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Objectives.To characterize the immunogenicity of a quadrivalent human papillomavirus vaccine (QHPV) in human immunodeficiency virus (HIV)–infected children, we studied their immune responses to 3 or 4 doses.
Methods.HIV-infected children aged 7–12 years with a CD4 cell percentage of ≥15% of lymphocytes, received 3 doses of QHPV with or without a fourth dose after 72 weeks. Type-specific and cross-reactive antibodies and cell-mediated immunity were measured.
Results.Type-specific antibodies to HPV6, 11, and 16 were detected in 100% and ≥94% of children at 4 and 72 weeks, respectively, after the third QHPV dose. Corresponding numbers for HPV18 were 97% and 76%, respectively. A fourth QHPV dose increased seropositivity to ≥96% for all vaccine genotypes. Four weeks after the third QHPV dose, 67% of vaccinees seroconverted to HPV31, an HPV16-related genotype not in the vaccine; 69% and 39% of vaccinees developed mucosal HPV16 and 18 immunoglobulin G antibodies, respectively; and 60% and 52% of vaccinees developed cytotoxic T lymphocytes (CTLs) for HPV16 and 31, respectively.
Conclusions.Three QHPV doses generated robust and persistent antibodies to HPV6, 11, and 16 but comparatively weaker responses to HPV18. A fourth dose increased antibodies against all vaccine genotypes in an anamnestic fashion. CTLs and mucosal antibodies against vaccine genotypes, as well as cross-reactive antibodies and CTL against nonvaccine genotypes, were detected.
Human papillomavirus (HPV) causes almost all cervical and anal cancers and is responsible for 30%–50% of vulvar, vaginal, penile, and oropharyngeal cancers [1]. The oncogenicity of HPV infections is type specific and associated with viral persistence [2, 3]. Human immunodeficiency virus (HIV)–infected women and men have a higher incidence of HPV-related neoplasias and invasive cancers, compared with the general population [4, 5], which is likely related to failure to clear oncogenic HPV infections [3, 6, 7]. HIV-infected adults also have high rates of genital warts, which are often recalcitrant to conventional therapies [8, 9]. Compared with HIV-infected adult women, HIV-infected adolescents are 3-fold as likely to develop high-grade squamous epithelial lesions as a result of HPV infections [7], suggesting that they have a heightened vulnerability to the oncogenic effects of HPV infections and that special emphasis should be placed in devising strategies to protect them.
HPV16 and 18 account for approximately 70% of cervical cancers and approximately 90% of the other HPV-associated anogenital and oropharyngeal cancers [10–12]. HPV6 and 11 account for 90% of genital warts. Two HPV vaccines are commercially available: a quadrivalent vaccine (QHPV) against HPV6, 11, 16, and 18 (Gardasil, Merck) and a bivalent vaccine against HPV16 and 18 (Cervarix, GlaxoSmithKline). Both vaccines are 98%–100% effective in protecting immunocompetent women against cervical infections with the vaccine genotypes [13–15]. QHPV confers protection in immunocompetent individuals against vulvar, vaginal, penile, and anal precancerous lesions and genital warts [16–18].
The mechanisms of protection of the HPV vaccines have not been completely elucidated, and immune correlates of protection have not been established. The vaccines, which contain the L1 HPV major capsid protein in a virus-like particle conformation, stimulate type-specific neutralizing antibodies, which are thought to play an important role in preventing HPV infection [13, 19, 20]. However, these vaccines also stimulate cell-mediated immunity (CMI) in immunocompetent hosts [21], which may also contribute to protection. Reports that adult women remain protected against HPV infection after loss of detectable antibody [22] and the observations that 1 or 2 doses of HPV vaccine may be as protective against HPV-associated cervical neoplasias as 3 doses of vaccine in the first few years after vaccination, despite inducing lower antibody titers [23], further emphasize the need to elucidate the mechanism(s) of protection by HPV vaccines and to identify an immune correlate of protection.
We and others showed that QHPV is generally safe and immunogenic in HIV-infected children and men who have sex with men [24, 25]. Here we report on the decay of HPV type–specific antibodies in HIV-infected children at 72 weeks after completing a standard 3-dose regimen and on the subsequent response to a fourth QHPV dose. We also describe mucosal and CMI responses to vaccine genotypes and cross-reactive responses to HPV31, which is not in the vaccine but is genetically related to HPV16.
HIV-infected children 7–12 years old with a CD4 cell percentage of ≥15% of lymphocytes and without other immunosuppressive conditions were enrolled after informed consent was obtained from the caregiver and assent was obtained from the subject in accordance with local ethical review committee guidelines. Subjects were randomly assigned at a 3:1 ratio to receive QHPV (the Rx-Immediate group) or placebo (the Rx-Deferred group) at weeks 0, 8, and 24 as previously described [24]. At week 96, Rx-Immediate subjects received a fourth QHPV dose, and Rx-Deferred subjects started the 3-dose standard regimen. Figure 1 summarizes the interventions and the time points when blood and oral secretions were collected for serum and mucosal antibody assays and for CMI.
Serum type-specific, neutralizing HPV6, 11, 16, and 18 antibodies were measured by competitive Luminex immunoassay (cLIA) as previously described [26]. Results were expressed in milli-Merck units (mMU) per milliliter, using assay-defined positive thresholds. The serostatus cutoff was the antibody titer level within the assay's quantifiable range that reliably distinguished "negative" from "positive" samples. The serostatus cutoffs were originally determined by testing approximately 500 samples and determining the percentage of positive samples at 11 different cutoffs (from 8 mMU/mL to 48 mMU/mL in increments of 4 mMU/mL). Prior to testing, sera were classified into panels according to their potential for being a true positive or negative on the basis of clinical history (number of sex partners, history of sexually transmitted diseases, or history of an abnormal Papanicolaou smear) and HPV polymerase chain reaction (PCR) results. The serostatus cutoff was selected as the lowest concentration such that all or nearly all of the known PCR-negative samples and likely negative samples yielded negative results. The resulting serostatus cutoffs for HPV types 6, 11, 16, and 18 were 20, 16, 20, and 24 mMU/mL, respectively.
Total immunoglobulin G (IgG) anti-HPV6, 11, 16, 18, and 31 antibodies were measured by LIA as previously described [27]. Results were expressed in mMU per milliliter, using assay-defined positive thresholds.
Oral secretions were collected using OraSure kits (OraSure Technologies). Only IgG and immunoglobulin A (IgA) antibodies against HPV16 and 18 were measured using the enzyme-linked immunosorbent assay (ELISA) described in the Supplementary Materials. Results were expressed in titers corresponding to the highest dilution ≥2-fold above background. Seroconversion was defined by a negative result at baseline followed by a positive result at week 28.
A previously described interferon γ (IFN-γ) enzyme-linked immunospot assay (ELISPOT) assay [28] was adapted for HPV16 and 31 (Supplementary Materials). Assays were performed using peripheral blood mononuclear cells (PBMCs) separated from blood shipped overnight. To differentiate CD4– from CD8–mediated responses, PBMCs were depleted of CD8+ cells using magnetic beads (Stem Cell Technologies) prior to stimulation for the ELISPOT assay, as previously described [29]. Results were expressed as spot-forming cells (SFCs) per 106 PBMCs. Response was defined by 2-fold higher SFCs in HPV-stimulated wells, compared with control, and by SFCs greater than or equal to the mean + 2 SDs of the composite baseline SFCs for the entire study population.
cLIA and LIA results were described using geometric mean titers (GMTs) and 95% confidence intervals (CIs). Results below the lower limit of quantitation (LOQ) were arbitrarily assigned a value of ≤50% of the LOQ. cLIA and LIA comparisons were performed using parametric tests. ELISPOT and ELISA results were described by medians and 95% CIs and were analyzed using nonparametric tests. Univariate linear regression was used to identify predictors of week 96 cLIA titers. For categorical variables with >2 categories, Tukey-Kramer simulation-based adjusted P values were used when F tests were statistically significant (P < .05).
The baseline characteristics are shown in Table 1. All but 2 participants were receiving highly active antiretroviral therapy.
Four weeks after completion of a standard 3-dose regimen, the proportions of seropositives measured by cLIA were 100% for HPV6, 11, and 16 in the Rx-Immediate and Rx-Deferred groups, 97% for HPV18 in the Rx-Immediate group, and 100% for HPV18 in the Rx-Deferred group. Titers are shown in Figure 2A–D. The cLIA titers in the Rx-Immediate group rapidly decreased over the first year after the third QHPV dose (from 2.2-fold to 6.3-fold for all genotypes). This was followed by a much slower 1.0–1.1-fold decrease in the subsequent 6 months. At 18 months after the third QHPV dose, HPV6, 11, 16, and 18 cLIA seropositivity in the Rx-Immediate group was 94%, 97%, 99%, and 76%, respectively.
