Age-related differences in reporting of drug-associated liver injury: Data-mining of the WHO Safety Report Database

Background/aims: Children, adults and the elderly exhibit differing frequency and manifestations of drug-induced liver injury, which may be due to physiological changes associated with development and/or aging. WHO Safety Report Database data-mining analyses assessed the impact of age on liver event reporting frequency with different phenotypes. Methods: 236 drugs associated with hepatotoxicity in the WHO Safety Report Database were evaluated using the Empirical Bayes Geometric Mean (EBGM) of the relative reporting ratio with 90% confidence interval (EB05 and EB95) calculated for 3 different age groups, 0-17, 18-64, and >65 years (or elderly), for overall, serious (acute liver failure), hepatocellular, and cholestatic liver injury. Results: Overall, cases of age 0-17, 18-64, and 65 years or older comprised 6%, 62%, and 32% of liver event reports. Acute liver failure and hepatocellular injury were more frequently reported among children compared to adults and the elderly while reports with cholestatic injury were more frequent among the elderly (p<0.00001). Twenty-nine drugs, including anti-retrovirals, CNS agents, and antimetabolites, were associated with significantly higher reporting frequency among children vs. others, while 10 drugs were associated with significantly higher reporting frequency among the elderly. Regarding drug characteristics, a potential to cause mitochondrial dysfunction was more prevalent among the drugs with increased pediatric reporting frequency while high lipophilicity and biliary excretion were more common among the drugs associated with higher reporting frequency in the elderly. Conclusion: Our analysis identified age-specific phenotypes in reported liver events and potential drug properties associated with age-specific hepatotoxicity. Further analyses are warranted to better understand potential age-specific susceptibility.Master of Public Healt

A Mediterranean undercurrent seeding experiment (AMUSE) : part II: RAFOS float data report, May 1993-March 1995

This is the final data report of all acoustically tracked RAFOS data collected in 1993-1995 during A Mediterranean Undercurrent Seeding Experiment (AMUSE). The overall objective of the program was to observe directly the spreading pathways by which Mediterranean Water enters the North Atlantic. This includes the direct observation of Mediterranean eddies (meddies), which is one mechanism that transports Mediterranean Water to the North Atlantic. The experiment was comprised of a repeated high-resolution expendable bathythermograph (XBT) section and RAFOS float deployments across the Mediterranean Undercurrent south of Portugal near 8.5°W. A total of 49 floats were deployed at a rate of about two floats per week on 23 cruises on the chartered Portuguese-based vessel, Kialoa II, and one cruise on the R/V Endeavor. The floats were ballasted for 1100 or 1200 decibars (db) to seed the lower salinity core of the Mediterranean Undercurrent. The objectives of the Lagrangian float study were (1) to identify where meddies form, (2) to make the first direct estimate of meddy formation frequency, (3) to estimate the fraction of time meddies are being formed, and (4) to determine the pathways by which Mediterranean Water which is not trapped in meddies enters the North Atlantic.Funding was provided by the National Science Foundation through Grant No. OCE-91-01033 to the Woods Hole Oceanographic Institution and Grant No. OCE-91-00724 to Scripps Institution of Oceanography, and by the Luso-American Foundation for Development through Grant No. 54/93 to the University of Lisbon

XMM-Newton Observation of an X-ray Trail Between the Spiral Galaxy NGC6872 and the Central Elliptical NGC6876 in the Pavo Group

We present XMM-Newton observations of a trail of enhanced X-rayemission extending along the 8'.7 X 4' region between the spiral NGC6872 and the dominant elliptical NGC6876 in the Pavo Group,the first known X-ray trail associated with a spiral galaxy in a poor galaxy group and, with projected length of 90 kpc, one of the longest X-ray trails observed in any system. The X-ray surface brightness in the trail region is roughly constant beyond ~20 kpc of NGC6876 in the direction of NGC6872. The trail is hotter (~ 1 keV) than the undisturbed Pavo IGM (~0.5 keV) and has low metal abundances (0.2 Zsolar). The 0.5-2 keV luminosity of the trail, measured using a 67 X 90 kpc rectangular region, is 6.6 X 10^{40} erg/s. We compare the properties of gas in the trail to the spectral properties of gas in the spiral NGC6872 and in the elliptical NGC6876 to constrain its origin. We suggest that the X-ray trail is either IGM gas gravitationally focused into a Bondi-Hoyle wake, a thermal mixture of ~64% Pavo IGM gas with ~36% galaxy gas that has been removed from the spiral NGC6872 by turbulent viscous stripping, or both, due to the spiral's supersonic motion at angle xi ~ 40 degrees with respect to the plane of the sky, past the Pavo group center (NGC6876) through the densest region of the Pavo IGM. Assuming xi = 40 degrees and a filling factor eta in a cylindrical volume with radius 33 kpc and projected length 90 kpc, the mean electron density and total hot gas mass in the trail is 9.5 X 10^{-4}*eta^{-1/2} cm^{-3} and 1.1 X 10^{10}*eta^{1/2} Msolar, respectively.Comment: typos corrected in Eq. 7 & 8, figures and discussion unchanged, 39 pages, 11 postscript figures, submitted to Ap

