Explore the vast range of titles available.

Bivalirudin, with selective use of glycoprotein (GP) IIb/IIIa inhibitor agents, is an accepted standard of care in primary percutaneous coronary intervention (PPCI). We aimed to compare antithrombotic therapy with bivalirudin or unfractionated heparin during this procedure. In our open-label, randomised controlled trial, we enrolled consecutive adults scheduled for angiography in the context of a PPCI presentation at Liverpool Heart and Chest Hospital (Liverpool, UK) with a strategy of delayed consent. Before angiography, we randomly allocated patients (1:1; stratified by age [<75 years vs ≥75 years] and presence of cardiogenic shock [yes vs no]) to heparin (70 U/kg) or bivalirudin (bolus 0·75 mg/kg; infusion 1·75 mg/kg per h). Patients were followed up for 28 days. The primary efficacy outcome was a composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target lesion revascularisation. The primary safety outcome was incidence of major bleeding (type 3–5 as per Bleeding Academic Research Consortium definitions). This study is registered with ClinicalTrials.gov, number NCT01519518. Between Feb 7, 2012, and Nov 20, 2013, 1829 of 1917 patients undergoing emergency angiography at our centre (representing 97% of trial-naive presentations) were randomly allocated treatment, with 1812 included in the final analyses. 751 (83%) of 905 patients in the bivalirudin group and 740 (82%) of 907 patients in the heparin group had a percutaneous coronary intervention. The rate of GP IIb/IIIa inhibitor use was much the same between groups (122 patients [13%] in the bivalirudin group and 140 patients [15%] in the heparin group). The primary efficacy outcome occurred in 79 (8·7%) of 905 patients in the bivalirudin group and 52 (5·7%) of 907 patients in the heparin group (absolute risk difference 3·0%; relative risk [RR] 1·52, 95% CI 1·09–2·13, p=0·01). The primary safety outcome occurred in 32 (3·5%) of 905 patients in the bivalirudin group and 28 (3·1%) of 907 patients in the heparin group (0·4%; 1·15, 0·70–1·89, p=0·59). Compared with bivalirudin, heparin reduces the incidence of major adverse ischaemic events in the setting of PPCI, with no increase in bleeding complications. Systematic use of heparin rather than bivalirudin would reduce drug costs substantially. Liverpool Heart and Chest Hospital, UK National Institute of Health Research, The Medicines Company, AstraZeneca, The Bentley Drivers Club (UK).

Eukaryotic initiation factor 4E (eIF4E) serves as a regulatory hub for oncogene-driven protein synthesis and is considered a promising anticancer target. Here we screen a fragment library against eIF4E and identify a ligand-binding site with previously unknown function. Follow-up structure-based design yields a low nM tool compound ( 4 , K d  = 0.09 µM; LE 0.38), which disrupts the eIF4E:eIF4G interaction, inhibits translation in cell lysates, and demonstrates target engagement with eIF4E in intact cells (EC 50  = 2 µM). By coupling targeted protein degradation with genetic rescue using eIF4E mutants, we show that disruption of both the canonical eIF4G and non-canonical binding sites is likely required to drive a strong cellular effect. This work highlights the power of fragment-based drug discovery to identify pockets in difficult-to-drug proteins and how this approach can be combined with genetic characterization and degrader technology to probe protein function in complex biological systems. A structure-guided fragment screen identified a compound, which interacts with a ligand-binding site of unknown function in eukaryotic initiation factor 4E (eIF4E). X-ray crystallography was used to characterise binding and target engagment was shown in cells.

Background Previous studies have demonstrated the feasibility of primary percutaneous coronary intervention (PPCI) in carefully selected nonagenarians. Although current guidelines recommend immediate revascularization in patients with ST elevation myocardial infarction (STEMI) it remains unclear whether PPCI reduces mortality in nonagenarians. The objective of this study is to compare mortality in nonagenarians presenting via the PPCI pathway who undergo coronary intervention, versus those who are managed medically. Methods and results A total of 111 consecutive nonagenarians who presented to our tertiary center via the PPCI pathway between July 2013 and December 2018 with myocardial infarction were included. Clinical and angiographic details were collected alongside data on all-cause mortality. The final diagnosis was STEMI in 98 (88.3%) and NSTEMI in 13 (11.7%). PPCI was performed in 42 (37.8%), while 69 (62.2%) were medically managed. A significant number of the medically managed cohort had atrial fibrillation (23.2% vs 2.4% p  = 0.003) and presented with a completed infarct (43.5% vs 4.8% p  = 0.001). Other baseline and clinical variables were well matched in both groups. There was a trend towards increased 30-day mortality in the medically managed group (40.6% vs 23.8% p  = 0.07). Kaplan Meier survival analysis demonstrated a significant difference in survival by 3 years (48.1% vs 21.7% p  = 0.01). This was the case even when those with completed infarcts were excluded (44.3% vs 14.6%, p  = 0.01). Conclusion In this series of selected nonagenarians presenting with acute myocardial infarction, those undergoing PPCI appeared to have a lower mortality compared to those managed medically.

