A genome-wide screen for variants influencing certolizumab pegol response in a moderate to severe rheumatoid arthritis population

Certolizumab pegol (CZP) is a PEGylated Fc-free tumor necrosis factor (TNF) inhibitor antibody approved for use in the treatment of rheumatoid arthritis (RA), Crohn's disease, psoriatic arthritis, axial spondyloarthritis and psoriasis. In a clinical trial of patients with severe RA, CZP improved disease symptoms in approximately half of patients. However, variability in CZP efficacy remains a problem for clinicians, thus, the aim of this study was to identify genetic variants predictive of CZP response. We performed a genome-wide association study (GWAS) of 302 RA patients treated with CZP in the REALISTIC trial to identify common single nucleotide polymorphisms (SNPs) associated with treatment response. Wholeexome sequencing was also performed for 74 CZP extreme responders and non-responders within the same population, as well as 1546 population controls. No common SNPs or rare functional variants were significantly associated with CZP response, though a non-significant enrichment in the RA-implicated KCNK5 gene was observed. Two SNPs near spondin- 1 and semaphorin-4G approached genome-wide significance. The results of the current study did not provide an unambiguous predictor of CZP response

Joint host-pathogen genomic analysis identifies hepatitis B virus mutations associated with human NTCP and HLA class I variation.

Evolutionary changes in the hepatitis B virus (HBV) genome could reflect its adaptation to host-induced selective pressure. Leveraging paired human exome and ultra-deep HBV genome-sequencing data from 567 affected individuals with chronic hepatitis B, we comprehensively searched for the signatures of this evolutionary process by conducting "genome-to-genome" association tests between all human genetic variants and viral mutations. We identified significant associations between an East Asian-specific missense variant in the gene encoding the HBV entry receptor NTCP (rs2296651, NTCP S267F) and mutations within the receptor-binding region of HBV preS1. Through in silico modeling and in vitro preS1-NTCP binding assays, we observed that the associated HBV mutations are in proximity to the NTCP variant when bound and together partially increase binding affinity to NTCP S267F. Furthermore, we identified significant associations between HLA-A variation and viral mutations in HLA-A-restricted T cell epitopes. We used in silico binding prediction tools to evaluate the impact of the associated HBV mutations on HLA presentation and observed that mutations that result in weaker binding affinities to their cognate HLA alleles were enriched. Overall, our results suggest the emergence of HBV escape mutations that might alter the interaction between HBV PreS1 and its cellular receptor NTCP during viral entry into hepatocytes and confirm the role of HLA class I restriction in inducing HBV epitope variations

Plasma lipid profiles discriminate bacterial from viral infection in febrile children

Fever is the most common reason that children present to Emergency Departments. Clinical signs and symptoms suggestive of bacterial infection are often non-specific, and there is no definitive test for the accurate diagnosis of infection. The 'omics' approaches to identifying biomarkers from the host-response to bacterial infection are promising. In this study, lipidomic analysis was carried out with plasma samples obtained from febrile children with confirmed bacterial infection (n = 20) and confirmed viral infection (n = 20). We show for the first time that bacterial and viral infection produces distinct profile in the host lipidome. Some species of glycerophosphoinositol, sphingomyelin, lysophosphatidylcholine and cholesterol sulfate were higher in the confirmed virus infected group, while some species of fatty acids, glycerophosphocholine, glycerophosphoserine, lactosylceramide and bilirubin were lower in the confirmed virus infected group when compared with confirmed bacterial infected group. A combination of three lipids achieved an area under the receiver operating characteristic (ROC) curve of 0.911 (95% CI 0.81 to 0.98). This pilot study demonstrates the potential of metabolic biomarkers to assist clinicians in distinguishing bacterial from viral infection in febrile children, to facilitate effective clinical management and to the limit inappropriate use of antibiotics

Great Solar Bursts Of October 19, 22 And 23, 1989

Itapetinga measurements at 48 GHz with the multibeam technique are used to determine the relative position of solar burst centroid of emission with high spatial accuracy and time resolution. For the Great Bursts of October 19,22, 1989, with a large production of relativistic'particles, and October 23, it is suggested that, at 48 GHz, the bursts might have originated in more then one source in space and time. Additionally the October 19 and 22 Ground Level Events exhibited very unusual intensity-time profiles including double component structures for the onset phase. The Bern observatory spectral radio emission data show a strong spectral flattening typical for large source inhomogeneties. The interpretation for this is that large solar flares are a superposition of a few strong bursts (separated both in space and time) in the same flaring region. © 2002 COSPAR. Published by Elsevier Science Ltd. All rights reserved.291221012104Brown, J.C., Correia, E., Farnik, F., Garcia, H., Henoux, J.-C., (1994) Solar Phys, 153, p. 19Cramp, J.L., Duldig, M.L., Humble, J.E., (1993) Proc. 23 ICRC, 3, p. 51Costa, J.E.R., Correia, E., Kaufmann, P., Magun, A., Hermann, R., (1995) Solar Phys, 159, p. 157Correia, E., Costa, J.E.R., Kaufmann, P., Magun, A., Hermann, R., (1995) Solar Phys, , acceptChertok, I.M., Fomichev, V.V., Gorgutsa, R.V., Hilderbrandt, I., Kruger, A., (1994) Proc. Workshop on Coronal Magnetic Energy Release, pp. 16-20. , GermanyMay, 1De Jager, C., Jonge, G., (1978) Solar Phys, 58, p. 127Gentile, L.C., (1993) Journ. Geophys. Res, 98, pp. 21-107. , 23 ICRCHanaoka, Y., (1996) Solar Phys, 165, p. 275Hermann, R., Rolli, E., Correia, E., Costa, J.E.R., (1994) Solar Phys, 149, p. 155Hermann, R., Magun, A., Costa, J.E.R., Correia, E., Kaufmann, P., (1992) Solar Phys, 142, p. 157Klein, K.-L., Trottet, G., Aurab, H., Magun, A., Michon, Y., (1996) Adv. Space Res, 17 (4-5), p. 247Kaufmann, P., Strauss, F.M., Opher, R., Laporte, C., (1980) Astron. Astrophys, 81, p. 58Lee, J.W., Gary, D.E., Zirin, H., (1994) Solar Phys, 152, p. 409Miroshnichenko, L.I., Perez-Peraza, J., Vashenyuk, E.V., Rodriguez-Frias, M.D., (1995) Proc. 24 ICRC, 4, p. 34Nemzek, R.J., Belian, R.D., Cayton, T.E., Raeves, G.D., (1994) Journ. Geophys. Res, 99, p. 4221Petrov, V.M., Makhmutov, V.S., Panova, N.A., Shurshakov, V.A., Dachev, Ts., (1994) Adv. Space Res, 14, p. 645(1989) Solar Geophysical Data, , US Dept. of Commerce, Boulder, ColoradoShea, M.A., Smart, D.F., Wilson, M., Fluckiger, E.O., (1991) Geophys. Res. Letters, 18, p. 829Stoker, P.H., Bieber, J., Evenson, P., (1995) Proc. 24 ICRC, 4, p. 224Torsti, J., Anttila, A., Vainio, R., Kocharov, L.G., (1995) Proc. 24 ICRC, 4, p. 139Vilmer, N., Kane, S.R., Trottet, G., (1982) Astron. Astrophys, 108, p. 30