Stochastic beamforming for cochlear implant coding

Cochlear implants are prosthetic devices used to provide hearing to people who would otherwise be profoundly deaf. The deliberate addition of noise to the electrode signals could increase the amount of information transmitted, but standard cochlear implants do not replicate the noise characteristic of normal hearing because if noise is added in an uncontrolled manner with a limited number of electrodes then it will almost certainly lead to worse performance. Only if partially independent stochastic activity can be achieved in each nerve fibre can mechanisms like suprathreshold stochastic resonance be effective. We are investigating the use of stochastic beamforming to achieve greater independence. The strategy involves presenting each electrode with a linear combination of independent Gaussian noise sources. Because the cochlea is filled with conductive salt solutions, the noise currents from the electrodes interact and the effective stimulus for each nerve fibre will therefore be a different weighted sum of the noise sources. To some extent therefore, the effective stimulus for a nerve fibre will be independent of the effective stimulus of neighbouring fibres. For a particular patient, the electrode position and the amount of current spread are fixed. The objective is therefore to find the linear combination of noise sources that leads to the greatest independence between nerve discharges. In this theoretical study we show that it is possible to get one independent point of excitation (one null) for each electrode and that stochastic beamforming can greatly decrease the correlation between the noise exciting different regions of the cochlea. © 2007 Copyright SPIE - The International Society for Optical Engineering

Multi-compartment profiling of cacterial and host metabolites identifies intestinal dysbiosis and its functional consequences in the critically ill child

Adverse physiology and antibiotic exposure devastate the intestinal microbiome in critical illness. Time and cost implications limit the immediate clinical potential of microbial sequencing to identify or treat intestinal dysbiosis. Here, we examined whether metabolic profiling is a feasible method of monitoring intestinal dysbiosis in critically ill children. Prospective multicenter cohort study. Three U.K.-based PICUs. Mechanically ventilated critically ill (n = 60) and age-matched healthy children (n = 55). Collection of urine and fecal samples in children admitted to the PICU. A single fecal and urine sample was collected in healthy controls. Untargeted and targeted metabolic profiling using 1H-nuclear magnetic resonance spectroscopy and liquid chromatography-mass spectrometry or urine and fecal samples. This was integrated with analysis of fecal bacterial 16S ribosomal RNA profiles and clinical disease severity indicators. We observed separation of global urinary and fecal metabolic profiles in critically ill compared with healthy children. Urinary excretion of mammalian-microbial co-metabolites hippurate, 4-cresol sulphate, and formate were reduced in critical illness compared with healthy children. Reduced fecal excretion of short-chain fatty acids (including butyrate, propionate, and acetate) were observed in the patient cohort, demonstrating that these metabolites also distinguished between critical illness and health. Dysregulation of intestinal bile metabolism was evidenced by increased primary and reduced secondary fecal bile acid excretion. Fecal butyrate correlated with days free of intensive care at 30 days (r = 0.38; p = 0.03), while urinary formate correlated inversely with vasopressor requirement (r = -0.2; p = 0.037). Disruption to the functional activity of the intestinal microbiome may result in worsening organ failure in the critically ill child. Profiling of bacterial metabolites in fecal and urine samples may support identification and treatment of intestinal dysbiosis in critical illness.This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited

A single dose of pegfilgrastim compared with daily filgrastim for supporting neutrophil recovery in patients treated for low-to-intermediate risk acute myeloid leukemia: results from a randomized, double-blind, phase 2 trial

Background: Patients with acute myeloid leukemia (AML) are often neutropenic as a result of their disease. Furthermore, these patients typically experience profound neutropenia following induction and/or consolidation chemotherapy and this may result in serious, potentially life-threatening, infection. This randomized, double-blind, phase 2 clinical trial compared the efficacy and tolerability of pegfilgrastim with filgrastim for assisting neutrophil recovery following induction and consolidation chemotherapy for de novo AML in patients with low-to-intermediate risk cytogenetics. Methods: Patients (n = 84) received one or two courses of standard induction chemotherapy (idarubicin + cytarabine), followed by one course of consolidation therapy (high-dose cytarabine) if complete remission was achieved. They were randomized to receive either single-dose pegfilgrastim 6 mg or daily filgrastim 5 μg/kg, beginning 24 hours after induction and consolidation chemotherapy. Results: The median time to recovery from severe neutropenia was 22.0 days for both pegfilgrastim (n = 42) and filgrastim (n = 41) groups during Induction 1 (difference 0.0 days; 95% CI: -1.9 to 1.9). During Consolidation, recovery occurred after a median of 17.0 days for pegfilgrastim versus 16.5 days for filgrastim (difference 0.5 days; 95% CI: -1.1 to 2.1). Therapeutic pegfilgrastim serum concentrations were maintained throughout neutropenia. Pegfilgrastim was well tolerated, with an adverse event profile similar to that of filgrastim. Conclusion: These data suggest no clinically meaningful difference between a single dose of pegfilgrastim and multiple daily doses of filgrastim for shortening the duration of severe neutropenia following chemotherapy in de novo AML patients with low-to-intermediate risk cytogenetics

Non-solvolytic synthesis of aqueous soluble TiO2 nanoparticles and real-time dynamic measurements of the nanoparticle formation.

