Safety and immunogenicity of a varicella vaccine without human serum albumin (HSA) versus a HSA-containing formulation administered in the second year of life:A phase III, double-blind, randomized study

BACKGROUND: A new formulation of the live-attenuated varicella vaccine Varilrix (GSK) produced without human serum albumin (HSA) was developed to minimize a theoretical risk of transmission of infectious diseases. A previous study showed that the vaccine was immunologically non-inferior to the HSA-containing vaccine and well-tolerated in toddlers; low-grade fever was numerically higher in children receiving the vaccine without HSA, but the study lacked power to conclude on this difference. METHODS: In this phase III, double-blind, multi-center study, healthy 12-23-month-olds were randomized (1:1) to receive two doses of the varicella vaccine without (Var-HSA group) or with HSA (Varand#8201;+and#8201;HSA group) at days 0 and 42. The primary objective compared safety of the vaccines in terms of incidence of fever andgt;and#8201;39.0and#8201;and#176;C in the 15-day period post-first vaccination. The objective was considered met if the upper limit of the 95% confidence interval for the between-group difference in the incidence of fever andgt;and#8201;39.0and#8201;and#176;C was and#8804;5% (Var-HSA group minus Varand#8201;+and#8201;HSA group). Safety, reactogenicity and immune responses were evaluated. RESULTS: Six hundred fifteen children in the Var-HSA group and 616 in the Varand#8201;+and#8201;HSA group received and#8805;1 vaccination. Fever andgt;and#8201;39.0and#8201;and#176;C was reported in 3.9 and 5.2% of participants in the Var-HSA and Varand#8201;+and#8201;HSA groups, with a between-group difference of -and#8201;1.29 (95% confidence interval: -and#8201;3.72-1.08); therefore, the primary objective was achieved. Fever rates post-each dose and the incidence of solicited local and general adverse events (AEs) were comparable between groups. Unsolicited AEs were reported for 43.9 and 36.5% of children in the Var-HSA group and 45.8 and 36.0% of children in the Varand#8201;+and#8201;HSA group, during 43and#8201;days post-dose 1 and 2, respectively. Serious AEs occurred in 2.1% (group Var-HSA) and 2.4% (group Varand#8201;+and#8201;HSA) of children, throughout the study. In a sub-cohort of 364 children, all had anti-varicella-zoster virus antibody concentrations and#8805;50 mIU/mL post-dose 2; comparable geometric mean concentrations were observed between the groups. CONCLUSIONS: The varicella vaccine formulated without HSA did not induce higher rates of fever during the 15and#8201;day-post-vaccination period, as compared with the original HSA-containing vaccine. The two vaccines displayed similar safety and immunogenicity profiles in toddlers. TRIAL REGISTRATION:NCT02570126 , registered on 5 October 2015 (www.clinicaltrials.gov).</p

Immunological non-inferiority of a new fully liquid presentation of the MenACWY-CRM vaccine to the licensed vaccine : results from a randomized, controlled, observer-blind study in adolescents and young adult

A fully liquid MenACWY-CRM vaccine presentation has been developed, modifying the meningococcal serogroup A (MenA) component from lyophilized to liquid. The safety and immunogenicity of the liquid presentation at the end of the intended shelf-life (aged for 24 or 30 months) were compared to the licensed lyophilized/liquid presentation. This multicenter, randomized (1:1), observer-blind, phase 2b study (NCT03433482) enrolled adolescents and young adults (age 10-40 years). In part 1, 844 participants received one dose of liquid presentation stored for approximately 24 months or licensed presentation. In part 2, 846 participants received one dose of liquid presentation stored for approximately 30 months or licensed presentation. After storage, the MenA free saccharide (FS) level was approximately 25% and O-acetylation was approximately 45%. The primary objective was to demonstrate non-inferiority of the liquid presentation to licensed presentation, as measured by human serum bactericidal assay (hSBA) geometric mean titers (GMTs) against MenA, 1-month post-vaccination. Immune responses against each vaccine serogroup were similar between groups. Between-group ratios of hSBA GMTs for MenA were 1.21 (part 1) and 1.11 (part 2), with two-sided 95% confidence interval lower limits (0.94 and 0.87, respectively) greater than the prespecified non-inferiority margin (0.5), thus meeting the primary study objective. No safety concerns were identified. Despite reduced O-acetylation of MenA and increased FS content, serogroup-specific immune responses induced by the fully liquid presentation were similar to those induced by the licensed MenACWY-CRM vaccine, with non-inferior anti-MenA responses. The safety profiles of the vaccine presentations were similar.GlaxoSmithKline Biologicals SAhttps://www.tandfonline.com/journals/KHVIMedical Microbiolog

