A population approach to characterise amisulpride pharmacokinetics in older people and Alzheimer's disease

Introduction Current prescribing guidelines for the antipsychotic amisulpride are based largely on pharmacokinetic (PK) studies in young adults, and there is a relative absence of data on older patients, who are at greatest risk of developing adverse events. Methods This study aimed to develop a population PK model for amisulpride specifically in older people, by combining data from a richly sampled phase 1, single (50 mg) dose study in healthy older people (n = 20, 65–79 years), with a clinical dataset obtained during off label, low-dose (25–75 mg daily) amisulpride prescribing in older people with Alzheimer’s disease (AD) (n = 25, 69–92 years), as part of an observational study. Results After introducing a scaling factor based on body weight, age accounted for 20 % of the inter-individual variability in drug clearance (CL), resulting in a 54 % difference in CL between those aged 65 and those aged 85 years, and higher blood concentrations in older patients. Discussion These findings argue for the consideration of age and weight-based dose stratification to optimise amisulpride prescribing in older people, particularly in those aged 85 years and above

All-sky search of NAUTILUS data

A search for periodic gravitational-wave signals from isolated neutron stars in the NAUTILUS detector data is presented. We have analyzed half a year of data over the frequency band $$Hz, the spindown range$$ Hz/s and over the entire sky. We have divided the data into 2 day stretches and we have analyzed each stretch coherently using matched filtering. We have imposed a low threshold for the optimal detection statistic to obtain a set of candidates that are further examined for coincidences among various data stretches. For some candidates we have also investigated the change of the signal-to-noise ratio when we increase the observation time from two to four days. Our analysis has not revealed any gravitational-wave signals. Therefore we have imposed upper limits on the dimensionless gravitational-wave amplitude over the parameter space that we have searched. Depending on frequency, our upper limit ranges from $3.4 \times 10^{-23}$ to $1.3 \times 10^{-22}$. We have attempted a statistical verification of the hypotheses leading to our conclusions. We estimate that our upper limit is accurate to within 18%.Comment: LaTeX, 12 page

Initial operation of the International Gravitational Event Collaboration

The International Gravitational Event Collaboration, IGEC, is a coordinated effort by research groups operating gravitational wave detectors working towards the detection of millisecond bursts of gravitational waves. Here we report on the current IGEC resonant bar observatory, its data analysis procedures, the main properties of the first exchanged data set. Even though the available data set is not complete, in the years 1997 and 1998 up to four detectors were operating simultaneously. Preliminary results are mentioned.Comment: 8 pages, 2 figures, 3 tables; Proceeding of the GWDAW'99. Submitted to the International Journal of Modern Physic

Misidentification subtype of Alzheimer's disease psychosis predicts a faster cognitive decline

The presence of psychosis is associated with more rapid decline in Alzheimer's disease (AD), but the impact of paranoid (persecutory delusions) and misidentification (misperceptions and/or hallucinations) subtypes of psychosis on the speed of decline in AD is still unclear. Here we analysed data on Alzheimer's Disease Neuroimaging Initiative (ADNI)2 participants with late mild cognitive impairment or AD and we described individual trajectories of Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog) scores using a semi-mechanistic, logistic model, with a mixed effects based approach, which accounted for drop-out, and adjusted for baseline Mini Mental State Examination scores. The covariate model included psychosis subtypes, age, gender, education, medications and Apo-e ε4 genotype. We found that ADAS-cog rate of increase was doubled in misidentification (βr,misid_subtype =0.63, p=0.031) and mixed (both subtypes) ((βr,mixed_subtype =0.70, p=0.003) compared to non-psychotic (or paranoid) subjects suggesting that the misidentification subtype may represent a distinct AD sub-phenotype associated with an accelerated pathological process. This article is protected by copyright. All rights reserved

Soil Salinity Assessing and Mapping Using Several Statistical and Distribution Techniques in Arid and Semi-Arid Ecosystems, Egypt

Oasis lands in Egypt are commonly described as salty soils; therefore, waterlogging and higher soil salinity are major obstacles to sustainable agricultural development. This study aims to map and assess soil salinization at El-Farafra Oasis in the Egypt Western Desert based on salinity indices, Imaging Spectroscopy (IS), and statistical techniques. The regression model was developed to test the relationship between the electrical conductivity (ECe) of 70 surface soil samples and seven salinity indices (SI 1, SI 2, SI 5, SI 6, SI 7, SI 8, and SI 9) to produce soil salinity maps depending on Landsat-8 (OLI) images. The investigations of soil salinization and salinity indices were validated in a studied area based on 30 soil samples; the obtained results represented that all salinity indices have shown satisfactory correlations between ECe values for each soil sample site and salinity indices, except for the SI 5 index that present non-significant correlations with R2 value of 0.2688. The SI 8 index shows a higher negative significant correlation with ECe and an R2 value of 0.6356. There is a significant positive correlation at the (p < 0.01) level between SI 9 and ECe (r = 0.514), a non-significant correlation at the (p < 0.05) level between soil ECe and SI 1 index (r = 0.495), and the best-verified salinity index was for SI 7 that has a low estimated RMSE error of 8.58. Finally, the highest standard error (R2) was represented as ECe (dS m−1) with an R2 of 0.881, and the lowest one was SI 9 with an R2 of 0.428, according to Tukey’s test analysis. Therefore, observing and investigating soil salinity are essential requirements for appropriate natural resource management plans in the future

