Is elevated creatinine level a contraindication to endovascular aneurysm repair?

AbstractPurposeIt is widely believed that chronic renal insufficiency (CRI) greatly increases the risk associated with endovascular abdominal aortic aneurysm repair (EVAR) and is a relative contraindication to the procedure and to the use of intra-arterial contrast agents (IACA). We reviewed a 5-year EVAR experience to determine whether the procedure and use of IACA have an important deleterious effect on renal function in patients with and without pre-existing CRI.MethodsEndovascular aneurysm repair (EVAR) was performed in 200 patients with a variety of endografts, with intra-arterial contrast agents. The patients were retrospectively assigned to three groups on the basis of preoperative serum creatinine concentration (Cr): group 1 (n = 108), Cr less than 1.5 mg/dL (normal range); group 2 (n = 65), Cr 1.5 to 2.0 mg/dL; group 3 (n = 27), Cr 2.1 to 3.5 mg/dL. No patients had undergone hemodialysis. In groups 2 and 3, patients received hydration perioperatively, and received mannitol intraoperatively; no nephrotoxic drugs were administered during the procedure, other than nonionic contrast agent (Omnipaque 350).ResultsThe incidence of postoperative complications between the three study groups was not statistically different. In group 1 a transient increase in serum Cr (>30% over baseline and >1.4 mg/dL) was noted in three patients (2.7%), two of whom (1.9%) required temporary hemodialysis and one (0.9%) who died of renal failure. In group 2 a transient increase in serum Cr was noted in two patients (3.1%); both patients (3.1%) required temporary hemodialysis, and one patient (1.5%) died of renal failure. In group 3 a transient increase in serum Cr was noted in two patients (7.4%); one patient (3.7%) required temporary hemodialysis, and one patient (3.7%) died of renal failure. Perioperative hypotension significantly increased the risk for elevated serum Cr and death (P < .05), and larger contrast volume was associated with an increase in serum Cr (P < .05) during the postoperative period.ConclusionsEVAR with intra-arterial contrast agents can be accomplished in patients with chronic renal insufficiency who do not require dialysis, with limited and acceptable morbidity and mortality, similar to that observed with open aneurysm repair. Contrary to other reports in which perioperative precautions were not used, our study shows that with EVAR the risk for worsening renal failure, dialysis, and death is only slightly, and not significantly, greater in patients with preoperative chronic renal insufficiency compared with patients with normal renal function. Perioperative hypotension and increased contrast volume are significant risk factors for postoperative increase in serum Cr and death. With appropriate precautions such as averting perioperative hypotension and limiting the volume of nonionic contrast agents, elevated Cr need not be a contraindication to EVAR with intra-arterial contrast agents

Genome-wide association study of survival from sepsis due to pneumonia: an observational cohort study

BACKGROUND: Sepsis continues to be a major cause of death, disability, and health-care expenditure worldwide. Despite evidence suggesting that host genetics can influence sepsis outcomes, no specific loci have yet been convincingly replicated. The aim of this study was to identify genetic variants that influence sepsis survival. METHODS: We did a genome-wide association study in three independent cohorts of white adult patients admitted to intensive care units with sepsis, severe sepsis, or septic shock (as defined by the International Consensus Criteria) due to pneumonia or intra-abdominal infection (cohorts 1-3, n=2534 patients). The primary outcome was 28 day survival. Results for the cohort of patients with sepsis due to pneumonia were combined in a meta-analysis of 1553 patients from all three cohorts, of whom 359 died within 28 days of admission to the intensive-care unit. The most significantly associated single nucleotide polymorphisms (SNPs) were genotyped in a further 538 white patients with sepsis due to pneumonia (cohort 4), of whom 106 died. FINDINGS: In the genome-wide meta-analysis of three independent pneumonia cohorts (cohorts 1-3), common variants in the FER gene were strongly associated with survival (p=9·7 × 10(-8)). Further genotyping of the top associated SNP (rs4957796) in the additional cohort (cohort 4) resulted in a combined p value of 5·6 × 10(-8) (odds ratio 0·56, 95% CI 0·45-0·69). In a time-to-event analysis, each allele reduced the mortality over 28 days by 44% (hazard ratio for death 0·56, 95% CI 0·45-0·69; likelihood ratio test p=3·4 × 10(-9), after adjustment for age and stratification by cohort). Mortality was 9·5% in patients carrying the CC genotype, 15·2% in those carrying the TC genotype, and 25·3% in those carrying the TT genotype. No significant genetic associations were identified when patients with sepsis due to pneumonia and intra-abdominal infection were combined. INTERPRETATION: We have identified common variants in the FER gene that associate with a reduced risk of death from sepsis due to pneumonia. The FER gene and associated molecular pathways are potential novel targets for therapy or prevention and candidates for the development of biomarkers for risk stratification. FUNDING: European Commission and the Wellcome Trust

Identification of road user related risk factors, deliverable 4.1 of the H2020 project SafetyCube.

