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The mammalian circadian systems consist of indigenous, self-sustained 24-h rhythm generators. They comprise many genes, molecules, and regulators. To decode their systematic controls, a robust computational approach was employed. It integrates transcription-factor-occupancy and time-series gene-expression data as input. The model equations were constructed and solved to determine the transcriptional regulatory logics in the mouse transcriptome network. This hypothesizes to explore the underlying mechanisms of combinatorial transcriptional regulations for circadian rhythms in mouse. We reconstructed the quantitative transcriptional-regulatory networks for circadian gene regulation at a dynamic scale. Transcriptional-simulations with virtually knocked-out mutants were performed to estimate their influence on networks. The potential transcriptional-regulators-combinations modulating the circadian rhythms were identified. Of them, CLOCK/CRY1 double knockout preserves the highest modulating capacity. Our quantitative framework offers a quick, robust, and physiologically relevant way to characterize the druggable targets to modulate the circadian rhythms at a dynamic scale effectively.The current research reports the effects of low-intensity extremely high frequency electromagnetic irradiation (EMI) of 51.8 GHz and 53.0 GHz on green microalga Parachlorella kessleri RA-002 isolated in Armenia. EMI demonstrated different effects on the growth properties of microalgae under various conditions. Under aerobic conditions a positive effect of EMI on the growth rate of P. kessleri and the content of photosynthetic pigments were observed. The data obtained indicates a significant role of O2, since the enhancing effect of EMI was determined only under aerobic conditions. Meanwhile under anaerobic conditions EMI with both frequencies caused inhibition of algal growth and a decrease in the amount of photosynthetic pigments. EMI also inhibited the yield of H2 production in P. kessleri, which was partially restored after 5-day cultivation due to the existence of protective mechanisms in this alga. The results might indicate membrane-bound mechanisms of EMI action on algae, which can be associated with the effects on photosynthetic pigments and membrane-associated enzymes responsible for H2 production. The results are useful for the development of algae biotechnology and the possibility of using EMI as a factor which regulates the production of biomass and biohydrogen by green microalgae.A rapid, highly sensitive and simple high-performance liquid chromatographic-tandem mass spectrometric (LC-MS) assay is developed and validated for the quantification of leuprolide a Gonadotropin Releasing Hormone analog (GnRH) in human plasma. Moreover, various parameters of the method stability are determined. After the addition of stable isotope (internal standard), the leuprolide was extracted from human plasma by a C18 solid phase micro extraction (MEPS) cartridge and directly injected into LC-MS/MS system. Chromatographic separation was achieved using a Waters Atlantis HILIC, C18, 150 × 2.1 mm, 5 μ column. Mobile phase was a mixture of acetate buffer (pH 3) and acetonitrile (25/75). Drug detection was performed by MS using electrospray ionization in positive mode. Multiple reaction monitoring (MRM) with a tandem mass spectrometer was used to detect the analytes. Precursor to product ion transitions of m/z 605.5 → m/z 110.2 and m/z 609.1 → m/z 249.1 were used to quantify leuprolide and leuprolide-13C6-15N, respectively. Sample analysis time was 3 min for each injection. The assay exhibited a linear dynamic range of 0.0500-40 ng/ml for each analyte with a lower limit of quantification (LLOQ) of 0.0500 ng/ml. Furthermore, a complete analytic validation was carried out, including tests on The specificity, precision, accuracy, matrix effect and stability under different storage conditions. Importantly, the obtained results established an acceptable precision and accuracy for concentration over standard curve range. Nevertheless, it is to emphasize the simplicity, rapidity and also the high precision and accuracy of this novel LC-MS method, offering useful information about solution stability. find more Finally, this work is a good alternative to quantify Leuprolide concentration in human blood, especially on human clinic trials step.Solid phase micro extraction-Gas Chromatography/Mass Spectrometry (SPME-GC/MS) analysis was performed in exhaled breath samples of 48 healthy volunteers 20 non-smokers, 10 smokers and 18 e-cigarette (EC, vape) users. Each volunteer provided 1 L of exhaled breath in a pre-cleaned Tedlar bag, in which an SPME fiber was exposed to absorb the emitted breath volatile organic compounds (VOCs). The acquired data were processed using multivariate data analysis (MDA) methods in order to identify the characteristic chemicals of the three groups. The results revealed that the breath of non-smokers demonstrated inverse correlation with a variety of molecules related to the breath from smokers including furan, toluene, 2-butanone and other organic substances. Vapers were distinguished from smokers by the chemical speciation of the e-liquids, such as that of esters (e.g. ethyl acetate), terpenes (e.g. α-pinene, β-pinene, d-limonene, p-cymene, etc.) and oxygenated compounds (e.g. 3-hexen-1-ol, benzaldehyde, hexanal, decanal, etc). Two classification models were developed (a) using principal component analysis (PCA) with hierarchical cluster analysis (HCA) and (b) using partial least squares-discriminant analysis (PLS-DA). Both models were validated using 8 new samples (4 vapers and 4 smokers), collected in addition to the 48 samples of the calibration set. The combination of GC/MS breath analysis and MDA contributed successfully in classifying the volunteers into their respective groups and highlighted the relevant characteristic VOCs. The respective dynamic combination (SPME-GC/MS and MDA) provides a means for long term non-invasive