AimRevascularisation of CTOs is a technically challenging procedure and complex cases often require dual access. Advancements in techniques have made bi-radial access more feasible. However, the limited evidence suggests that in patients with complex lesions radial access is associated with lower success rates. Our primary outcome was to determine how effective bi-radial access is compared to femoral.MethodsThis was a retrospective single centre observational study. Patients who had undergone CTO-PCI between January 2014 and January 2018, that required dual-access, were enrolled. They were separated into bi-radial access and radio-femoral or bi-femoral access. Every angiogram was reviewed independently to calculate a JCTO score (a measure of lesion complexity). Data on demographics, co-morbidities, complications, lesion characteristics, radiation and contrast dose were collected. Standard univariate analyses were performed to look for any tends that predicted failure to revascularise.ResultsIn total, 150 cases were identified, 109 bi-radial, 41 femoral (36 radio-femoral and 5 bi-femoral) access. Although there was no statistically significant difference in success rate for revascularisation between the radial and femoral groups (87% vs 78%; p = 0.17), there was a trend in favour of radial access. The average JCTO score was 3 vs 4 (p=0.04) indicating that those undergoing femoral procedures had more complex lesions. When only comparing cases with a JCTO score of ≥4, success rates were equivalent (78.1% vs 80.9% p = >0.99).Although statistical significance was not reached due to the overall small population, the following were associated with CTO-PCI failure: raised BMI, poor renal function, previous CABG, a higher JCTO score, CTO length > 20mm, presence of a >45° bend within the diseased segment and the absence of collateral vessels. The radial access group had shorter procedure lengths (111 minutes (68–137) vs 147 minutes (100–165); p=0.02), reduced radiation exposure (dose area product 17452 CGYcm2 (9827–23958) vs 23651 CGYcm2 (15303–27016); p=0.05) and required less contrast (237 mls (180–320) vs 315 mls (256–345); p= 0.04). There was also a reduction in mean length of in-hospital stay (0.38 ± 1.3 vs 0.61 ± 1.1 days [p=0.02]). A trend towards a higher rate of complications was noted in the femoral group [10.1% vs 19.5% p=0.12] (table 1 and table 2).Abstract 58 Table 1Baseline demographicAbstract 58 Table 2Lesion characteristic and outcomeConclusionBi-radial access is a safe alternative to radio-femoral or bi-femoral access in CTO-PCI. Previous studies have suggested that more complex cases require femoral access. However, when only JCTO ≥4 patients were compared there was equivalent rates of success. We use 7 French sheaths routinely in bi-radial access. This provides more support and may partly explain why success rates are comparable. With shorter length of stay, fewer complications, and less contrast/radiation used in radial cases we suggest that even in complex CTO-PCI cases, bi-radial access is an effective and safer alternative.Conflict of InterestNone

Ball lightning is a natural phenomenon that occurs in the atmosphere. However due to its brevity and rarity, its occurrence is not well understood. Three models based on electromagnetic properties are discussed in this paper to explain the rare phenomenon of ball lightning. The first model incorporates the idea of electron bunching, electrons moving with different velocities. This creates a plasma bubble by recombining electrons with ionized gas to form plasma that is stabilized by a standing microwave. The second model explains the idea of streamers being tangled and linked in a magnetic field while stabilized by the conservation of helicity. The third model is a lab created skyrmion that when evaluated exhibits qualities similar to ball lightning.

Ball lightning is a natural phenomenon that occurs in the atmosphere. However due to its brevity and rarity, its occurrence is not well understood. Three models based on electromagnetic properties are discussed in this paper to explain the rare phenomenon of ball lightning. The first model incorporates the idea of electron bunching, electrons moving with different velocities. This creates a plasma bubble by recombining electrons with ionized gas to form plasma that is stabilized by a standing microwave. The second model explains the idea of streamers being tangled and linked in a magnetic field while stabilized by the conservation of helicity. The third model is a lab created skyrmion that when evaluated exhibits qualities similar to ball lightning.

[...]the model ignores the main benefits of a routine invasive strategy over a selective invasive strategy, namely reductions in recurrent non-fatal myocardial infarction, 3 admission rates, revascularisations and costs during follow-up.