Heterogeneity of CYP3A isoforms metabolizing erythromycin and cortisol

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/109905/1/cptclpt19923.pd

Inter- and Intra-Observer Agreement of PD-L1 SP142 Scoring in Breast Carcinoma:A Large Multi-Institutional International Study

The assessment of PD-L1 expression in TNBC is a prerequisite for selecting patients for immunotherapy. The accurate assessment of PD-L1 is pivotal, but the data suggest poor reproducibility. A total of 100 core biopsies were stained using the VENTANA Roche SP142 assay, scanned and scored by 12 pathologists. Absolute agreement, consensus scoring, Cohen's Kappa and intraclass correlation coefficient (ICC) were assessed. A second scoring round after a washout period to assess intra-observer agreement was carried out. Absolute agreement occurred in 52% and 60% of cases in the first and second round, respectively. Overall agreement was substantial (Kappa 0.654-0.655) and higher for expert pathologists, particularly on scoring TNBC (6.00 vs. 0.568 in the second round). The intra-observer agreement was substantial to almost perfect (Kappa: 0.667-0.956), regardless of PD-L1 scoring experience. The expert scorers were more concordant in evaluating staining percentage compared with the non-experienced scorers (R2 = 0.920 vs. 0.890). Discordance predominantly occurred in low-expressing cases around the 1% value. Some technical reasons contributed to the discordance. The study shows reassuringly strong inter- and intra-observer concordance among pathologists in PD-L1 scoring. A proportion of low-expressors remain challenging to assess, and these would benefit from addressing the technical issues, testing a different sample and/or referring for expert opinions

Veterans health administration hepatitis B testing and treatment with anti-CD20 antibody administration

AIM: To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement. METHODS: We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002-2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the χ2 test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group. RESULTS: Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely prior HBV vaccination, and 76% (6022/7903) were HBV negative. In those with chronic HBV infection, ≤ 37% received HBV antiviral treatment during the high risk period while 21% to 23% of those with past or resolved HBV, respectively, received HBV antiviral treatment. During and 12 mo after anti-CD20 Ab, the rate of hepatitis was significantly greater in those HBV positive vs negative (P = 0.001). The mortality rate was 35%-40% in chronic or past hepatitis B and 26%-31% in hepatitis B negative. In those pretreatment HBV negative, 16 (0.3%) developed acute hepatitis B of 4947 tested during anti-CD20Ab treatment and follow-up. CONCLUSION: While HBV testing of Veterans has increased prior to anti-CD20 Ab, few HBV+ patients received HBV antivirals, suggesting electronic health record algorithms may enhance health outcomes

Echinacea purpurea Significantly Induces Cytochrome P450 3A Activity but Does Not Alter Lopinavir‐Ritonavir Exposure in Healthy Subjects

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90291/1/phco.30.8.797.pd

A Search for Parent-of-Origin Effects on Honey Bee Gene Expression

Parent-specific gene expression (PSGE) is little known outside of mammals and plants. PSGE occurs when the expression level of a gene depends on whether an allele was inherited from the mother or the father. Kin selection theory predicts that there should be extensive PSGE in social insects because social insect parents can gain inclusive fitness benefits by silencing parental alleles in female offspring. We searched for evidence of PSGE in honey bees using transcriptomes from reciprocal crosses between European and Africanized strains. We found 46 transcripts with significant parent-of-origin effects on gene expression, many of which overexpressed the maternal allele. Interestingly, we also found a large proportion of genes showing a bias toward maternal alleles in only one of the reciprocal crosses. These results indicate that PSGE may occur in social insects. The nonreciprocal effects could be largely driven by hybrid incompatibility between these strains. Future work will help to determine if these are indeed parent-of-origin effects that can modulate inclusive fitness benefits

Groundwater “fast paths” in the Snake River Plain aquifer: Radiogenic isotope ratios as natural groundwater tracers

Preferential flow paths are expected in many groundwater systems and must be located because they can greatly affect contaminant transport. The fundamental characteristics of radiogenic isotope ratios in chemically evolving waters make them highly effective as preferential flow path indicators. These ratios tend to be more easily interpreted than solute-concentration data because their response to water-rock interaction is less complex. We demonstrate this approach with groundwater {sup 87}Sr/{sup 86}Sr ratios in the Snake River Plain aquifer within and near the Idaho National Engineering and Environmental Laboratory. These data reveal slow-flow zones as lower {sup 87}Sr/{sup 86}Sr areas created by prolonged interaction with the host basalts and a relatively fast flowing zone as a high {sup 87}Sr/{sup 86}Sr area