High Plasma Levels of Betaine, a Trimethylamine N-Oxide Related Metabolite, are Associated with Severity of Cirrhosis

Background and Aims: The gut microbiome-related metabolites betaine and trimethylamine N-oxide (TMAO) affect major health issues. In cirrhosis, betaine metabolism may be diminished because of impaired hepatic betaine homocysteine methyltransferase activity, whereas TMAO generation from trimethylamine may be altered because of impaired hepatic flavin monooxygenase expression. Here, we determined plasma betaine and TMAO levels in patients with end-stage liver disease and assessed their relationships with liver disease severity. Methods: Plasma betaine and TMAO concentrations were measured by nuclear magnetic resonance spectroscopy in 129 cirrhotic patients (TransplantLines cohort study; NCT03272841) and compared with levels from 4837 participants of the PREVEND cohort study. Disease severity was assessed by Child-Pugh-Turcotte (CPT) classification and Model for End-stage Liver Disease (MELD) score. Results: Plasma betaine was on average 60% higher (p < .001), whereas TMAO was not significantly lower in cirrhotic patients vs. PREVEND population (p = .44). After liver transplantation (n = 13), betaine decreased (p = .017; p = .36 vs. PREVEND population), whereas TMAO levels tended to increase (p = .085) to higher levels than in the PREVEND population (p = .003). Betaine levels were positively associated with the CPT stage and MELD score (both p < .001). The association with the MELD score remained in the fully adjusted analysis (p < .001). The association of TMAO with the MELD score did not reach significance (p = .11). Neither betaine nor TMAO levels were associated with mortality on the waiting list for liver transplantation (adjusted p = .78 and p = .44, respectively). Conclusion: Plasma betaine levels are elevated in cirrhotic patients in parallel with disease severity and decrease after liver transplantation

GNSS multi-frequency receiver single-satellite measurement validation method

A method is presented for real-time validation of GNSS measurements of a single receiver, where data from each satellite are independently processed. A geometry- free observation model is used with a reparameterized form of the unknowns to overcome rank deficiency of the model. The ionosphere error and non-constant biases such as multipath are assumed changing relatively smoothly as a function of time. Data validation and detection of errors are based on statistical testing of the observation residuals using the detection–identification–adaptation approach. The method is applicable to any GNSS with any number of frequencies. The performance of validation method was evaluated using multi-frequency data from three GNSS (GPS, GLONASS, and Galileo) that span 3 days in a test site at Curtin University, Australia. Performance of the method in detection and identification of outliers in code observations, and detection of cycle slips in phase data were examined. Results show that the success rates vary according to precision of observations and their number as well as size of the errors. The method capability is demonstrated when processing four IOV Galileo satellites in a single-point-positioning mode and in another test by comparing its performance with Bernese software in detection of cycle slips in precise point-positioning processing using GPS data

A Fine-Mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder

Major depressive disorder (MDD) is a psychiatric disorder that is characterized -amongst others- by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f.>0.1, r2>0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P = 6.8E−7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P = 1.2E−6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P = 9.9E−7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833

IRNSS/NavIC and GPS: a single- and dual-system L5 analysis

The Indian Regional Navigation Satellite System (IRNSS) has recently (May 2016) become fully operational. In this contribution, for the fully operational IRNSS as a stand-alone system and also in combination with GPS, we provide a first assessment of L5 integer ambiguity resolution and positioning performance. While our empirical analyses are based on the data collected by two JAVAD receivers at Curtin University, Perth, Australia, our formal analyses are carried out for various onshore locations within the IRNSS service area. We study the noise characteristics (carrier-to-noise density, measurement precision, time correlation), the integer ambiguity resolution performance (success rates and ambiguity dilution of precision), and the positioning performance (ambiguity float and ambiguity fixed). The results show that our empirical outcomes are consistent with their formal counterparts and that the GPS L5-data have a lower noise level than that of IRNSS L5-data, particularly in case of the code data. The underlying model in our assessments varies from stand-alone IRNSS (L5) to IRNSS (Formula presented.) GPS (L5), from unconstrained to height-constrained and from kinematic to static. Significant improvements in ambiguity resolution and positioning performance are achievable upon integrating L5-data of IRNSS with GPS

Thrombospondin-1 in Early Flow-Related Remodeling of Mesenteric Arteries from Young Normotensive and Spontaneously Hypertensive Rats

We tested the hypotheses that TSP-1 participates in the initiation of remodeling of small muscular arteries in response to altered blood flow and that the N-terminal domain of TSP-1 (hepI) can reverse the pathological inward remodeling of resistance arteries from SHR