A fourth dose of QHPV administered to Rx-Immediate participants increased cLIA titers against all vaccine-contained genotypes to 100% seropositivity for HPV6, 11, and 16 and to 96% for HPV18. cLIA titers at 4 weeks after the fourth QHPV dose were significantly higher than those at 4 weeks after the third QHPV dose for all genotypes (Figure 2A–D; P < .0001). Both the magnitude and the kinetics of the antibody response to the fourth QHPV dose indicated an anamnestic response. This was further demonstrated by the comparison of the antibody response in Rx-Immediate subjects (corresponding to 1 week after the fourth dose) and Rx-Deferred subjects (corresponding to 1 week after the first dose) at week 97. Using week 96 antibody concentrations as a reference, the Rx-Immediate group had geometric mean fold-rises (GMFRs) of 11, 8, 6, and 10, respectively for HPV6, 11, 16, and 18, whereas the Rx-Deferred group had GMFRs of 2, 1, 1, and 1, respectively. Furthermore, the 17 Rx-Immediate subjects who seroreverted for HPV18 between weeks 28 and 96 had an HPV18 GMFR of 10 (95% CI, 3–32), which was similar to that of the 79 Rx-Immediate subjects who maintained seropositivity between weeks 28 and 96 and was significantly higher (P = .003) than that of 24 Rx-Deferred subjects (P = .003).
Antibody responses after a single dose of QHPV were studied only in Rx-Deferred subjects (Figure 2A–D). Four weeks after the first QHPV dose, 22 of 24 subjects (92%) seroconverted to HPV6 and 11, 21 (86%) seroconverted to HPV16, and 8 (33%) seroconverted to HPV18.
Total serum IgG antibody responses to QHPV were measured by LIA at entry and week 28. LIA is less HPV-type specific than cLIA and can detect cross-reactive antibodies. The LIA and cLIA antibody results for HPV6, 11, 16, and 18, were highly correlated, with coefficients of correlation of 0.69–0.97 and P values of < .0001 for all genotypes. LIA detected antibodies against HPV31, which is not included in QHPV but is genetically related to HPV16. These significantly increased in the Rx-Immediate group, from a GMT of 1.4 mMU/mL (95% CI, 1.3–1.6) at baseline to a GMT of 29.3 mMU/mL (95% CI, 22.3–38.3) at week 28 (P < .0001), but not in the Rx-Deferred group. HPV16 and 31 LIA titers were highly correlated (P < .0001; Figure 3). Using 5 mMU/mL as a positive threshold, 86% of the Rx-Immediate subjects (79 of 92) seroconverted to HPV31 after the third QHPV dose.
Oral secretions collected at baseline and week 28 were tested for HPV16- and 18-specific IgG and IgA by ELISA. Sixty-one (69%) and 35 (39%) of 89 subjects with paired samples in the Rx-Immediate group developed HPV16 and 18 mucosal IgG antibodies, respectively, after vaccination; median antibody titers, corresponding to the highest positive serum dilution, were 23 for both genotypes. Compared with subjects who failed to develop HPV-specific mucosal IgG, those who developed mucosal antibodies had significantly higher serum antibody concentrations (GMT, 8354 mMU/mL [95% CI, 6248–11 170] vs 1687 mMU/mL [95% CI, 1107–2572] for HPV16 [P < .0001]; GMT, 3893 mMU/mL [95% CI, 2530–5989] vs 420 mMU/mL [95% CI, 263–671] for HPV28 [P < .0001]). There were no mucosal HPV-specific IgG increases in the Rx-Deferred subjects before vaccination. Mucosal HPV16- or 18-specific IgA antibodies were not detected in Rx-Immediate or Rx-Deferred subjects.
At baseline, there were no HPV16 IFN-γ ELISPOT responses in 60 Rx-Immediate or 21 Rx-Deferred subjects (Figure 4A). At week 28, ELISPOT responses were present in 60% of Rx-Immediate subjects (36 of 60) and in 5% of Rx-Deferred subjects (1 of 21) (P < .001). There were no significant ELISPOT changes between weeks 28 and 96 when the fourth QHPV dose was administered in the Rx-Immediate group and when the first QHPV dose was administered in the Rx-Deferred group. At week 100, Rx-Immediate and Rx-Deferred subjects showed increases in ELISPOT values, although they were not statistically significant (P = .09 and 0.26, respectively). At week 100, 72% of Rx-Immediate subjects (31 of 43) versus 37% of Rx-Deferred subjects (7 of 9) had HPV16 ELISPOT responses (P = .01), reflecting the higher number of QHPV doses.
We performed parallel ELISPOT assays using whole and CD8-depleted PBMCs. The difference between whole and CD8-depleted results was interpreted as a measure of cytotoxic T lymphocytes (CTLs). Among 30 subjects in the Rx-Immediate group who developed HPV16 ELISPOT responses after the third QHPV dose, CD8 depletion almost completely abrogated the response (Figure 4B), indicating that the ELISPOT assay primarily detected CTLs.
Correlation analyses of week 28 HPV16 ELISPOT results with nadir CD4 cell counts and percentages, entry CD4 and CD8 cell counts and percentages, and HIV load showed only a weak association with entry CD4 cell counts (ρ = 0.24; P = .06). There was a weak correlation at week 28 between HPV16 ELISPOT and cLIA results (ρ = 0.25; P = .06).
Cross-reactive CMI was measured using HPV31-specific IFN-γ ELISPOT (Figure 4C and 4D). Fifty-two percent of subjects in the Rx-Immediate group (31 of 60) and 5% in the Rx-Deferred group (1 of 21) developed HPV31 responses at week 28 (P < .0001). These responses were also completely abrogated by CD8 depletion (data not shown). Week 28 HPV31 and 16 ELISPOT values in the Rx-Immediate group were highly correlated (P < .0001).
To determine the factors that influenced the cLIA antibody persistence after QHPV vaccination in HIV-infected children, several independent variables, including age, sex, race, ethnicity, CD4 cell count, CD8 count, CD19 cell counts and/or percentages HIV viral load, IFN-γ ELISPOT results (where available), and HPV antibody concentrations at week 28 were used in a univariate analysis in which the outcome measure was the week 96 HPV antibody concentrations in Rx-Immediate subjects. Higher HPV antibody concentrations at week 28 were the strongest predictors of higher antibody concentrations at week 96 for all HPV genotypes (P < .0001). Other variables significantly associated with this outcome were CD4 cell counts and/or percentages for all genotypes and week 28 ELISPOT results for HPV16 (P ≤ .04). Entry CD8 cell counts and/or percentages and HIV load were negatively correlated with HPV antibody concentrations at week 96. In a multivariate analysis with week 96 HPV16 antibody concentration as the outcome measure and CD4 cell percentage, HIV load, ELISPOT, and week 28 HPV antibody concentrations as predictors, only the week 28 antibody concentrations remained significantly associated with persistence.
We showed that, at 72 weeks after the last vaccination, >90% of HIV-infected children remained cLIA seropositive for HPV6, 11, and 16 but that only 76% remained positive for HPV18. Studies of similar length in immunocompetent children showed >90% cLIA antibody persistence for all vaccine genotypes [30]. The antibodies produced by HIV-infected children in response to QHPV rapidly decayed within the first 48 weeks after the last vaccination and much slower thereafter, up to 72 weeks. Assuming that the antibody decay between 48 and 72 weeks after the last vaccination represents steady state, we estimated by linear regression that 50% of the HIV-infected children might become cLIA seronegative to the vaccine genotypes 4–5 years after the standard vaccination regimen. A follow-up study of this cohort is in progress to determine antibody persistence over 5 years.
HPV antibody persistence in this study was influenced by several factors, the most important of which was the antibody titer achieved at the completion of the vaccination regimen. In addition, traditional markers of HIV-associated loss of immune competence, including CD4 and CD8 absolute and relative cell numbers and HIV load, also correlated with persistence. It is interesting to note that we previously found in HIV-infected subjects that antibodies measured 4 weeks after the completion of the 3-dose standard HPV vaccination regimen were not affected by CD4 cell counts or percentages [24]. It is possible that significantly reduced CD4 cell percentage may impact the conversion of plasmablasts into memory B cells with a downstream effect of reduced measurable persistent antibodies.
A fourth dose of QHPV significantly increased the antibody concentrations through an anamnestic response against all HPV genotypes in the vaccine, including in participants who had lost antibodies at 72 weeks. Furthermore, unlike the 3-dose QHPV regimen [24], the fourth dose of vaccine brought the anti-HPV18 antibody concentrations of the HIV-infected children to levels comparable to those achieved after a 3-dose regimen in uninfected same-age historical controls [30, 31]. The antibody titer generated after primary vaccination determines the antibody persistence. However, the importance of persistent neutralizing antibodies against HPV with respect to protection against HPV-associated neoplasias has been disputed. Immunocompetent women vaccinated with QHPV maintained protection against HPV-associated cervical neoplasias even after their cLIA antibody titers fell below the assay-defined positive threshold [22]. This disconnect has been ascribed to a lack of sensitivity of the cLIA test [27] and/or to the ability of the vaccine to generate anamnestic responses in seroreverters. However, more studies are needed to clarify the latter, because if protection exclusively resulted from neutralizing antibodies generated by the vaccine, these antibodies might have to be present at the time of exposure. Typically, neutralizing antibodies do not block cell-to-cell transmission. Hence, if the virus established infection because of a lack of neutralizing antibodies at the time of exposure, antibodies raised by an anamnestic response might not be able to clear the infection.