Measurement of the cosmic ray spectrum above 4×10184{\times}10^{18} eV using inclined events detected with the Pierre Auger Observatory

A measurement of the cosmic-ray spectrum for energies exceeding $4{\times}10^{18}$ eV is presented, which is based on the analysis of showers with zenith angles greater than $60^{\circ}$ detected with the Pierre Auger Observatory between 1 January 2004 and 31 December 2013. The measured spectrum confirms a flux suppression at the highest energies. Above $5.3{\times}10^{18}$ eV, the "ankle", the flux can be described by a power law $E^{-\gamma}$ with index $\gamma=2.70 \pm 0.02 \,\text{(stat)} \pm 0.1\,\text{(sys)}$ followed by a smooth suppression region. For the energy ($E_\text{s}$) at which the spectral flux has fallen to one-half of its extrapolated value in the absence of suppression, we find $E_\text{s}=(5.12\pm0.25\,\text{(stat)}^{+1.0}_{-1.2}\,\text{(sys)}){\times}10^{19}$ eV.Comment: Replaced with published version. Added journal reference and DO

Energy Estimation of Cosmic Rays with the Engineering Radio Array of the Pierre Auger Observatory

The Auger Engineering Radio Array (AERA) is part of the Pierre Auger Observatory and is used to detect the radio emission of cosmic-ray air showers. These observations are compared to the data of the surface detector stations of the Observatory, which provide well-calibrated information on the cosmic-ray energies and arrival directions. The response of the radio stations in the 30 to 80 MHz regime has been thoroughly calibrated to enable the reconstruction of the incoming electric field. For the latter, the energy deposit per area is determined from the radio pulses at each observer position and is interpolated using a two-dimensional function that takes into account signal asymmetries due to interference between the geomagnetic and charge-excess emission components. The spatial integral over the signal distribution gives a direct measurement of the energy transferred from the primary cosmic ray into radio emission in the AERA frequency range. We measure 15.8 MeV of radiation energy for a 1 EeV air shower arriving perpendicularly to the geomagnetic field. This radiation energy -- corrected for geometrical effects -- is used as a cosmic-ray energy estimator. Performing an absolute energy calibration against the surface-detector information, we observe that this radio-energy estimator scales quadratically with the cosmic-ray energy as expected for coherent emission. We find an energy resolution of the radio reconstruction of 22% for the data set and 17% for a high-quality subset containing only events with at least five radio stations with signal.Comment: Replaced with published version. Added journal reference and DO

Measurement of the Radiation Energy in the Radio Signal of Extensive Air Showers as a Universal Estimator of Cosmic-Ray Energy

We measure the energy emitted by extensive air showers in the form of radio emission in the frequency range from 30 to 80 MHz. Exploiting the accurate energy scale of the Pierre Auger Observatory, we obtain a radiation energy of 15.8 \pm 0.7 (stat) \pm 6.7 (sys) MeV for cosmic rays with an energy of 1 EeV arriving perpendicularly to a geomagnetic field of 0.24 G, scaling quadratically with the cosmic-ray energy. A comparison with predictions from state-of-the-art first-principle calculations shows agreement with our measurement. The radiation energy provides direct access to the calorimetric energy in the electromagnetic cascade of extensive air showers. Comparison with our result thus allows the direct calibration of any cosmic-ray radio detector against the well-established energy scale of the Pierre Auger Observatory.Comment: Replaced with published version. Added journal reference and DOI. Supplemental material in the ancillary file

