts called for educational and training materials on how to apply the NPCCSS (17- and 5-domains) for clinicians working in NPC.Conclusions: In achieving a consensus on the use of the 17-domain NPCCSS scale as the first choice for assessing clinical severity of NPC in clinical trial settings but prioritising the domains in the 5-domain NPCCSS scale for routine clinical practice, this study can help to inform future discussion around the use of the existing NPC clinical severity scales. For routine clinical practice, the study helps provide clarity on which scale is favoured by a significant proportion of a representative body of experts, in this case, the 5-domain NPCCSS scale

Validation of an automated seizure detection algorithm for term neonates

Objective: The objective of this study was to validate the performance of a seizure detection algorithm (SDA) developed by our group, on previously unseen, prolonged, unedited EEG recordings from 70 babies from 2 centres. Methods: EEGs of 70 babies (35 seizure, 35 non-seizure) were annotated for seizures by experts as the gold standard. The SDA was tested on the EEGs at a range of sensitivity settings. Annotations from the expert and SDA were compared using event and epoch based metrics. The effect of seizure duration on SDA performance was also analysed. Results: Between sensitivity settings of 0.5 and 0.3, the algorithm achieved seizure detection rates of 52.6–75.0%, with false detection (FD) rates of 0.04–0.36 FD/h for event based analysis, which was deemed to be acceptable in a clinical environment. Time based comparison of expert and SDA annotations using Cohen’s Kappa Index revealed a best performing SDA threshold of 0.4 (Kappa 0.630). The SDA showed improved detection performance with longer seizures. Conclusion: The SDA achieved promising performance and warrants further testing in a live clinical evaluation. Significance: The SDA has the potential to improve seizure detection and provide a robust tool for comparing treatment regimens

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

Neonatal Seizure Management - Is the Timing of Treatment Critical?

Objective: To assess the impact of the time to treatment of the first electrographic seizure on subsequent seizure burden and describe overall seizure management in a large neonatal cohort. Study design: Newborns (36-44 weeks of gestation) requiring electroencephalographic (EEG) monitoring recruited to 2 multicenter European studies were included. Infants who received antiseizure medication exclusively after electrographic seizure onset were grouped based on the time to treatment of the first seizure: antiseizure medication within 1 hour, between 1 and 2 hours, and after 2 hours. Outcomes measured were seizure burden, maximum seizure burden, status epilepticus, number of seizures, and antiseizure medication dose over the first 24 hours after seizure onset. Results: Out of 472 newborns recruited, 154 (32.6%) had confirmed electrographic seizures. Sixty-nine infants received antiseizure medication exclusively after the onset of electrographic seizure, including 21 infants within 1 hour of seizure onset, 15 between 1 and 2 hours after seizure onset, and 33 at >2 hours after seizure onset. Significantly lower seizure burden and fewer seizures were noted in the infants treated with antiseizure medication within 1 hour of seizure onset (P =.029 and.035, respectively). Overall, 258 of 472 infants (54.7%) received antiseizure medication during the study period, of whom 40 without electrographic seizures received treatment exclusively during EEG monitoring and 11 with electrographic seizures received no treatment. Conclusions: Treatment of neonatal seizures may be time-critical, but more research is needed to confirm this. Improvements in neonatal seizure diagnosis and treatment are also needed