In HIV-infected children, the HPV16 antibody and CTL responses to QHPV were positively correlated. Hence, in this population, antibody responses to QHPV may reflect not only B-cell immunity but the overall immunogenicity of the vaccine. Our data suggest that HIV-infected children may require additional doses of QHPV to achieve the same level of immune protection as same-age uninfected historical controls do for HPV18. Since HPV18 is the second most common cause of genital cancers overall and, in some areas, may even cause more cancers than HPV16 [32–34], it is very important to further investigate the short- and long-term consequences of a weaker antibody response to HPV18 in HIV-infected children and adolescents.
HPV-specific immune responses at the portal of entry of HPV, mucosa and skin, probably play a pivotal role in the fate of infection. On the basis of recent evidence that a common mucosal immune system ensures a level of uniformity in responses at mucosal surfaces of different systems after systemic administration of vaccines [35–37], we used oral secretions to evaluate mucosal responses to QHPV. The presence of the HPV16- and 18-specific antibodies in the oral secretions most likely resulted from transudation of serum antibodies, since HPV-specific IgG antibodies, but not IgA antibodies, were detected in the oral secretions, and the mucosal and serum IgG antibody concentrations were highly correlated. This was also in agreement with earlier studies involving immunocompetent vaccinees [38]. Mucosal antibodies against HPV16 and 18 were detected only in 69% and 35%, respectively, of the 89 subjects tested in our study. This is in contrast to studies involving immunocompetent vaccinees, where 100% of participants had HPV16 antibodies in the oral fluid (HPV18 was not examined) [38]. There are differences between the assays used to measure HPV antibodies in our study and the previous study that may partially account for the disparity between these studies. Furthermore, innate and/or adaptive local CMI, which were not examined in this study, may also play a role in mucosal protection against HPV. More studies are needed to completely characterize mucosal responses to QHPV in HIV-infected and -uninfected individuals.
QHPV generated HPV16 CTLs in a majority of our vaccinees. HPV-specific CTLs are thought to play a critical role in the natural history of HPV, being responsible for the clearance of established HPV genital infection [39]. QHPV was previously shown to induce CMI in immunocompetent individuals [21, 40, 41], but the participation of CMI in vaccine-induced protection is less well understood. Animal studies that showed that passively transferred antibodies resulted in complete protection against HPV infection [42] did not investigate innate or adaptive CMI. In contrast, de novo infection with HPV genotypes contained in the vaccines has been demonstrated in vaccinated women [43, 44]. These infections are typically transient, suggesting the participation of innate or adaptive CMI in the clearance of the infections incompletely controlled by neutralizing antibodies, and underscore the important role that vaccine-generated CTL may play in the overall protection conferred by QHPV.
There are clinical data to suggest that HPV vaccines generate limited cross-protection against HPV genotypes not included in vaccines. This cross-protection was observed between genotypes that belong to the same family [45]. Cross-reactive antibody responses were demonstrated in healthy recipients of HPV vaccines [46, 47]. This is the first published study to demonstrate that QHPV also generates cross-reactive antibodies in HIV-infected individuals. We also show cross-reactive CTL responses to QHPV. The correlation between HPV cross-reactive immune responses against nonvaccine genotypes and cross-protection has not been studied. Hence, the importance of the cross-reactive immune responses for protection against infection with vaccine-related HPV genotypes remains to be established.
The information generated in this report was limited by the relatively small study population, by its relatively homogeneous HIV disease characteristics, and by the limited follow-up after the fourth QHPV dose. Our main vaccine immunogenicity outcome measures were HPV neutralizing antibodies, which may underrepresent the overall humoral protection conferred by QHPV, either because neutralizing antibodies represent one of several antibody-mediated protective mechanisms generated by the vaccine or because the assay used to measure neutralizing antibodies has limited sensitivity [27]. We did not assess HPV18 CTLs, which, retrospectively, would have been an important measure of immunogenicity of the vaccine in our study population, considering the lower levels of HPV18 neutralizing and mucosal antibodies.
In conclusion, the standard 3-dose QHPV vaccination regimen generated robust antibody responses against HPV6, 11, and 16 that lasted for at least 72 weeks in HIV-infected children with good control of viral replication and high CD4 cell counts. Antibody responses to HPV18 were lower both in serum and oral secretions, and almost a quarter of the study participants lost HPV18 serum antibodies 72 weeks after completion of the 3-dose standard vaccination regimen. In the absence of certainty regarding the mechanism of protection of the HPV vaccines and of an immune correlate of protection, the clinical implications of the lower HPV18 antibody response in the HIV-infected population are unclear. Efficacy trials of QHPV are needed to determine whether additional doses of vaccine are needed for full protection of HIV-infected individuals against the oncogenic genotypes in QHPV.
Supplementary materials are available at The Journal of Infectious Diseases online (http://jid.oxfordjournals.org/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.
Acknowledgments.We thank the IMPAACT/PACTG P1047 participants, clinical site personnel and teams, Dr Terry Fenton for statistical advice and critical review of the manuscript, Dr Ed Handelsman for critical review of the manuscript and support in developing the study, and Ms Julie Patterson for technical support.
The following clinical sites and personnel are acknowledged for their contribution to IMPAACT trial P1047: Children's National Medical Center, Washington, DC (Deidre Thompson, Jennifer Sween, and Steven Zeichner); Children's Hospital of Michigan (Ellen C. Moore, MD; Chokechai Rongkavilit, MD; Elizabeth Secord, MD; and Ulyssa Hancock RN, BSN); SUNY Stony Brook, NY (Denise Ferraro, RN; Erin Infanzon; and Michele Kelly, PNP); St. Jude/UTHSC (Jill Utech, MSN; Sandra Jones, PNP; Nehali Patel, MD; and Lennie Lott, RN); Tulane/LSU Maternal/Child (Russell B. Van Dyke, MD; Margarita Silio, MD; Cheryl Borne, RN; and Sheila Bradford, RN); NYU NY NICHD (Sandra Deygoo, MS; William Borkowsky, MD; Siham Akleh, RN; and Sulachni Chandwani, MD); Duke University MC Ped (Margaret Donnelly, PA; Mary Jo Hasseett, RN; Joan Wilson, RN; and Kareema Whitfield, BS); Rush University/Cook County Hospital, Chicago (James B. McAuley, MD, MPH; Nike Mourikes, MD; Maureen Haak, RN, MSN; and Kenneth Boyer, MD); USC LA (LaShonda Spencer, MD; James Homans, MD; Michael Neely, MD; and Andrea Kovacs, MD); Miller Children's Hospital, Long Beach, CA (Audra Deveikis, MD; Jagmohan Batra, MD; Susan Marks, RN; and Janielle Jackson-Alvarez, RN); Chicago Children's (Jennifer Armstrong, Ruth Williams, and Eric Cagwin); Children's Hospital Orange County (Stephanie Osborne, BS, RN, CCRC; and Antonio Arrieta, MD); Bronx-Lebanon Hospital (Mavis Dummit, RN; Caroline Nubel, RN; Stefan Hagmann, MD; and Murli Purswani, MD); Texas Children's Hosptial (Faith Minglana, RN, BSN; Chivon McMullen-Jackson, RN, BSN; Mary E. Paul, MD; and William T. Shearer, MD, PhD); San Juan City Hospital, PR (Midnela Acevedo-Flores, MT, MD; Milagros Gonzáles-Diaz, MD; Lizbeth Fabrega, BS, MS; and Wanda Marrero, RN); University of Florida, Jacksonville (Mobeen Rathore, MD; Ayesha Mirza, MD; Kathy Thoma, MA; and Chas Griggs, Med); University of Colorado–Denver (Mark Abzug, Emily Barr, Megan Canon, and Carol Salbenblatt); Seattle Children's Hospital (Lisa Frenkel, MD; Ann Melvin, MD, MPH; and Joycelyn Thomas, BS, RN); 5057–Strong Memorial Hospital, Rochester, NY (Geoffrey A. Weinberg, MD; Barbra Murante, RN, MS, PNP; Susan Laverty, RN; and Francis Gigliotti, MD); Howard University, Washington, DC (Helga Finke-Castro, MD; Sohail Rana, MD; Connie Nguyen, RPh; and Patricia Houston, MS); UCSD Maternal, Child, and Adolescent (Stephen A. Spector, MD; Rolando Viani, MD, MTP; Kimberly Norris, RN; and Jeanne Manning, RN); Boston Medical Center Ped. HIV (Ellen R. Cooper, MD; Diana Clarke, PharmD; and Laureen Kay, RN); SUNY Downstate Medical Center, Children's Hospital (H. J. Moallem, J. M. Kaye, and D. Swindel); South Florida CDC, Ft. Lauderdale (Ana Puga, MD; Kathleen Graham, PharmD; Lisa Bridges, RN; and Richard Sellars, RN); NJ Medical School; UCLA–Los Angeles/Brazil AIDS Consortium; Mt. Sinai Hosp Med Center; Chicago, Women's and Children's HIV; Univ. of Miami Ped. Perinatal HIV/AIDS; Jacobi Medical Center Bronx; University of California–San Francisco; University of Puerto Rico Ped. HIV/AIDS Research Program; WNE Maternal Pediatric Adolescent AIDS; Connecticut Children's Medical Center; and Jacobi Medical Center, Bronx, NY (Marlene Burey, RN, MSHS; Raphaelle Auguste, RN, BSN; Elaine Perez, RN, MS; and Francisco Reinoso, RN, BSN).
