Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice

Influenza viruses continuously circulate in the human population and escape recognition by virus neutralizing antibodies induced by prior infection or vaccination through accumulation of mutations in the surface proteins hemagglutinin (HA) and neuraminidase (NA). Various strategies to develop a vaccine that provides broad protection against different influenza A viruses are under investigation, including use of recombinant (r) viral vectors and adjuvants. The replication-deficient modified vaccinia virus Ankara (MVA) is a promising vaccine vector that efficiently induces B and T cell responses specific for the antigen of interest. It is assumed that live vaccine vectors do not require an adjuvant to be immunogenic as the vector already mediates recruitment and activation of immune cells. To address this topic, BALB/c mice were vaccinated with either protein- or rMVA-based HA influenza vaccines, formulated with or without the saponin-based Matrix-M™ adjuvant. Co-formulation with Matrix-M significantly increased HA vaccine immunogenicity, resulting in antigen-specific humoral and cellular immune responses comparable to those induced by unadjuvanted rMVA-HA. Of special interest, rMVA-HA immunogenicity was also enhanced by addition of Matrix-M, demonstrated by enhanced HA inhibition antibody titres and cellular immune responses. Matrix-M added to either protein- or rMVA-based HA vaccines mediated recruitment and activation of antigen-presenting cells and lymphocytes to the draining lymph node 24 and 48 h post-vaccination. Taken together, these results suggest that adjuvants can be used not only with protein-based vaccines but also in combination with rMVA to increase vaccine immunogenicity, which may be a step forward to generate new and more effective influenza vaccines

Who Did the Arthroplasty? Hip Fracture Surgery Reoperation Rates are Not Affected by Type of Training-An Analysis of the HEALTH Database

OBJECTIVES: This study compares outcomes for patients with displaced femoral neck fractures undergoing hemiarthroplasty (HA) or total hip arthroplasty (THA) by surgeons of different fellowship training. DESIGN: Retrospective review of HEALTH trial data. SETTING: Eighty clinical sites across 10 countries. PATIENTS/PARTICIPANTS: One thousand four hundred forty-one patients ≥50 years with low-energy hip fractures requiring surgical intervention. INTERVENTION: Patients were randomized to either HA or THA groups in the initial data set. Surgeons' fellowship training was ascertained retrospectively, and outcomes were compared. MAIN OUTCOME MEASUREMENTS: The main outcome was an unplanned secondary procedure at 24 months. Secondary outcomes included death, serious adverse events, prosthetic joint infection (PJI), dislocation, discharge disposition, an

Abundances of the elements in the solar system

A review of the abundances and condensation temperatures of the elements and their nuclides in the solar nebula and in chondritic meteorites. Abundances of the elements in some neighboring stars are also discussed.Comment: 42 pages, 11 tables, 8 figures, chapter, In Landolt- B\"ornstein, New Series, Vol. VI/4B, Chap. 4.4, J.E. Tr\"umper (ed.), Berlin, Heidelberg, New York: Springer-Verlag, p. 560-63

Mapping and characterization of structural variation in 17,795 human genomes

A key goal of whole-genome sequencing for studies of human genetics is to interrogate all forms of variation, including single-nucleotide variants, small insertion or deletion (indel) variants and structural variants. However, tools and resources for the study of structural variants have lagged behind those for smaller variants. Here we used a scalable pipeline1 to map and characterize structural variants in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest, to our knowledge, whole-genome-sequencing-based structural variant resource so far. On average, individuals carry 2.9 rare structural variants that alter coding regions; these variants affect the dosage or structure of 4.2 genes and account for 4.0–11.2% of rare high-impact coding alleles. Using a computational model, we estimate that structural variants account for 17.2% of rare alleles genome-wide, with predicted deleterious effects that are equivalent to loss-of-function coding alleles; approximately 90% of such structural variants are noncoding deletions (mean 19.1 per genome). We report 158,991 ultra-rare structural variants and show that 2% of individuals carry ultra-rare megabase-scale structural variants, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and noncoding elements, and reveal trends that relate to element class and conservation. This work will help to guide the analysis and interpretation of structural variants in the era of whole-genome sequencing

Heterozygosis For Cyp21a2 Mutation Considered As 21-hydroxylase Deficiency In Neonatal Screening

