Real-world evidence on the strategy of olmesartan-based triple single-pill combination in Korean hypertensive patients: a prospective, multicenter, observational study (RESOLVE-PRO).

BACKGROUND: In this prospective, multicenter, non-comparative observational study, the effectiveness and safety of the triple single-pill combination (SPC) of olmesartan/amlodipine/hydrochlorothiazide (OM/AML/HCTZ) were evaluated in a real clinical practice setting in Korean patients with essential hypertension. METHODS: A total of 3752 patients were enrolled and followed for 12 months after administration of OM/AML/HCTZ. Primary endpoint was change from baseline to month 6 in the mean systolic blood pressure (SBP). Secondary endpoints included changes from baseline in the mean SBP at month 3, 9, 12 and the mean diastolic blood pressure (DBP) at month 3, 6, 9, 12; changes in the mean SBP/DBP according to age and underlying risk factors; and blood pressure control rate (%) at different time points. Adherence to and satisfaction with OM/AML/HCTZ treatment among patients and physicians were assessed by medication possession ratio (MPR) and numeric rating scale, respectively, as exploratory endpoints. Safety was evaluated by the incidence and severity of adverse events (AEs) as well as the discontinuation rate due to AEs. RESULTS: OM/AML/HCTZ administration led to significant reductions in the mean SBP/DBP by 11.5/6.6, 12.3/7.0, 12.3/7.2, and 12.8/7.4 mmHg from baseline to month 3, 6, 9 and 12, respectively (P < 0.0001). The BP reductions were maintained throughout the 1-year observation period in all patients with different age groups and risk factors (diabetes mellitus, cardiovascular disease, and renal disease). The BP control rate (%) of < 140/90 mmHg was 65.9, 67.9, 68.9, and 70.6% at month 3, 6, 9, and 12, respectively. The mean MPR during the observation period was 0.96. The safety results were consistent with the previously reported safety profile of OM/AML/HCTZ. CONCLUSIONS: Treatment with the triple SPC of OM/AML/HCTZ demonstrated significant effectiveness in reducing SBP/DBP and achieving target BP control with high adherence over the 1-year observation period in Korean hypertensive patients and was well-tolerated. TRIAL REGISTRATION: CRIS, KCT0002196 , Registered 3 May 2016.

Circadian Gene Selection for Time-to-event Phenotype by Integrating CNV and RNAseq Data.

BACKGROUND: The endogenous circadian clock, which controls daily rhythms in the expression of at least half of the mammalian genome, has a major influence on cell physiology. Consequently, disruption of the circadian system is associated with wide range of diseases including cancer. While several circadian clock genes have been associated with cancer progression, little is known about the survival when two or more platforms are considered together. Our goal was to determine if survival outcomes are associated with circadian clock function. To accomplish this goal, we developed a Bayesian hierarchical survival model coupled with the global local shrinkage prior and applied this model to available RNASeq and Copy Number Variation data to select significant circadian genes associates with cancer progression. RESULTS: Using a Bayesian shrinkage approach with the Bayesian accelerated failure time (AFT) model we showed the circadian clock associated gene DEC1 is positively correlated to survival outcome in breast cancer patients. The R package circgene implementing the methodology is available at https://github.com/MAITYA02/circgene. CONCLUSIONS: The proposed Bayesian hierarchical model is the first shrinkage prior based model in its kind which integrates two omics platforms to identify the significant circadian gene for cancer survival.

Bayesian structural equation modeling in multiple omics data with application to circadian genes.

MOTIVATION: It is well known that the integration among different data-sources is reliable because of its potential of unveiling new functionalities of the genomic expressions, which might be dormant in a single-source analysis. Moreover, different studies have justified the more powerful analyses of multi-platform data. Toward this, in this study, we consider the circadian genes' omics profile, such as copy number changes and RNA-sequence data along with their survival response. We develop a Bayesian structural equation modeling coupled with linear regressions and log normal accelerated failure-time regression to integrate the information between these two platforms to predict the survival of the subjects. We place conjugate priors on the regression parameters and derive the Gibbs sampler using the conditional distributions of them. RESULTS: Our extensive simulation study shows that the integrative model provides a better fit to the data than its closest competitor. The analyses of glioblastoma cancer data and the breast cancer data from TCGA, the largest genomics and transcriptomics database, support our findings. AVAILABILITY AND IMPLEMENTATION: The developed method is wrapped in R package available at https://github.com/MAITYA02/semmcmc. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Grain Refinement of Al-Si-Fe-Cu-Zn-Mn Based Alloy by Al-Ti-B Alloy and Its Effect on Mechanical Properties.