Disclaimer.The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases (NIAID), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), or the National Institutes of Health (NIH).
Financial support.This work was supported by General Clinical Research Centers Program, National Center for Research Resources, NIH (grant number 5 MO1-RR00069); National Institute of Allergy and Infectious Diseases, NIH (grants number U01AI068632 and 1 U01 AI068616) and by Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH (grants number N01-HD-3-3345 and N01-HD-33162).
Potential conflicts of interest.Dr Saah and Ms Brown are employees of Merck Research Laboratories; Dr Bryan was an employee of Merck Research Laboratories when this study was conducted; Dr Weinberg receives research grants from Merck; Dr Moscicki is a consultant for Merck and receives travel and meeting support form GlaxoSmithKline; Dr Levin is a consultant for Merck and for GlaxoSmithKline, receives research grants from GlaxoSmithKline and Merck, and receives intellectual property royalties for Zostavax, which is manufactured by Merck. All other authors report no potential conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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Robson: Why I turned down England
Things could have turned out so differently for Bradford Citys manager if only hed seized his chance back in 1996, writes Joe Lovejoy
Robson, looking to burnish his managerial reputation with Bradford City in the basement of the First Division, revealed last week that he turned down the England job before it was given to Glenn Hoddle.
The erstwhile "Captain Marvel" had worked under Terry Venables at Euro 96 and was being groomed by the Football Association to succeed him, but Venables's abrupt departure after the tournament took Robson by surprise and he declined the invitation to take over then because of his inexperience.
"I thought Terry would go on longer, which would have suited me," he said. "If he'd taken England to the 1998 World Cup and I could have worked with him there, that would have done me nicely.
"But when Terry quit and the FA…


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I talked with last_highlander about this around the same time you [Christen] and he were talking about it. Sorry I didn't respond until now. I wanted time to really think about it. When he and I talked about it, I asked him, "Assuming it's possible to be 'in love' with someone, is it possible to be 'in hate'?" We got into defining the different kinds of love, and I don't really remember why I was even asking, but I want to think about your question now.
I believe two things about love, and neither cast it in a very good light. (I've discovered I have interesting beliefs about other ideas like Hope and Friendship, so you can ask me about them, too, if you want.) The first is that love is a contract with grief. The second is that it's a form of temporary insanity that sometimes isn't so temporary.
Love to me is heartache. It's getting a puppy from the pound and knowing that, no matter how old that dog lives to be, it will still die before you do. True love is a contract with grief. It's saying, "Okay, I'm allowing myself to be hurt. Maybe not today, maybe not even ten years from today. But someday, yes, I'm going to be hurt." Sometimes you're not hurt, and that's when you get a happy ending, but most times, you are hurt, and that's just life.
When I've fallen in love, I've always fallen fast and without reservation, and for a while, it's amazing. But the higher you fly, the harder you fall. And I fall hard. When the love is over, I can't just let it go. My last serious relationship ended in July 2007 and it took me almost a year—to the day—to get over it. I wasn't better in a week, or a month, or even in six months time. I still think about it.
I believe that when you love someone—truly love them, I mean—they get inside you and even after it ends, a little piece of them is still there, like a splinter you can't get rid of. And maybe you don't want to get rid of them; I don't know. But they're there, whether you want them or not, and they'll shape who you are from that point forward, whether or not they're actually in your life anymore.
People use the word love to define a plethora of feelings: "I love that coat" or "I just loved your chocolate cake" or the ever-dangerous "I love you"… It's completely clichéd to say, "I love you, but I'm not in love with you" but there is some truth to it, heart-wrenching as it is to hear. We love our pets, but generally speaking, we're not in love with them. Same goes for our parents, our siblings, and our children. (There are exceptions to this rule, of course, but that could be an entirely different discussion.) It's a different kind of love—just as strong, surely, or maybe even stronger, sometimes—but still not in love. To be in love with someone basically means that you love them the same way you love your brother or sister or dog—that is, you want to cherish and care for them—but you also want to sleep with them. That is, know them… biblically. "In love" means romantic, intimate, sexual love.
Still, in love is also a contract with grief. Romantic love is usually more fleeting than any other kind and after it's over, we question whether we really felt it at all. It's difficult to qualify, impossible to study objectively, and often mistaken for obsession (and visa versa). People in love look at the world and say, "What? Are you all crazy? Can't you see we're in love?" The world looks at people in love and says, "Are you guys insane? You're sure as hell acting insane." That is, it's insanity to be in love; it goes against all our biological imperatives and social mores and forces us to take less-than-sane actions, sometimes for the good… sometimes not. And then, after it's ended, we look back and say, "Yeah, that was pretty idiotic for me/her/us to have done."
All that said—grief and craziness aside—I also believe it's necessary to love another being for a human to be whole. "To have loved and lost," as Shakespeare said, "is better than to have never loved at all." I know that's also a cliché, but clichés are such because they're generally true. Loving oneself is difficult, but that—in our world today, at least—is the ultimate goal, so loving someone else can help us learn to love ourselves. And having someone return your love is an act o faith in itself—you have to believe that person when they tell you they love you; if you don't believe it, they might as well not even say it. And they might not ever say it, but if you believe it, it's as good as if they tell you every day.
I guess I don't have a very romantic or idealistic idea about Love itself, but I do think it's a practically necessary emotion for us to employ to grow as humans. When I reread some other responses, I'll admit it sounds mercenary the way I think about it, but either way, love is in our lives. I'm glad that the love in your life doesn't seem to be comprised of heartache or insanity, the way mine has been.


text: "Chicken & Vagina in the Morning" rough sketchpad featuring Tom Litrenta by BBQWhore published on 2011-08-31T16:12:02Z Nutritional!!! Genre Acoustic heartfelt honey track Comment by BBQWhore @jtskyy: Thank you! Really Enjoying the newest remixes on your page! 2013/03/24 18:06:59 +0000 Comment by AaronFrye beep 2011/09/01 01:53:26 +0000 Comment by AaronFrye shit's funny as hell, but you should change the battery in your smoke detector if you're gonna be smokin that much crack! keep rockin that craziness! 2011/09/01 01:52:30 +0000


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Kukla's Korner Hockey
Report- Draft Headed To Pittsburgh
by Paul on 10/25/11 at 02:10 PM ET
Comments (14)
via Pierre LeBrun of ESPN,
The NHL will announce later this week that the June 2012 NHL draft will be held in Pittsburgh, two sources confirmed to ESPN.com Tuesday.
It has been rumored for months that the annual draft would be held at the new CONSOL Energy Center, but now the league will finally make it official.
The Pittsburgh Post-Gazette reported as much in Sunday's edition, while the Pittsburgh Tribune-Review also reported it Tuesday morning.
This past year's draft was held in Minnesota. The event last visited Pittsburgh in 1997, when Joe Thornton was selected with the first overall pick by the Boston Bruins.
Filed in: NHL Teams, Pittsburgh Penguins, NHL Talk, | KK Hockey | Permalink
I think it's long past time for the NHL to shine a spotlight on Pittsburgh. Most casual hockey fans probably don't even know they have a team. The 2012 Who's-The-Next-Crosby Annual NHL Lottery sponsored by the Commissioner's Crosby Fan Club and hosted by Sidney Crosby should be a big hit and give the NHL an opportunity to finally showcase the one true talent in the NHL. I hear Sidney Crosby might be there.
Posted by awould on 10/25/11 at 03:43 PM ET
The hell? They hosted in 1997, and they get it again already?
Wouldn't Winnipeg make more sense if the league really wants to make a splash there?
At this rate, I'm really starting to hope Crosby never comes back because this has gotten beyond asinine.
Posted by Primis on 10/25/11 at 04:09 PM ET
You guys think this is bad. Wait until they announce that Pittsburgh will be hosting the 2013 Winter Classic.
Would anyone be surprised?
Posted by WingsFanInBeanLand from where free agents no longer dare. on 10/25/11 at 04:51 PM ET
You poor little Wings, why are you guys so upset everytime you read Pens. The world is against us, the world loves Pitts, boo hoo, you guys are the biggest babies in sports. Don't care for Pitts, not my team, don't have a team, have to say though, can't stand the Wings, because the fans and this attitute that the NHL hates us.
Shut up already, we get it, you hate Crosby and Pitts, yada yada yada, cry a river.
Oh, my word to type at the bottom starts with 87, kuklas loves Sidney, what the hell, so sick of this, next time it will be 71,
Posted by Roboshow on 10/25/11 at 05:06 PM ET
I guess the formula for getting the draft/winter classic/all star game, and a winning team is to file for bankruptcy twice almost lose the team twice and then arrange to get the #1 and #2 overall draft picks three or four times. How is this league surviving without #87 ??????
Posted by Down River Dan on 10/25/11 at 05:43 PM ET
Oh, my word to type at the bottom starts with 87, kuklas loves Sidney, what the hell, so sick of this, next time it will be 71,
good one! i'm sure if that made sense it would be hilarious.