Design and baseline characteristics of the finerenone in reducing cardiovascular mortality and morbidity in diabetic kidney disease trial

Background: Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. Patients and Methods: The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate >= 25 mL/min/1.73 m(2) and albuminuria (urinary albumin-to-creatinine ratio >= 30 to <= 5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level alpha = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. Conclusions: FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049

Safety and immunogenicity of a varicella vaccine without human serum albumin (HSA) versus a HSA-containing formulation administered in the second year of life: a phase III, double-blind, randomized study

Background: a new formulation of the live-attenuated varicella vaccine Varilrix (GSK) produced without human serum albumin (HSA) was developed to minimize a theoretical risk of transmission of infectious diseases. A previous study showed that the vaccine was immunologically non-inferior to the HSA-containing vaccine and well-tolerated in toddlers; low-grade fever was numerically higher in children receiving the vaccine without HSA, but the study lacked power to conclude on this difference. Methods: in this phase III, double-blind, multi-center study, healthy 12–23-month-olds were randomized (1:1) to receive two doses of the varicella vaccine without (Var-HSA group) or with HSA (Var + HSA group) at days 0 and 42. The primary objective compared safety of the vaccines in terms of incidence of fever &gt; 39.0 °C in the 15-day period post-first vaccination. The objective was considered met if the upper limit of the 95% confidence interval for the between-group difference in the incidence of fever &gt; 39.0 °C was ≤5% (Var-HSA group minus Var + HSA group). Safety, reactogenicity and immune responses were evaluated. Results: six hundred fifteen children in the Var-HSA group and 616 in the Var + HSA group received ≥1 vaccination. Fever &gt; 39.0 °C was reported in 3.9 and 5.2% of participants in the Var-HSA and Var + HSA groups, with a between-group difference of − 1.29 (95% confidence interval: − 3.72–1.08); therefore, the primary objective was achieved. Fever rates post-each dose and the incidence of solicited local and general adverse events (AEs) were comparable between groups. Unsolicited AEs were reported for 43.9 and 36.5% of children in the Var-HSA group and 45.8 and 36.0% of children in the Var + HSA group, during 43 days post-dose 1 and 2, respectively. Serious AEs occurred in 2.1% (group Var-HSA) and 2.4% (group Var + HSA) of children, throughout the study. In a sub-cohort of 364 children, all had anti-varicella-zoster virus antibody concentrations ≥50 mIU/mL post-dose 2; comparable geometric mean concentrations were observed between the groups. Conclusions: the varicella vaccine formulated without HSA did not induce higher rates of fever during the 15 day-post-vaccination period, as compared with the original HSA-containing vaccine. The two vaccines displayed similar safety and immunogenicity profiles in toddlers

Käytännön kosteikkosuunnittelu

Maatalouden vesiensuojelua edistetään monin tavoin. Ravinteita ja eroosioainesta sisältäviä valumavesiä pyritään puhdistamaan erilaisissa kosteikoissa. Tämä opas on kirjoitettu avuksi pienimuotoisten kosteikkojen perustamiseen. Oppaassa esitetään käytännönläheisesti kosteikon toteuttamisen eri vaiheet paikan valinnasta suunnitteluun ja rakentamiseen. Vuonna 2010 julkaistun painoksen tiedot on saatettu ajantasalle. Julkaisu on toteutettu osana Tehoa maatalouden vesiensuojeluun (TEHO) -hanketta ja päivitetty TEHO Plus -hankkeen toimesta. Oppaan toivotaan lisäävän kiinnostusta kosteikkojen suunnitteluun ja edelleen niiden rakentamiseen