An integrated model of care for neurological infections: the first six years of referrals to a specialist service at a university teaching hospital in Northwest England

Background A specialist neurological infectious disease service has been run jointly by the departments of infectious disease and neurology at the Royal Liverpool University Hospital since 2005. We sought to describe the referral case mix and outcomes of the first six years of referrals to the service. Methods Retrospective service review. Results Of 242 adults referred to the service, 231 (95 %) were inpatients. Neurological infections were confirmed in 155 (64 %), indicating a high degree of selection before referral. Viral meningitis (35 cases), bacterial meningitis (33) and encephalitis (22) accounted for 38 % of referrals and 61 % of confirmed neurological infections. Although an infrequent diagnosis (n = 19), neurological TB caused the longest admission (median 23, range 5 – 119 days). A proven or probable microbiological diagnosis was found in 100/155 cases (64.5 %). For the whole cohort, altered sensorium, older age and longer hospital stay were associated with poor outcome (death or neurological disability); viral meningitis was associated with good outcome. In multivariate analysis altered sensorium remained significantly associated with poor outcome, adjusted odds ratio 3.04 (95 % confidence interval 1.28 – 7.22, p = 0.01). Conclusions A service of this type provides important specialist care and a focus for training and clinical research on complex neurological infections

Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

Detection of Fused Genes in Eukaryotic Genomes using Gene deFuser: Analysis of the Tetrahymena thermophila genome

<p>Abstract</p> <p>Background</p> <p>Fused genes are important sources of data for studies of evolution and protein function. To date no service has been made available online to aid in the large-scale identification of fused genes in sequenced genomes. We have developed a program, Gene deFuser, that analyzes uploaded protein sequence files for characteristics of gene fusion events and presents the results in a convenient web interface.</p> <p>Results</p> <p>To test the ability of this software to detect fusions on a genome-wide scale, we analyzed the 24,725 gene models predicted for the ciliated protozoan <it>Tetrahymena thermophila</it>. Gene deFuser detected members of eight of the nine families of gene fusions known or predicted in this species and identified nineteen new families of fused genes, each containing between one and twelve members. In addition to these genuine fusions, Gene deFuser also detected a particular type of gene misannotation, in which two independent genes were predicted as a single transcript by gene annotation tools. Twenty-nine of the artifacts detected by Gene deFuser in the initial annotation have been corrected in subsequent versions, with a total of 25 annotation artifacts (about 1/3 of the total fusions identified) remaining in the most recent annotation.</p> <p>Conclusions</p> <p>The newly identified <it>Tetrahymena </it>fusions belong to classes of genes involved in processes such as phospholipid synthesis, nuclear export, and surface antigen generation. These results highlight the potential of Gene deFuser to reveal a large number of novel fused genes in evolutionarily isolated organisms. Gene deFuser may also prove useful as an ancillary tool for detecting fusion artifacts during gene model annotation.</p

Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women

Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity. We performed a prospective cohort study of VLCD-induced weight loss of 10% in ten grades 2-3 obese postmenopausal women in a metabolic unit. Baseline and post weight loss evaluation included fasting plasma analyzed by mass spectrometry, adipose tissue transcription by RNA sequencing, stool 16S rRNA sequencing for fecal microbiota, fecal bile acids by mass spectrometry, and urinary metabolic phenotyping by H-NMR spectroscopy. Outcome measures included mixed model correlations between changes in fecal microbiota and bile acid composition with changes in plasma metabolite and adipose tissue gene expression pathways. Alterations in the urinary metabolic phenotype following VLCD-induced weight loss were consistent with starvation ketosis, protein sparing, and disruptions to the functional status of the gut microbiota. We show that the core microbiome was preserved during VLCD-induced weight loss, but with changes in several groups of bacterial taxa with functional implications. UniFrac analysis showed overall parallel shifts in community structure, corresponding to reduced abundance of the genus Roseburia and increased Christensenellaceae;g__ (unknown genus). Imputed microbial functions showed changes in fat and carbohydrate metabolism. A significant fall in fecal total bile acid concentration and reduced deconjugation and 7-α-dihydroxylation were accompanied by significant changes in several bacterial taxa. Individual bile acids in feces correlated with amino acid, purine, and lipid metabolic pathways in plasma. Furthermore, several fecal bile acids and bacterial species correlated with altered gene expression pathways in adipose tissue. VLCD dietary intervention in obese women changed the composition of several fecal microbial populations while preserving the core fecal microbiome. Changes in individual microbial taxa and their functions correlated with variations in the plasma metabolome, fecal bile acid composition, and adipose tissue transcriptome

