The Optimal Route of Administration of the Glycoprotein IIb/IIIa Receptor Antagonist Abciximab During Percutaneous Coronary Intervention; Intravenous Versus Intracoronary

The use of the glycoprotein (GP) IIb/IIIa receptor antagonist Abciximab has over the years become an important part of the anticoagulant regimen in patients with acute coronary syndrome undergoing percutaneous coronary intervention. Abciximab is a potent inhibitor of platelet aggregation and thrombus formation, but other mechanisms, such as suppression of the inflammatory pathways, have also been proposed to contribute to the benefits of Abciximab

The association of microalbuminuria with mortality in patients with acute myocardial infarction. A ten-year follow-up study

Our study evaluates the long-term effect of microalbuminuria on mortality among patients with acute myocardial infarction. We followed 151 patients from 1996 to 2007 to investigate if microalbuminuria is a risk factor in coronary heart disease. All patients admitted with acute myocardial infarction in 1996 were included. At baseline, we recorded urinary albumin/creatinine concentration ratio, body mass index, blood pressure, left ventricle ejection fraction by echocardiography, smoking status, medication, diabetes, age, and gender. Deaths were traced in 2007 by means of the Danish Personal Identification Register. Microalbuminuria, defined as a urinary albumin/creatinine concentration ratio above 0.65 mg/mmoL, occurred in 50% of the patients and was associated with increased all-cause mortality. Thus, 68% of the patients with microalbuminuria versus 48% of the patients without microalbuminuria had died during the 10 years of follow-up (P=0.04). The crude hazard ratio for death associated with microalbuminuria was 1.78 (CI: 1.18–2.68) (P=0.006), whereas the gender- and age-adjusted hazard ratio was 1.71 (CI: 1.03–2.83) (P=0.04). We concluded that microalbuminuria in hospitalized patients with acute myocardial infarction is prognostic for increased long-term mortality. We recommend measurement of microalbuminuria to be included as a baseline risk factor in patients with acute myocardial infarction and in future trials in patients with coronary heart disease

Impact of CMV PCR Blips in Recipients of Solid Organ and Hematopoietic Stem Cell Transplantation

Background: Viral blips reflecting polymerase chain reaction (PCR) artefacts or transient low-level replication are well described in the human immunodeficiency virus setting. However, the epidemiology of such blips in transplant recipients screened for cytomegalovirus (CMV) with PCR remains uncertain and was investigated in a cohort of solid organ and hematopoietic stem cell recipients. // Methods: Eligible recipients had known donor/recipient CMV IgG serostatus, and 3 CMV PCRs ≥. The CMV PCR triplicates (3 consecutive CMV PCRs) were defined; the first CMV PCR was always negative, and the time between the second and third samples was 7 days ≤. A positive second but negative third sample represented a blip. Odds ratio (OR) for factors associated with a triplicate being a blip was estimated by binomial regression adjusted for repeated measurements. Whether blips affected the hazard ratio (HR) for subsequent CMV infection was determined with a Cox model. // Results: 851 recipients generated 3883 CMV PCR triplicates. The OR of a triplicate representing a blip decreased with increasing viral load of the second sample (vs 273 IU/mL; >273-910 IU/mL: odds ratio [OR], 0.2; 95% confidence interval [CI], 0.1-0.5; >910 IU/mL: OR, 0.08; 95% CI, 0.02-0.2; P ≤ 0.0002) and increased with intermediary-/low-risk serostatus (vs high risk) (OR, 2.8; 95% CI, 1.2-5.5; P = 0.01). Cumulative exposure to DNAemia in the CMV blips greater than 910 IU/mL indicated increased HR of subsequent CMV infection (HR, 4.6; 95% CI, 1.2-17.2; P = 0.02). // Conclusions: Cytomegalovirus blips are frequent; particularly when the viral load of the first positive PCR is < 910 IU/mL, and serostatus risk is intermediary/low. Accumulating blips suggest intermittent low-level replication. If blips are suspected, confirmation of ongoing replication before initiation of treatment is prudent

A field system for measuring plant and soil carbon fluxes using stable isotope methods

There is a lack of field methods for measuring plant and soil processes controlling soil organic matter (SOM) turnover over diurnal, seasonal, and longer time-scales with which to develop datasets for modelling. We describe an automated field system for measuring plant and soil carbon fluxes over such time-scales using stable isotope methods, and we assess its performance. The system comprises 24 large (1-m deep, 0.8-m diameter) cylindrical lysimeters connected to gas-flux chambers and instruments. The lysimeters contain intact, naturally-structured C3 soil planted with a C4 grass. Fluxes of CO2 and their 13C isotope composition are measured 3-times daily in each lysimeter, and the isotope composition is used to partition the fluxes between plant and soil sources. We investigate the following potential sources of error in the measurement system and show they do not significantly affect the measured CO2 fluxes or isotope signatures: gas leaks; the rate of gas flow through sampling loops; instrument precision and drift; the concentration-dependence of isotope measurements; and the linearity of CO2 accumulation in the chambers and associated isotope fractionation resulting from different rates of 13CO2 and 12CO2 diffusion from the soil. For the loamy grassland soil and US prairie grass (Bouteloua dactyloides) tested, the precision of CO2 flux measurements was ± 0.04 % and that of the flux partitioning ± 0.40 %. We give examples of diurnal and seasonal patterns of plant and soil C fluxes and soil temperature and moisture. We discuss the limitations of the isotope methodology for partitioning fluxes as applied in our system. We conclude the system is suitable for measuring net ecosystem respiration fluxes and their plant and soil components with sufficient precision to resolve diurnal and seasonal pattern

