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The present study aimed to use detailed phenotyping for the claw disorder digital dermatitis (DD) considering specific DD stages in 2 housing systems (conventional cubicle barns [CON] and compost-bedded pack barns [CBPB]) to infer possible genotype × housing system interactions. The DD stages included 2,980 observations for the 3 traits DD-sick, DD-acute, and DD-chronic from 1,311 Holstein-Friesian and 399 Fleckvieh-Simmental cows. Selection of the 5 CBPB and 5 CON herds was based on a specific protocol to achieve a high level of herd similarity with regard to climate, feeding, milking system, and location, but with pronounced housing-system differences. Five other farms had a "mixed system" with 2 subherds, one representing CBPB and the other one CON. The CBPB system was represented by 899 cows (1,530 observations), and 811 cows (1,450 observations) represented the CON system. The average disease prevalence was 20.47% for DD-sick, 13.88% for DD-acute, and 5.34% for DD-chronic, with a higher prevalence in CON than in CBPB. After quality control of 50K genotypes, 38,495 SNPs from 926 cows remained for the ongoing genomic analyses. Genetic parameters for DD-sick, DD-acute, and DD-chronic were estimated by applying single-step approaches for single-trait repeatability animal models considering the whole dataset, and separately for the CON and CBPB subsets. Genetic correlations between same DD traits from different housing systems, and between DD-sick, DD-chronic, and DD-acute, were estimated via bivariate animal models. Heritabilities based on the whole dataset were 0.16 for DD-sick, 0.14 for DD-acute, and 0.11 for DD-chronic. A slight increase of heritabilities and genetic variances was observed in CON compared with the "well-being" CBPB system, indicating a stronger genetic differentiation of diseases in a more challenging environment. Genetic correlations between same DD traits recorded in CON or CBPB were close to 0.80, disproving obvious genotype × housing system interactions. Genetic correlations among DD-sick, DD-acute and DD-chronic ranged from 0.58 to 0.81. SNP main effects and SNP × housing system interaction effects were estimated simultaneously via GWAS, considering only the phenotypes from genotyped cows. Ongoing annotations of potential candidate genes focused on chromosomal segments 100 kb upstream and downstream from the significantly associated candidate SNP. GWAS for main effects indicated heterogeneous Manhattan plots especially for DD-acute and DD-chronic, indicating particularities in disease pathogenesis. Nevertheless, a few shared annotated potential candidate genes, that is, METTL25, AFF3, PRKG1 , and TENM4 for DD-sick and DD-acute, were identified. These genes have direct or indirect effects on disease resistance or immunology. For the SNP × housing system interaction, the annotated genes ASXL1 and NOL4L on BTA 13 were relevant for DD-sick and DD-acute. Overall, the very similar genetic parameters for the same traits in different environments and negligible genotype × housing system interactions indicate only minor effects on genetic evaluations for DD due to housing-system particularities. [ABSTRACT FROM AUTHOR]

Abstract The slurry infiltration process plays a crucial role in the slurry shield tunneling process, during which a filter cake is expected to form on the tunnel face to transmit the support pressure. This paper proposed a coupled computational fluid dynamics (CFD)-discrete element method (DEM) numerical approach to investigate the slurry infiltration and filter cake formation by modeling the slurry filtration column test, which incorporates the particles, fluid phase, and their interactions. The Simplified Johnson-Kendall-Roberts (SJKR) model was employed to consider the cohesion effect between slurry particles. The validity of the current approach was verified based on the Kozeny-Carman Equation modified by Ergun (1952). The slurry filtration process was divided into four stages with different characteristics of filter cake porosity and pressure drop. Influences of some key model parameters including externally-applied pressure, friction coefficient and cohesion energy density on filter cake formation were investigated and the underlying mechanisms were explored. The law of pressure variation within the filter cake was proposed. A linear relationship between pressure drop ratio and porosity of filter cake was established, which will be useful for predicting the effectiveness of support pressure transmission due to slurry filtration. [ABSTRACT FROM AUTHOR]

The most common approach in dairy cattle to prove genotype by environment interactions is a multiple-trait model application, and considering the same traits in different environments as different traits. We enhanced such concepts by defining continuous phenotypic, genetic, and genomic herd descriptors, and applying random regression sire models. Traits of interest were test-day traits for milk yield, fat percentage, protein percentage, and somatic cell score, considering 267,393 records from 32,707 first-lactation Holstein cows. Cows were born in the years 2010 to 2013, and kept in 52 large-scale herds from 2 federal states of north-east Germany. The average number of genotyped cows per herd (45,613 single nucleotide polymorphism markers per cow) was 133.5 (range: 45 to 415 genotyped cows). Genomic herd descriptors were (1) the level of linkage disequilibrium (r²) within specific chromosome segments, and (2) the average allele frequency for single nucleotide polymorphisms in close distance to a functional mutation. Genetic herd descriptors were the (1) intra-herd inbreeding coefficient, and (2) the percentage of daughters from foreign sires. Phenotypic herd descriptors were (1) herd size, and (2) the herd mean for nonreturn rate. Most correlations among herd descriptors were close to 0, indicating independence of genomic, genetic, and phenotypic characteristics. Heritabilities for milk yield increased with increasing intraherd linkage disequilibrium, inbreeding, and herd size. Genetic correlations in same traits between adjacent levels of herd descriptors were close to 1, but declined for descriptor levels in greater distance. Genetic correlation declines were more obvious for somatic cell score, compared with test-day traits with larger heritabilities (fat percentage and protein percentage). Also, for milk yield, alterations of herd descriptor levels had an obvious effect on heritabilities and genetic correlations. By trend, multiple trait model results (based on created discrete herd classes) confirmed the random regression estimates. Identified alterations of breeding values in dependency of herd descriptors suggest utilization of specific sires for specific herd structures, offering new possibilities to improve sire selection strategies. Regarding genomic selection designs and genetic gain transfer into commercial herds, cow herds for the utilization in cow training sets should reflect the genomic, genetic, and phenotypic pattern of the broad population. [ABSTRACT FROM AUTHOR]