Climate Change – Refining the Impacts for Ireland: STRIVE Report (2001-CD-C3-M1) ISBN: 978-1-84095-297-1

International Context: As a mid-latitude country Ireland can expect its future temperature changes to mirror quite closely those of the globe as a whole. Best estimates of global temperature change by the end of the present century are currently in the region 1.8–4.0°C1. Regional Context: Weighted Ensemble Downscaling from Global Climate Models Global climate models (GCMs) have greatly improved in reliability and resolution as computing power has increased and better inputs from earth observation have become available. Despite this, they remain too coarse in terms of their grid size to enable climate scenarios at the scale necessary for impact analysis to be achieved. This study employs a statistical downscaling approach to overcome these difficulties and also to provide new information on model uncertainty with a view to reducing uncertainty in key sectors such as water resource management, agriculture and biodiversity

Reconstruction of primary vertices at the ATLAS experiment in Run 1 proton–proton collisions at the LHC

This paper presents the method and performance of primary vertex reconstruction in proton–proton collision data recorded by the ATLAS experiment during Run 1 of the LHC. The studies presented focus on data taken during 2012 at a centre-of-mass energy of √s=8 TeV. The performance has been measured as a function of the number of interactions per bunch crossing over a wide range, from one to seventy. The measurement of the position and size of the luminous region and its use as a constraint to improve the primary vertex resolution are discussed. A longitudinal vertex position resolution of about 30μm is achieved for events with high multiplicity of reconstructed tracks. The transverse position resolution is better than 20μm and is dominated by the precision on the size of the luminous region. An analytical model is proposed to describe the primary vertex reconstruction efficiency as a function of the number of interactions per bunch crossing and of the longitudinal size of the luminous region. Agreement between the data and the predictions of this model is better than 3% up to seventy interactions per bunch crossing

Interventions for hyperhidrosis in secondary care : a systematic review and value-of-information analysis

Background: Hyperhidrosis is uncontrollable excessive sweating that occurs at rest, regardless of temperature. The symptoms of hyperhidrosis can significantly affect quality of life. The management of hyperhidrosis is uncertain and variable. Objective: To establish the expected value of undertaking additional research to determine the most effective interventions for the management of refractory primary hyperhidrosis in secondary care. Methods: A systematic review and economic model, including a value-of-information (VOI) analysis. Treatments to be prescribed by dermatologists and minor surgical treatments for hyperhidrosis of the hands, feet and axillae were reviewed; as endoscopic thoracic sympathectomy (ETS) is incontestably an end-of-line treatment, it was not reviewed further. Fifteen databases (e.g. CENTRAL, PubMed and PsycINFO), conference proceedings and trial registers were searched from inception to July 2016. Systematic review methods were followed. Pairwise meta-analyses were conducted for comparisons between botulinum toxin (BTX) injections and placebo for axillary hyperhidrosis, but otherwise, owing to evidence limitations, data were synthesised narratively. A decision-analytic model assessed the cost-effectiveness and VOI of five treatments (iontophoresis, medication, BTX, curettage, ETS) in 64 different sequences for axillary hyperhidrosis only. Results and conclusions: Fifty studies were included in the effectiveness review: 32 randomised controlled trials (RCTs), 17 non-RCTs and one large prospective case series. Most studies were small, rated as having a high risk of bias and poorly reported. The interventions assessed in the review were iontophoresis, BTX, anticholinergic medications, curettage and newer energy-based technologies that damage the sweat gland (e.g. laser, microwave). There is moderate-quality evidence of a large statistically significant effect of BTX on axillary hyperhidrosis symptoms, compared with placebo. There was weak but consistent evidence for iontophoresis for palmar hyperhidrosis. Evidence for other interventions was of low or very low quality. For axillary hyperhidrosis cost-effectiveness results indicated that iontophoresis, BTX, medication, curettage and ETS was the most cost-effective sequence (probability 0.8), with an incremental cost-effectiveness ratio of £9304 per quality-adjusted life-year. Uncertainty associated with study bias was not reflected in the economic results. Patients and clinicians attending an end-of-project workshop were satisfied with the sequence of treatments for axillary hyperhidrosis identified as being cost-effective. All patient advisors considered that the Hyperhidrosis Quality of Life Index was superior to other tools commonly used in hyperhidrosis research for assessing quality of life. Limitations: The evidence for the clinical effectiveness and safety of second-line treatments for primary hyperhidrosis is limited. This meant that there was insufficient evidence to draw conclusions for most interventions assessed and the cost-effectiveness analysis was restricted to hyperhidrosis of the axilla. Future work: Based on anecdotal evidence and inference from evidence for the axillae, participants agreed that a trial of BTX (with anaesthesia) compared with iontophoresis for palmar hyperhidrosis would be most useful. The VOI analysis indicates that further research into the effectiveness of existing medications might be worthwhile, but it is unclear that such trials are of clinical importance. Research that established a robust estimate of the annual incidence of axillary hyperhidrosis in the UK population would reduce the uncertainty in future VOI analyses