PDRMIP: a precipitation driver and response model intercomparison project - protocol and preliminary results

PDRMIP investigates the role of various drivers of climate change for mean and extreme precipitation changes, based on multiple climate model output and energy budget analyses. As the global temperature increases with changing climate, precipitation rates and patterns are affected through a wide range of physical mechanisms. The globally averaged intensity of extreme precipitation also changes more rapidly than the globally averaged precipitation rate. While some aspects of the regional variation in precipitation predicted by climate models appear robust, there is still a large degree of inter-model differences unaccounted for. Individual drivers of climate change initially alter the energy budget of the atmosphere leading to distinct rapid adjustments involving changes in precipitation. Differences in how these rapid adjustment processes manifest themselves within models are likely to explain a large fraction of the present model spread and needs better quantifications to improve precipitation predictions. Here, we introduce the Precipitation Driver and Response Model Intercomparison Project (PDRMIP), where a set of idealized experiments designed to understand the role of different climate forcing mechanisms were performed by a large set of climate models. PDRMIP focuses on understanding how precipitation changes relating to rapid adjustments and slower responses to climate forcings are represented across models. Initial results show that rapid adjustments account for large regional differences in hydrological sensitivity across multiple drivers. The PDRMIP results are expected to dramatically improve our understanding of the causes of the present diversity in future climate projections

Live well, die well – an international cohort study on experiences, concerns and preferences of patients in the last phase of life: the research protocol of the iLIVE study

Introduction Adequately addressing the needs of patients at the end of life and their relatives is pivotal in preventing unnecessary suffering and optimising their quality of life. The purpose of the iLIVE study is to contribute to high-quality personalised care at the end of life in different countries and cultures, by investigating the experiences, concerns, preferences and use of care of terminally ill patients and their families. Methods and analysis The iLIVE study is an international cohort study in which patients with an estimated life expectancy of 6 months or less are followed up until they die. In total, 2200 patients will be included in 11 countries, that is, 200 per country. In addition, one relative per patient is invited to participate. All participants will be asked to fill in a questionnaire, at baseline and after 4 weeks. If a patient dies within 6 months of follow-up, the relative will be asked to fill in a post-bereavement questionnaire. Healthcare use in the last week of life will be evaluated as well; healthcare staff who attended the patient will be asked to fill in a brief questionnaire to evaluate the care that was provided. Qualitative interviews will be conducted with patients, relatives and healthcare professionals in all countries to gain more in-depth insights. Ethics and dissemination The cohort study has been approved by ethics committees and the institutional review boards (IRBs) of participating institutes in all countries. Results will be disseminated through the project website, publications in scientific journals and at conferences. Within the project, there will be a working group focusing on enhancing the engagement of the community at large with the reality of death and dying. Trial registration number NCT04271085

Germline polymorphisms in an enhancer of PSIP1 are associated with progression-free survival in epithelial ovarian cancer.