Posted by awould on 10/25/11 at 05:48 PM ET
Don't care for Pitts, not my team, don't have a team, have to say though, can't stand the Wings, because the fans and this attitute that the NHL hates us.
Well, if some guy who can't even take a stand and pick a team doesn't like Detroit fans then we'd all better change our ways.
Posted by awould on 10/25/11 at 03:48 PM ET
Posted by Garth on 10/25/11 at 06:46 PM ET
awould- for those not logged in, you have to write in the scramble word to post, my word happened to start with your favorite # 87.
Garth- your right, I can't stand up and pick a team, such a loser, I wish I could wear a jersey with some guys name on it and when I talk about the team, include myself as part of the team, the "we" complex. http://www.grantland.com/story/_/id/7116518/what-do-mean-we
Posted by Roboshow on 10/25/11 at 07:21 PM ET
Posted by Roboshow on 10/25/11 at 05:21 PM ET
Thanks for clarifying. If you have to explain a joke, it isn't funny. Which was sort of my point.
I can't stand up and pick a team, such a loser,
I agree, you probably are. You can't find a team to cheer for yet you can find a team to hate on. That says a lot. And hating on the Red Wings puts you on a pretty large bandwagon, so at least you won't get lonely.
I wonder what it feels like to watch a game and not care who wins?
I wish I could wear a jersey with some guys name on it and when I talk about the team, include myself as part of the team, the "we" complex.
This is like a grab-bag of generic anti-sports themes. You clearly have nothing useful to offer.
Posted by awould on 10/25/11 at 07:32 PM ET
The NHL's continuing fellatio to a city that almost lost its franchise, twice, continues unabated.
Posted by Red Winger from Sault Ste Marie, MI on 10/25/11 at 07:43 PM ET
Posted by JBM on 10/26/11 at 05:24 AM ET
Whoa…..WIngs fans have their bitterness on today! I guess 2 ugly losses in a row will do that to you.
I am always amused by the bipolar-ness (if that's a word) of the Wings fans, alternatively martyrs because the NHL done did them wrong and yet smug and selfrighteous about their team. You all really need to get over yourselves. When you complain this much about every little percieved slight, you make yourselves look really bad and undermine the great tradition that the Wings have.
Posted by VAHockeyFan on 10/26/11 at 12:23 PM ET
People are actually upset over this? Get over it. It's the draft! When Detroit gets a new building you can bet they'll be hosting a draft and an All Star game.
PS don't be surprised to see Pittsburgh get an ASG game in the next handful of years. It's common sense, not favoritism.
Posted by Russian Rocket on 10/26/11 at 01:39 PM ET
People are actually upset over this?
I'm not upset about it at all. I don't care where they have the draft. I just think it's become a parody of itself how much the NHL shoves Pittsburgh down our throats.
a new building you can bet they'll be hosting a draft and an All Star game
Obviously a new arena deserves attention, it's good to show off a new arena wherever it is. Unless, apparently, it's a new arena in Phoenix, where they've never held an All-Star game or a draft. You'd think a new arena in Phoenix, where Bettman has gone out of his way to get a foothold, would've been given the opportunity at least once.
Posted by awould on 10/26/11 at 02:05 PM ET
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Celeb spotting: Aamir, Karisma, Akshay & Twinkle Khanna
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Our shutterbugs spotted Twinkle Khanna with her hubby Akshay Kumar in Bandra. The actor came to dine at the Nido restaurant with his family and close friends.
Like a caring husband, Akshay Kumar helped Twinkle Khanna to come down from stairs and walk towards their car.
While Akshay was dressed casually in a black T-shirt and pants, his wife Twinkle looked lovely in a black jumpsuit.
Actor Dhanush who was last seen in Raanjhanaa was spotted wearing casuals at the Mumbai airport.
Bollywood star Aamir Khan was seen sporting a new look, when he visited Vidhu Vinod Chopra studios in Mumbai last night.
Vidhu Vinod Chopra is producing Aamir Khan's upcoming film 'PK'.
Along with Aamir Khan, the film also stars Anushka Sharma and Sushant Singh Rajput. The film is all set to release on 18th of December.
Bollywood actress Karisma Kapoor attended the launch of a jewellery store 'Rare Heritage' in Mumbai.
The actress looked pretty in a white and gold anarkali dress teaming it with gold coloured jhumkas.
She was recently seen in Dubai celebrating her sister Bebo's birthday along with Saif Ali Khan.
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Our shutterbugs spotted Twinkle Khanna with her hubby Akshay Kumar in Bandra. The actor came to dine at the Nido restaurant with his family and close friends.
Akshay shows his dare-devil side once again at Revfest The actor launched a new bike for a leading brand
Aamir, Akshay & Karan made Twinkle's book launch a fun event! Also seen here was Dimple Kapadia
Kareena, Sonam & Karisma's perfect travel outfit! Also spotted at the airport were Sushant Singh Rajput & Amitabh Bachchan
Amitabh Bachchan and Rajesh Khanna were rivals. Really? Here's a look at our veteran actors!
Shocking photoshoot of Akshay Khanna and Karisma! When Karisma Kapoor got grabbed in the crotch by Akshay Khanna!
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Celeb spotting: B-town stars at PVR Spotted: Akshay Kumar with family and Shilpa Shetty with husband
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Newtown gunman used earplugs during massacre
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Asian Cup finals in favour of an acclimatisation training camp in Singapore.
"The camp in Singapore will give us a good indication of what to expect at the Asian Cup," declared Socceroos coach Graham Arnold last week. "Acclimatisation will be a key to success at the tournament so training and playing in Singapore will get us in good shape for the conditions that we will face for the tournament."
Welcome news indeed, and proof of the gravity with which Football Federation Australia is holding the Socceroos' maiden venture into Asian competition.
Over the past couple of months we've seen how the Australian clubs in the ACL have been caught with their trousers around their ankles by supposedly inferior opponents, particularly in tired-looking second-half displays by Adelaide in Vietnam and Sydney in Indonesia.
Sure, a lack of regular match action has some claims, but the A-League sides have comfortably proven that simply turning up a few days beforehand and expecting to roll over the opposition is a theory fast losing credibility down under.
As Arnold added in a far-ranging interview with the Sydney Morning Herald over the weekend, "They're 50 per cent better at home, so when we go to these types of nations we have to make sure we have a minimum of a week to prepare properly, otherwise we'll get ourselves into trouble." A little tactless perhaps, but spot on.
Of course, the climatic conundrum is effectively multiplied for Arnold. Not only is Australia, geographically, not even in Asia, the basis of his Asian Cup squad will come from the English Premiership, a league played across the northern winter save for a few months of relative sunshine at its beginning and end. Derby days in Liverpool and London aren't exactly the ideal preparation for an Asian Cup opener against Oman in Bangkok.
Then there's Australia's glaring lack of experience playing in the types of conditions you can expect in Thailand in July. The Socceroos have played just three matches on Asian soil since joining the AFC 16 months ago with only four players - Scott McDonald, Michael Beauchamp, Luke Wilkshire and Brett Holman, not exactly what you'd call the big guns - involved in all three of the away trips to Kuwait City, Manama and Guangzhou.
Worryingly for Arnold, the list of those who haven't been involved in any of the three trips, for a variety of reasons, includes World Cup stars Tim Cahill, Brett Emerton, Josh Kennedy, Harry Kewell and Craig Moore.
Cahill, Kennedy, Kewell and Moore are the quartet giving Arnold most headaches with just 10 weeks until Australia's cup opener. All four are rated by Arnold as a major concern with the coach now openly saying that if any of them make it, it will be a fantastic luxury for the side.
Arnold and team manager Gary Moretti jetted over to Europe a week ago to assess the players' progress and build some bridges with a handful of (particularly English) club managers. Once again the cause of the Australian national team doesn't exactly seem in the best interests of the clubs with a healthy chunk of pre-season set to be missed if the Socceroos make it all the way to the final. Cahill, for instance, hasn't had a proper break for four years after playing in the 2004 Olympics, 2005 Confederations Cup and last year's World Cup.
Any absences from those four might open the door for one of Rob Baan's up-and-coming under-23s who have been pitting their wits against Asia's best sides leading into next year's Olympics in Beijing. "I'm definitely taking some young players to the Asian Cup - some will be train-on players and some will be in the actual squad," Arnold has said.
Baan's Olyroos captain is Mark Milligan, a player who was a surprising choice by Guus Hiddink 12 months ago for Germany and one who adds crucial versatility across the defence and midfield. Milligan has also been in action for Sydney FC in the ACL.
The other player making a dramatic statement of intent is Bruce Djite. The powerful US-born forward has been knocking down the door after becoming an ever-present for the under-23s under Baan and has also been elevated to the post of No.1 striker at Adelaide United after Shengqing Qu's release.