A data set including 57,868 records for calf birth weight (CABW) and 9,462 records for weight at first insemination (IBW) were used for the estimation of direct and maternal genetic effects in Holstein Friesian dairy cattle. Furthermore, CABW and IBW were correlated with test-day production records and health traits in first-lactation cows, and with nonreturn rates in heifers. Health traits considered overall disease categories from the International Committee for Animal Recording diagnosis key, including the general disease status, diarrhea, respiratory diseases, mastitis, claw disorders, female fertility disorders, and metabolic disorders. For single-trait measurements of CABW and IBW, animal models with maternal genetic effects were applied. The direct heritability was 0.47 for CABW and 0.20 for IBW, and the direct genetic correlation between CABW and IBW was 0.31. A moderate maternal heritability (0.19) was identified for CABW, but the maternal genetic effect was close to zero for IBW. The correlation between direct and maternal genetic effects was antagonistic for CABW (-0.39) and for IBW (-0.24). In bivariate animal models, only weak genetic and phenotypic correlations were identified between CABW and IBW with either test-day production or health traits in early lactation. Apart from metabolic disorders, there was a general tendency for increasing disease susceptibilities with increasing CABW. The genetic correlation between IBW and nonreturn rates in heifers after 56 d and after 90 d was slightly positive (0.18), but close to zero when correlating nonreturn rates with CABW. For the longitudinal BW structure from birth to the age of 24 mo, random regression models with the timedependent covariate "age in months" were applied. Evaluation criteria (Bayesian information criterion and residual variances) suggested Legendre polynomials of order 3 to modeling the longitudinal body weight (BW) structure. Direct heritabilities around birth and insemination dates were slightly larger than estimates for CABW and IBW from the single-trait models, but maternal heritabilities were exactly the same from both models. Genetic correlations between BW were close to 1 for neighboring age classes, but decreased with increasing time spans. The genetic correlation between BW at d 0 (birth date) and at 24 mo was even negative (-0.20). Random regression model estimates confirmed the antagonistic relationship between direct and maternal genetic effects, especially during calfhood. This study based on a large data set in dairy cattle confirmed genetic parameters and (co)variance components for BW as identified in beef cattle populations. However, BW records from an early stage of life were inappropriate early predictors for dairy cow health and productivity. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Plants of the genus Cimicifuga have long been used as an ethnomedicine in China, Europe, and North America for its high medicinal value and health benefits. Their dried rhizomes are widely used for treating wind-heat headache, toothache, aphtha, sore throat, measles, spot poison, archoptosis, and uterine prolapse. In addition, it is used as a dietary supplement for preventing women menopausal symptoms and osteoporosis. Aim of the review This paper aims to provide up-to-date information on the genus Cimicifuga , including botanical characterization, medicinal resources, traditional medicinal uses, phytochemistry, quality control, pharmacological research as well as the toxicology. The possible structural-activity relationships and molecular mechanisms of the bioactive constituents are discussed in ways that contribute to the structural optimization and preclinical safety assessment for further drug design. Materials and methods The relevant information on Cimicifuga was collected from scientific databases (such as Google Scholar, PubMed, SciFinder Scholar, Science Direct, CNKI, Baidu Scholar, Web of Science, China Knowledge Resource Integrated Database), Chinese herbal classics, ethnobotanical books, PhD and MSc dissertations, Chinese Pharmacopoeia, published articles in peer-reviewed journals, local magazines, and unpublished materials. In addition, the Plant List (TPL, www.theplantlist.org ) was also used to validate the scientific names and synonyms of this plant. The literature cited in this review dated from 1953 to 2017. Results The majority of chemical constituents of this plant include triterpenoid glycosides, phenylpropanoids, nitrogenous compounds, chromones, flavonoids and 4 α -methyl steroid. Among them, the primary bioactive constituents are believed to be present in the triterpene glycoside fraction. To date, investigation of seven Cimicifuga spp. plants led to the identification of more than 457 compounds. Years of pharmacological research proved that the crude extracts and certain pure compounds obtained from Cimicifuga exhibited menopausal syndrome-treatment, anti-osteoporosis, antiviral, antitumor, antioxidant and antiangiogenic activities. On the other hand, Cimicifuga plant-induced toxicities of liver, cardiovascular, central and peripheral nervous systems have also been reported. Therefore, safety consideration should be placed into a high priority for herbal medicine Cimicifuga therapy in the early stages of development and clinical trials. Conclusions This review presents information on botany, medicinal resources, and traditional medicinal history of some Cimicifuga plants. Modern pharmacology researchers have validated many traditional uses of Cimicifuga species. As the quality control and safety assessment of Cimicifuga plants is still incomplete, only a small part of the plant is permitted to be used as medicines. Expansion of medicinal resources in Cimicifuga is urgently needed to enable its full use. Currently research primarily focuses on the triterpenoid glycosides but there are many other types of compounds which may possess new biological activities however the systematic studies of these compounds are lacking. Extensive study is required on Cimicifuga plant before it can be fully used in clinics as a potent drug candidate. [ABSTRACT FROM AUTHOR]

• The initiation behavior is very sensitive to wellbore shape. • The initiation location is mainly controlled by wellbore shape under near-equal stress state. • The initiation location is mainly controlled by stress in layer with high-deviation stress. • The X shaped fractures prefer an externally-expanded wellbore. • In the intermediate stress state, multiple fractures with high tortuosity from non-circular wellbore are easily created. In this study, a numerical model is proposed based on the dual toughness and strength criterion for fracture initiation to determine the fracture initiation location and initiation pressure. In the model, hydraulic fractures emanate from a noncircular convex wellbore, which is considered as a jointed cross between an ellipse and a circle. Numerical studies were performed to explore the behaviors associated with fracture initiation under different stress combinations. The results indicate that the initiation pressure is sensitive to the geometric parameters of the wellbore. The initiation location is mainly controlled by the wellbore shape under a near-equal stress state characterized by the ratio of deviation (S) to mean (P) stresses (S/P < 0.10); if S/P > 0.50, the initiation location is dominated by the stress state. For an intermediate stress state (0.10 ≤ S/P ≤ 0.50), the initiation location is affected by both the stress state and wellbore shape; multiple fractures are easier to initiate in the presence of a noncircular wellbore and tend to develop into an X shape. In addition, X-shaped fractures prefer externally expanded wellbores. The subsequent propagations of the X-shaped fractures were also modeled, and these fractures exhibited a strong near-well tortuosity. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the effect of dietary calcium on plasma lipoprotein profile in castrated and ovariectomized hamsters. Methods: Male, castrated, female and ovariectomized hamsters (n=36 each group) were randomly divided into three sub-groups (n=12) and fed one of the three diets containing 0, 2, and 8 g calcium per kg diet for a period of six weeks. Changes in plasma lipoprotein profile were monitored at the end of week 0, 3 and 6. Results: Plasma total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C), triacylglycerols (TG) and TC/HDL-C were decreased only in intact female and ovariectomized hamsters. In contrast, three levels of dietary calcium had no effect on lipoprotein profiles in both intact male and castrated hamsters. Conclusion: Beneficial modification of lipoprotein profile by dietary calcium was gender-dependent at least in hamsters. [Copyright &y& Elsevier]