Highly aqueously dispersible (soluble) TiO2 nanoparticles are usually synthesized by a solution-based sol-gel (solvolysis/condensation) process, and no direct precipitation of titania has been reported. This paper proposes a new approach to synthesize stable TiO2 nanoparticles by a non-solvolytic method - direct liquid phase precipitation at room temperature. Ligand-capped TiO2 nanoparticles are more readily solubilized compared to uncapped TiO2 nanoparticles, and these capped materials show distinct optical absorbance/emission behaviors. The influence of ligands, way of reactant feeding, and post-treatment on the shape, size, crystalline structure, and surface chemistry of the TiO2 nanoparticles has been thoroughly investigated by the combined use of X-ray diffraction, transmission electron microscopy, UV-visible (UV-vis) spectroscopy, and photoluminescence (PL). It is found that all above variables have significant effects on the size, shape, and dispersivity of the final TiO2 nanoparticles. For the first time, real-time UV-vis spectroscopy and PL are used to dynamically detect the formation and growth of TiO2 nanoparticles in solution. These real-time measurements show that the precipitation process begins to nucleate after an initial inhibition period of about 1 h, thereafter a particle growth occurs and reaches the maximum point after 2 h. The synthesis reaction is essentially completed after 4 h.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Mendelian adult-onset leukodystrophy genes in Alzheimer´s disease. Critical influence of CSF1R and NOTCH3

Mendelian adult-onset leukodystrophies are a spectrum of rare inherited progressive neurodegenerative disorders affecting the white matter of the central nervous system. Among these, Cerebral Autosomal Dominant and Recessive Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL and CARASIL), Cerebroretinal vasculopathy (CRV), Metachromatic leukodystrophy (MLD), Hereditary diffuse Leukoencephalopathy with spheroids (HDLS), Vanishing white matter disease (VWM) present with rapidly progressive dementia as dominant feature and are caused by mutations in NOTCH3, HTRA1, TREX1, ARSA, CSF1R, EIF2B1, EIF2B2, EIF2B3, EIF2B4, EIF2B5, respectively. Given the rare incidence of these disorders and the lack of unequivocally diagnostic features, leukodystrophies are frequently misdiagnosed with common sporadic dementing diseases such as Alzheimer’s disease (AD), raising the question of whether these overlapping phenotypes may be explained by shared genetic risk factors. To investigate this intriguing hypothesis, we have combined gene expression analysis 1) in 6 different AD mouse strains (APPPS1, HOTASTPM, HETASTPM, TPM, TAS10 and TAU), at 5 different developmental stages (Embryo [E15], 2 months, 4 months, 8 months and 18 months), 2) in APPPS1 primary cortical neurons under stress conditions (oxygen-glucose deprivation) and single-variant and single-gene (c-alpha and SKAT tests) based genetic screening in a cohort composed of 332 Caucasian late-onset AD patients and 676 Caucasian elderly controls. Csf1r was significantly overexpressed (Log2FC>1, adj. p-val<0.05) in the cortex and hippocampus of aged HOTASTPM mice with extensive Aβ core dense plaque pathology. We identified 3 likely pathogenic mutations in CSF1R TK domain (p.L868R, p.Q691H and p.H703Y) in our discovery and validation cohort, composed of 465 AD and MCI Caucasian patients from the UK. Moreover, NOTCH3 was a significant hit in the c-alpha test (adj p-val = 0.01). Adult onset Mendelian leukodystrophy genes are not common factors implicated in AD. Nevertheless, our study suggests a potential pathogenic link between NOTCH3, CSF1R and sporadic LOAD, that warrants further investigation

Early Ipswichian (last interglacial) sea level rise in the channel region : Stone Point Site of Special Scientific Interest, Hampshire, England

Constraining the speed of sea level rise at the start of an interglacial is important to understanding the size of the ‘window of opportunity’ available for hominin migration. This is particularly important during the last interglacial when there is no evidence for significant hominin occupation anywhere in Britain. There are very few finer grained fossiliferous sequences in the Channel region that can be used to constrain sea level rise and they are preserved only to the north of the Channel, in England. Of these, the sequence at Stone Point SSSI is by far the most complete. Data from this sequence has been previously reported, and discussed at a Quaternary Research Association Field Meeting, where a number of further questions were raised that necessitated further data generation. In this paper, we report new data from this sequence – thin section analysis, isotopic determinations on ostracod shells, new Optical Stimulated Luminescence ages and Amino Acid Recem analyses. These show early sea level rise in this sequence, starting during the pre-temperate vegetation zone IpI, but no early warming. The implications of this almost certainly last interglacial sequence for the human colonisation of Britain and our understanding of the stratigraphic relationship of interglacial estuarine deposits with their related fluvial terrace sequences is explored

ABCA7 p.G215S as potential protective factor for Alzheimer’s disease

Genome-wide association studies (GWASs) have been effective approaches to dissect common genetic variability underlying complex diseases in a systematic and unbiased way. Recently, GWASs have led to the discovery of over 20 susceptibility loci for Alzheimer’s disease (AD). Despite the evidence showing the contribution of these loci to AD pathogenesis, their genetic architecture has not been extensively investigated, leaving the possibility that low frequency and rare coding variants may also occur and contribute to the risk of disease. We have used exome and genome sequencing data to analyse the single independent and joint effect of rare and low frequency protein coding variants in 9 AD GWAS loci with the strongest effect sizes after APOE (BIN1, CLU, CR1, PICALM, MS4A6A, ABCA7, EPHA1, CD33, CD2AP) in a cohort of 332 sporadic AD cases and 676 elderly controls of British and North American ancestry. We identified coding variability in ABCA7 as contributing to AD risk. This locus harbors a low frequency coding variant (p.G215S, rs72973581, MAF=4.3%) conferring a modest but statistically significant protection against AD (p-value= 6x10-4, OR=0.57, 95% CI 0.41-0.80). Notably, our results are not driven by an enrichment of loss of function variants in ABCA7, recently reported as main pathogenic factor underlying AD risk at this locus. In summary, our study confirms the role of ABCA7 in AD and provide new insights that should address functional studies

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