Search for Periodic Gravitational Wave Sources with the EXPLORER detector

We have developed a procedure for the search of signals from periodic sources in the data of gravitational wave detectors. We report here the analysis of one year of data from the resonant detector Explorer, searching for sources located in the Galactic Center (GC). No signals with amplitude greater than h-bar = 2.9×10–24, in the range 921.32–921.38 Hz, were observed using data collected over a time period of 95.7 days, for a source located at alpha= 17.70±0.01 h and delta= –29.00±0.05 deg. Our procedure can be extended for any assumed position in the sky and for a more general all-sky search, with the proper frequency correction to account for the spin-down and Doppler effects

A Web-based spatial decision supporting system for land management and soil conservation

Abstract. Today it is evident that there are many contrasting demands on our landscape (e.g. food security, more sustainable agriculture, higher income in rural areas, etc.) as well as many land degradation problems. It has been proved that providing operational answers to these demands and problems is extremely difficult. Here we aim to demonstrate that a spatial decision support system based on geospatial cyberinfrastructure (GCI) can address all of the above, so producing a smart system for supporting decision making for agriculture, forestry, and urban planning with respect to the landscape. In this paper, we discuss methods and results of a special kind of GCI architecture, one that is highly focused on land management and soil conservation. The system allows us to obtain dynamic, multidisciplinary, multiscale, and multifunctional answers to agriculture, forestry, and urban planning issues through the Web. The system has been applied to and tested in an area of about 20 000 ha in the south of Italy, within the framework of a European LIFE+ project (SOILCONSWEB). The paper reports – as a case study – results from two different applications dealing with agriculture (olive growth tool) and environmental protection (soil capability to protect groundwater). Developed with the help of end users, the system is starting to be adopted by local communities. The system indirectly explores a change of paradigm for soil and landscape scientists. Indeed, the potential benefit is shown of overcoming current disciplinary fragmentation over landscape issues by offering – through a smart Web-based system – truly integrated geospatial knowledge that may be directly and freely used by any end user (www.landconsultingweb.eu). This may help bridge the last very important divide between scientists working on the landscape and end users

Whole exome sequencing in fetuses with isolated increased nuchal translucency: a systematic review and meta-analysis.

OBJECTIVE: To estimate the incremental yield of detecting pathogenic or likely pathogenic diagnostic genetic variants (DGV) by whole exome sequencing (WES) over standard karyotype and chromosomal microarray (CMA) analyses in fetuses with isolated increased nuchal translucency (NT) and normal fetal anatomy at the time of 11-14 weeks scan. MATERIALS AND METHODS: Medline and Embase databases were searched. Inclusion criteria were fetuses with NT >95th percentile, normal karyotype and CMA and no associated structural anomalies at the time of the 11-14 weeks scan. The primary outcome was to estimate the incremental yield of detecting pathogenic or likely pathogenic genetic variants by WES over standard karyotype and CMA analyses in fetuses with isolated increased nuchal translucency. The secondary outcomes were the detection of a genetic variant of unknown significance. Sub-analysis according to different NT cutoffs (between 3.0 and 5.5 mm and > 5.5 mm) and considering fetuses with isolated NT in which fetal anatomy was confirmed to be normal at the anomaly scan were also performed. Random effects model meta-analyses of proportion were used to analyze the data. RESULTS: Eight articles (324 fetuses) were included in the systematic review. Of the fetuses with negative standard karyotype and CMA analysis, the 8.07% (95% CI 5.4-11.3) had pathogenic or likely pathogenic genetic variants detected exclusively by WES. When stratifying the analysis according to NT cutoffs, genetic anomalies detected exclusively at WES analysis were found in 44.70% (95% CI 26.8-63.4) of fetuses with NT between 3.0 mm and 5.5 mm and 55.3% (95% CI 36.6-73.2) in those fetuses with NT >5.5 mm and positive WES results. The 7.84% (95% CI 1.6-18.2) had variants of unknown significance identified by WES. When considering fetuses with isolated increased NT and normal fetal anatomy at the anomaly scan, the rate of pathogenic or likely pathogenic genetic variants detected by WES was 3.87% (95% CI 1.6-7.1), while variants of unknown significance were detected in 4.27% (95% CI 2.2-7.0) of cases. CONCLUSIONS: Pathogenic and likely pathogenic genetic variants detected by WES are present in a significant proportion of fetuses with increased NT but normal standard karyotype and CMA analysis, also when no anomalies are detected at the anomaly scan. Further large studies sharing objective protocols of imaging assessment are needed to confirm these findings and to elucidate which gene panels should be assessed in fetuses with isolated increased NT to rule out associated genetic anomalies, which may potentially impact post-natal outcomes

RNA editing signature during myeloid leukemia cell differentiation

Adenosine deaminases acting on RNA (ADARs) are key proteins for hematopoietic stem cell self-renewal and for survival of differentiating progenitor cells. However, their specific role in myeloid cell maturation has been poorly investigated. Here we show that ADAR1 is present at basal level in the primary myeloid leukemia cells obtained from patients at diagnosis as well as in myeloid U-937 and THP1 cell lines and its expression correlates with the editing levels. Upon phorbol-myristate acetate or Vitamin D3/granulocyte macrophage colony-stimulating factor (GM-CSF)-driven differentiation, both ADAR1 and ADAR2 enzymes are upregulated, with a concomitant global increase of A-to-I RNA editing. ADAR1 silencing caused an editing decrease at specific ADAR1 target genes, without, however, interfering with cell differentiation or with ADAR2 activity. Remarkably, ADAR2 is absent in the undifferentiated cell stage, due to its elimination through the ubiquitin–proteasome pathway, being strongly upregulated at the end of the differentiation process. Of note, peripheral blood monocytes display editing events at the selected targets similar to those found in differentiated cell lines. Taken together, the data indicate that ADAR enzymes play important and distinct roles in myeloid cells