Abstract: Stand density is the number of trees standing in the process of tree growth on the unit area, it stands to grow development, stability, forest production, quality and other factors have important links. Based on a survey of different densities of Larix principis plantation, the thesis adopts the Hegyi model which using a single wood competition index model to calculate the competition index, proposing crown width competition index. Then fit the crown width, diameter at chest height and relative crown width competition index and derive the equation. It suggests that when the competition index were 0.8, 0.6, 0.4, 0.2, management density of Larix principis plantation. It can provide some basis for management of Larix principis plantations [Copyright &y& Elsevier]

Abstract: Human diets contain phytosterols and their oxidation products. We investigated effect of β-sitosterol (Si), stigmasterol (St), β-sitosterol oxidation products (SiOP) and stigmasterol oxidation products (StOP) on plasma total cholesterol and their interaction with the gene expression of enzymes, proteins and transporters involved in cholesterol absorption and metabolism. Sixty male hamsters were fed the control diet or one of four experimental diets containing 0.1% Si, 0.1% SiOP, 0.1% St and 0.1% StOP, respectively, for six weeks. SiOP and StOP groups had the relative liver weights greater than their corresponding non-oxidized forms, indicating they were possibly toxic. Results showed both Si and St groups reduced while SiOP and StOP hamsters lost the capacity of lowering plasma total cholesterol (TC), low-density lipoprotein cholesterol (LDL) and triacylglycerols (TG) compared with the control group. Si and St but not SiOP and StOP were anti-atherosclerotic. RT-PCR analysis demonstrated Si and St but not SiOP and StOP down-regulated mRNA levels of intestinal acyl CoA: cholesterol acyltransferase (ACAT2) and microsomal triglyceride protein (MTP). Aortas from Si and St hamsters relaxed better than those from the control and their corresponding SiOP and StOP-treated hamsters. It was concluded that Si and St not SiOP and StOP were beneficial in improving lipoprotein profile and aortic function. [Copyright &y& Elsevier]

Abstract: Clopidogrel has become the mainstay oral antiplatelet regimen to prevent recurrent ischemic events after acute coronary syndromes or stent placement. However, there is marked interindividual variability in the antiplatelet effects of clopidogrel, and a reduced response to this drug may be a risk factor for ischemic complications. Pharmacogenomic analyses, including candidate-gene and genome-wide association studies, have confirmed that genetic polymorphisms in the hepatic cytochrome P450 (CYP) 2C19 dominantly affect the antiplatelet effects of clopidogrel. CYP2C19 reduced-function alleles have been associated with a significant decrease in clopidogrel responsiveness and a higher risk of adverse cardiac events including stent thrombosis, myocardial infarction, and death in several prospective studies, although these effects were not reproduced in a recent large randomized study that included a randomized control group. The US Food and Drug Administration addressed this issue by adding a boxed warning to the clopidogrel label and suggesting that adjusting the clopidogrel dose or using alternative antiplatelet agents should be potentially implemented for high-risk individuals who are identified based on the CYP2C19 genotype. Although it is promising that CYP2C19 genotyping could be used to guide personalized antiplatelet clopidogrel therapy, currently there is insufficient evidence to recommend routine genetic testing. Prospective randomized clinical trials are necessary to validate this pharmacogenomic approach to clopidogrel therapy. In the most recent trial, paraoxonase-1 (PON1) was identified as a crucial new enzyme for clopidogrel bioactivation, with its common Q192R polymorphism determining the rate of active metabolite and the clinical activity of clopidogrel. Further studies are needed to investigate the comprehensive influence of a number of different polymorphisms of CYP2C19 and PON1 variant alleles or other genetic variants on clopidogrel in various ethnic populations. [Copyright &y& Elsevier]

Abstract: Warfarin is the most widely prescribed oral anticoagulant, but there is greater than 10-fold interindividual variability in the dose required to attain a therapeutic response. Information from pharmacogenomics, the study of the interaction of an individual''s genotype and drug response, can help optimize drug efficacy while minimizing adverse drug reactions. Pharmacogenetic analysis of two genes, the warfarin metabolic enzyme CYP2C9 and warfarin target enzyme, vitamin K epoxide reductase complex 1 VKORC1, confirmed their influence on warfarin maintenance dose. Possession of CYP2C9⁎2 or CYP2C9⁎3 variant alleles, which result in decreased enzyme activity, is associated with a significant decrease in the mean warfarin dose. Several single nucleotide polymorphisms (SNPs) in VKORC1 are associated with warfarin dose across the normal dose range. Haplotypes based on these SNPs explain a large fraction of the interindividual variation in warfarin dose, and VKORC1 has an approximately three-fold greater effect than CYP2C9. Algorithms incorporating genetic (CYP2C9 and VKORC1), demographic, and clinical factors to estimate the warfarin dosage, could potentially minimize the risk of over dose during warfarin induction. [Copyright &y& Elsevier]

The aim of the present study was an in-depth genomic analysis to understand the genomic mechanisms of the 3 claw disorders dermatitis digitalis (DD), interdigital hyperplasia (HYP), and sole ulcer (SU). In this regard, we estimated genetic parameters based on genomic relationship matrices, performed genome-wide association studies, annotated potential candidate genes, and inferred genetic associations with breeding goal traits considering the most important chromosomal segments. As a further novelty of this study, we inferred possible SNP × heat stress interactions for claw disorders. The study consisted of 17,264 first-lactation Holstein Friesian cows kept in 50 large-scale contract herds. The disease prevalence was 15.96, 2.36, and 8.20% for DD, HYP, and SU, respectively. The remaining breeding goal traits consisted of type traits of the feet and leg composite, female fertility, health traits, and 305-d production traits. The final genotype data set included 44,474 SNPs from the 17,264 genotyped cows. Heritabilities for DD, HYP, and SU were estimated in linear and threshold models considering the genomic relationship matrix (G matrix). Genetic correlations with breeding goal traits based on G were estimated in a series of bivariate linear models, which were verified via SNP effect correlations for specific chromosome segments (i.e., segments harboring potential candidate genes for DD, HYP, and SU). Genome-wide association studies were performed for all traits in a case-control design by applying a single SNP linear mixed model. Furthermore, for DD, HYP, and SU, we modeled SNP × heat stress interactions in genome-wide association studies. Single nucleotide polymorphism-based heritabilities were 0.04 and 0.08 for DD, 0.03 and 0.10 for SU, and 0.03 and 0.23 for HYP from linear and threshold models, respectively. The genetic correlations between DD, HYP, and SU with conformation traits from the feet and leg composite were positive throughout, indicating the value of indirect selection on conformation traits to improve claw health. Genetic correlations between DD, SU, and HYP with other breeding goal traits indicated impaired female fertility, impaired udder health status, and productivity decline of diseased cows. Genetic correlations among DD, SU, and HYP were moderate to large, indicating that different claw disorders have similar genetic mechanisms. Nevertheless, we identified disease-specific potential candidate genes, and genetic associations based on the surrounding SNPs partly differed from the genetic correlations. Especially for candidate genes contributing to 2 traits simultaneously, correlations based on SNP effects from the respective chromosome segment were close to 1 or to −1. In this regard, we annotated the candidate genes KRT33A and KRT33B for HYP and DD, KIF27 for HYP and calving to first insemination, and MAN1A1 for SU and the production traits. For SNP × heat stress interactions, we identified significant SNPs on BTA 2, 4, 5, 7, 8, 9, 13, 22, 25, and 28, and we annotated the potential candidate genes FSIP2 , CLCN1 , ADGRV1 , DOP1A , THBD , and RHOBTB1. Results indicate gene-specific mechanisms of the claw disorders only in specific environments. [ABSTRACT FROM AUTHOR]