Steroid 21-hydroxylase deficiency (21-OHD) accounts for more than 90% of congenital adrenal hyperplasia. CAH newborn screening, in general, is based on 17-hydroxyprogesterone dosage (17-OHP), however it is complicated by the fact that healthy preterm infants have high levels of 17-OHP resulting in false positive cases. We report on molecular features of a boy born pre-term (GA = 30 weeks; weight = 1,390 g) with elevated levels of 17-OHP (91.2 nmol/L, normal < 40) upon neonatal screening who was treated as having CAH up to the age of 8 months. He was brought to us for molecular diagnosis. Medication was gradually suspended and serum 17-OHP dosages mantained normal. The p.V281 L mutation was found in compound heterozygous status with a group of nucleotide alterations located at the 3′ end intron 4 and 5′ end exon 5 corresponding to the splice site acceptor region. Molecular studies continued in order to exclude the possibility of a nonclassical 21-OHD form. The group of three nucleotide changes was demonstrated to be a normal variant since they failed to interfere with the normal splicing process upon minigene studies.52813881392White, P.C., Speiser, P.W., Congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2000) Endocr Rev, 21, pp. 245-291Riepe, F.G., Sippell, W.G., Recent advances in diagnosis, treatment, and outcome of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (2007) Rev Endocr Metab Disord, 8 (4), pp. 349-363New, M., Lorenzen, F., Lerner, A.J., Kohn, B., Oberfield, S.E., Pollack, M.S., Genotyping steroid 21-hydroxylase deficiency: Hormonal reference data (1983) J Clin Endocrinol Metab, 57, pp. 320-326Azziz, R., Hincapie, L.A., Knochenhauer, E.S., Dewailly, D., Fox, L., Boots, L.R., Screening for 21-hydroxylase-deficient nonclassic adrenal hyperplasia among hyperandrogenic women (1999) Fertil Steril, 72, pp. 915-925Bachega, T.A., Brenlha, E.M., Billerbeck, A.E., Marcondes, J.A., Madureira, G., Arnhold, I.J., Mendonca, B.B., Variable ACTH-stimulated 17-hydroxyprogesterone values in 21-hydroxylase deficiency carriers are not related to the different CYP21 gene mutations (2002) J Clin Endocrinol Metab, 87 (2), pp. 786-790Pang, S., Hotchkiss, J., Drash, A.L., Levine, L.S., New, M., Microfilter paper method for 17-hydroxyprogesterone radioimmunoassay: Its application for rapid screening for congenital adrenal hyperplasia (1977) J Clin Endocrinol Metab, 45, pp. 1003-1008Valentino, R., Tommaselli, A.P., Rossi, R., Lombardi, G., Varrone, S., A pilot study for neonatal screening of congenital adrenal hyperplasia due to 21-hydroxylase and 11-hydroxylase deficiency in Campania region (1990) J Endocrinol lnvest, 13, pp. 221-225Janzen, N., Peter, M., Sander, S., Steuerwald, U., Terhardt, M., Holtkamp, U., Sander, J., Newborn screening for congenital adrenal hyperplasia: Additional steroid profile using liquid chromatography-tandem mass spectrometry (2007) J Clin Endocrinol Metab, 92 (7), pp. 2581-2589Pang, S., Murphey, W., Levine, L.S., Lorenzen, F., Levy, D., Lerner, A.J., Rondanini, G.F., New, M., A pilot newborn screening for congenital adrenal hyperplasia in Alaska (1982) J Clin Endocrinol Metab, 55, pp. 413-420Nordenström, A., Wedell, A., Hagenfeldt, L., Marcus, C., Larsson, A., Neonatal screening for congenital adrenal hyperplasia: 17-hydroxyprogesterone levels and CYP21 genotypes in preterm infants (2001) Pediatrics, 108 (4), pp. E68Cardoso, C.B., Fonseca, A.A., Oliveira Mde, F., Pereira, B.B., Guimarães, M.M., Congenital adrenal hyperplasia newborn screening: Rio de Janeiro experience. Arq Bras Endocrinol (2005) Metabol, 49 (1), pp. 112-119Silveira, EL, D.S., Bachega, T.A., van der, Linden Nader, I., Gross, J.L., Elnecave, R.H., The actual incidence of congenital adrenal hyperplasia in Brazil may not be as high as inferred-an estimate based on a public neonatal screening program in the state of Goiás (2008) J Pediatr Endocrinol Metab, 21 (5), pp. 455-460Sambrook, J., Fritsch, E.F., Maniatis, T.E., (1989) Molecular Cloning, a Laboratory Manual, , New York: Cold Spring HarborAraujo, M., Sanches, M.R., Suzuki, L.A., Guerra-Jr, G., Farah, S.B., De Mello, M.P., Molecular analysis of CYP21 and C4 genes in Brazilian families with the classical form of steroid 21-hydroxylase deficiency (1996) Braz J Med Biol Res, 29, pp. 1-13Wilson, R.C., Wei, J.Q., Cheng, K.C., Mercado, A.B., New, M., Rapid deoxyribonucleic acid analysis by allele-specific polymerase chain reaction for detection of mutations in the steroid 21-hydroxylase gene (1995) J Clin Endocrinol Metab, 80 (5), pp. 1635-1640Lau, I.F., Soardi, F.C., Lemos-Marini, S.H., Guerra-Jr, G., Baptista, M.T., De Mello, M.P., H28+C insertion in the CYP21 gene: A novel frameshift mutation in Brazilian patient with the classical form of 21-hydroxylase deficiency (2001) J Clin Endocrinol Metab, 86, pp. 5877-5880Higashi, Y., Yoshioka, H., Yamane, M., Gotoh, O., Fujii-Kuriyama, Y., Complete nucleotide sequence of two steroid 21-hydroxylase genes tandemly arranged in human chromosome: A pseudogene and a genuine gene (1986) Proc Natl Acad Sci USA, 83, pp. 2841-2845Wilson, R.C., Nimkarn, S., Dumic, M., Obeid, J., Azar, M.R., Najmabadi, H., Ethnic-specific distribution of mutations in 716 patients with congenital adrenal hyperplasia owing to 21-hydroxylase deficiency (2007) Mol Genet Metab, 90 (4), pp. 414-421Tusie-Luna, M.T., Traktman, P., White, P.C., Determination of functional effects of mutations in the steroid 21-hydroxylase gene (CYP21) using recombinant vaccinia virus (1990) J Biol Chem, 265 (34), pp. 20916-20922Higashi, Y., Hiromasa, T., Tanae, A., Miki, T., Nakura, J., Kondo, T., Effects of individual mutations in the P-450(C21) pseudogene on the P-450(C21) activity and their distribution in the patient genomes of congenital steroid 21-hydroxylase deficiency (1991) J Biochem, 109 (4), pp. 638-644Bachega, T.A., Billerbeck, A.E., Madureira, G., Marcondes, J.A., Longui, C.A., Leite, M.V., Molecular genotyping in Brazilian patients with the classical and nonclassical forms of 21-hydroxylase deficiency (1998) J Clin Endocrinol Metab, 83 (12), pp. 4416-441