We investigated the effects of Al-5.0wt%Ti-1.0wt%B addition on the microstructure and mechanical properties of the as-extruded Al-0.15wt%Si-0.2wt%Fe-0.3wt%Cu-0.15wt%Zn-0.9wt%Mn based alloys. The Aluminum alloy melt was held at 800 °C and then poured into a mould at 200 °C. Aluminum alloys were hot-extruded into a rod that was 12 mm in thickness with a reduction ratio of 38:1. AlTiB addition to Al-0.15Si-0.2Fe-0.3Cu-0.15Zn-0.9Mn based alloys resulted in the formation of Al3Ti and TiB2 intermetallic compounds and grain refinement. With increasing of addition AlTiB, ultimate tensile strength increased from 93.38 to 99.02 to 100.01 MPa. The tensile strength of the as-extruded alloys was improved due to the formation of intermetallic compounds and grain refinement.

Anti-neuroinflammatory effects of sesquiterpenoids isolated from Nardostachys jatamansi.

Two new nardosinone-type sesquiterpenoids, namely kanshone J (1) and kanshone K (2) along with seven known terpenoids (3-9) were isolated from the rhizomes and roots of Nardostachys jatamansi DC (Valerianaceae). The structures of these compounds were determined mainly by analysis of 1D-, 2D-NMR and MS data. In addition, the absolute configuration of compound 1 was assigned by application of the modified Mosher's method. In an initial assay to evaluate their anti-neuroinflammatory effects, compounds 1-5 and 9 exhibited dose-dependent inhibitory effects on lipopolysaccharide (LPS)-induced nitric oxide (NO) production in BV2 cells, with IC50 values ranging from 2.43 to 46.54 µM. Particularly, desoxo-narchinol A (3) and narchinol B (4) significantly inhibited LPS-induced NO overproduction in BV2 cells with IC50 values of 3.48 ±â€¯0.47 and 2.43 ±â€¯0.23 µM, respectively. Furthermore, compounds 3 and 4 exhibited anti-neuroinflammatory effects by inhibiting the production of pro-inflammatory mediators, including prostaglandin E2 (PGE2), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) proteins, and pro-inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α (TNF)-α, in LPS-stimulated BV2 and primary microglial cells.

Differential expression of selected candidate genes in bovine embryos produced in vitro and cultured with chemicals modulating lipid metabolism.

Lipid accumulated in embryos produced in vitro has been linked to reductions in both quality and postcryopreservation viability. Therefore, the objective of the present study was to investigate the influence of lipid-reducing chemicals on embryo development, quality, and postcryopreservation viability, in addition to expression profiles of selected lipid metabolism-regulating genes. Bovine cumulus-oocyte complexes were matured and fertilized in vitro; eight-cell stage embryos were cultured in IVC medium supplemented with phenazine ethosulfate (PES), L-carnitine (LC), PES + LC, or no supplementation (control). Culturing embryos in medium with LC increased (P < 0.05) blastocyst rate (38.8%) compared with the other groups (control = 28.1%, PES = 27.1%, PES + LC = 26.3%). Embryos cultured with supplements had greater total cell number and fewer apoptotic cells than the control. Cytoplasmic lipid content was reduced, whereas mitochondria density was increased in embryos treated with culture supplements; this was linked to altered expression profiles of selected genes regulating lipid metabolism. For example, transcript abundance of transmembrane lipid gene (SGPP1) was greater in LC- and PES-treated embryos, and they had increased postcryopreservation hatching ability (indicative of embryo cryotolerance). In conclusion, the two lipid metabolism regulators added to the culture media had improved embryo quality and cryotolerance, but embryo development rate and downstream lipid metabolism-regulating genes were more influenced with LC supplementation.

Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy.

