Evaluation of the impact of the GRACE risk score on the management and outcome of patients hospitalised with non-ST elevation acute coronary syndrome in the UK: protocol of the UKGRIS cluster-randomised registry-based trial

Introduction For non-ST-segment elevation acute coronary syndrome (NSTEACS) there is a gap between the use of class 1 guideline recommended therapies and clinical practice. The GRACE risk score is recommended in international guidelines for the risk stratification of NSTEACS, but its impact on adherence to guideline-indicated treatments and reducing adverse clinical outcomes is unknown. The objective of the UKGRIS trial is to assess the effectiveness of the GRACE risk score tool and associated treatment recommendations on the use of guideline-indicated care and clinical outcomes. Methods and Analysis The UK GRACE Risk Score Intervention Study (UKGRIS), a parallel-group cluster randomised registry-based controlled trial, will allocate hospitals in a 1:1 ratio to manage NSTEACS by standard care or according to the GRACE risk score and associated international guidelines. UKGRIS will recruit a minimum of 3000 patients from at least 30 English National Health Service hospitals and collect healthcare data from national electronic health records. The co-primary endpoints are the use of guideline-indicated therapies, and the composite of cardiovascular death, non-fatal myocardial infarction, new onset heart failure hospitalisation or cardiovascular readmission at 12 months. Secondary endpoints include duration of inpatient hospital stay over 12 months, EQ-5D-5L responses and utilities, unscheduled revascularisation and the components of the composite endpoint over 12 months follow-up. Ethics and Dissemination The study has ethical approval (North East - Tyne & Wear South Research Ethics Committee ref: 4/NE/1180). Findings will be announced at relevant conferences and published in peer-reviewed journals in line with the funder’s open access policy. Registration ISRCTN29731761, registered 12th January 2017

Heart Rate and Use of Beta-Blockers in Stable Outpatients with Coronary Artery Disease

<p><b>Background:</b> Heart rate (HR) is an emerging risk factor in coronary artery disease (CAD). However, there is little contemporary data regarding HR and the use of HR-lowering medications, particularly beta-blockers, among patients with stable CAD in routine clinical practice. The goal of the present analysis was to describe HR in such patients, overall and in relation to beta-blocker use, and to describe the determinants of HR.</p> <p><b>Methods and Findings:</b> CLARIFY is an international, prospective, observational, longitudinal registry of outpatients with stable CAD, defined as prior myocardial infarction or revascularization procedure, evidence of coronary stenosis of >50%, or chest pain associated with proven myocardial ischemia. A total of 33,438 patients from 45 countries in Europe, the Americas, Africa, Middle East, and Asia/Pacific were enrolled between November 2009 and July 2010. Most of the 33,177 patients included in this analysis were men (77.5%). Mean (SD) age was 64.2 (10.5) years, HR by pulse was 68.3 (10.6) bpm, and by electrocardiogram was 67.2 (11.4) bpm. Overall, 44.0% had HR≥70 bpm. Beta-blockers were used in 75.1% of patients and another 14.4% had intolerance or contraindications to beta-blocker therapy. Among 24,910 patients on beta-blockers, 41.1% had HR≥70 bpm. HR≥70 bpm was independently associated with higher prevalence and severity of angina, more frequent evidence of myocardial ischemia, and lack of use of HR-lowering agents.</p> <p><b>Conclusions:</b> Despite a high rate of use of beta-blockers, stable CAD patients often have resting HR≥70 bpm, which was associated with an overall worse health status, more frequent angina and ischemia. Further HR lowering is possible in many patients with CAD. Whether it will improve symptoms and outcomes is being tested.</p&gt

DNA barcoding unveils skate (Chondrichthyes: Rajidae) species diversity in ‘ray’ products sold across Ireland and the UK

Skates are widely consumed across the globe, but many large species are subject toconsiderable concern regarding their conservation and management. Within Europesuch issues have recently driven policy changes so that, for the first time, reports ofskate landings now have to be made under species-specific names. Total allowablecatches have also been established for many groups, which have been set to zero fora number of the most vulnerable species (e.g., Dipturus batis, Raja undulata andRostoraja alba. Whilst accurate species identification has become an important issuefor landings, the sale of skates is still usually made under a blanket term of “skate”or “ray”. The matter of identifying species of skate is further complicated by theirmorphologically conservative nature and the fact that they are commercially valuedfor their wings. Thus, before sale their bodies are usually discarded (i.e., “winged”)and often skinned, making morphological identification impossible. For the firsttime, DNA barcoding (of the mitochondrial COI gene) was applied to samples ofskate wings from retail outlets across the British Isles, providing insight into whichspecies are sold for consumption. A total of 98 wing samples were analysed, revealingthat six species were sold; blonde ray (Raja brachyura), spotted ray (Raja montagui),thornback ray (Raja clavata), cuckoo ray (Leucoraja naevus) small-eyed ray (Rajamicroocellata) and shagreen ray (Leucoraja fullonica). Statistical testing demonstratedthat there were significant differences in the species sold in the distinct retail groupswhich suggests complex drivers behind the patterns of sale in skates. The results alsoindicate that endangered species are not commonly being passed on to consumers.In addition, the practice of selling skate wings under ambiguous labels is highlightedas it makes it extremely difficult for consumers to exercise a right to avoid speciesof conservation concern. Interestingly, a single retailer chain labelled their wings asoriginating from three smaller-growing species (generally to be considered of lowerconservation concern); of the six samples analysed from this company a third weremislabelled and originated from the thornback ray (a larger species that is currentlyundergoing population declines)

Prevalence of myocardial hypertrophy in a population of asymptomatic Swedish Maine coon cats

<p>Abstract</p> <p>Background</p> <p>Maine coon cats have a familial disposition for developing hypertrophic cardiomyopathy (HCM) with evidence of an autosomal dominant mode of inheritance <abbrgrp><abbr bid="B1">1</abbr></abbrgrp>. The current mode to diagnose HCM is by use of echocardiography. However, definite reference criteria have not been established. The objective of the study was to determine the prevalence of echocardigraphic changes consistent with hypertrophic cardiomyopathy in Swedish Maine coon cats, and to compare echocardiographic measurements with previously published reference values.</p> <p>Methods</p> <p>All cats over the age of 8 months owned by breeders living in Stockholm, listed on the website of the Maine Coon breeders in Sweden by February 2001, were invited to participate in the study. Physical examination and M-mode and 2D echocardiographic examinations were performed in all cats.</p> <p>Results</p> <p>Examinations of 42 asymptomatic Maine coon cats (10 males and 32 females) were performed. The age of the cats ranged from 0,7 to 9,3 years with a mean of 4,8 ± 2,3 years. Four cats (9,5%) had a diastolic interventricular septal (IVSd) or left ventricular free wall (LVPWd) thickness exceeding 6,0 mm. In 3 of these cats the hypertrophy was segmental. Two cats (4,8%) had systolic anterior motion (SAM) of the mitral valve without concomitant hypertrophy. Five cats (11,9%) had IVSd or LVPWd exceeding 5,0 mm but less than 6,0 mm.</p> <p>Conclusion</p> <p>Depending on the reference values used, the prevalence of HCM in this study varied from 9,5% to 26,2%. Our study suggests that the left ventricular wall thickness of a normal cat is 5,0 mm or less, rather than 6,0 mm, previously used by most cardiologists. Appropriate echocardiographic reference values for Maine coon cats, and diagnostic criteria for HCM need to be further investigated.</p

Studies on the actin-binding protein HS1 in platelets

<p>Abstract</p> <p>Background</p> <p>The platelet cytoskeleton mediates the dramatic change in platelet morphology that takes place upon activation and stabilizes thrombus formation. The Arp2/3 complex plays a vital role in these processes, providing the protrusive force for lamellipodia formation. The Arp2/3 complex is highly regulated by a number of actin-binding proteins including the haematopoietic-specific protein HS1 and its homologue cortactin. The present study investigates the role of HS1 in platelets using HS1^-/-mice.</p> <p>Results</p> <p>The present results demonstrate that HS1 is not required for platelet activation, shape change or aggregation. Platelets from HS1^-/-mice spread normally on a variety of adhesion proteins and have normal F-actin and Arp2/3 complex distributions. Clot retraction, an actin-dependent process, is also normal in these mice. Platelet aggregation and secretion is indistinguishable between knock out and littermates and there is no increase in bleeding using the tail bleeding assay.</p> <p>Conclusion</p> <p>This study concludes that HS1 does not play a major role in platelet function. It is possible that a role for HS1 is masked by the presence of cortactin.</p

A seesaw model for intermolecular gating in the kinesin motor protein

Recent structural observations of kinesin-1, the founding member of the kinesin group of motor proteins, have led to substantial gains in our understanding of this molecular machine. Kinesin-1, similar to many kinesin family members, assembles to form homodimers that use alternating ATPase cycles of the catalytic motor domains, or “heads”, to proceed unidirectionally along its partner filament (the microtubule) via a hand-over-hand mechanism. Cryo-electron microscopy has now revealed 8-Å resolution, 3D reconstructions of kinesin-1•microtubule complexes for all three of this motor’s principal nucleotide-state intermediates (ADP-bound, no-nucleotide, and ATP analog), the first time filament co-complexes of any cytoskeletal motor have been visualized at this level of detail. These reconstructions comprehensively describe nucleotide-dependent changes in a monomeric head domain at the secondary structure level, and this information has been combined with atomic-resolution crystallography data to synthesize an atomic-level "seesaw" mechanism describing how microtubules activate kinesin’s ATP-sensing machinery. The new structural information revises or replaces key details of earlier models of kinesin’s ATPase cycle that were based principally on crystal structures of free kinesin, and demonstrates that high-resolution characterization of the kinesin–microtubule complex is essential for understanding the structural basis of the cycle. I discuss the broader implications of the seesaw mechanism within the cycle of a fully functional kinesin dimer and show how the seesaw can account for two types of "gating" that keep the ATPase cycles of the two heads out of sync during processive movement

FAK acts as a suppressor of RTK-MAP kinase signalling in Drosophila melanogaster epithelia and human cancer cells

Receptor Tyrosine Kinases (RTKs) and Focal Adhesion Kinase (FAK) regulate multiple signalling pathways, including mitogen-activated protein (MAP) kinase pathway. FAK interacts with several RTKs but little is known about how FAK regulates their downstream signalling. Here we investigated how FAK regulates signalling resulting from the overexpression of the RTKs RET and EGFR. FAK suppressed RTKs signalling in Drosophila melanogaster epithelia by impairing MAPK pathway. This regulation was also observed in MDA-MB-231 human breast cancer cells, suggesting it is a conserved phenomenon in humans. Mechanistically, FAK reduced receptor recycling into the plasma membrane, which resulted in lower MAPK activation. Conversely, increasing the membrane pool of the receptor increased MAPK pathway signalling. FAK is widely considered as a therapeutic target in cancer biology; however, it also has tumour suppressor properties in some contexts. Therefore, the FAK-mediated negative regulation of RTK/MAPK signalling described here may have potential implications in the designing of therapy strategies for RTK-driven tumours

Male reproductive health and environmental xenoestrogens

EHP is a publication of the U.S. government. Publication of EHP lies in the public domain and is therefore without copyright. Research articles from EHP may be used freely; however, articles from the News section of EHP may contain photographs or figures copyrighted by other commercial organizations and individuals that may not be used without obtaining prior approval from both the EHP editors and the holder of the copyright. Use of any materials published in EHP should be acknowledged (for example, "Reproduced with permission from Environmental Health Perspectives") and a reference provided for the article from which the material was reproduced.Male reproductive health has deteriorated in many countries during the last few decades. In the 1990s, declining semen quality has been reported from Belgium, Denmark, France, and Great Britain. The incidence of testicular cancer has increased during the same time incidences of hypospadias and cryptorchidism also appear to be increasing. Similar reproductive problems occur in many wildlife species. There are marked geographic differences in the prevalence of male reproductive disorders. While the reasons for these differences are currently unknown, both clinical and laboratory research suggest that the adverse changes may be inter-related and have a common origin in fetal life or childhood. Exposure of the male fetus to supranormal levels of estrogens, such as diethlylstilbestrol, can result in the above-mentioned reproductive defects. The growing number of reports demonstrating that common environmental contaminants and natural factors possess estrogenic activity presents the working hypothesis that the adverse trends in male reproductive health may be, at least in part, associated with exposure to estrogenic or other hormonally active (e.g., antiandrogenic) environmental chemicals during fetal and childhood development. An extensive research program is needed to understand the extent of the problem, its underlying etiology, and the development of a strategy for prevention and intervention.Supported by EU Contract BMH4-CT96-0314

Laser-Assisted In Vitro Fertilization Facilitates Fertilization of Vitrified-Warmed C57BL/6 Mouse Oocytes with Fresh and Frozen-Thawed Spermatozoa, Producing Live Pups

The utility of cryopreserved mouse gametes for reproduction of transgenic mice depends on development of assisted reproductive technologies, including vitrification of unfertilized mouse oocytes. Due to hardening of the zona pellucida, spermatozoa are often unable to penetrate vitrified-warmed (V-W) oocytes. Laser-assisted in vitro fertilization (LAIVF) facilitates fertilization by allowing easier penetration of spermatozoa through a perforation in the zona. We investigated the efficiency of V-W C57BL/6NTac oocytes drilled by the XYClone laser, compared to fresh oocytes. By using DAP213 for cryoprotection, 83% (1,470/1,762) of vitrified oocytes were recovered after warming and 78% were viable. Four groups were evaluated for two-cell embryo and live offspring efficiency: 1) LAIVF using V-W oocytes, 2) LAIVF using fresh oocytes, 3) conventional IVF using V-W oocytes and 4) conventional IVF using fresh oocytes. First, the groups were tested using fresh C57BL/6NTac spermatozoa (74% motile, 15 million/ml). LAIVF markedly improved the two-cell embryo efficiency using both V-W (76%, 229/298) and fresh oocytes (69%, 135/197), compared to conventional IVF (7%, 12/182; 6%, 14/235, respectively). Then, frozen-thawed C57BL/6NTac spermatozoa (35% motile, 15 million/ml) were used and LAIVF was again found to enhance fertilization efficiency, with two-cell embryo rates of 87% (298/343) using V-W oocytes (P<0.05, compared to fresh spermatozoa), and 73% (195/266) using fresh oocytes. Conventional IVF with frozen-thawed spermatozoa using V-W (6%, 10/168) and fresh (5%, 15/323) oocytes produced few two-cell embryos. Although live offspring efficiency following embryo transfer was greater with conventional IVF (35%, 18/51; LAIVF: 6%, 50/784), advantage was seen with LAIVF in live offspring obtained from total oocytes (5%, 50/1,010; conventional IVF: 2%, 18/908). Our results demonstrated that zona-drilled V-W mouse oocytes can be used for IVF procedures using both fresh and frozen-thawed spermatozoa, producing live pups. The ability to cryopreserve mouse gametes for LAIVF may facilitate management of large-scale transgenic mouse production facilities.National Institutes of Health (U.S.) (NIH National Research Service Award (T32-RR070036))National Institutes of Health (U.S.) (NIH National Cancer Institute Program Project (P01CA10451)