• Complex hydraulic fractures still can be created under high stress level. • The growth of the stress level tends to improve fracture complexity in same stress difference. • The alteration in vertical or horizontal maximum stress can significantly affect the morphology of hydraulic fractures. • The intersection with multiple closely spaced joints form stepped morphology features. Compared with shallow reservoirs of shale gas, the high stress and plasticity of shale reservoirs under deep conditions significantly impact the propagation of hydraulic fractures. The study investigates the characteristics of hydraulic fracture propagation in deep shale reservoirs by conducting true triaxial fracturing tests at different stress levels and combinations under circumstances close to the original in-situ stress of the target reservoir. Specifically, it includes comparative experiments under high and low-stress levels, variable stress combinations with equal stress differences, and experiments on the influence of maximum and minimum horizontal in-situ stress, respectively. Through a series of experimental studies, it has been shown that the fracture roughness is relatively low at high stress levels. Fractures can still generate complex and multiple fractures when subject to high-stress conditions. Amongst, natural fissures or weak surfaces still dominate the complex fracture morphology. In the case of a higher in-situ stress level with the same stress difference value brings about a more complex hydraulic fracture morphology as a result of a smaller stress-difference coefficient. The Intersection of hydraulic fractures with multiple parallel weak surfaces creates hydraulic fractures in stepped shape, which can cause drastic fluctuations in injection pressure. The research results provide a reference for on-site deep shale reservoir stimulation and optimization of a fracturing design. [ABSTRACT FROM AUTHOR]

• Different types of filter cakes were obtained using CFD-DEM coupled simulations. • Slurry infiltration was closely related to the dynamic change of pore structure. • Quantitative correlations were established between pressure drop and pore throat size. The slurry filtration process at a tunnel face plays an important role in supporting pressure transmission, which is crucial to the stability of a tunnel face during shield tunneling. In this paper, a series of coupled computational fluid dynamics (CFD)–discrete element method (DEM) numerical simulations were carried out to model the slurry filtration column test. A simplified JKR (Johnson-Kendall-Roberts) model was used to simulate the cohesion between slurry particles. Four types of filter cake formation were identified under different combinations of size ratios between slurry and sand particles, and cohesion between slurry particles according to morphology and pore pressure distribution characteristics. These types were external filter cake, external & internal filter cake, internal filter cake & deep penetration and external & internal filter cake & deep penetration. The contact-based analysis of the constriction (void throat) sizes reveals that the dynamic evolution of the pore structure is closely related to the slurry infiltration process, i.e., the infiltration of slurry particles tends to seal the infiltration channel, which prevents infiltration of any more particles. The variation of D c50 (the median constriction size) is closely related to the infiltration state of the slurry particles. The pressure drop within the filter cake becomes significant, i.e., the filter cake will become effective, only when the ratio of D c50 to the size of slurry particles is below a threshold value. The current study provides new insight into the fundamental mechanism underlying the slurry filtration process during shield tunneling. [ABSTRACT FROM AUTHOR]

Bromide and natural organic matter (NOM) are both precursors of halogenated disinfection byproducts (DBPs) in drinking water. During drinking water treatment process, chloride-form anion-exchange resin adsorption is expected to be capable of removing these DBP precursors and in the meantime releasing chloride ions. The released chloride as well as the chloride initially present in source water could be oxidized through electrolysis to generate free chlorine for disinfection. Based on the above assumptions, we developed a new disinfection approach using chloride-form anion-exchange resin adsorption followed by electrolysis to control halogenated DBPs. Parameter setup and optimization were performed for resin adsorption and electrolysis processes. Results showed that 93.7% of NOM and 90% of bromide could be removed at a resin dose of 20 mL per 2 L of simulated source water sample with a contact time of 1 h. Meanwhile, 49.5 mg/L of chloride was released from the resin to the water sample via anion-exchange, and the released chloride was further oxidized by electrolysis (Ti/RuO 2 –IrO 2 anode and graphite cathode, current intensity of 0.4 A) to generate free chlorine (5 mg/L as Cl 2) within 192 s. With this new approach, formation of total organic halogen, four trihalomethanes, and five haloacetic acids was reduced by 86.4%, 98.5%, and 93.2%, respectively, compared with chemical chlorination alone. Although the new approach might enhance the formation of some phenolic DBPs by decreasing bromide levels in source water, the overall cytotoxicity of the water samples treated with the new approach was significantly decreased by 68.8% according to a human hepatoma cell cytotoxicity assay. Notably, disinfection ability evaluation showed that the new approach achieved 3.36-log 10 reductions of three seeded bacteria (Escherichia coli , Pseudomonas aeruginosa , and Staphylococcus aureus) in 19 s, suggesting that it was not only effective to E. coli but also effective to the chlorine-resistant bacteria (P. aeruginosa and S. aureus). Image 1 • A disinfection approach of resin adsorption followed by electrolysis was developed. • The new approach could decrease the formation of TOX, four THMs, and five HAAs. • Cytotoxicity of water samples treated with the new approach was reduced by 68.8%. • The new approach achieved 3.36-log 10 reductions of three seeded bacteria quickly. [ABSTRACT FROM AUTHOR]

