Primary BSI rates varied widely among participating centers and declined during the study period. BSIs were strongly associated with central venous catheter access. Further studies are needed to determine the reasons for variance in rates between centers and among various types of hemodialysis access.
Meningococcal disease remains a global public health concern despite the wide availability of polysaccharide and polysaccharide-protein conjugate vaccines. The latter often afford a greater duration and scope of protection compared with the former. A novel quadrivalent meningococcal conjugate vaccine, Menveo(®) (MenACWY-CRM; Novartis Vacines, Bellaria-Rosia, Italy) has recently been licensed in Europe, the USA, Canada and other countries to protect adolescents and adults against disease caused by serogroups A, C, W-135 and Y. MenACWY-CRM has an immunogenicity and tolerability profile in adolescents and adults supported by an extensive clinical development program. MenACWY-CRM induced immune responses that were at least as good as those induced by Menactra(®) (MenACWY-D; Sanofi Pasteur [Swiftwater, PA, USA]), a quadrivalent meningococcal polysaccharide-protein conjugate vaccine) against serogroups A, C, W-135 and Y. Immune responses were also observed in a population of subjects 56-65 years of age. Published information also shows immunogenicity in infants, toddlers and children. Tolerability outcomes were similar for MenACWY-CRM, MenACWY-D and a plain polysaccharide quadrivalent vaccine against meningococcal serogroups A, C, W-135 and Y. Given its potential for protecting infants and persons over 55 years of age, MenACWY-CRM offers promise to fulfil an unmet global need for preventing invasive meningococcal disease in vulnerable populations for which no vaccine is available.
We report here on experimental and theoretical efforts to determine how best to combine drugs that inhibit HER2 and AKT in HER2+ breast cancers. We accomplished this by measuring cellular and molecular responses to lapatinib and the AKT inhibitors (AKTi) GSK690693 and GSK2141795 in a panel of 22 HER2+ breast cancer cell lines carrying wild type or mutant PIK3CA. We observed that combinations of lapatinib plus AKTi were synergistic in HER2+/PIK3CAmut cell lines but not in HER2+/PIK3CAwt cell lines. We measured changes in phospho-protein levels in 15 cell lines after treatment with lapatinib, AKTi or lapatinib + AKTi to shed light on the underlying signaling dynamics. This revealed that p-S6RP levels were less well attenuated by lapatinib in HER2+/PIK3CAmut cells compared to HER2+/PIK3CAwt cells and that lapatinib + AKTi reduced p-S6RP levels to those achieved in HER2+/PIK3CAwt cells with lapatinib alone. We also found that that compensatory up-regulation of p-HER3 and p-HER2 is blunted in PIK3CAmut cells following lapatinib + AKTi treatment. Responses of HER2+ SKBR3 cells transfected with lentiviruses carrying control or PIK3CAmut sequences were similar to those observed in HER2+/PIK3CAmut cell lines but not in HER2+/PIK3CAwt cell lines. We used a nonlinear ordinary differential equation model to support the idea that PIK3CA mutations act as downstream activators of AKT that blunt lapatinib inhibition of downstream AKT signaling and that the effects of PIK3CA mutations can be countered by combining lapatinib with an AKTi. This combination does not confer substantial benefit beyond lapatinib in HER2+/PIK3CAwt cells.
A variety of assays for the diagnosis human herpesvirus 8 (HHV-8) infection have been reported. We compared several such assays with a panel of 88 specimens from human immunodeficiency virus (HIV)-infected patients with Kaposi's sarcoma (KS) (current-KS patients; n ؍ 30), HIV-infected patients who later developed KS (later-KS patients; n ؍ 13), HIV-infected patients without KS (no-KS patients; n ؍ 25), and healthy blood donors (n ؍ 20). PCR assays were also performed with purified peripheral blood mononuclear cells (PBMCs) to confirm positive serologic test results. The order of sensitivity of the serologic assays (most to least) in detecting HHV-8 infection in current-KS patients was the mouse monoclonal antibody-enhanced immunofluorescence assay (MIFA) for lytic antigen (97%), the orfK8.1 peptide enzyme immunoassay (EIA) (87%), the orf65 peptide EIA (87%), MIFA for latent antigen (83%), the Advanced Biotechnologies, Inc., EIA (80%), and the orf65 immunoblot assay (80%). Combination of the results of the two peptide EIAs (combined peptide EIAs) increased the sensitivity to 93%. For detection of infection in later-KS patients, the MIFA for lytic antigen (100%), the orfK8.1 peptide EIA (85%), and combined peptide EIAs (92%) were the most sensitive. Smaller percentages of no-KS patients were found to be positive (16 to 56%). Most positive specimens from the current-KS and later-KS groups were positive by multiple assays, while positive specimens from the no-KS group tended to be positive only by a single assay. PCR with PBMCs for portions of the HHV-8 orf65 and gB genes were positive for less than half of current-KS and later-KS patients and even fewer of the no-KS patients. The concordance between serologic assays was high. We propose screening by the combined peptide EIAs. For specimens that test weakly positive, we recommend that MIFA for lytic antigen be done. A positive result with a titer of >1:40 would be called HHV-8 positive. A negative or low titer would be called HHV-8 negative. If a population has a high percentage of persons who test positive by the combined peptide EIAs, then a MIFA could be performed with the negative specimens to determine if any positive specimens are being missed. Alternatively, if a population has a low percentage that test positive, then a MIFA could be performed with a subset of the negative specimens for the same reason. As described above, only a titer of >1:40 would be considered HHV-8 positive.
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