An assessment of smartphone and low-cost multi-GNSS single-frequency RTK positioning for low, medium and high ionospheric disturbance periods

The emerging GNSSs make single-frequency (SF) RTK positioning possible. In this contribution two different types of low-cost (few hundred USDs) RTK receivers are analyzed, which can track L1 GPS, B1 BDS, E1 Galileo and L1 QZSS, or any combinations thereof, for a location in Dunedin, New Zealand. These SF RTK receivers can potentially give competitive ambiguity resolution and positioning performance to that of more expensive (thousands USDs) dual-frequency (DF) GPS receivers. A smartphone implementation of one of these SF receiver types is also evaluated. The least-squares variance component estimation (LS-VCE) procedure is first used to formulate a realistic stochastic model, which assures that our receivers at hand can achieve the best possible ambiguity resolution and RTK positioning performance. The best performing low-cost SF RTK receiver types are then assessed against DF GPS receivers and survey-grade antennas. Real data with ionospheric disturbances at low, medium and high levels are analyzed, while making use of the ionosphere-weighted model. It will be demonstrated that when the presence of the residual ionospheric delays increases, instantaneous RTK positioning is not possible for any of the receivers, and a multi-epoch model is necessary to use. It is finally shown that the low-cost SF RTK performance can remain competitive to that of more expensive DF GPS receivers even when the ionospheric disturbance level reaches a Kp-index of 7-, i.e. for a strong geomagnetic storm, for the baseline at hand

Palliative chemotherapy or best supportive care? A prospective study explaining patients' treatment preference and choice

Item does not contain fulltextIn palliative cancer treatment, the choice between palliative chemotherapy and best supportive care may be difficult. In the decision-making process, giving information as well as patients' values and preferences become important issues. Patients, however, may have a treatment preference before they even meet their medical oncologist. An insight into the patient's decision-making process can support clinicians having to inform their patients. Patients (n=207) with metastatic cancer, aged 18 years or older, able to speak Dutch, for whom palliative chemotherapy was a treatment option, were eligible for the study. We assessed the following before they consulted their medical oncologist: (1) socio-demographic characteristics, (2) disease-related variables, (3) quality-of-life indices, (4) attitudes and (5) preferences for treatment, information and participation in decision-making. The actual treatment decision, assessed after it had been made, was the main study outcome. Of 207 eligible patients, 140 patients (68%) participated in the study. At baseline, 68% preferred to undergo chemotherapy rather than wait watchfully. Eventually, 78% chose chemotherapy. Treatment preference (odds ratio (OR)=10.3, confidence interval (CI) 2.8-38.0) and a deferring style of decision-making (OR=4.9, CI 1.4-17.2) best predicted the actual treatment choice. Treatment preference (total explained variance=38.2%) was predicted, in turn, by patients' striving for length of life (29.5%), less striving for quality of life (6.1%) and experienced control over the cause of disease (2.6%). Patients' actual treatment choice was most strongly predicted by their preconsultation treatment preference. Since treatment preference is positively explained by striving for length of life, and negatively by striving for quality of life, it is questionable whether the purpose of palliative treatment is made clear. This, paradoxically, emphasises the need for further attention to the process of information giving and shared decision-making

Multi-locus genome-wide association analysis supports the role of glutamatergic synaptic transmission in the etiology of major depressive disorder

Major depressive disorder (MDD) is a common psychiatric illness characterized by low mood and loss of interest in pleasurable activities. Despite years of effort, recent genome-wide association studies (GWAS) have identified few susceptibility variants or genes that are robustly associated with MDD. Standard single-SNP (single nucleotide polymorphism)-based GWAS analysis typically has limited power to deal with the extensive heterogeneity and substantial polygenic contribution of individually weak genetic effects underlying the pathogenesis of MDD. Here, we report an alternative, gene-set-based association analysis of MDD in an effort to identify groups of biologically related genetic variants that are involved in the same molecular function or cellular processes and exhibit a significant level of aggregated association with MDD. In particular, we used a text-mining-based data analysis to prioritize candidate gene sets implicated in MDD and conducted a multi-locus association analysis to look for enriched signals of nominally associated MDD susceptibility loci within each of the gene sets. Our primary analysis is based on the meta-analysis of three large MDD GWAS data sets (total N = 4346 cases and 4430 controls). After correction for multiple testing, we found that genes involved in glutamatergic synaptic neurotransmission were significantly associated with MDD (set-based association P = 6.9 X 10(-4)). This result is consistent with previous studies that support a role of the glutamatergic system in synaptic plasticity and MDD and support the potential utility of targeting glutamatergic neurotransmission in the treatment of MDD