Complex shock interactions on the lips of hypersonic vehicles typically induce severe aerodynamic thermal loads. Considering a V-shaped blunt leading edge as the simplified model of the lip, the design, optimization, and performance of secondary recirculation jets for reducing aerodynamic thermal loads are investigated. The secondary recirculation jet scheme is crucial in reshaping the shock interaction structures, allowing the high-pressure gas downstream of the main shock structures to be transported back into the upstream flow field. Numerical results show that setting the bleed hole of the secondary recirculation jet scheme upstream of the shock wave/boundary layer interaction region yields the greatest reduction in heat flux. The combined effect of the oblique shock upstream of the blow hole and the bow shock at the windward edge of the bleed hole weakens the shock wave/boundary layer interaction structure, thereby reducing the associated heat flux peak. Prior to optimization, the scheme reduces the heat flux peak by approximately 25%. Once the critical design parameters have been optimized and a stagnation bulge has been introduced, the scheme achieves excellent heat flux peak reduction ability of approximately 43%. Simulations under a wide range of freestream conditions show that the optimal scheme has strong applicability to nonzero attack and sideslip angles and is suitable for hypersonic flows below Mach 9.0. In general, the secondary recirculation jet scheme designed in this work exhibits excellent ability to reduce the peak and average values of the heat flux. • A new passive heat flux reduction scheme suitable for the VSBLE model is designed and optimized. • The bleed hole of the secondary recirculation jet scheme is preferably set upstream of the SWBLI region. • The new scheme has satisfactory heat flux reduction ability of the peak and average values after optimizing. • The optimal scheme is suitable for flows with attack angle, sideslip angle, and wide Mach number. [ABSTRACT FROM AUTHOR]

Genetic evaluations of local cattle breeds are hampered due to small reference groups or biased due to the utilization of SNP effects estimated in other large populations. Against this background, there is a lack of studies addressing the possible advantage of whole-genome sequences (WGS) or consideration of specific variants from WGS data in genomic predictions for local breeds with small population size. Consequently, the aim of this study was to compare genetic parameters and accuracies of genomic estimated breeding values (GEBV) for 305-d production traits, fat-to protein ratio (FPR), and somatic cell score (SCS) at the first test date after calving and confirmation traits of the endangered German Black Pied cattle (DSN) breed using 4 different marker panels: (1) the commercial 50K Illumina BovineSNP50 BeadChip, (2) a customized 200K chip designed for DSN (DSN200K) which considers the most important variants for DSN from WGS, (3) randomly generated 200K chips based on WGS data, and (4) a WGS panel. The same number of animals was considered for all marker panel analyses (i.e., 1,811 genotyped or sequenced cows for conformation traits, 2,383 cows for lactation production traits, and 2,420 cows for FPR and SCS). Mixed models for the estimation of genetic parameters directly included the respective genomic relationship matrix from the different marker panels plus the trait-specific fixed effects. For the calculation of GEBV accuracies, we applied repeated random subsampling validation. In the process of separate cross-validations per trait, we created a validation set including 20% of cows with masked phenotypes, and a training set comprising 80% of the cows. The cows were selected randomly in a procedure with 10 replicates considering replacements in the different scenarios. The accuracy was defined as the correlation between the direct GEBV and the phenotypes with subtracted corresponding fixed effects for the cows in the validation set. For FPR and SCS, as well as for lactation production traits, heritabilities were largest based on WGS data, but the increase compared with the 50K or DSN200K applications was quite small in the range from 0.01 to 0.03. Also, for most of the conformation traits, heritabilities were largest based on WGS and DSN200K data, but the increase was in the range of the corresponding standard error. Accordingly, GEBV accuracies for most of the studied traits were highest based on WGS data or when utilizing the DSN200K chip, but the accuracy differences across the marker panels were quite small and nonsignificant. In conclusion, WGS data and the DSN200K chip only contributed to minor improvements in genomic predictions, still justifying the use of the commercial 50K chip. Nevertheless, WGS and the 200KDSN chip harbor breed-specific variants, which are valuable for studying causal genetic mechanisms in the endangered DSN population. [ABSTRACT FROM AUTHOR]

• Platelet microRNAs were screened for links with platelet reactivity in healthy subjects. • The associated microRNAs were validated in clopidogrel-treated patients with ACS. • Platelet miR-223/126/150 influenced the clopidogrel antiplatelet effect. [ABSTRACT FROM AUTHOR]

SOX2 has been viewed as a critical oncoprotein in osteosarcoma. Emerging evidence show that inducing the degradation of transcription factors such as SOX2 is a promising strategy to make them druggable. Here, we show that neogambogic acid (NGA), an active ingredient in garcinia, significantly inhibited the proliferation of osteosarcoma cells with ubiquitin proteasome-mediated degradation of SOX2 in vitro and in vivo. We further identified USP9x as a bona fide deubiquitinase for SOX2 and NGA directly interacts with USP9x in cells. Moreover, knockdown of USP9x inhibited the proliferation and colony formation of osteosarcoma cells, which could be rescued by overexpression of SOX2. Consistent with this, knockdown of USP9x inhibited the proliferation of osteosarcoma cells in a xenograft mouse model. Collectively, we identify USP9x as the first deubiquitinating enzyme for controlling the stability of SOX2 and USP9x is a direct target for NGA. We propose that targeting the USP9x/SOX2 axis represents a novel strategy for the therapeutic of osteosarcoma and other SOX2 related cancers. [ABSTRACT FROM AUTHOR]

Personalized antiplatelet treatment in patients with acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) remains challenging in clinical practice. The present study aimed to explore the benefit of genotype-guided antiplatelet treatment with P2Y12 inhibitors in patients with ACS or undergoing PCI. A literature search was conducted (from inception to September 2018) in the PUBMED, EMBASE and Cochrane databases. Studies were included in which the genotype-guided P2Y12 inhibitor antiplatelet strategy was compared with the standard strategy in patients with ACS or undergoing PCI. The endpoints were high on-treatment platelet reactivity (HTPR), major adverse cardiovascular events including all-cause mortality, myocardial infarction (MI), stent thrombosis (ST), stroke and target-vessel revascularization (TVR), and major bleedings. A total of 3377 patients in 9 studies (5 RCTs and 4 non-RCTs) were included, in which 91% of the patients were diagnosed with ACS and 88.5% underwent PCI. A total of 1639 patients (48.5%) were assigned to the genotype-guided group, and 1738 (51.4%) assigned to the conventional or standard (STD) group, with an average follow-up time of 7.6 months. After the pooled analysis, significantly lower risks of HTPR (HR: 0.32, 95% CI: 0.18–0.55, P < 10−4), all-cause mortality (HR: 0.55, 95% CI: 0.37–0.83, p = 0.005), MI (HR: 0.43, 95% CI: 0.27–0.67, p = 0.0002) and ST (HR: 0.39, 95% CI: 0.16–0.97, p = 0.004) were observed in the genotype-guided group compared to the STD group. No significant between-group difference was found for the risk of stroke, TVR, and major bleedings after the pooled analysis. Genotype-guided antiplatelet treatment could decrease the risks of HTPR, all-cause mortality, MI and ST in patients with ACS or undergoing PCI. • Inadequate antiplatelet with P2Y12 inhibitor of clopidogrel is strongly predicted by CYP2C19 loss-of-function alleles. • There is controversy over the benefit of genotype-guided antiplatelet treatment with P2Y12 inhibitors. • Genotype-guided antiplatelet treatment could decrease the risks of HTPR and MACEs in ACS or PCI patients. [ABSTRACT FROM AUTHOR]