Climate Change: Scenarios & Impacts for Ireland (2000-LS-5.2.1-M1) ISBN:1-84095-115-X

The Third Assessment Report of the Intergovernmental Panel on Climate Change (IPCC, 2001) is the most authoritative assessment of global climate change to date. Produced by several hundred leading scientists in various areas of climate studies, its principal conclusions include the following: • Global average temperature has increased by 0.6 ± 0.2°C since 1860 with accelerated warming apparent in the latter decades of the 20th century. A further increase of 1.5–6.0°C from 1990 to 2100 is projected, depending on how emissions of greenhouse gases increase over the period. • The 20th century was the warmest of the last millennium in the Northern Hemisphere, with the 1990s being the warmest decade and 1998 the warmest year. Warming has been more pronounced at night than during the day. • Reductions in the extent of snow cover of 10% have occurred in the past 40 years, with a widespread retreat also of mountain glaciers outside the polar regions. Sea-ice thickness in the Arctic has declined by about 40% during late summer/early autumn, though no comparable reduction has taken place in winter. In the Antarctic, no similar trends have been observed. One of the most serious impacts on global sea level could result from a catastrophic failure of grounded ice in West Antarctica. This is, however, considered unlikely over the coming century. • Global sea level has risen by 0.1–0.2 m over the past century, an order of magnitude larger than the average rate over the past three millennia. A rise of approximately 0.5 m is considered likely during the period 1990–2100. • Precipitation has increased over the land masses of the temperate regions by 0.5–1.0% per decade. Frequencies of more intense rainfall events appear to be increasing also in the Northern Hemisphere. In contrast, decreases in rainfall over the tropics have been observed, though this trend has weakened in recent years. More frequent warm-phase El Niño events are occurring in the Pacific Basin. Precipitation increases are projected, particularly for winter, for middle and high latitudes in the Northern Hemisphere and for Antarctica. • No significant trends in the tropical cyclone climatology have been detected. These global trends have implications for the future course of Ireland’s climate which it is judicious to anticipate. This report presents an assessment of the magnitude and likely impacts of climate change in Ireland over the course of the current century. It approaches this by establishing scenarios for future Irish climate based on global climate model projections for the middle and last quarter of the present century. These projections are then used to assess probable impacts in key sectors such as agriculture, forestry, water resources, the coastal and marine environments and on biodiversity. The purpose of the report is to firstly identify where vulnerability to climate change exists in Ireland and what adjustments are likely in the operation of environmental systems in response to such changes. In some sectors, e.g. agriculture, some new opportunities may arise. In other instances, e.g. water resource management, long-term planning strategies will be necessary to mitigate adverse impacts. Long lead times for adjustment characterise many sectors, e.g. forestry, and it is important to provide as much advance warning of likely changes as possible to enable adaptation to commence early. By anticipating change it may be possible to minimise adverse impacts and to maximise positive aspects of global climate change

Climate Change: Scenarios & Impacts for Ireland (2000-LS-5.2.1-M1) ISBN:1-84095-115-X

