Evaluation of immunogenicity and safety of VARIVAX™ New Seed Process (NSP) in children

Prior to availability of an effective vaccine, an estimated 4 million cases of varicella occurred annually in the United States, resulting in 10,000 hospitalizations and over 100 deaths. With the increased usage of a two-dose varicella vaccine (as recommended by the ACIP), approval of other VZV-containing products and the adoption of varicella vaccination in additional countries, the demand for VZV-containing vaccines has increased. This study (NCT02062502) evaluated the safety, tolerability, and immunogenicity of VARIVAX™ (VAR, varicella vaccine live) manufactured using a new seed manufacturing process (VARNSP) compared to the currently licensed VAR. Healthy children 12–23 months were randomized (1:1) into Group 1 (2 doses of VARNSP given concomitantly with M-M-R™ II, ∼3 months apart) versus  Group 2 (2 doses of VAR given concomitantly with M-M-R™ II, ∼3 months apart).  Serum samples collected prior to vaccination on Day 1 and 6 weeks Postdose 1 were tested for antibody to VZV using a glycoprotein enzyme-linked immunosorbent assay (gpELISA).  Safety was assessed Days 1 to 42 following each vaccination. Six weeks Postdose 1, the response rate (percent of subjects with VZV antibody titer ≥5 gpELISA units/mL) of VARNSP was non-inferior compared to VAR.  Vaccine-related adverse events (AEs) were comparable with the exception of measles-like rash, where a greater number of rashes were observed with VAR than VARNSP.  The 2 vaccination groups were comparable with incidence rates of AEs, injection-site AEs, vaccine-related AEs, systemic AEs, and serious AEs. This new process is an important innovation for the extreme demand of sustaining sufficient supplies of varicella vaccine to protect our communities against diseases caused by VZV

Marine productivity leads organic matter preservation in sapropel S1: palynological evidence from a core east of the Nile River outflow

The formation of Eastern Mediterranean organic matter rich deposits known as sapropels is the results of two mechanisms: (enhanced) marine productivity and preservation of organic material at depth. However, their relative contribution and their leads and lags with respect to each other remain elusive. Here, we address these questions by studying sediments deposited prior to, during, and after the most recent sapropel (S1, ∼10–6 calibrated ka before present, BP) with an integrated marine and terrestrial palynological approach, combined with existing and newly generated geochemical data. The studied core was retrieved from an area under strong influence of the Nile outflow and has high average sediment accumulation rates allowing a high temporal resolution (of several decades to centuries). Marine productivity, as reconstructed with total dinocyst accumulation rates (ARs) and biogenic CaCO3 content, starts to increase ∼1 ka prior to sapropel formation. A shift in the dinocyst taxa contributing to the productivity signal at sapropel onset indicates the rapid development of (seasonal) water column stratification. Pollen and spore ARs also increase prior to sapropel onset, but a few centuries after the increase in marine productivity. Hence, the first shift to a high marine productivity system before sapropel deposition may have been mostly favoured by the injection of nutrients via shoaling of the nutricline with a minor contribution of nutrients from land via river input and flooding of the shelves. Pollen assemblages indicate a gradual change across the sapropel onset from a savanna-like, through coastal marsh expansion, toward an open woodland assemblage, which is consistent with enhanced Nile influence and delta development. At sapropel onset a marked shift in pollen ARs could suggest increased preservation under anoxia. However, major shifts in pollen assemblages and signs of selective- or partial decomposition of terrestrial palynomorphs are absent. We therefore suggest that the high pollen ARs largely result from an increased influx of pollen by enhanced Nile discharge and extension of the freshwater plume. Three centuries after the sapropel onset, dinocyst ARs and CaCO3 content indicate that marine productivity starts to decrease, while sapropel deposition continued. Organic carbon content decreased only later and less dramatically. This may be explained by a shift in the dominance of the organisms contributing to marine productivity, to an enhanced preservation of organic matter, or a combination of both

『源氏大鏡』三類本 本文と校異（三）若紫―花宴

The formation of Eastern Mediterranean organic matter rich deposits known as sapropels is the results of two mechanisms: (enhanced) marine productivity and preservation of organic material at depth. However, their relative contribution and their leads and lags with respect to each other remain elusive. Here, we address these questions by studying sediments deposited prior to, during, and after the most recent sapropel (S1, ∼10–6 calibrated ka before present, BP) with an integrated marine and terrestrial palynological approach, combined with existing and newly generated geochemical data. The studied core was retrieved from an area under strong influence of the Nile outflow and has high average sediment accumulation rates allowing a high temporal resolution (of several decades to centuries). Marine productivity, as reconstructed with total dinocyst accumulation rates (ARs) and biogenic CaCO3 content, starts to increase ∼1 ka prior to sapropel formation. A shift in the dinocyst taxa contributing to the productivity signal at sapropel onset indicates the rapid development of (seasonal) water column stratification. Pollen and spore ARs also increase prior to sapropel onset, but a few centuries after the increase in marine productivity. Hence, the first shift to a high marine productivity system before sapropel deposition may have been mostly favoured by the injection of nutrients via shoaling of the nutricline with a minor contribution of nutrients from land via river input and flooding of the shelves. Pollen assemblages indicate a gradual change across the sapropel onset from a savanna-like, through coastal marsh expansion, toward an open woodland assemblage, which is consistent with enhanced Nile influence and delta development. At sapropel onset a marked shift in pollen ARs could suggest increased preservation under anoxia. However, major shifts in pollen assemblages and signs of selective- or partial decomposition of terrestrial palynomorphs are absent. We therefore suggest that the high pollen ARs largely result from an increased influx of pollen by enhanced Nile discharge and extension of the freshwater plume. Three centuries after the sapropel onset, dinocyst ARs and CaCO3 content indicate that marine productivity starts to decrease, while sapropel deposition continued. Organic carbon content decreased only later and less dramatically. This may be explained by a shift in the dominance of the organisms contributing to marine productivity, to an enhanced preservation of organic matter, or a combination of both