Background Both platelet-derived microRNAs and the genotype of CYP2C19*2 were implicated for the variability of clopidogrel antiplatelet responsiveness. However, their interaction on the antiplatelet responsiveness of clopidogrel in patients with acute coronary syndrome (ACS) remains unknown. Methods Consecutive clopidogrel-treated patients with ACS were recruited, with their antiplatelet responsiveness evaluated by the relative platelet inhibition (RI), as measured by light transmittance aggregometry (LTA) at baseline and 5 days' after the maintenance treatment of clopidogrel. Extreme cases were selected according to the octiles of RI value. Expression of the microRNAs targeting the mRNAs of P2RY12 was analyzed in the platelet of the extreme cases. Genotyping of CYP2C19*2 was performed for each extreme case. Results Among the included 272 ACS patients, 21 cases were screened as the extremely high-responders with RI > 84%, and 18 as the extremely low-responders with RI < 10%. Bioinformatics tools predicted the candidate microRNAs of miR-223, miR-221, and miR-21 could bind directly to the mRNA of P2RY12. Compared with the extremely low-responders, the expression of miR-223, miR-221, and miR-21 was significantly higher in the extremely high-responders (miR-223: 7.18 ± 2.95 vs. 0.99 ± 0.64, p = 0.022; miR-221: 3.60 ± 2.54 vs. 1.14 ± 0.81, p = 0.004; miR-21: 4.36 ± 3.33 vs. 2.31 ± 1.69, p = 0.01). ROC curve showed ideal discriminatory power of the platelet-derived miRNAs for the prediction of clopidogrel antiplatelet responsiveness (c-index = 0.70 for miR-223; c-index = 0.76 for miR-221; c-index = 0.79 for miR-21). After stratified by the carrier status of CYP2C19*2, the association between platelet-derived miRNAs and clopidogrel antiplatelet responsiveness could be found only in CYP2C19*2 carriers, but not in non-carriers. Conclusions Platelet-derived miRNAs (miR-223, miR-221 and miR-21) are independently associated with clopidogrel antiplatelet responsiveness in ACS patients. However, the association could be influenced by the interaction with CYP2C19*2 genotype. [ABSTRACT FROM AUTHOR]

Microvascular endothelial cells (CMECs) oxidative damage resulting from hypoxia/reoxygenation (H/R) injury is responsible for microcirculation perfusion disturbances and the progression of cardiac dysfunction. However, few strategies are available to reverse such pathologies. Here, we studied the effects and mechanisms of liraglutide on CEMCs oxidative damage, focusing in particular on calcium overload-triggered free radical injury signals and the GLP-1R/PI3K/Akt/survivin survival pathways. The results indicate that H/R increased IP3R expression but reduced SERCA2a expression, which rapidly raised intracellular Ca 2+ levels, subsequently leading to Ca 2+ -dependent xanthine oxidase (XO) activation, reactive oxygen species (ROS) production and the cellular apoptosis of CMECs. However, liraglutide pretreatment abrogated Ca 2+ -mediated oxidative apoptosis. Furthermore, liraglutide regulated the rate of IP3R/SERCA2a gene transcription and conserved SERCA2a-ATPase activity via the maintenance of ATP production under H/R, which drove excessive Ca 2+ reflux to the sarcoplasmic reticulum (SR) and inhibited Ca 2+ release from the SR, ultimately restoring Ca 2+ homeostasis. Furthermore, the regulatory role of liraglutide on Ca 2+ balance in conjunction with its up-regulation of superoxide dismutase, glutathione and glutathione peroxidase collectively scavenged the excess ROS under H/R. Moreover, we showed that liraglutide strengthened Akt phosphorylation and subsequently survivin expression. In addition, both the blockade of the GLP-1R/PI3K/Akt pathways and the siRNA-mediated knockdown of survivin abolished the protective effects of liraglutide on SR-Ca 2+ function and CMECs oxidative apoptosis. In summary, this study confirmed that H/R induced CMECs oxidative damage through the SR-Ca 2+ –XO–ROS injury signals and that liraglutide pretreatment may suppress such CMECs damage through the PI3K/Akt/survivin pathways. [ABSTRACT FROM AUTHOR]

Purpose Hypertension is a very important risk factor for cardiac vascular disease. The previous studies showed that mitochondrial DNA mutations are associated with cardiovascular disease, including hypertension. Methods In this study we did systematical analysis on the total 22 mitochondrial tRNAs and the clinical, genetic and molecular changes of 140 Chinese hypertension and 124 controls. Results This analysis identified 22 nucleotide changes among 15 different tRNA genes. There are 15 mutations with CI (Conservation index) larger than 75%. Of these, there are 26 patients with CI larger than 75% in the HTN group, higher than the 6 subjects in the control group ( P = 0.00). The tRNA Phe G586A, tRNA Lys G8313A and tRNA His G12147A mutations create highly conservative base-pairings on the D-stem, tRNA Lys G8342A on the T-stem, tRNA Phe T616C, tRNA Ala T5628C, tRNA Tyr G5856A and tRNA Thr A15924G on the AC stem, tRNA Leu(CUN) G12300A on the AC loop, tRNA Met C4467T, tRNA Trp T5578C, tRNA Lys A8296G, tRNA Arg T10463C and tRNA Thr C15891T on ACC stem, and tRNA Ser(UCN) C7492T on D-A junction, while the other tRNA variants were polymorphisms. The pedigrees of PLAH 78 carrying the T5578C, PLAH 84 carrying the C4467T, PLAH 60 carrying the T5628C and PLAH 118 carrying the C7492T mutation exhibited maternal transmission of essential hypertension. Sequence analysis of their mitochondrial genomes revealed the presence of T5578C, C4467T, T5628C or C7492T mutations but the absence of other functionally significant mutations in all matrilineal relatives of these families. Conclusions These tRNAs mutations, associated with altered structures of tRNAs and mitochondrial dysfunction, may contribute to the hypertension in Chinese population. A lot of work still should be done for the mechanism and functional effect of the mtDNA mutation on hypertension. [ABSTRACT FROM AUTHOR]