Copyright © Marc Fox and Soccerphile.com
World Soccer News


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Official Figs For Italo Trailer Here
Figs For Italo Production Stills
DelanoCelli productions copyright 2015
18:48 minutes, USA, 2015
Camera: Shot on the Cannon 7D and C100
Shooting Format: 1920 x 1080p - 23.98fps - AVCHD 35mbs
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Blog: Mud-slinging at Matalan
Leonie Barrie | 5 July 2006
There's been a lot of talk in recent years of mid-market retailers being squeezed by discounters at one end and upmarket brands at the other, but as those in the middle – like M&S – have got their acts together, so the competition at the bottom of the market has become considerably tougher. Just look at the saga of Matalan, which was once worth more than GBP3bn but is now struggling to keep up with the likes of Tesco and Primark and is currently embroiled in a boardroom battle with its founder. There's not much to report yet from today's annual meeting, but as long as John Hargreaves continues to dominate the headlines by either trying to sell his remaining stake in the company – or buy it back – then it looks like there are plenty more twists to come in this particular saga.
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Surviving in a declining market is the biggest challenge for discount/mass-market retailers and suppliers of commodity products such as basic T-shirts, hoodies or cotton men's shirts – which is why it...
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Using your fabric scraps this banner is a very sweet way to add color to your holidays!
This is a fun two-sided banner all done in the hoop with easy to follow step-by-step instructions to guide you. You are hooping stabilizer only, appliqueing your fabric over the top, applying backing fabric behind your hoop, finishing the edges and eyelets and cutting away the stabilizer.
There are 3 variations: Tentflaps with the doorway cutout, tentflaps with a doorway and a matching blank for you to personalize. Mix them up or repeat your favorite tent in different fabrics and thread colors. The hardest part is deciding which colors to use!
Yes, you can also personalize this banner... Simply add letters or designs from your embroidery machine or personal files to the banner blank included.
4 sizes - 4", 5", 6" and 7"PICTURED is the 4" size.
Exact sizes:4x4 hoop - 3.92" x 3.87"5x7 hoop - 5" x 4.95"6x10 hoop - 6" x 5.96"Megahoops - 7" x 6.96"
Availability: In stock
- TENT BANNER In The Hoop Project in the format of your choice.- Easy to follow Step-by-Step instructions – simply cut as you sew!- Easy to follow Assembly instructions!
Make A Banner ITH Project
Vintage Camper Banner ITH Project
Car Banner ITH Project
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Go back to » Food & Drink
Food & Drink
Liquid Indulgence
Members offer: 10% discount
Liquid Indulgence is a specialist wine and spirits company for those who want the best.
Fine Drinks Cooperative
Members offer: 20% discount on your first order then 10% discount thereafter
Fine Drinks Cooperative (FDC) prides itself on the exclusivity of the still and sparkling wines that it is able to offer to its customers.
Members offer: 10% discount
Inspired by continental cantinas and markets this liquid deli from Scotland sells liqueurs, spirits, whiskies, oils and vinegars, lovingly sourced from small producers, predominantly across the UK, who share Angus and Frances's passion for food and drink.


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Catalan Institution for Research and Advanced Studies
Catalan Institution for Research and Advanced Studies
ICREA, Catalan Institution for Research and Advanced Studies, is a foundation jointly promoted by the Catalan Government through its Ministry of Innovation, Universities and Enterprise, and the Catalan Foundation for Research and Innovation . ICREA was created in 2000 aiming to boost the research system of Catalonia via the recruitment of top scientists for the Catalan R&D system, scientists capable of leading new research groups, strengthening existing groups, and opening up novel forefront lines of research.To achieve its objectives ICREA works closely with Catalan universities and research centres based in Catalonia by means of long-term agreements that allow ICREA researchers to integrate in research groups within these universities and centres.Cooperation, international openness and excellence are ICREA's hallmarks.In the period 2000-2008, ICREA has hired a total of 222 tenured research professors in different areas of research: 32,5% in life and medical science, 27% in experimental science and mathematics, 10% in social science, 13,5% in different fields of humanities and 17% in technology. Wikipedia.
Laboratorios Del Dr Esteve S.A., Fundacio Privada Institute Of Recerca Of La Sida Ca, Catalan Institution for Research, Advanced Studies and University of Washington | Date: 2017-03-20
The invention relates to peptides comprising part or all of a conserved element within a Center-of-Tree (COT) sequence derived from a family of polypeptides encoded by naturally occurring variants of HIV. The invention also relates to immunogenic compositions and vaccines comprising said peptides. The invention also relates to methods for the identification of HIV controller patients based on the detection of the T cells of the patient to mount a cytotoxic T cell response against said peptides and to methods for the identification of immunogenic peptides within a family of variant polypeptides.
Fundacio Institute Of Ciencies Fotoniques Icfo, Catalan Institution for Research and Advanced Studies | Date: 2015-03-27
An optical parametric oscillator (3) is configured to provide first ultrashort output pulses comprising light of a first wavelength and second ultrashort output pulses comprising light of a second wavelength, wherein at least one of the first and second wavelengths is independently controllable. The optical parametric oscillator (3) comprises an optical resonator (10) containing first and second nonlinear optical elements (11, 12) and comprising an output coupler (13), an input system (14) configured to provide first pump pulses to the first nonlinear optical element (11) and second pump pulses to the second nonlinear optical element (12), and a control system (15).
Costa A.,University Pompeu Fabra |
Costa A.,Catalan Institution for Research and Advanced Studies |
Sebastian-Galles N.,University Pompeu Fabra
Nature Reviews Neuroscience | Year: 2014
The ability to speak two languages often marvels monolinguals, although bilinguals report no difficulties in achieving this feat. Here, we examine how learning and using two languages affect language acquisition and processing as well as various aspects of cognition. We do so by addressing three main questions. First, how do infants who are exposed to two languages acquire them without apparent difficulty? Second, how does language processing differ between monolingual and bilingual adults? Last, what are the collateral effects of bilingualism on the executive control system across the lifespan? Research in all three areas has not only provided some fascinating insights into bilingualism but also revealed new issues related to brain plasticity and language learning. © 2014 Macmillan Publishers Limited. All rights reserved.
Sanchez-Palencia L.,University Paris - Sud |
Lewenstein M.,Catalan Institution for Research and Advanced Studies
Nature Physics | Year: 2010
When attempting to understand the role of disorder in condensed-matter physics, we face considerable experimental and theoretical difficulties, and many questions are still open. Two of the most challenging onesdebated for decadesconcern the effect of disorder on superconductivity and quantum magnetism. We review recent progress in the field of ultracold atomic gases, which should pave the way towards the realization of versatile quantum simulators, which help solve these questions. In addition, ultracold gases offer original practical and conceptual approaches, which open new perspectives to the field of disordered systems. © 2010 Macmillan Publishers Limited. All rights reserved.
Corning Inc., ICFO - Institute of Photonic Sciences, Catalan Institution for Research and Advanced Studies | Date: 2016-02-16
Described herein are improved dewetting methods and improved patterned articles produced using such methods. The improved methods and articles generally implement continuous ultra-thin metal-containing films or film stacks as the materials to be dewetted. For example, a method can involve the steps of providing a substrate that has a continuous ultra-thin metal-containing film or film stack disposed on a surface thereof, and dewetting at least a portion of the continuous ultra-thin metal-containing film or film stack to produce a plurality of discrete metal-containing dewetted islands on the surface of the substrate.
Moyano A.,University of Barcelona |
Rios R.,Catalan Institution for Research and Advanced Studies
Chemical Reviews | Year: 2011
Asymmetric organocatalysis has been providing powerful and practical methods for the highly stereo-controlled construction of a huge variety of carbo- and heterocyclic compounds. In the case of polycyclic systems, either fused, bridged, or spiranic ring arrangements can be accessed. Around 150 different small chiral organic molecules have been proven to be useful catalysts in asymmetric cyclization, annulation, and cycloaddition processes. Some of these processes such as ntramolecular aldol reactions, intramolecular aza-Michael reactions, or Diels-Alder cycloadditions, have reached impressive levels of stereoselective control and are increasingly being used in enantioselective total syntheses. Polyene cyclizations, domino processes, combination of organocatalysis with transition metal-based catalysis and/or biocatalysis, polymer-supported and supramolecular-gel-supported catalysts, self-assembled organocatalysts, and multiphase homogeneous catalysis and flow chemistry are experiencing a fast growth.
Lehner B.,Center for Genomic Regulation CRG and UPF |
Lehner B.,Catalan Institution for Research and Advanced Studies
Nature Reviews Genetics | Year: 2013
To what extent can variation in phenotypic traits such as disease risk be accurately predicted in individuals? In this Review, I highlight recent studies in model organisms that are relevant both to the challenge of accurately predicting phenotypic variation from individual genome sequences ('whole-genome reverse genetics') and for understanding why, in many cases, this may be impossible. These studies argue that only by combining genetic knowledge with in vivo measurements of biological states will it be possible to make accurate genetic predictions for individual humans. © 2013 Macmillan Publishers Limited. All rights reserved.
Gonzalez C.,Barcelona Institute for Research in Biomedicine |
Gonzalez C.,Catalan Institution for Research and Advanced Studies
Nature Reviews Cancer | Year: 2013
For decades, lower-model organisms such as Drosophila melanogaster have often provided the first glimpse into the mechanism of action of human cancer-related proteins, thus making a substantial contribution to elucidating the molecular basis of the disease. More recently, D. melanogaster strains that are engineered to recapitulate key aspects of specific types of human cancer have been paving the way for the future role of this 'workhorse' of biomedical research, helping to further investigate the process of malignancy, and serving as platforms for therapeutic drug discovery.© 2013 Macmillan Publishers Limited. All rights reserved.