Women with epithelial ovarian cancer (EOC) are usually treated with platinum/taxane therapy after cytoreductive surgery but there is considerable inter-individual variation in response. To identify germline single-nucleotide polymorphisms (SNPs) that contribute to variations in individual responses to chemotherapy, we carried out a multi-phase genome-wide association study (GWAS) in 1,244 women diagnosed with serous EOC who were treated with the same first-line chemotherapy, carboplatin and paclitaxel. We identified two SNPs (rs7874043 and rs72700653) in TTC39B (best P=7x10-5, HR=1.90, for rs7874043) associated with progression-free survival (PFS). Functional analyses show that both SNPs lie in a putative regulatory element (PRE) that physically interacts with the promoters of PSIP1, CCDC171 and an alternative promoter of TTC39B. The C allele of rs7874043 is associated with poor PFS and showed increased binding of the Sp1 transcription factor, which is critical for chromatin interactions with PSIP1. Silencing of PSIP1 significantly impaired DNA damage-induced Rad51 nuclear foci and reduced cell viability in ovarian cancer lines. PSIP1 (PC4 and SFRS1 Interacting Protein 1) is known to protect cells from stress-induced apoptosis, and high expression is associated with poor PFS in EOC patients. We therefore suggest that the minor allele of rs7874043 confers poor PFS by increasing PSIP1 expression.This project has been supported by a grant from Cancer Australia. The Mayo Clinic GWAS was supported by R01CA114343 (Haplotype-based genome screen for ovarian cancer loci). The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith. The AOCS was supported by the U.S. Army Medical Research and Materiel Command under DAMD17-01-1-0729, the National Health and Medical Research Council (NHMRC) of Australia (grants 400281, 400413), Cancer Council Victoria, Cancer Council Queensland, Cancer Council New South Wales, Cancer Council South Australia, The Cancer Foundation of Western Australia, and Cancer Council Tasmania. G. Chenevix-Trench is a Senior Principal Research fellow of the NHMRC. Y. Lu is funded by NHMRC grant 496675, S. MacGregor is supported by an NHMRC career development award, S. Edwards and J. French are supported by Fellowships from the National Breast Cancer Foundation (NBCF) Australia. The QIMR Berghofer groups were supported by NHMRC project grants (1051698 to SM and 1058415 to SLE and JDF) and a Weekend to End Women’s Cancer Research Grant (to SLE). A deFazio is funded by the University of Sydney Cancer Research Fund and A deFazio and PR Harnett are funded by the Cancer Institute NSW through the Sydney-West Translational Cancer Research Centre. B. Gao is supported by NHMRC and Cancer Institute NSW scholarship. KBM and MO’R are funded by CR-UK. The Bavarian study (BAV) was supported by ELAN Funds of the University of Erlangen-Nuremberg. HSK would like to thank Ira Schwaab for her tireless work on sample preparation. The Belgian study (BEL) was funded by Nationaal Kankerplan and we would like to thank Gilian Peuteman, Thomas Van Brussel and Dominiek Smeets for technical assistance. The Japanese study (JPN) was funded by a Grant-in-Aid for the Third Term Comprehensive 10-Year Strategy for Cancer Control from the Ministry of Health, Labour and Welfare. The International Collaborative Ovarian Neoplasm study (ICON)7 trial team would like to thank the Medical Research Council (MRC) Clinical Trial Unit (CTU) at the University of London (UCL), the ICON7 Translational Research Sub-group, and the University of Leeds for their work on the coordination of samples and data from the ICON7 trial. The LAX study (Women’s Cancer Program) was supported by the American Cancer Society Early Detection Professorship (120950-SIOP-06-258-06-COUN) and Entertainment Industry Foundation. Funding for MALOVA (MAL) was provided by research grant RO1 CA 61107 from the National Cancer Institute, Bethesda, MD; research grant 94 222 52 from the Danish Cancer Society, Copenhagen, Denmark; and the Mermaid I project. The Mayo Clinic study (MAYO) was supported by R01 CA122443, P50 CA136393. The Oregon study (ORE) was funded by the Sherie Hildreth Ovarian Cancer Research Fund and the OHSU Foundation. We would like to thank all members of Scottish Gynaecological Clinical Trials group and the SCOTROC1 investigators. SCOTROC1 (SRO) was funded by Cancer Research UK, and the SCOTROC biological studies were supported by Cancer Research UK (grant C536/A6689). RSH receives support from NIH/NIGMS grant K08GM089941, NIH/NCI grant R21 CA139278, NIH/NIGMS grant UO1GM61393, University of Chicago Cancer Center Support Grant (#P30 CA14599) and Breast Cancer SPORE Career Development Award.This is the final version of the article. It first appeared from Impact Journals via http://dx.doi.org/10.18632/oncotarget.704

Common variants at theCHEK2gene locus and risk of epithelial ovarian cancer

Genome-wide association studies have identified 20 genomic regions associated with risk of epithelial ovarian cancer (EOC), but many additional risk variants may exist. Here, we evaluated associations between common genetic variants [single nucleotide polymorphisms (SNPs) and indels] in DNA repair genes and EOC risk. We genotyped 2896 common variants at 143 gene loci in DNA samples from 15 397 patients with invasive EOC and controls. We found evidence of associations with EOC risk for variants at FANCA, EXO1, E2F4, E2F2, CREB5 and CHEK2 genes (P ≤ 0.001). The strongest risk association was for CHEK2 SNP rs17507066 with serous EOC (P = 4.74 x 10(-7)). Additional genotyping and imputation of genotypes from the 1000 genomes project identified a slightly more significant association for CHEK2 SNP rs6005807 (r (2) with rs17507066 = 0.84, odds ratio (OR) 1.17, 95% CI 1.11-1.24, P = 1.1×10(-7)). We identified 293 variants in the region with likelihood ratios of less than 1:100 for representing the causal variant. Functional annotation identified 25 candidate SNPs that alter transcription factor binding sites within regulatory elements active in EOC precursor tissues. In The Cancer Genome Atlas dataset, CHEK2 gene expression was significantly higher in primary EOCs compared to normal fallopian tube tissues (P = 3.72×10(-8)). We also identified an association between genotypes of the candidate causal SNP rs12166475 (r (2) = 0.99 with rs6005807) and CHEK2 expression (P = 2.70×10(-8)). These data suggest that common variants at 22q12.1 are associated with risk of serous EOC and CHEK2 as a plausible target susceptibility gene.Other Research Uni