High-dose clopidogrel has been recommended to overcome clopidogrel non-responsiveness in patients undergoing percutaneous coronary intervention (PCI), especially those with CYP2C19 loss-of-function genotypes. However, there is controversy over the pharmacodynamics and clinical effects of the strategy. This meta-analysis was conducted to evaluate the antiplatelet effects of high-dose clopidogrel according to CYP2C19*2 alleles in patients undergoing PCI. Methods Based on PubMed, Cochrane, and EMBASE prior to June 1st, 2014, a systematic review and meta-analysis was conducted to evaluate the antiplatelet effects of high-dose clopidogrel on platelet reactivity and clinical outcomes in PCI treated patients according to CYP2C19*2 genotypes. The reported outcomes including on-treatment platelet reactivity (OTPR), high on-treatment platelet reactivity (HTPR), major adverse cardiovascular events (MACE), stent thrombosis and composite cardiovascular events. Results Nineteen studies involving 10,960 patients were included. After high-dose clopidogrel administration (600/900mg loading dose and/or 150mg/day maintenance dose), compared with non-carriers, carriers of CYP2C19*2 genotype had significantly increased OTPR (SMD for VASP assay: 0.69, 95% CI: 0.48-0.90, p=4×10-4; for VerifyNow P2Y12 assay: 0.70, 95% CI: 0.54-0.85, p<10-5; for LTA assay:0.58, 95% CI: 0.48-0.69, p=4×10-4). The incidence rate of HTPR was higher in CYP2C19*2 carriers after high-dose clopidogrel treatment (RR: 1.21, 95% CI:1.05-1.39, p=0.008 for cutoff PRI >50% by VASP assay; RR: 1.69, 95% CI: 1.44-1.98, p<1×10-4 for cutoff PRU >230 by VerifyNow P2Y12 assay). As for clinical outcomes, CYP2C19*2 was associated with higher risk for MACE (RR: 1.68, 95% CI: 1.19- 2.37, p=0.003), stent thrombosis (RR: 1.75, 95% CI: 1.31-2.34, p=0.0001), as well as composite cardiovascular events (RR: 1.82, 95% CI: 1.42- 2.34, p<10-5) after treated by high-dose clopidogrel. Conclusion High-dose clopidogrel could not overcome the variability of clopidogrel antiplatelet effects between the CYP2C19 *2 carriers and non-carriers in patients treated with PCI. [ABSTRACT FROM AUTHOR]

Abstract: Marsupenaeus japonicus is a shrimp species of great value in the Chinese aquaculture industry. Given the susceptibility to viral diseases, research efforts have focused on the molecular characteristics of the shrimp's immune mechanisms. Ferritin is well known for its iron storage function, but studies have also addressed its immune function in response to pathogens. In this study, an M. japonicus ferritin cDNA was identified by homology cloning and rapid amplification of cDNA ends-PCR. The full-length cDNA is 1244bp long and contains an open reading frame (513bp) that encodes a highly conserved protein of 170 amino acids. Quantitative real-time PCR detection of ferritin revealed high expression in eight tested tissues, with the highest levels in hemocytes—consistent with the iron storage capacity of ferritin. We infected M. japonicus with white spot syndrome virus and validated the model by viral copy analysis and histopathology, which demonstrated an increase in viral copies along with acute degeneration of tissues. Transcripts of ferritin increased by 3.1-fold, 2.1-fold, and 1.5-fold in the hepatopancreas, gill, and midgut at 24h post-injection, suggesting that ferritin played an important role in the immune response of M. japonicus. [Copyright &y& Elsevier]

Abstract: Background: The main challenge for warfarin anticoagulation is the risk for hemorrhagic complications. Although certain pharmacogenetic factors may explain the individual variabilities about the therapeutic warfarin dose requirement, the genetic factors to warfarin hemorrhagic complications due to over-anticoagulation are largely unknown. To interpret the potential role of warfarin-related genotypes on over-anticoagulation and hemorrhagic complications, we conducted a meta-analysis based on 22 published studies. Methods: A comprehensive search was applied to the reports on over-anticoagulation and hemorrhagic complications published prior to December 31, 2012 in PubMed and EMBASE. References were identified by strict inclusion and exclusion criteria, with additional information obtained by consulting with the authors of primary studies. The roles of genotypes in CYP2C9 and VKORC1 on over-anticoagulation (INR >4) and hemorrhagic complications were analyzed by Revman 5.0.2 software. Results: A total of 6272 patients in 22 reports were included in the meta-analysis, including studies of 18 from Caucasians (3 from both Caucasian and African–American), 3 from Asians, and 1 from Brazilians. Compared to CYP2C9 wild genotype (CYP2C9*1), both CYP2C9*2 (rs 1799853, c. 430 C>T, p. Arg144Cys) and *3 (rs 1057910, c. 1075 A>C, p. Ile359Leu) confer significantly higher risk for warfarin over-anticoagulation and hemorrhagic complications. After stratification by CYP2C9 allele status, significantly higher risk for hemorrhagic complications was found only in carriers of at least 1 copy of CYP2C9*3 [For total hemorrhages: *1/*3 HR: 2.05 (1.36–3.10), p<0.001; *3/*3 HR: 4.87 (1.38–17.14), p=0.01; For major hemorrhages: *1/*3 HR: 2.43 (1.17–5.06), p=0.02; *3/*3 HR: 4.81 (0.95–24.22), p=0.06]. Furthermore, similar susceptibility of total hemorrhage by CYP2C9 genotypes was observed in Caucasians and Asians. After stratification by the occurrence time, both CYP2C9*2 and *3 are risk factors for over-anticoagulation within 30days of warfarin treatment [*2 HR: 1.64 (1.11–2.43), p=0.01; *3 HR: 2.48 (1.56–3.96), p<0.001], and only CYP2C9*3 showed higher risk for over-anticoagulation after 30days [HR: 1.86 (1.08–3.20), P=0.03]. For VKORC1 c. −1639G>A (rs 9923231) genotypes, GA and AA contributed significantly higher risk for over-anticoagulation within 30days [HR: 2.14 (1.75–2.62), p<0.001], but not for over-anticoagulation after 30days [HR:0.78 (0.46–1.33), p=0.36]. No significant association was found between VKORC1 genotypes and hemorrhagic complications. Conclusions: Both CYP2C9 and VKORC1 genotypes are associated with an increased risk for warfarin over-anticoagulation, with VKORC1 c. −1639G>A more sensitive early in the course of anticoagulation. CYP2C9*3 is the main genetic risk factor for warfarin hemorrhagic complications. [Copyright &y& Elsevier]