BACKGROUND AND PURPOSE: Mutations of the skeletal muscle sodium channel gene SCN4A, which is located on chromosome 17q23-25, are associated with various neuromuscular disorders that are labeled collectively as skeletal muscle sodium channelopathy. These disorders include hyperkalemic periodic paralysis (HYPP), hypokalemic periodic paralysis, paramyotonia congenita (PMC), potassium-aggravated myotonia, and congenital myasthenic syndrome. This study analyzed the clinical and mutational spectra of skeletal muscle sodium channelopathy in Korean subjects. METHODS: Six unrelated Korean patients with periodic paralysis or nondystrophic myotonia associated with SCN4A mutations were included in the study. For the mutational analysis of SCN4A, we performed a full sequence analysis of the gene using the patients' DNA. We also analyzed the patients' clinical history, physical findings, laboratory tests, and responses to treatment. RESULTS: We identified four different mutations (one of which was novel) in all of the patients examined. The novel heterozygous missense mutation, p.R225W, was found in one patient with mild nonpainful myotonia. Our patients exhibited various clinical phenotypes: pure myotonia in four, and PMC in one, and HYPP in one. The four patients with pure myotonia were initially diagnosed as having myotonia congenita (MC), but a previous analysis revealed no CLCN1 mutation. CONCLUSIONS: Clinical differentiating between sodium-channel myotonia (SCM) and MC is not easy, and it is suggested that a mutational analysis of both SCN4A and CLCN1 is essential for the differential diagnosis of SCM and MC.

Influence of moving background on line bisection performance in the normal elderly versus patients with hemispatial neglect.

OBJECTIVE: Previous studies have shown that when healthy young participants bisect stationary lines on a moving background (MB) or optokinetic stimulation, they perceive the stationary line moving in the opposite direction of the MB (illusory motion [IM]), and they displace their bisection mark in the direction of the IM. This study attempted to learn whether IM also influences attentional biases of the healthy elderly and patients with hemispatial neglect. DESIGN: In experiment 1, healthy elderly participants and patients with neglect bisected lines in conditions where IM was absent or present. To better understand the MB dichotomy between the healthy elderly and neglect patients, in experiment 2, participants' eye movements were recorded using an infrared eye tracker. RESULTS: In experiment 1, healthy elderly participants' biases occurred in the opposite direction of MB when IM was present but in the same direction of MB when IM was absent. In contrast, neglect patients' biases occurred in the same direction of MB regardless of conditions. Eye movements reflect the spatial direction of attention. In experiment 2, the healthy elderly participants were able to selectively attend to the line, whereas neglect patients were impaired in that they fixated on the line. CONCLUSIONS: These results suggest that the healthy elderly can selectively fixate on a line, and with MB, they perceive the stationary line moving, resulting in a bisection bias in the direction of the IM. In contrast, when there is an MB, the patients with neglect are impaired in that they fixate on the line. Thus, they do not perceive IM; instead, they are primarily influenced by the MB.

Effect of medium milieu on sperm penetration and pronuclear formation of bovine oocytes matured in vitro.

The purpose of the present study was to investigate the optimal concentration of osmolarity, calcium and bicarbonate for sperm penetration and formation of pronuclei (PN), and to investigate the time required for capacitation, penetration across the zona pellucida and formation of PN in bovine cumulus-free oocytes matured in vitro. Bovine follicular oocytes collected at slaughter were matured and fertilized in vitro. Bovine sperm penetrated the zona pellucida in medium containing 240 to 440 mOsm, whereas PN formation was observed in a narrow range of osmolarities, from 280 to 360 mOsm. Maximal penetration by spermatozoa and PN formation was obtained in the medium with 2.5 mM calcium. High rates of spermatozoa penetration were observed in the medium with 37 to 49 mM NaHCO3. However, PN were formed regardless of the concentration of NaHCO3. The times required for sperm capacitation and penetration through the zona pellucida were 260 and 50 min, respectively. The first development of PN was recorded at 120 min after sperm penetration. Therefore, our study suggests that fertilization ability of spermatozoa in vitro appears to be more stable in high concentrations of NaCI. Oocytes are more sensitive to osmotic stress than spermatozoa. Calcium is required for both sperm penetration and PN formation in cumulus-free oocytes, but bicarbonate may be needed mainly for the penetration of spermatozoa.