Cardiovascular MRI in clinical trials: expanded applications through novel surrogate endpoints

Recent advances in cardiovascular magnetic resonance (CMR) now allow the accurate and reproducible measurement of many aspects of cardiac and vascular structure and function, with prognostic data emerging for several key imaging biomarkers. These biomarkers are increasingly used in the evaluation of new drugs, devices and lifestyle modifications for the prevention and treatment of cardiovascular disease. This review outlines a conceptual framework for the application of imaging biomarkers to clinical trials, highlights several important CMR techniques which are in use in randomised studies, and reviews certain aspects of trial design, conduct and interpretation in relation to the use of CMR

A Static Aeroelastic Analysis of a Flexible Wing Mini Unmanned Aerial Vehicle

The static aeroelastic behavior of the Nighthawk mini unmanned aerial vehicle is examined using a combined experimental and computational approach. Three wings are examined. In order of increasing stiffness they are: a flexible wing, a stiff wing, and a fictitious rigid wing with zero deflection. Photogrammetry is used during wind tunnel testing to measure the average deflected shape of the flexible and stiff wings during flight. The independent variables during wind tunnel tests are angle of attack (ranging from −5.1° through 13.4°) and velocity, which is 20 mph, 30 mph, and 40 mph. Roll angle and yaw angle are control variables, held constant at 0°. The measured deflection of each wing is used to adjust the wing shape for computational fluid dynamics analysis. Solutions are obtained for the flexible, stiff, and undeflected (or rigid) wings using a steady-state viscous flow solver with a Spalart- Allmaras turbulence model. The flexible and stiff wings experience two forms of deformation during flight. They bend upward along the span increasing the dihedral, and the leading edge twists downward (wing washout). The amplitude of deflection is greatest for the flexible wing. As a result, the flexible wing is more stable, but also exhibits worse static aerodynamic performance. The rigid wing has the greatest lift (CL max = 1.29) and the highest lift-to-drag ratio ( L/Dmax = 10.2). Stall occurs first near the root for all three wings. None of the wings stall at the tip in the range of angles of attack tested. A separation bubble forms under the wing at angles of attack less than 8°. This separation decreases the overall lift. It is most prominent on the flexible wing

NHEJ protects mycobacteria in stationary phase against the harmful effects of desiccation

The physiological role of the non-homologous end-joining (NHEJ) pathway in the repair of DNA double-strand breaks (DSBs) was examined in Mycobacterium smegmatis using DNA repair mutants (DeltarecA, Deltaku, DeltaligD, Deltaku/ligD, DeltarecA/ku/ligD). Wild-type and mutant strains were exposed to a range of doses of ionizing radiation at specific points in their life-cycle. NHEJ-mutant strains (Deltaku, DeltaligD, Deltaku/ligD) were significantly more sensitive to ionizing radiation (IR) during stationary phase than wild-type M. smegmatis. However, there was little difference in IR sensitivity between NHEJ-mutant and wild-type strains in logarithmic phase. Similarly, NHEJ-mutant strains were more sensitive to prolonged desiccation than wild-type M. smegmatis. A DeltarecA mutant strain was more sensitive to desiccation and IR during both stationary and especially in logarithmic phase, compared to wild-type strain, but it was significantly less sensitive to IR than the DeltarecA/ku/ligD triple mutant during stationary phase. These data suggest that NHEJ and homologous recombination are the preferred DSB repair pathways employed by M. smegmatis during stationary and logarithmic phases, respectively