The Third Assessment Report of the Intergovernmental Panel on Climate Change (IPCC, 2001) is the most authoritative assessment of global climate change to date. Produced by several hundred leading scientists in various areas of climate studies, its principal conclusions include the following: • Global average temperature has increased by 0.6 ± 0.2°C since 1860 with accelerated warming apparent in the latter decades of the 20th century. A further increase of 1.5–6.0°C from 1990 to 2100 is projected, depending on how emissions of greenhouse gases increase over the period. • The 20th century was the warmest of the last millennium in the Northern Hemisphere, with the 1990s being the warmest decade and 1998 the warmest year. Warming has been more pronounced at night than during the day. • Reductions in the extent of snow cover of 10% have occurred in the past 40 years, with a widespread retreat also of mountain glaciers outside the polar regions. Sea-ice thickness in the Arctic has declined by about 40% during late summer/early autumn, though no comparable reduction has taken place in winter. In the Antarctic, no similar trends have been observed. One of the most serious impacts on global sea level could result from a catastrophic failure of grounded ice in West Antarctica. This is, however, considered unlikely over the coming century. • Global sea level has risen by 0.1–0.2 m over the past century, an order of magnitude larger than the average rate over the past three millennia. A rise of approximately 0.5 m is considered likely during the period 1990–2100. • Precipitation has increased over the land masses of the temperate regions by 0.5–1.0% per decade. Frequencies of more intense rainfall events appear to be increasing also in the Northern Hemisphere. In contrast, decreases in rainfall over the tropics have been observed, though this trend has weakened in recent years. More frequent warm-phase El Niño events are occurring in the Pacific Basin. Precipitation increases are projected, particularly for winter, for middle and high latitudes in the Northern Hemisphere and for Antarctica. • No significant trends in the tropical cyclone climatology have been detected. These global trends have implications for the future course of Ireland’s climate which it is judicious to anticipate. This report presents an assessment of the magnitude and likely impacts of climate change in Ireland over the course of the current century. It approaches this by establishing scenarios for future Irish climate based on global climate model projections for the middle and last quarter of the present century. These projections are then used to assess probable impacts in key sectors such as agriculture, forestry, water resources, the coastal and marine environments and on biodiversity. The purpose of the report is to firstly identify where vulnerability to climate change exists in Ireland and what adjustments are likely in the operation of environmental systems in response to such changes. In some sectors, e.g. agriculture, some new opportunities may arise. In other instances, e.g. water resource management, long-term planning strategies will be necessary to mitigate adverse impacts. Long lead times for adjustment characterise many sectors, e.g. forestry, and it is important to provide as much advance warning of likely changes as possible to enable adaptation to commence early. By anticipating change it may be possible to minimise adverse impacts and to maximise positive aspects of global climate change

Climate Change: Scenarios & Impacts for Ireland (2000-LS-5.2.1-M1) ISBN:1-84095-115-X

The Third Assessment Report of the Intergovernmental Panel on Climate Change (IPCC, 2001) is the most authoritative assessment of global climate change to date. Produced by several hundred leading scientists in various areas of climate studies, its principal conclusions include the following: • Global average temperature has increased by 0.6 ± 0.2°C since 1860 with accelerated warming apparent in the latter decades of the 20th century. A further increase of 1.5–6.0°C from 1990 to 2100 is projected, depending on how emissions of greenhouse gases increase over the period. • The 20th century was the warmest of the last millennium in the Northern Hemisphere, with the 1990s being the warmest decade and 1998 the warmest year. Warming has been more pronounced at night than during the day. • Reductions in the extent of snow cover of 10% have occurred in the past 40 years, with a widespread retreat also of mountain glaciers outside the polar regions. Sea-ice thickness in the Arctic has declined by about 40% during late summer/early autumn, though no comparable reduction has taken place in winter. In the Antarctic, no similar trends have been observed. One of the most serious impacts on global sea level could result from a catastrophic failure of grounded ice in West Antarctica. This is, however, considered unlikely over the coming century. • Global sea level has risen by 0.1–0.2 m over the past century, an order of magnitude larger than the average rate over the past three millennia. A rise of approximately 0.5 m is considered likely during the period 1990–2100. • Precipitation has increased over the land masses of the temperate regions by 0.5–1.0% per decade. Frequencies of more intense rainfall events appear to be increasing also in the Northern Hemisphere. In contrast, decreases in rainfall over the tropics have been observed, though this trend has weakened in recent years. More frequent warm-phase El Niño events are occurring in the Pacific Basin. Precipitation increases are projected, particularly for winter, for middle and high latitudes in the Northern Hemisphere and for Antarctica. • No significant trends in the tropical cyclone climatology have been detected. These global trends have implications for the future course of Ireland’s climate which it is judicious to anticipate. This report presents an assessment of the magnitude and likely impacts of climate change in Ireland over the course of the current century. It approaches this by establishing scenarios for future Irish climate based on global climate model projections for the middle and last quarter of the present century. These projections are then used to assess probable impacts in key sectors such as agriculture, forestry, water resources, the coastal and marine environments and on biodiversity. The purpose of the report is to firstly identify where vulnerability to climate change exists in Ireland and what adjustments are likely in the operation of environmental systems in response to such changes. In some sectors, e.g. agriculture, some new opportunities may arise. In other instances, e.g. water resource management, long-term planning strategies will be necessary to mitigate adverse impacts. Long lead times for adjustment characterise many sectors, e.g. forestry, and it is important to provide as much advance warning of likely changes as possible to enable adaptation to commence early. By anticipating change it may be possible to minimise adverse impacts and to maximise positive aspects of global climate change