monitoring of the population's health status for early detection purposes.Gas chromatography-mass spectrometry (GC-MS) is an ideal tool for analyzing the intermediates of tricarboxylic acid cycle and glycolysis, sugars, organic acids and amino acids, etc. High-throughput metabolomics methods are required by large-scale clinical researches, and time of flight mass spectrometry (TOF MS) having fast scanning rate is preferable for rapid GC. Quadrupole MS (qMS) instruments have 95% market share, and their potential in rapid metabolomics is worth being studied. In this work, a within 15-min GC program was established and matched by qMS scanning for plasma metabolome analysis after N-methyl-N-(trimethylsilyl)-trifluoroacetamide derivatization. Compared to the longer-time program GC-qMS method, the rapid GC-qMS method had nearly no metabolome information loss, and it had excellent profile performance in repeatability, intra-day and inter-day precision, sampling range, linearity and extraction recovery. Compared to TOF MS, qMS achieved similar results in investigating lung cancer serum metabolic disruptions. Partial least squares-discriminant analysis revealed that the two datasets acquired by qMS and TOF MS had very similar model parameters, and most of top ranked differential metabolites were the same. This study provides a rapid and economical GC-qMS metabolomics method for researchers. Still, MS having faster scanning rate and higher sensitivity are recommended, if possible, to detect more small peaks and some co-eluted peaks.Exposure to repeated stress is associated with the occurrence and development of many prevalent diseases. Here, we evaluated the impact of a repeated restraint stress (RRS) paradigm on male Wistar rats and compared global plasma metabolites in stressed and unstressed rats using an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC/Q-TOF-MS) approach and multivariate statistical analysis. The data showed that ten days of RRS induced weight loss and anxiety-like behavior, possibly through elevating plasma corticosterone levels in rats. Different metabolic characteristics were found between the two groups. Seventeen differential metabolites were identified and considered as potential biomarkers in the stress process, including histidine metabolism, neurotransmitter synthesis, and bile acid metabolism. Furthermore, l-carnosine, an identified metabolite, was examined in the same model and found to attenuate weight loss and anxiety-like behavior in RRS rats. Hence, these findings describe the metabolomic profiling of repeated stress and provide new insights into the pathophysiological mechanism of stress-induced deflections and potential pharmacological interventions.This article explores general practitioners' (GPs) persuasive efforts in cases where biomedical evidence is absent but expected. Health insurance in Western countries is based on the biomedical ideal that legitimate complaints should have objective causes detectable by medical examination. For GPs responsible for assessing sickness and incapacity for work, the demand for objective evidence can be problematic what if they as experts deem that a patient is in fact sick and eligible for benefits, but are unable to provide objective evidence to that fact? How can they convince bureaucrats in the insurance system to accept their judgment? Taking 'medically unexplained symptoms' as my case, I draw on focus group and follow-up interviews with GPs in Norway to explore how GPs attempt to persuade bureaucrats to accept their professional judgment. Proposing the concept of 'rhetorical work', I reconstruct a typology of such work that doctors engage in to influence bureaucratic decision-making and provide long-term health benefits for patients. I then discuss the potential societal implications of GPs' rhetorical practices and the applications of the concept of rhetorical work in future research.The triage of acute stroke patients is increasingly dependent on four-dimensional CTA (4D-CTA) imaging. In this work, we present a convolutional neural network (CNN) for image-level detection of intracranial anterior circulation artery occlusions in 4D-CTA. The method uses a normalized 3D time-to-signal (TTS) representation of the input image, which is sensitive to differences in the global arrival times caused by the potential presence of vascular pathologies. The TTS map presents the time within the cranial cavity at which the signal reaches a percentage of the maximum signal intensity, corrected for the baseline intensity. The method was trained and validated on (n=214) patient images and tested on an independent set of (n=279) patient images. This test set included all consecutive suspected-stroke patients admitted to our hospital in 2018. The accuracy, sensitivity, and specificity were 92%, 95%, and 92%. The area under the receiver operating characteristics curve was 0.98 (95% CI 0.95- 0.99). These results show the feasibility of automated stroke triage in 4D-CTA.

To assess the cost-effectiveness of a brief cognitive behavioural intervention for patients with medically unexplained physical symptoms (MUPS) provided by a mental health nurse practitioner (MHNP) in primary care in comparison with usual care.

We performed an economic evaluation from a societal perspective alongside a cluster randomised controlled trial with 12months follow-up. The primary outcome was quality-adjusted life-years (QALYs). Secondary outcomes were the RAND-36 physical component summary score (PCS), somatic symptom severity (Patient Health Questionnaire (PHQ-15), and anxiety and depression symptoms (Hospital Anxiety and Depression Scale (HADS)). Missing data were imputed using multiple imputation. We used non-parametric bootstrapping to estimate statistical uncertainty. The bootstrapped cost-effect pairs were used to estimate cost-effectiveness planes and cost-effectiveness acceptability curves.

Mean total costs in the intervention group were significantly lower than in the usual care group (mean difference-2300€, 95% CI -3257 to -134).