Safety CaUsation, Benefits and Efficiency (SafetyCube) is a European Commission supported Horizon 2020 project with the objective of developing an innovative road safety Decision Support System (DSS). The DSS will enable policy-makers and stakeholders to select and implement the most appropriate strategies, measures, and cost-effective approaches to reduce casualties of all road user types and all severities. This document is the first deliverable (4.1) of work package 4 which is dedicated to identifying and assessing human related risk factors and corresponding countermeasures as well as their effect on road safety. The focus of deliverable 4.1 is on identification and assessment of risk factors and describes the corresponding operational procedure and corresponding outcomes. The following steps have been carried out: Identification of human related risk factors – creation of a taxonomy Consultation of relevant stakeholders and policy papers for identification of topic with high priority (‘hot topics’) Systematic literature search and selection of relevant studies on identified risk factors •Coding of studies •Analysis of risk factors on basis of coded studies •Synopses of risk factors, including accident scenarios The core output of this task are synopses of risk factors which will be available through the DSS. Within the synopses, each risk factor was analysed systematically on basis of scientific studies and is further assigned to one of four levels of risk (marked with a colour code). Essential information of the more than 180 included studies were coded and will also be available in the database of the DSS. Furthermore, the synopses contain theoretical background on the risk factor and are prepared in different sections with different levels of detail for an academic as well as a non-academic audience. These sections are readable independently. It is important to note that the relationship between road safety and road user related risk factors is a difficult task. For some risk factors the available studies focused more on conditions of the behaviour (in which situations the behaviour is shown or which groups are more likely to show this behaviour) rather than the risk factor itself. Therefore, it cannot be concluded that those risk factors that have not often been studied or have to rely more indirect and arguably weaker methodologies, e.g. self-reports , do not increase the chance of a crash occurring. The following analysed risk factors were assessed as ‘risky’, ‘probably risky’ or ‘unclear’. No risk factors were identified as ‘probably not risky’. Risky Probably risky Unclear • Influenced driving – alcohol • Influenced Driving – drugs (legal & illegal) • Speeding and inappropriate speed • Traffic rule violations – red light running • Distraction – cell phone use (hand held) • Distraction – cell phone use (hands free) • Distraction – cell phone use (texting) • Fatigue – sleep disorders – sleep apnea • Risk taking – overtaking • Risk taking – close following behaviour • Insufficient knowledge and skills • Functional impairment – cognitive impairment • Functional impairment – vision loss • Diseases and disorders – diabetes • Personal factors – sensation seeking • Personal factors – ADHD • Emotions – anger, aggression • Fatigue – Not enough sleep/driving while tired • Distraction – conversation with passengers • Distraction – outside of vehicle • Distraction – cognitive overload and inattention • Functional impairment – hearing loss (few studies) • Observation errors (few studies) • Distraction – music – entertainment systems (many studies, mixed results) • Distraction – operating devices (many studies, mixed results) The next step in SafetyCube’s WP4 is to identify and assess the effectiveness of measures and to establish a link to the identified risk factors. The work of this first task indicates a set of risk factors that should be centre of attention when identifying corresponding road safety measures (category ‘risky’)

Pedestrian Injury and Human Behaviour: Observing Road-Rule Violations at High-Incident Intersections

Background Human behaviour is an obvious, yet under-studied factor in pedestrian injury. Behavioural interventions that address rule violations by pedestrians and motorists could potentially reduce the frequency of pedestrian injury. In this study, a method was developed to examine road-rule non-compliance by pedestrians and motorists. The purpose of the study was to examine the potential association between violations made by pedestrians and motorists at signalized intersections, and collisions between pedestrians and motor-vehicles. The underlying hypothesis is that high-incident pedestrian intersections are likely to vary with respect to their aetiology, and thus are likely to require individualized interventions – based on the type and rate of pedestrian and motorist violation. Methods High-incident pedestrian injury intersections in Vancouver, Canada were identified using geographic information systems. Road-rule violations by pedestrians and motorists were documented at each incident hotspot by a team of observers at several different time periods during the day. Results Approximately 9,000 pedestrians and 18,000 vehicles were observed in total. In total for all observed intersections, over 2000 (21%) pedestrians committed one of the observed pedestrian road-crossing violations, while approximately 1000 (5.9%) drivers committed one of the observed motorist violations. Great variability in road-rule violations was observed between intersections, and also within intersections at different observation periods. Conclusions Both motorists and pedestrians were frequently observed committing road-rule violations at signalized intersections, suggesting a potential human behavioural contribution to pedestrian injury at the study sites. These results suggest that each intersection may have unique mechanisms that contribute to pedestrian injury, and may require targeted behavioural interventions. The method described in this study provides the basis for understanding the relationship between violations and pedestrian injury risk at urban intersections. Findings could be applied to targeted prevention campaigns designed to reduce the number of pedestrian injuries at signalized intersections

Integrative Approach to Pain Genetics Identifies Pain Sensitivity Loci across Diseases

Identifying human genes relevant for the processing of pain requires difficult-to-conduct and expensive large-scale clinical trials. Here, we examine a novel integrative paradigm for data-driven discovery of pain gene candidates, taking advantage of the vast amount of existing disease-related clinical literature and gene expression microarray data stored in large international repositories. First, thousands of diseases were ranked according to a disease-specific pain index (DSPI), derived from Medical Subject Heading (MESH) annotations in MEDLINE. Second, gene expression profiles of 121 of these human diseases were obtained from public sources. Third, genes with expression variation significantly correlated with DSPI across diseases were selected as candidate pain genes. Finally, selected candidate pain genes were genotyped in an independent human cohort and prospectively evaluated for significant association between variants and measures of pain sensitivity. The strongest signal was with rs4512126 (5q32, ABLIM3, P = 1.3×10−10) for the sensitivity to cold pressor pain in males, but not in females. Significant associations were also observed with rs12548828, rs7826700 and rs1075791 on 8q22.2 within NCALD (P = 1.7×10−4, 1.8×10−4, and 2.2×10−4 respectively). Our results demonstrate the utility of a novel paradigm that integrates publicly available disease-specific gene expression data with clinical data curated from MEDLINE to facilitate the discovery of pain-relevant genes. This data-derived list of pain gene candidates enables additional focused and efficient biological studies validating additional candidates

THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: Enzymes.

The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15542. Enzymes are one of the six major pharmacological targets into which the Guide is divided, with the others being: G protein-coupled receptors, ion channels, nuclear hormone receptors, catalytic receptors and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate