Richard Evans

Effect of remote ischemic preconditioning on clinical outcomes in patients undergoing coronary artery bypass graft surgery (ERICCA): rationale and study design of a multi-centre randomized double-blinded controlled clinical trial.

BackgroundNovel cardioprotective strategies are required to improve clinical outcomes in high risk patients undergoing coronary artery bypass graft (CABG)xa0±xa0valve surgery. Remote ischemic preconditioning (RIC), in which brief episodes of non-lethal ischemia and reperfusion are applied to the arm or leg, has been demonstrated to reduce perioperative myocardial injury following CABGxa0±xa0valve surgery. Whether RIC can improve clinical outcomes in this setting is unknown and is investigated in the effect of remote ischemic preconditioning on clinical outcomes (ERICCA) trial in patients undergoing CABG surgery. (ClinicalTrials.gov Identifier: NCT01247545).MethodsThe ERICCA trial is a multicentre randomized double-blinded controlled clinical trial which will recruit 1,610 high-risk patients (Additive Euroscore ≥xa05) undergoing CABGxa0±xa0valve surgery using blood cardioplegia via 27 tertiary centres over 2xa0years. The primary combined endpoint will be cardiovascular death, non-fatal myocardial infarction, coronary revascularization and stroke at 1xa0year. Secondary endpoints will include peri-operative myocardial and acute kidney injury, intensive care unit and hospital stay, inotrope score, left ventricular ejection fraction, changes of quality of life and exercise tolerance. Patients will be randomized to receive after induction of anesthesia either RIC (4 cycles of 5xa0min inflation to 200xa0mmHg and 5xa0min deflation of a blood pressure cuff placed on the upper arm) or sham RIC (4 cycles of simulated inflations and deflations of the blood pressure cuff).ImplicationsThe findings from the ERICCA trial have the potential to demonstrate that RIC, a simple, non-invasive and virtually cost-free intervention, can improve clinical outcomes in higher-risk patients undergoing CABGxa0±xa0valve surgery.

Additive Mixture Effects of Estrogenic Chemicals in Human Cell-Based Assays Can Be Influenced by Inclusion of Chemicals with Differing Effect Profiles

A growing body of experimental evidence indicates that the in vitro effects of mixtures of estrogenic chemicals can be well predicted from the estrogenicity of their components by the concentration addition (CA) concept. However, some studies have observed small deviations from CA. Factors affecting the presence or observation of deviations could include: the type of chemical tested; number of mixture components; mixture design; and assay choice. We designed mixture experiments that address these factors, using mixtures with high numbers of components, chemicals from diverse chemical groups, assays with different in vitro endpoints and different mixture designs and ratios. Firstly, the effects of mixtures composed of up to 17 estrogenic chemicals were examined using estrogenicity assays with reporter-gene (ERLUX) and cell proliferation (ESCREEN) endpoints. Two mixture designs were used: 1) a ‘balanced’ design with components present in proportion to a common effect concentration (e.g. an EC10) and 2) a ‘non-balanced’ design with components in proportion to potential human tissue concentrations. Secondly, the individual and simultaneous ability of 16 potential modulator chemicals (each with minimal estrogenicity) to influence the assay outcome produced by a reference mixture of estrogenic chemicals was examined. Test chemicals included plasticizers, phthalates, metals, PCBs, phytoestrogens, PAHs, heterocyclic amines, antioxidants, UV filters, musks, PBDEs and parabens. In all the scenarios tested, the CA concept provided a good prediction of mixture effects. Modulation studies revealed that chemicals possessing minimal estrogenicity themselves could reduce (negatively modulate) the effect of a mixture of estrogenic chemicals. Whether the type of modulation we observed occurs in practice most likely depends on the chemical concentrations involved, and better information is required on likely human tissue concentrations of estrogens and of potential modulators. Successful prediction of the effects of diverse chemical combinations might be more likely if chemical profiling included consideration of effect modulation.

Should the scope of human mixture risk assessment span legislative/regulatory silos for chemicals?

Current chemicals regulation operates almost exclusively on a chemical-by-chemical basis, however there is concern that this approach may not be sufficiently protective if two or more chemicals have the same toxic effect. Humans are indisputably exposed to more than one chemical at a time, for example to the multiple chemicals found in food, air and drinking water, and in household and consumer products, and in cosmetics. Assessment of cumulative risk to human health and/or the environment from multiple chemicals and routes can be done in a mixture risk assessment (MRA). Whilst there is a broad consensus on the basic science of mixture toxicology, the path to regulatory implementation of MRA within chemical risk assessment is less clear. In this discussion piece we pose an open question: should the scope of human MRA cross legislative remits or silos? We define silos as, for instance, legislation that defines risk assessment practice for a subset of chemicals, usually on the basis of substance/product, media or process orientation. Currently any form of legal mandate for human MRA in the EU is limited to only a few pieces of legislation. We describe two lines of evidence, illustrated with selected examples, that are particularly pertinent to this question: 1) evidence that mixture effects have been shown for chemicals regulated in different silos and 2) evidence that humans are co-exposed to chemicals from different silos. We substantiate the position that, because there is no reason why chemicals allocated to specific regulatory silos would have non-overlapping risk profiles, then there is also no reason to expect that MRA limited only to chemicals within one silo can fully capture the risk that may be present to human consumers. Finally, we discuss possible options for implementation of MRA and we hope to prompt wider discussion of this issue.

Examining the feasibility of mixture risk assessment: A case study using a tiered approach with data of 67 pesticides from the Joint FAO/WHO Meeting on Pesticide Residues (JMPR)

The way in which mixture risk assessment (MRA) should be included in chemical risk assessment is a current topic of debate. We used data from 67 recent pesticide evaluations to build a case study using Hazard Index calculations to form risk estimates in a tiered MRA approach in line with a Framework proposed by WHO/IPCS. The case study is used to illustrate the approach and to add detail to the existing Framework, and includes many more chemicals than previous case studies. A low-tier MRA identified risk as being greater than acceptable, but refining risk estimates in higher tiers was not possible due to data requirements not being readily met. Our analysis identifies data requirements, which typically expand dramatically in higher tiers, as being the likely cause for an MRA to fail in many realistic cases. This forms a major obstacle to routine implementation of MRA and shows the need for systematic generation and collection of toxicological data. In low tiers, hazard quotient inspection identifies chemicals that contribute most to the HI value and thus require attention if further refinement is needed. Implementing MRA requires consensus on issues such as scope setting, criteria for performing refinement, and decision criteria for actions.

Response to A critique of the European Commission Document, "State of the Art Assessment of Endocrine Disrupters" by Rhomberg and colleagues--letter to the editor.

The European Commission is in the process of preparing regulatory activities for endocrine disrupting chemicals. In support of this process, the European Commission has asked for a summary of the state of endocrine disrupter science which was to be completed within 12 months. A draft version of our science summary was published by the European Commission in the summer of 2011, with the aim of generating feedback from stakeholders. We have received comments from EU member state authorities and from the European Chemical Industry (CEFIC, ECPA) and these were all taken into account in the final version of the science summary. The final version of the science summary was submitted as an annex to our final SOTA ED (Kortenkamp et al., 2011) which was completed on 23 December 2011. In their American Chemistry Council commissioned critique, Rhomberg et al. (2012) focus entirely on the draft version of the science summary, but largely ignore the main body of our report. Rhomberg et al. argue that because we did not use methodological approaches needed for comprehensive substance assessments, our report must be biased. This line of argumentation is deeply flawed. It might be the result of a lack of understanding of the distribution of competences in the European Union which the authors (all of them US or Canadian nationals) may not be familiar with. Rhomberg et al. seem to have assumed that the European Commission would base their policy initiatives on detailed risk assessments of a large number of chemicals, in terms of their endocrine disrupting properties. But the European Commission (the executive arm of the European Union) itself is not responsible for risk assessments of chemicals. Rather, it shapes the general principles of European Union chemicals policy of which risk assessment is but one element. Accordingly, the European Commission did not ask for detailed and in-depth risk assessments for a large number of chemicals to support their policy initiatives, nor is such an analysis needed as a foundation for policy. In the European Union, the task of detailed chemical evaluations and risk assessments falls in the first instance to industry and under well defined circumstances to European agencies such as the European Food Safety Authority or the European Chemicals Agency and to competent authorities of European Union member states. What the European Commission needed, and what it requested us to prepare, was a summary of endocrine disrupter science, primarily with the aim of assessing whether policy initiatives in this area are scientifically justified and called for. Accordingly, they commissioned an assessment of whether endocrine disruption is a problem, and whether there are indications that chemical exposures play a role in endocrine-related health outcomes or wildlife effects. A specific objective in relation to a clause of the European chemicals regulation REACH was to evaluate the scientific basis for the notion that endocrine disrupting substances might cause effects of a concern equivalent to the hazards posed by carcinogens, mutagens and reproductive and developmental toxicants. In line with these requirements, we prepared a science summary to assess the plausibility that xenobiotics might play a role in the aetiology of various health endpoints potentially related to endocrine disrupters. To achieve this aim, our assessment of the scientific evidence was based on the principles proposed by WHO/IPCS (2002) as a basis for attribution of effects to endocrine disruption (report chapter 3.16, p32). In dealing with this problem, it would have been inappropriate to utilize the causal criteria for assessing endocrine disrupters described in chapter 7 of the same report. This seems to have been entirely misunderstood by Rhomberg and colleagues. Rhomberg et al. have also overlooked the fact that we have dealt extensively with the issue of weight of evidence, both in the science summary and in the main part of our report (Kortenkamp et al., 2011). They ignore the complexity of developing weight of evidence approaches and seem to assume that such approaches are already available and agreed upon. However, this is not the case. As we have stressed in our report (Kortenkamp et al., 2011), weight of evidence approaches for endocrine disrupters are yet to Letter to the editor

Salvia officinalis for Hot Flushes: Towards Determination of Mechanism of Activity and Active Principles

Herbal medicinal products are commonly used in alternative treatment of menopausal hot flushes. In a recent clinical study, Salvia officinalis tincture was found to reduce hot flush frequency and intensity. The aim of the current study was the investigation of the mechanism(s) responsible for the anti-hot flush activity of S. officinalis and determination of its active principle(s). The 66% ethanolic tincture, as well as the n-hexane, CHCl₃, and aqueous ethanolic subextracts obtained from the tincture were studied in vitro for two of the most relevant activities, estrogenicity and selective serotonin reuptake inhibition. Because of an increased risk of menopausal women to suffer from Alzheimers disease, an in vitro acetylcholinesterase inhibition assay was also employed. No activity was observed in the selective serotonin reuptake inhibition or the acetylcholinesterase inhibition assays at the highest test concentrations. The tincture showed no estrogenic effects whereas the aqueous ethanolic subextract exhibited estrogenicity in the ERLUX assay with an EC₅₀ value of 64 µg/mL. Estrogenic activity-guided fractionation of the aqueous ethanolic subextract by a combination of reverse-phase vacuum liquid chromatography and gel chromatography identified luteolin-7-O-glucuronide (EC₅₀ 129 µg/mL) as the active component of the vacuum liquid chromatography fraction 4 (EC₅₀ 69 µg/mL). Luteolin-7-O-glucoside was identified as the putative estrogenic principle of the most potent minor fraction (7.6.7.6, EC₅₀ 0.7 µg/mL) obtained from the initial vacuum liquid chromatography fraction 7 (EC₅₀ 3 µg/mL). This study suggests the involvement of common and ubiquitous estrogenic flavonoids in the anti-hot flush effect of Salvia officinalis, a safe and commonly used herbal medicinal product during the menopause.

Neutrophil gelatinase-associated lipocalin prior to cardiac surgery predicts acute kidney injury and mortality

Objective We aimed to investigate whether preoperative serum neutrophil gelatinase-associated lipocalin (sNGALpre-op) predicted postoperative acute kidney injury (AKI) during hospitalisation and 1-year cardiovascular and all-cause mortality following adult cardiac surgery. Methods This study was a post hoc analysis of the Effect of Remote Ischemic Preconditioning on Clinical Outcomes in Patient Undergoing Coronary Artery Bypass Graft Surgery trial involving adult patients undergoing coronary artery bypass graft. Postoperative AKI within 72u2009hours was defined using the International Kidney Disease: Improving Global Outcomes classification. Results 1371 out of 1612 patients had data on sNGALpre-op. The overall 1-year cardiovascular and all-cause mortality was 5.2% (71/1371) and 7.7% (105/1371), respectively. There was an observed increase in the incidence of AKI from the first to the third tertile of sNGALpre-op (30.5%, 41.5% and 45.9%, respectively, p<0.001). There was also an increase in both cardiovascular and all-cause mortality from the first to the third tertile of sNGALpre-op, linear trend test with adjusted p=0.018u2009and p=0.013,u2009respectively. The adjusted HRs for those in the second and third tertiles of sNGALpre-op compared with the first tertile were 1.60 (95% CI 0.78 to 3.25) and 2.22 (95% CI 1.13 to 4.35) for cardiovascular mortality, and 1.25 (95% CI 0.71 to 2.22) and 1.91 (95% CI 1.13 to 3.25) for all-cause mortality at 1u2009year. Conclusion In a cohort of high-risk adult patients undergoing cardiac surgery, there was an increase in postoperative AKI and 1-year mortality from the first to the third tertile of preoperative serum NGAL. Those in the last tertile (>220u2009ng/L) had an estimated twofold increase risk of cardiovascular and all-cause mortality at 1u2009year. Clinical trial registration NCT101247545; Post-results.

Inability to confirm estrogenicity of the heterocyclic amine PhIP in two in vitro assays

2-Amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) is a heterocyclic amine which is found in food after cooking and which is a known mutagen. Reports from several laboratories have proposed that PhIP has estrogenic activity, which would classify PhIP as a xenoestrogen with human exposure via food. We tested PhIP in two cell-based assays for estrogenicity, both based on human cell lines but utilising different outcome measures: ERLUX (reporter-gene activation) and ESCREEN (cell proliferation). PhIP was inactive in both assays at concentrations spanning the picomolar to micromolar range. To eliminate supplier differences as an explanation for the disparity between these results and positive findings in the literature, we purchased PhIP from three suppliers and found no detectable estrogenic activity in any batch. (1)H NMR spectroscopy confirmed the chemical identity of the tested stock solutions. Correct assay performance was confirmed by including positive and vehicle controls on every assay plate, and by demonstrating the expected responses to a panel of known estrogens (estradiol, bisphenol A, and genistein). Our results differ from those in the literature and, whilst the exact reason for this is unknown, we discuss possible explanations of the disparity. Our results provide no in vitro evidence for the classification of PhIP as an estrogen.

Percutaneous Revascularization for Ischemic Ventricular Dysfunction: Rationale and Design of the REVIVED-BCIS2 Trial : Percutaneous Coronary Intervention for Ischemic Cardiomyopathy

OBJECTIVESnEvaluate whether PCI in combination with optimal medical therapy (OMT) will reduce all-cause death and hospitalization for HF compared to a strategy of OMT alone.nnnBACKGROUNDnIschemic cardiomyopathy (ICM) is the most common cause of heart failure (HF) and is associated with significant mortality and morbidity. Surgical revascularization has been shown to improve long-term outcomes in somexa0patients, but surgery itself carries a major early hazard. Percutaneous coronary intervention (PCI) may allow a better balance between risk and benefit.nnnMETHODSnREVIVED-BCIS2 is a prospective, multi-center, open-label, randomized controlled trial, funded by the National Institute for Health Research in the United Kingdom. Follow-up will be for at least 2 years from randomization. Secondary outcomes include left ventricular ejection fraction (LVEF), quality of life scores, appropriate implantable cardioverter defibrillator therapy and acute myocardial infarction. Patients with LVEF ≤35%, extensive coronary disease and demonstrable myocardial viability are eligible for inclusion and those with a myocardial infarction within 4 weeks, decompensated HF or sustained ventricular arrhythmias within 72 h are excluded. A trial of 700 patients has more than 85% power to detect a 30% relative reduction in hazard.nnnRESULTSnA total of 400 patients have been enrolled to date.nnnCONCLUSIONSnInternational guidelines do not provide firm recommendations on the role of PCI in managing severexa0ICM,xa0because of a lack of robust evidence. REVIVED-BCIS2 will provide the first randomized data on the efficacyxa0andxa0safety of PCI in ICM and has the potential to inform guidelines pertaining to both revascularization and HF. (Studyxa0ofxa0Efficacy andxa0Safety of Percutaneous Coronary Intervention to Improve Survival in Heart Failure [REVIVED-BCIS2]; NCT01920048) (REVascularisation for Ischaemic VEntricular Dysfunction; ISRCTN45979711).

Rationale and Design of: A Randomized tRial of Expedited transfer to a cardiac arrest center for non-ST elevation out-of-hospital cardiac arrest: The ARREST randomized controlled trial

Background Out‐of‐hospital cardiac arrest (OHCA) is a global public health issue. There is wide variation in both regional and inter‐hospital survival rates from OHCA and overall survival remains poor at 7%. Regionalization of care into cardiac arrest centers (CAC) improves outcomes following cardiac arrest from ST elevation myocardial infarction (STEMI) through concentration of services and greater provider experience. The International Liaison Committee on Resuscitation (ILCOR) recommends delivery of all post‐arrest patients to a CAC, but that randomized controlled trials are necessary in patients without ST elevation (STE). Methods/Design Following completion of a pilot randomized trial to assess safety and feasibility of conducting a large‐scale randomized controlled trial in patients following OHCA of presumed cardiac cause without STE, we present the rationale and design of A Randomized tRial of Expedited transfer to a cardiac arrest center for non‐ST elevation OHCA (ARREST). In total 860 patients will be enrolled and randomized (1:1) to expedited transfer to CAC (24/7 access to interventional cardiology facilities, cooling and goal‐directed therapies) or to the current standard of care, which comprises delivery to the nearest emergency department. Primary outcome is 30‐day all‐cause mortality and secondary outcomes are 30‐day and 3‐month neurological status and 3, 6 and 12‐month mortality. Patients will be followed up for one year after enrolment. Conclusion Post‐arrest care is time‐critical, requires a multi‐disciplinary approach and may be more optimally delivered in centers with greater provider experience. This trial would help to demonstrate if regionalization of post‐arrest care to CACs reduces mortality in patients without STE, which could dramatically reshape emergency care provision.