Management considerations of massive hemoptysis while on extracorporeal membrane oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is a life-saving procedure in patients with both respiratory and cardiac failure. Bleeding complications are common since patients must be maintained on anticoagulation. Massive hemoptysis is a rare complication of ECMO; however, it may result in death if not managed thoughtfully and expeditiously. METHODS: A retrospective chart review was performed of consecutive ECMO patients from 7/2010-8/2014 to identify episodes of massive hemoptysis. The management of and the outcomes in these patients were studied. Massive hemoptysis was defined as an inability to control bleeding (\u3e300 mL/day) from the endotracheal tube with conventional maneuvers, such as bronchoscopy with cold saline lavage, diluted epinephrine lavage and selective lung isolation. All of these episodes necessitated disconnecting the ventilator tubing and clamping the endotracheal tube, causing full airway tamponade. RESULTS: During the period of review, we identified 118 patients on ECMO and 3 (2.5%) patients had the complication of massive hemoptysis. One case was directly related to pulmonary catheter migration and the other two were spontaneous bleeding events that were propagated by antiplatelet agents. All three patients underwent bronchial artery embolization in the interventional radiology suite. Anticoagulation was held during the period of massive hemoptysis without any embolic complications. There was no recurrent bleed after appropriate intervention. All three patients were successfully separated from ECMO. CONCLUSIONS: Bleeding complications remain a major issue in patients on ECMO. Disconnection of the ventilator and clamping the endotracheal tube with full respiratory and cardiac support by V-A ECMO is safe. Early involvement of interventional radiology to embolize any potential sources of the bleed can prevent re-hemoptysis and enable continued cardiac and respiratory recovery

Sex-biased sound symbolism in english-language first names.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tSexual selection has resulted in sex-based size dimorphism in many mammals, including humans. In Western societies, average to taller stature men and comparatively shorter, slimmer women have higher reproductive success and are typically considered more attractive. This size dimorphism also extends to vocalisations in many species, again including humans, with larger individuals exhibiting lower formant frequencies than smaller individuals. Further, across many languages there are associations between phonemes and the expression of size (e.g. large /a, o/, small /i, e/), consistent with the frequency-size relationship in vocalisations. We suggest that naming preferences are a product of this frequency-size relationship, driving male names to sound larger and female names smaller, through sound symbolism. In a 10-year dataset of the most popular British, Australian and American names we show that male names are significantly more likely to contain larger sounding phonemes (e.g. "Thomas"), while female names are significantly more likely to contain smaller phonemes (e.g. "Emily"). The desire of parents to have comparatively larger, more masculine sons, and smaller, more feminine daughters, and the increased social success that accompanies more sex-stereotyped names, is likely to be driving English-language first names to exploit sound symbolism of size in line with sexual body size dimorphism.BJP is supported by a grant from The Fyssen Foundation

Can the Timeframe of Reported UAS Sightings Help Regulators?

Remotely controlled small aircraft, otherwise known as Unmanned Aircraft Systems (UAS) or drones have started to impact the United States National Airspace System by interfering with the safe flight of aircraft. As the UAS industry continues its expected growth into the future, lawmakers, as well as regulators at the Federal Aviation Administration (FAA) and the aviation community must be able to predict when there will be more UAS craft in the air that could cause an interruption to air traffic so that more resources can be allocated optimally to counter the threat of UAS craft. The purpose of this study to determine if there is seasonal variation in the calendar year when a plane would be more likely to encounter a UAS using reported sightings data from the FAA. The data collected contained 36 months of sightings from June 2015 – July 2018. This study will give the aviation community the ability to better forecast high demand of reported sightings. Regulators and anyone operating within the manned airspace would be better informed by knowing what times of the year yield a higher frequency of UAS sightings so that appropriate mitigation and safety strategies can be developed and followed. Further, the FAA can also engage in preemptive educational strategies in an effort to avoid unsafe incidents. According to the results, the months of May and June, followed by December and January, will have the highest incidence of UAS sightings

Regulation of Membrane Targeting of the G Protein-coupled Receptor Kinase 2 by Protein Kinase A and Its Anchoring Protein AKAP79

The beta 2 adrenergic receptor (beta 2AR) undergoes desensitization by a process involving its phosphorylation by both protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs). The protein kinase A-anchoring protein AKAP79 influences beta 2AR phosphorylation by complexing PKA with the receptor at the membrane. Here we show that AKAP79 also regulates the ability of GRK2 to phosphorylate agonist-occupied receptors. In human embryonic kidney 293 cells, overexpression of AKAP79 enhances agonist-induced phosphorylation of both the beta 2AR and a mutant of the receptor that cannot be phosphorylated by PKA (beta 2AR/PKA-). Mutants of AKAP79 that do not bind PKA or target to the beta 2AR markedly inhibit phosphorylation of beta 2AR/PKA-. We show that PKA directly phosphorylates GRK2 on serine 685. This modification increases Gbeta gamma subunit binding to GRK2 and thus enhances the ability of the kinase to translocate to the membrane and phosphorylate the receptor. Abrogation of the phosphorylation of serine 685 on GRK2 by mutagenesis (S685A) or by expression of a dominant negative AKAP79 mutant reduces GRK2-mediated translocation to beta 2AR and phosphorylation of agonist-occupied beta 2AR, thus reducing subsequent receptor internalization. Agonist-stimulated PKA-mediated phosphorylation of GRK2 may represent a mechanism for enhancing receptor phosphorylation and desensitization

Reinventing fisheries management

This article presents the events and outcome of an international symposium on fisheries management titled, "Reinventing Fisheries Management", held at the Fisheries Centre of the University of British Columbia, Vancouver, Canada, 21-23 February 1996. The title itself suggests that the topics would reach beyond present day paradigm as indeed they did

Characterisation of re-entrant circuit (or rotational activity) in vitro using the HL1-6 myocyte cell line

Fibrillation is the most common arrhythmia observed in clinical practice. Understanding of the mechanisms underlying its initiation and maintenance remains incomplete. Functional re-entries are potential drivers of the arrhythmia. Two main concepts are still debated, the “leading circle” and the “spiral wave or rotor” theories. The homogeneous subclone of the HL1 atrial-derived cardiomyocyte cell line, HL1-6, spontaneously exhibits re-entry on a microscopic scale due to its slow conduction velocity and the presence of triggers, making it possible to examine re-entry at the cellular level. We therefore investigated the re-entry cores in cell monolayers through the use of fluorescence optical mapping at high spatiotemporal resolution in order to obtain insights into the mechanisms of re-entry. Re-entries in HL1-6 myocytes required at least two triggers and a minimum colony area to initiate (3.5 to 6.4 mm2). After electrical activity was completely stopped and re-started by varying the extracellular K+ concentration, re-entries never returned to the same location while 35% of triggers re-appeared at the same position. A conduction delay algorithm also allows visualisation of the core of the re-entries. This work has revealed that the core of re-entries is conduction blocks constituted by lines and/or groups of cells rather than the round area assumed by the other concepts of functional re-entry. This highlights the importance of experimentation at the microscopic level in the study of re-entry mechanisms

Obese Subjects Show Sex-Specific Differences in Right Ventricular Hypertrophy

As right ventricular (RV) remodeling in obesity remains underinvestigated, and the impact of left ventricular (LV) diastolic dysfunction on RV hypertrophy is unknown, we aimed to investigate whether (1) sex-specific patterns of RV remodeling exist in obesity and (2) LV diastolic dysfunction in obesity is related to RV hypertrophy.Seven hundred thirty-nine subjects (women, n=345; men, n=394) without identifiable cardiovascular risk factors (body mass index [BMI], 15.3-59.2 kg/m2) underwent cardiovascular magnetic resonance (1.5 T) to measure RV mass (g), RV end-diastolic volume (mL), RV mass/volume ratio, and LV diastolic peak filling rate (mL/s). All subjects were normotensive (average, 119±11/73±8 mm Hg), normoglycaemic (4.8±0.5 mmol/L), and normocholesterolaemic (4.8±0.9 mmol/L) at the time of scanning. Across both sexes, there was a moderately strong positive correlation between BMI and RV mass (men, +0.8 g per BMI point increase; women, +1.0 g per BMI point increase; both P<0.001). Whereas women exhibited RV cavity dilatation (RV end-diastolic volume, +1.0 mL per BMI point increase; P<0.001), BMI was not correlated with RV end-diastolic volume in men (R=0.04; P=0.51). Concentric RV remodeling was present in both sexes, with RV mass/volume ratio being positively correlated to BMI (men, R=0.41; women, R=0.51; both P<0.001). Irrespective of sex, the LV peak filling rate was negatively correlated with both RV mass (men, R=-0.43; women, R=-0.44; both P<0.001) and RV mass/volume ratio (men, R=-0.37; women, R=-0.35; both P<0.001).A sex difference in RV remodeling exists in obesity. Whereas men exhibit concentric RV remodeling, women exhibit a mixed pattern of eccentric and concentric remodeling. Regardless of sex, reduced LV diastolic function is associated with concentric RV remodeling