Ballester P.,Institute of Chemical Research of Catalonia |
Ballester P.,Catalan Institution for Research and Advanced Studies
Accounts of Chemical Research | Year: 2013
Chemical intuition suggests that anions and π-aromatic systems would repel each other. Typically, we think of cations as being attracted to electron-rich π-systems of aromatic rings, and the cation-π interaction, a well-established noncovalent interaction, plays an important role in nature. Therefore the anion-π interaction can be considered the opposite of the cation-π interaction. Computational studies of simple models of anion-π interactions have provided estimates of the factors that govern the binding geometry and the binding energy, leading to a general consensus about the nature of these interactions. In order to attract an anion, the charge distribution of the aromatic system has to be reversed, usually through the decoration of the aromatic systems with strongly electron-withdrawing groups. Researchers have little doubt about the existence of attractive anion-π interactions in the gas phase and in the solid state. The bonding energies assigned to anion-π interactions from quantum chemical calculations and gas phase experiments are significant and compare well with the values obtained for cation-π interactions. In solution, however, there are few examples of attractive anion-π interactions.In this Account, I describe several examples of neutral molecular receptors that bind anions in solution either solely through anion-π interactions or as a combination of anion-π interactions and hydrogen bonding. In the latter cases, the strength of the anion-π interaction is indirectly detected as a modulation of the stronger hydrogen bonding interaction (enforced proximity). The dissection of the energy contribution of the anion-π interaction to the overall binding is complex, which requires the use of appropriate reference systems.This Account gives an overview the experimental efforts to determine the binding energies that can be expected from anion-π interactions in solution with examples that center around the recognition of halides. The studies show that anion-π interactions also exist in solution, and the free energy of binding estimated for these attractive interactions is less than 1 kcal/mol for each substituted phenyl groups. The quantification of anion-π interactions in solution relies on the use of molecular recognition model systems; therefore researchers need to consider how the structure of the model system can alter the magnitude of the observed energy values. In addition, the recognition of anions in solution requires the use of salts (ion pairs) as precursors, which complicates the analysis of the titration data and the corresponding estimate of the binding strength. In solution, the weak binding energies suggest that anion-π interactions are not as significant for the selective or enhanced binding of anions but offer potential applications in catalysis and transport within functional synthetic and biological systems. © 2012 American Chemical Society.
Lehner B.,Catalan Institution for Research and Advanced Studies
PLoS Genetics | Year: 2010
Gene expression responds to changes in conditions but also stochastically among individuals. In budding yeast, both expression responsiveness across conditions ("plasticity") and cell-to-cell variation ("noise") have been quantified for thousands of genes and found to correlate across genes. It has been argued therefore that noise and plasticity may be strongly coupled and mechanistically linked. This is consistent with some theoretical ideas, but a strong coupling between noise and plasticity also has the potential to introduce cost-benefit conflicts during evolution. For example, if high plasticity is beneficial (genes need to respond to the environment), but noise is detrimental (fluctuations are harmful), then strong coupling should be disfavored. Here, evidence is presented that cost-benefit conflicts do occur and that they constrain the evolution of gene expression and promoter usage. In contrast to recent assertions, coupling between noise and plasticity is not a general property, but one associated with particular mechanisms of transcription initiation. Further, promoter architectures associated with coupling are avoided when noise is most likely to be detrimental, and noise and plasticity are largely independent traits for core cellular components. In contrast, when genes are duplicated noise-plasticity coupling increases, consistent with reduced detrimental affects of expression variation. Noise-plasticity coupling is, therefore, an evolvable trait that may constrain the emergence of highly responsive gene expression and be selected against during evolution. Further, the global quantitative data in yeast suggest that one mechanism that relieves the constraints imposed by noise-plasticity coupling is gene duplication, providing an example of how duplication can facilitate escape from adaptive conflicts. © 2010 Ben Lehner.


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April 25, 2012 Wednesday, we were exited to join technology Enthusiast in lalit Hotel, New Delhi.
The Group of Microsoft Professionals, Imagine Cup Winners, Students are waiting for Startup of IMAGINE CUP 2012 (India) Final Event. Finally ICIndia-2012 final started at 10:00 AM with tremendous Style. The auditorium of "The Lalit Hotel" was totally "HOUSEFULL" . Some question was really thoughtful till Starting of Event :
· Who's going to Sydney this year?
· Where is your imagination taking today?
The Session of Microsoft Professional "Lee Anne Caylor" was really awesome. Her view like "Majority of apps on the phone comes from Students. Because you guys think crazy" , "Future innovators start here… "Imagination can make the impossible possible", "Where is your imagination taking you?"… Etc was really important for a person who want to jump from general life to technical life and technical life to Entrepreneur life.After "Lee Anne Vaylor"'s Session the session of "Gari Arora" was with full of joy and knowledge.Her question "where is. Your imagination taking you?" and theory behind "corporate citizenship" leave a question for Us . With statement "Empower !! Imagine !! Realize !!" she edds her session. And after that Demo and presentation of Several projects come into Stage, Which was really awesome.
The main teams were Imaginary (Innovative Thinkers), Jeevan (KinectoTherapy), Poseidon (The D Labs) , which give tremendous ideas for Students as well as Microsoft. After this Demo Session the Prize distribution stated which was full of Glamour & Joy. For Prize distribution Chief gust was "Microsoft COO: B. Kevin Turner". He describes the whole history of Imagine cup and other Microsoft Students Events & programs. Beside him there was many India's & World wide Microsoft Professionals on the Stage for Describing TECHNOLOGY. Some Key Points of This Event was:
- Solution for Dylexia By D-Labs Team.
- Project JAL from team POSEIDON hes serious application in India.
- Where is your Imagination taking You?


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1.Loris Classic Cuts
7 Smylie Dr
12.17 mi
Beauty Salons
2.Classic Cuts Hairstyling
639 2nd Street Pike
13.42 mi
BarbersBeauty Salons
3.Claudio & Co Classic Cuts Beauty Shop
8011 Pine Rd
19.27 mi
BarbersBeauty Salons
4.Classic Cutting Inc
3245 Amber St Ste 17
23.63 mi
Sewing Contractors
5.Classic Cuts
2327 E Clearfield St
23.87 mi
Beauty Salons
6.Classic Cuts Barber Shop
625 Lincoln Blvd
27.35 mi
7.Charlie's Classic Cuts
184 State Route 35
29.59 mi
BarbersBeauty Salons
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I always have a great experience at Its All About Me Hair Salon. My stylist is all about my hair being healthy. She makes sure my hair is getting what it needs and she always gives sound advice about the best practices for my hair. I must say my hair has grown tremendously and continues to grow. I highly recommend anyone who wants their hair healthy to call and get a consultation. The owner of the salon is very professional and goes out of her way to make sure everyone has a great experience. She has been doing my hair for over 15 years and she will continue. She is my go to person on any advice I need about my hair, she has never been wrong. I always get compliments on my hair and I CONSTANTLY POINT THEM IN HER DIRECTION. I trust her with any and every fiber of my hair and for that reason I trust the hand picked staff that work in the salon to do my hair as well. Its All About Me is a fine shop with great people who are at the top of their game.
About 2 weeks ago I got a HORRIBLE haircut at a different salon... I went in yesterday to Essentials to have it fixed. Andrea did an excellent job fixing the horrible mess that was my hair! I've been struggling to find a good stylist and I think I may have just found one!
Robert James Salon & Spa has the most talented staff. I love my hair and spa treatments every time. I have been a loyal client for over 7 years. Highly recommend this place!
Great salon. Very nice inside. Have been going here for about seven years and will never leave. I was referred to them seven years ago and refer people all the time.
I have been going there about 6 years or more. All the ladies are the best. Friendly and the very best service.Love everything about the place.
I have found a place my kids and I both love. The girls are great with kids and I love the way my color looks every time I leave.
Went there once. Elisha did an amazing job. So fantastic. I would recommend anyone to her. I'm definitely going back.
Been all around Trenton and my two boys seem to get the freshest cuts here. Spacious waiting area and good music.
wonderful black owned beauty supply store right in the heart of Trenton, New Jersey.
love my hair! love the place. awesome


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Megan Glenn is the founder of her own environmentally sustainable business and has volunteered almost 700 hours in her lifetime. She is participating in the Duke of Edinburgh Award which recognizes youth self-development and leadership. It appears, Glenn is just getting started.
She was invited as a guest speaker for this year's Carleton Serves event on September 24th, in which she spoke about her experiences in and out of school, working with her business, Good Vibes, and her various volunteer adventures. Her stories emphasized a positive and motivating message about the importance of student engagement which she sees as the practice of learning outside the classroom
Background, Good Vibes and Volunteering
Glenn grew up out in the countryside of Kemptiville and Merrickville, Ontario. In high school, she was awarded the Governor Generals Award for Volunteerism for contributing over 600 hours of community service. She attended Dalhousie University in Halifax for three years, and then moved to Ottawa for a semester at Carleton University.