Boceprevir for chronic HCV genotype 1 infection in patients with prior treatment failure to peginterferon/ribavirin, including prior null response

International audienceBACKGROUND & AIMS:Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir.RESULTS:Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with <1-log10 decline in HCV-RNA after lead-in and 76% of those with ⩾ 1-log10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events.CONCLUSIONS:Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response

Overall safety profile of boceprevir plus peginterferon alfa-2b and ribavirin in patients with chronic hepatitis C genotype 1: a combined analysis of 3 phase 2/3 clinical trials

BACKGROUND & AIMS:Triple therapy with peginterferon/ribavirin (PR) plus an NS3 protease inhibitor has emerged as the standard-of-care for patients with chronic hepatitis C genotype-1. We provide a detailed safety analysis comparing PR to boceprevir plus PR (BOC/PR) across three phase 2/3 studies.METHODS:SPRINT-1 was an open-label phase 2 study in 595 treatment-naive patients. In the two phase 3 studies, 1500 patients (1097 treatment-naive, SPRINT-2; 403 treatment-failure, RESPOND-2) were randomized to receive PR alone, or one of two regimens where BOC was added to PR after a 4-wk PR lead-in. In this analysis, the respective BOC/PR and PR arms were combined for all three trials. The benefit of shortened duration of treatment using response-guided therapy (RGT) was also explored in the SPRINT-2 trial.RESULTS:Only two adverse events, anaemia and dysgeusia, occurred 20% more often with the BOC-containing regimens compared with PR. Nausea, diarrhoea and neutropenia were the only other common events with an incidence of at least 5% greater when BOC was added to the PR backbone. The proportions of patients reporting serious adverse events (AE), life-threatening AEs, and study drug discontinuation because of an AE were similar in the PR and BOC/PR arms. In treatment-naive patients, RGT generally did not result in a lower frequency of common AEs; however, RGT led to decreased exposure to all 3 study drugs and to a decrease in the mean duration of several clinically relevant AEs such as anaemia, neutropenia, fatigue and depression, as well as earlier normalization of haemoglobin and neutrophil counts.CONCLUSIONS:The safety profile of BOC combination therapy largely reflects the known profile of peginterferon and ribavirin, with incremental haematolgical effects and dysgeusia. Shorter treatment duration with RGT significantly reduced the duration of AEs

Tibolone and transdermal E(-2)/NETA for the treatment of female sexual dysfunction in naturally menopausal women: Results of a randomized active-controlled trial

IntroductionThere are some data to suggest that tibolone improves sexual function in postmenopausal women. However, evidence about the effects of tibolone on female sexual dysfunction is lacking.AimTo compare the efficacy on sexual function of tibolone 2.5 mg to continuous combined transdermal estradiol (E2)/norethisterone acetate (NETA) (50 microg/140 microg) in naturally postmenopausal women with sexual dysfunction.Main outcome measureDifferences between treatment groups in the change from baseline for the composite subscore of the arousal, desire, and satisfaction domains of the self-reported Female Sexual Function Index (FSFI).MethodsA multicenter, double-blind, randomized, clinical trial was performed. Sexual function was assessed with the FSFI at baseline, week 12, and week 24. The outcomes of the Female Sexual Distress Scale (FSDS) and the frequency of satisfying sexual events (daily diaries) were secondary end points.ResultsFour hundred three women, mean age 56, were included. Both therapies improved sexual function assessed by the FSFI. In the per protocol analysis, but not in the intent-to-treat analysis, the increase in FSFI scores was significantly larger in the tibolone group when compared with the E2/NETA patch group at week 24 (P = 0.036 and P = 0.025 for the composite subscore and total FSFI score, respectively). The satisfying sexual event rate increased from three to four times per 28 days at week 24 (P ConclusionsBoth treatments resulted to improved overall sexual function, as determined by scores on the FSFI, an increase in the frequency of sexual events, and a reduction in sexuality-related personal distress. The statistically significant higher FSFI scores in the tibolone group, when compared to the E2/NETA group, may be because of tibolone's combined estrogenic and androgenic properties.Esme A. Nijland, Willibrord C.M. Weijmar Schultz, Jörgen Nathorst-Boös, Frans A. Helmond, Rik H.W. Van Lunsen, Santiago Palacios, Robert J. Norman, Roel J. Mulder, and Susan R. Davi