Abstract: Background: paraoxonase-1 (PON1) was recently identified as the crucial enzyme for clopidogrel bioactivation, with PON1 Q192R (rs662) polymorphism determining the clopidogel antiplatelet efficacy. However, subsequent studies showed controversies over the findings. This study aimed to evaluate the impact of PON1 Q192R in parallel to that of CYP2C19*2 (rs4244285) on clopidogrel responsiveness in a cohort of Chinese patients with unstable angina pectoris. Material and methods: One hundred and eighty Chinese-Han patients diagnosed with unstable angina pectoris and treated with clopidogrel were consecutively recruited. Clopidogrel responsiveness, measured by relative platelet inhibition {RI=[(pretreatment aggregation-posttreatment aggregation at 5days)/(pretreatment aggregation)] x100%}, was assessed in relation to PON1 Q192R and CYP2C19*2 genotypes. RI values were stratified into four quartiles, with patients in quartile 1 defined as individuals of clopidogrel non-responsiveness. The contributions of PON1 Q192R and CYP2C19*2 to on-treatment platelet reactivity (OTPR) at 5days maintenance dose of clopidogrel were also evaluated. Results: For PON1 Q192R genotypes, RI values were significantly lower in patients with QR and RR alleles than in patients with QQ alleles (p=0.01). OTPR values at 5days maintenance dose of clopidogrel were similar across all the PON1 Q192R genotypes (p=0.41). PON1 192 QR and RR conferred increased risks for clopidogrel non-responsiveness [OR 3.64; 95% CI (1.21-10.92), p=0.02]. For CYP2C19*2 genotypes, compared to CYP2C19*1/*1 wild type carriers, CYP2C19*2 carriers showed a significantly higher OTPR (p=0.009), and a trend for lower RI values (p=0.06). An increased risk for clopidogrel non-responsiveness was found in patients with CYP2C19*2 genotype [OR 2.02; 95% CI (1.03-3.96), p=0.04]. Conclusions: Both PON1 Q192R and CYP2C19*2 genotypes influence clopidogrel responsiveness, with the impact of PON1 Q192R mainly on relative platelet inhibition instead of OTPR of clopidogrel. [Copyright &y& Elsevier]

Abstract: Introduction: Cytochrome P450 (CYP), ATP-binding cassette transporters (ABCB1), and paraoxonase-1 (PON1) play crucial roles in clopidogel absorption and bioactivation. Genetic polymorphisms in these genes have been associated with the variability of the response to clopidogrel, however their contribution to high on-treatment platelet reactivity (HPR) in clopidogrel treated Chinese patients is less known. Materials and methods: Five-hundred Chinese-Han patients treated with clopidogrel for acute coronary syndrome (ACS) were consecutively recruited from the Department of Geriatric Cardiology, General Hospital of Chinese People’s Liberation Army, from September 2010 to September 2012. We assessed the relations of CYP2C19*2 (rs4244285), CYP2C19*3 (rs4986893), CYP2C19*17 (rs12248560), PON1Q129R (rs662) and ABCB1C3435T (rs1045642) to the platelet aggregation after 5days maintenance dose of clopidogrel administration, and the risk for HPR. The cutoff of HPR was defined as 20μmol/L adenosine diphosphate (ADP)-induced platelet aggregation>50%. Results: Both CYP2C19*2 and *3 alleles were significantly associated with higher platelet aggregation after 5days maintenance dose of clopidogrel administration (P <0.00001and P =0.042, respectively). The platelet aggregation in carriers of at least one CYP2C19 loss-of-function allele (*2 or *3, accounted for 58% of the study population) was obviously higher than that in non-carriers (P <0.00001). Patients with the CYP2C19*2 allele had a higher risk of HPR than those with the CYP2C19 wild-type genotype [adjusted hazard ratio (HR), 1.56; 95% confidence interval(CI), 1.04–2.33, P =0.03]. The carriers of at least one CYP2C19 loss-of-function allele could also predict significantly greater risk of HPR compared with non-carriers (adjusted HR1.79,95% CI: 1.33–2.4,P =0.003). However, the carriage of CYP2C19*3 alone could not predict the risk of HPR significantly (adjusted HR, 1.5; 95% CI: 0.83–3, P =0.16). Significant relation of CYP2C19*17, PON1Q129R and ABCB1C3435T to the platelet aggregation was not found. Conclusion: In clopidogrel treated Chinese patients with ACS, carriers of at least one CYP2C19 loss-of-function allele could predict greater risk of HPR, with the impact mainly attributing to CYP2C19*2. Neither ABCB1 nor PON1 genotype could influence the antiplatelet response of clopidogrel in the cohort of Chinese patients. [Copyright &y& Elsevier]

Abstract: Introduction: Multiple warfarin pharmacogenetic algorithms have been confirmed to predict warfarin dose more accurately than clinical algorithm or the fixed-dose approach. However, their performance has never been objectively evaluated in patients under low intensity warfarin anticoagulation, which is optimal for prevention of thromboembolism in Asian patients. Material and methods: We sought to compare the performances of 8 eligible pharmacogenetic algorithms in a cohort of Chinese patients (n=282) under low intensity warfarin anticoagulation with target international normalized ratio (INR) ranged from 1.6 to 2.5. The performance of each algorithm was evaluated by calculating the percentage of patients whose predicted dose fell within 20% of their actual therapeutic dose (percentage within 20%), and the mean absolute error (MAE) between each predicted dose and actual stable dose. Results: In the entire cohort, the pharmacogenetic algorithms could predict warfarin dose with the average MAE of 0.87±0.17mg/day (0.73-1.17mg/day), and the average percentage within 20% of 43.8%±8.1% (29.1% - 52.1%). By pairwise comparison, warfarin dose prediction was significantly more accurate with the algorithms derived from Asian patients (48.6% – 50.0%) than those from Caucasian patients (29.1% - 39.7%; odds ratio [OR]: 1.61-3.36, p ≤0.02). Algorithms with additional covariates of INR values or CYP4F2*3 performed better than those without the covariates (adding INR: OR: 1.71 (1.08-2.72), p =0.029; adding CYP4F2*3: OR: 2.67(1.41-5.05), p =0.004). When the patients were stratified according to the dose range, the algorithms from Caucasian and racially mixed populations tended to perform better in higher dose group (≥4.5mg/day), and algorithms from Asian populations performed better in intermediate dose group (1.5-4.5mg/day). None of the algorithms performed well in lower dose group (≤1.5mg/day). Conclusions: No eligible pharmacogenetic algorithm could perform the best for all dosing range in the Chinese patients under low intensity warfarin anticoagulation. Construction of a refinement pharmacogenetic algorithm integrating 3 genotypes (CYP2C9, VKORC1 and CYP4F2) and INR data should be warranted to improve the warfarin dose prediction in such patients. [Copyright &y& Elsevier]