After taking time off school, Megan decided to focus on her passion for volunteer work. During that time, she had been participating in the Duke of Edinburgh Award which recognizes young people who are learning outside a 'formal' education, through a chosen skill. Glenn picked sewing.
"I absolutely love volunteering! It makes me feel connected to the local community." – Glenn
She decided to sell some of the pieces she made, kick-starting the idea for her business, Good Vibes. The project combines her love for environmental sustainability, sewing, and community service. Her goal was to support her local community and make a positive impact by selling handmade items from recycled materials. In turn for every item sold, Glenn would volunteer for an organization in the community for a certain number of hours.
"I know that I am very fortunate to have my family, my home, and my community. I want to share the experiences I have been fortunate enough to have, with other people, in any way that I can." – Glenn
"Nowadays, no one has time to put that much work into something that they could buy for super cheap." – Glenn
Through Good Vibes, Glenn has been given many different opportunities to share her experiences doing volunteer work. She sees events like Carleton Serves as a great platform to keep people informed about local initiatives and get people thinking about the benefit of participation, as well as connect with other like-minded individuals. She also thinks that it's important for students to know about initiatives similar to her project because she believes that thinking creatively can lead to discovering a completely new and unique way of helping the world.
"At any activity like Carleton Serves, I always hope to learn from people. Every single person has something that they can teach you, whether they're young or old." – Glenn
Glenn hopes to continue Good Vibes in order to keep sharing her story and promote the benefits of a sustainable lifestyle, as she believes that by sharing her stories, she can create an inspiring and positive impact. As for other future goals, she aims to complete her gold level of the Duke of Edinburgh Award in April and become an award leader in her community. She also plans to open up an Etsy shop in October for Good Vibes.
Learn more about Glenn and Good Vibes on her website: http://www.goodvibescrafts.ca
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LEE CATTERMOLE returns to Sunderland's starting line-up as the already-relegated Black Cats look to spring a surprise at Arsenal tonight.
Cattermole and Bryan Oviedo return to the side as David Moyes makes two changes to the team that started Saturday's 2-0 defeat to Swansea.
The pair replace injured duo Jason Denayer and Victor Anichebe, who drop out of the side that kicked off against the Swans.
The switches will almost certainly necessitate a change of formation, with Sunderland set to start in a 5-4-1 formation.
Oviedo and Javier Manquillo are expected to start as wing-backs, with Billy Jones playing at centre-half along with John O'Shea and Lamine Kone.
Alexis Sanchez has been passed fit to start for Arsenal, who need to win to keep their hopes of a place in next season's Champions League alive.
ARSENAL (3-4-2-1): Cech; Holding, Mustafi, Monreal; Bellerin, Ramsey, Xhaka, Gibbs; Ozil, Sanchez; Giroud.
Subs: Ospina (gk), Gabriel, Elneny, Coquelin, Iwobi, Walcott, Welbeck.
SUNDERLAND (5-4-1): Pickford; Manquillo, Jones, O'Shea, Kone, Oviedo; Larsson, Cattermole, Ndong, Borini; Defoe.
Subs: Mannone (gk), Love, Lescott, Rodwell, Gooch, Gibson, Januzaj.


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SOUTHWATER racing driver Jolyon Palmer wants points finishes from this weekend's GP2 races in Barcelona.
It will be Jolyon's second race weekend in GP2 series, which will see the third and fourth round of the Formula 1 feeder series take place.
In a solid performance in Turkey earlier this month Jolyon secured a top ten finish and ended as the best of this year's rookie drivers.
The 20-year-old is now hoping he can carry over his good form to the 4.655km Circuit de Catalunya circuit – a track he knows well.
"I'm looking forward to this weekend," said Jolyon, who races for Arden International. "We've already done two days of testing at Barcelona so I feel I know the track well. As in Turkey, the races will all come down to tyre degradation so I think this will be the main focus throughout the weekend. I'm hoping for my first points finish, as so far I've had decent pace but nothing to show for it."
Jolyon, son for of former Formula 1 driver Jonathan, stepped up to the GP2 series after a successful season in the FIA Formula Two Championship last year, in which he narrowly missed out on the title spot at the final round, finishing second overall.


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Argentina: 5/11/95-10/12/95Paperback £12.50 Info
A report starting off at Costenera Sur in Buenos Aires, heading south to Ushuaia, then north covering some of the more popular sites up to Iguazu. Travel information, accommodation & usual tips re health, money etc. Daily log, distributional checklist, systematic list and site notes.


text: Home See all Sony devices you can develop for Cameras Action Cam HDR-AS15 Action Cam HDR-AS15 Compact, rugged Wi-Fi® enabled HD video action camcorder1 High quality Full HD 1080p recording Ruggedized, waterproof housing with universal tripod mount included Built-in Wi-Fi® allows instant sharing to smartphone SteadyShot® image stabilization reduces blur Ultra wide angle Carl Zeiss® Lens (170-degree FOV) 4x Slow Motion video mode in HD Exmor® R CMOS Sensor for superb low light performanc. Simply "Press-n-Go" with large start and stop button Memory Stick Micro™ and Micro SD/SDHC compatible Built-In stereo mic HDMI® output for easy file transfer Mac® & PC compatible with upload to Facebook®, YouTube™ etc. Secure on flat and curved surfaces with 2 adhesive mounts Camera Remote API Develop for Sony cameras The Camera Remote API beta SDK allows you to develop apps to control a number of Sony cameras wirelessly from another device. Supported APIs/SDKs Camera Remote API beta Camera POV Action Cam Auto Non Flicker Auto Gain Control Imaging Sensor 1/2.3″ (7.77mm) back-illuminated Exmor® R CMOS Imaging Sensor BIONZ® image processor Pixel Gross: Approx.16800K pixels Effective Picture Resolution: Approx.11900K pixels (16:9) Color Filter System: RGB primary color filters Recording pixels (Still Image, 16:9): Approx.11900000 pixels Recording Memory Stick Micro™ (Mark 2), Micro SD/SDHC, Memory Card (Class 4 or Higher) Still Image Mode: JPEG Still Image Max Effective Resolution: 2.0 megapixels Video Format: MPEG4-AVC/H.264 Video Resolution: 1920×1080/30P (HQ), 1280×720/30P (STD,SLOW,SSLOW), 680×480/30P (VGA) Video Actual (Pixel): Approx.11900K pixels Video Signal: HD: HDTV 1080/60p Audio Format: MPEG-4 AAC-LC 2ch Built-in Microphone, Monoral Speaker Video Recording Rate (Average Bit Rate/VBR): HQ:Approx.16Mbps/ SSLOW:Approx.24Mbps/ SLOW:Approx.12Mbps/ STD:Approx.6Mbps/ VGA:Approx.3Mbps Still Image File Format: DCF Ver.2.0 compatible, Exif Ver.2.3 compatible, MPF Baseline compatible Still Image Size (Photo Mode): 2.0 megapixels 16:9 (1920×1080) Progressive Mode: Yes Optics and Lens specifications Lens Type: Carl Zeiss® Tessar® Lens Aperture: F2.8 Focal Length (35mm equivalent): f=15.3mm, f= 5/8 inch Minimum Focus Distance: Approx.11 7/8inch (Approx.30cm) Angle of View: 170° (without SteadyShot), 120° (with SteadyShot) Focal Distance: f=2.5mm, f=1/8inch Steady Shot Mode:Active: 21.3mm Exposure System Metering Modes: Multi-segment Exposure Settings: Auto Noise Reduction: Yes White Balance Mode: Auto Minimum Illumination: 6 lux Backlight Compensation Gain Control: Auto Drive System Shutter Speeds: Auto Control Range: 1/30 – 1/10,000 (30fps) User Interface Date / Time Stamp (Rec Date and Time) Recording time Indicator Battery Indicator On Screen Main Indicators: Recording Mode and Image stabilization Advanced Features Waterproof: Yes (In use with Waterproof Case (SPK-AS1)) Dustproof: Yes (In use with Waterproof Case (SPK-AS1)) Image Stabilization: SteadyShot™ image stabilization with Active mode Wi-Fi®: Send to Smartphone, Control with Smartphone Interval Recording every 5s, 10s, 30s or 60s Power Save Interfaces Memory Stick Micro™ and Micro SD/SDHC compatible Wi-Fi®: IEEE 802.11b/g/n(2.4GHz band) HD Output: HDMI Out (micro) USB Port(s): micro-B/USB2.0 Hi-speed (mass-storage) BRAVIA® Sync™: Yes Microphone Input: Stereo Minijack HDMI Terminal: Yes (micro) Weight and Measurements Dimensions: 31/32inch x 1 7/8inch x 3 1/4inch (24.5mm x 47.0mm x 82.0mm) Weight: 90g (with the supplied battery NP-BX1) Power Power Consumption (in Operation): 1.7W (in Display Panel operation) Power Requirements: 3.6V (battery pack) Battery Type: NP-BG1 (supplied) Charge on camcorder: Yes, takes about 4 hours with the supplied battery. In The Box Rechargeable Battery Pack (NP-BX1) Micro USB Cable Operating Guide Waterproof Case Adhesive Mount 1. Requires an active 802.11 Wi-Fi network (802.11n recommended).