Pharmacokinetics and Excretion of Gamma-Hydroxybutyrate (GHB) in Healthy Subjects

In Europe and the United States, the recreational use of gammahydroxy butyric acid (GHB) at dance clubs and "rave” parties has increased substantially. In addition, GHB is used to assist in the commission of sexual assaults. The aim of this controlled clinical study was to acquire pharmacokinetic profiles, detection times, and excretion rates in human subjects. Eight GHB-naïve volunteers were administered a single 25-mg/kg body weight oral dose of GHB, and plasma, urine, and oral fluid specimens were analyzed by using gas chromatography-mass spectrometry (GC-MS). Liquid-liquid extraction was performed after acid conversion of GHB to gamma-butyrolactone. Limits of quantitation of 0.1 (oral fluid), 0.2 (urine), and 0.5 µg/mL (plasma) could be achieved in the selected ion monitoring mode. GHB plasma peaks of 39.4 ± 25.2 µg/mL (mean ± SEM) occurred 20-45 min after administration. The terminal plasma elimination half-life was 30.4 ± 2.45 min, the distribution volume 52.7 ± 15.0 L, and the total clearance 1228 ± 233 µL/min. In oral fluid, GHB could be detected up to 360 min, with peak concentrations of 203 ± 92.4 µg/mL in the 10-min samples. In urine, 200 ± 71.8 and 230 ± 86.3 µg/mL, were the highest GHB levels measured at 30 and 60 min, respectively. Only 1.2 ± 0.2% of the dose was excreted, resulting in a detection window of 720 min. Common side-effects were confusion, sleepiness, and dizziness; euphoria and change of vital functions were not observed. GHB is extensively metabolized and rapidly eliminated in urine and oral fluid. Consequently, samples should be collected as soon as possible after ingestio

Pharmacokinetics and excretion of gamma-hydroxybutyrate (GHB) in healthy subjects

In Europe and the United States, the recreational use of gamma-hydroxy butyric acid (GHB) at dance clubs and "rave" parties has increased substantially. In addition, GHB is used to assist in the commission of sexual assaults. The aim of this controlled clinical study was to acquire pharmacokinetic profiles, detection times, and excretion rates in human subjects. Eight GHB-naïve volunteers were administered a single 25-mg/kg body weight oral dose of GHB, and plasma, urine, and oral fluid specimens were analyzed by using gas chromatography-mass spectrometry (GC-MS). Liquid-liquid extraction was performed after acid conversion of GHB to gamma-butyrolactone. Limits of quantitation of 0.1 (oral fluid), 0.2 (urine), and 0.5 microg/mL (plasma) could be achieved in the selected ion monitoring mode. GHB plasma peaks of 39.4 +/- 25.2 microg/mL (mean +/- SEM) occurred 20-45 min after administration. The terminal plasma elimination half-life was 30.4 +/- 2.45 min, the distribution volume 52.7 +/- 15.0 L, and the total clearance 1228 +/- 233 microL/min. In oral fluid, GHB could be detected up to 360 min, with peak concentrations of 203 +/- 92.4 microg/mL in the 10-min samples. In urine, 200 +/- 71.8 and 230 +/- 86.3 microg/mL, were the highest GHB levels measured at 30 and 60 min, respectively. Only 1.2 +/- 0.2% of the dose was excreted, resulting in a detection window of 720 min. Common side-effects were confusion, sleepiness, and dizziness; euphoria and change of vital functions were not observed. GHB is extensively metabolized and rapidly eliminated in urine and oral fluid. Consequently, samples should be collected as soon as possible after ingestion

Standardization and First Lessons Learned of the Prototype HB650 Cryomodule for PIP-II at Fermilab

International audienceThe prototype High Beta 650 MHz cryomodule (pHB650 CM) has been designed by an integrated design team, consisting of Fermilab (USA), CEA (France), STFC UKRI (UK), and RRCAT (India). The manufacturing and assembly of this prototype cryomodule is being done at Fermilab, whereas the production cryomodules will be manufactured and assembled by STFC-UKRI. As the first PIP-II cryomodule for which standardization was applied, the design, manufacturing and assembly of this cryomodule led to significant lessons being learnt and experiences gathered. These were incorporated into the design of the pre-production Single Spoke Resonator Type 2 cryomodule (ppSSR2 CM) and the pre-production Low Beta 650 MHz cryomodule (ppLB650 CM). This paper presents the pHB650 CM lessons learned and experiences gathered from the design to the lower coldmass assembly and how this cryomodule has a positive impact on all the next Proton Improvement Plan-II (PIP-II) cryomodules due to the standardization set up among SSR and 650 cryomodules

Impedance Measurements and Simulations on the TCTP and TDI LHC Collimators

The LHC collimation system is a critical element for the safe operation of the LHC machine and is subject to continuous performance monitoring, hardware upgrade and optimization. In this work we will address the impact on impedance of the upgrades performed on the TDI injection protection collimator, where the absorber material has been changed to mitigate the device heating observed in machine operation, and on selected secondary (TCS) and tertiary (TCT) collimators, where beam position monitors (BPM) have been embedded for faster jaw alignment. Concerning the TDI, we will present the RF measurements performed before and after the upgrade, comparing the result to heating and tune shift beam measurements. For the TCTs, we will study how the higher order modes (HOM) introduced by the BPM addition have been cured by means of ferrite placement in the device. The impedance mitigation campaign has been supported by RF measurements whose results are in good agreement with GdfidL and CST simulations. The presence of undamped low frequency modes is proved not to be detrimental to the safe LHC operation

Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer.

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa-such as genetics-can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment

Genome-wide association study of prostate-specific antigen levels identifies novel loci independent of prostate cancer

Prostate-specific antigen (PSA) levels have been used for detection and surveillance of prostate cancer (PCa). However, factors other than PCa - such as genetics - can impact PSA. Here we present findings from a genome-wide association study (GWAS) of PSA in 28,503 Kaiser Permanente whites and 17,428 men from replication cohorts. We detect 40 genome-wide significant (P<5 × 10-8) single-nucleotide polymorphisms (SNPs): 19 novel, 15 previously identified for PSA (14 of which were also PCa-associated), and 6 previously identified for PCa only. Further analysis incorporating PCa cases suggests that at least half of the 40 SNPs are PSA-associated independent of PCa. The 40 SNPs explain 9.5% of PSA variation in non-Hispanic whites, and the remaining GWAS SNPs explain an additional 31.7%; this percentage is higher in younger men, supporting the genetic basis of PSA levels. These findings provide important information about genetic markers for PSA that may improve PCa screening, thereby reducing over-diagnosis and over-treatment

A large multiethnic genome-wide association study of prostate cancer identifies novel risk variants and substantial ethnic differences.

UnlabelledA genome-wide association study (GWAS) of prostate cancer in Kaiser Permanente health plan members (7,783 cases, 38,595 controls; 80.3% non-Hispanic white, 4.9% African-American, 7.0% East Asian, and 7.8% Latino) revealed a new independent risk indel rs4646284 at the previously identified locus 6q25.3 that replicated in PEGASUS (N = 7,539) and the Multiethnic Cohort (N = 4,679) with an overall P = 1.0 × 10(-19) (OR, 1.18). Across the 6q25.3 locus, rs4646284 exhibited the strongest association with expression of SLC22A1 (P = 1.3 × 10(-23)) and SLC22A3 (P = 3.2 × 10(-52)). At the known 19q13.33 locus, rs2659124 (P = 1.3 × 10(-13); OR, 1.18) nominally replicated in PEGASUS. A risk score of 105 known risk SNPs was strongly associated with prostate cancer (P &lt; 1.0 × 10(-8)). Comparing the highest to lowest risk score deciles, the OR was 6.22 for non-Hispanic whites, 5.82 for Latinos, 3.77 for African-Americans, and 3.38 for East Asians. In non-Hispanic whites, the 105 risk SNPs explained approximately 7.6% of disease heritability. The entire GWAS array explained approximately 33.4% of heritability, with a 4.3-fold enrichment within DNaseI hypersensitivity sites (P = 0.004).SignificanceTaken together, our findings of independent risk variants, ethnic variation in existing SNP replication, and remaining unexplained heritability have important implications for further clarifying the genetic risk of prostate cancer. Our findings also suggest that there may be much promise in evaluating understudied variation, such as indels and ethnically diverse populations