Constraints on the Progenitor System of the Type Ia Supernova 2014J from Pre-Explosion Hubble Space Telescope Imaging

We constrain the properties of the progenitor system of the highly reddened Type Ia supernova (SN) 2014J in Messier 82 (M82; d ~ 3.5 Mpc). We determine the SN location using Keck-II K-band adaptive optics images, and we find no evidence for flux from a progenitor system in pre-explosion near-ultraviolet through near-infrared Hubble Space Telescope (HST) images. Our upper limits exclude systems having a bright red giant companion, including symbiotic novae with luminosities comparable to that of RS Ophiuchi. While the flux constraints are also inconsistent with predictions for comparatively cool He-donor systems (T < ~35,000 K), we cannot preclude a system similar to V445 Puppis. The progenitor constraints are robust across a wide range of R_V and A_V values, but significantly greater values than those inferred from the SN light curve and spectrum would yield proportionally brighter luminosity limits. The comparatively faint flux expected from a binary progenitor system consisting of white dwarf stars would not have been detected in the pre-explosion HST imaging. Infrared HST exposures yield more stringent constraints on the luminosities of very cool (T < 3000 K) companion stars than was possible in the case of SN Ia 2011fe.Comment: Accepted by ApJ 14 May 2014 with only minor revision

Dietary nitrate supplementation: effects on plasma nitrite and pulmonary O2 uptake dynamics during exercise in hypoxia and normoxia

Clinical TrialThis is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.We investigated the effects of dietary nitrate (NO3 (-)) supplementation on the concentration of plasma nitrite ([NO2 (-)]), oxygen uptake (V̇o2) kinetics, and exercise tolerance in normoxia (N) and hypoxia (H). In a double-blind, crossover study, 12 healthy subjects completed cycle exercise tests, twice in N (20.9% O2) and twice in H (13.1% O2). Subjects ingested either 140 ml/day of NO3 (-)-rich beetroot juice (8.4 mmol NO3; BR) or NO3 (-)-depleted beetroot juice (PL) for 3 days prior to moderate-intensity and severe-intensity exercise tests in H and N. Preexercise plasma [NO2 (-)] was significantly elevated in H-BR and N-BR compared with H-PL (P < 0.01) and N-PL (P < 0.01). The rate of decline in plasma [NO2 (-)] was greater during severe-intensity exercise in H-BR [-30 ± 22 nM/min, 95% confidence interval (CI); -44, -16] compared with H-PL (-7 ± 10 nM/min, 95% CI; -13, -1; P < 0.01) and in N-BR (-26 ± 19 nM/min, 95% CI; -38, -14) compared with N-PL (-1 ± 6 nM/min, 95% CI; -5, 2; P < 0.01). During moderate-intensity exercise, steady-state pulmonary V̇o2 was lower in H-BR (1.91 ± 0.28 l/min, 95% CI; 1.77, 2.13) compared with H-PL (2.05 ± 0.25 l/min, 95% CI; 1.93, 2.26; P = 0.02), and V̇o2 kinetics was faster in H-BR (τ: 24 ± 13 s, 95% CI; 15, 32) compared with H-PL (31 ± 11 s, 95% CI; 23, 38; P = 0.04). NO3 (-) supplementation had no significant effect on V̇o2 kinetics during severe-intensity exercise in hypoxia, or during moderate-intensity or severe-intensity exercise in normoxia. Tolerance to severe-intensity exercise was improved by NO3 (-) in hypoxia (H-PL: 197 ± 28; 95% CI; 173, 220 vs. H-BR: 214 ± 43 s, 95% CI; 177, 249; P = 0.04) but not normoxia. The metabolism of NO2 (-) during exercise is altered by NO3 (-) supplementation, exercise, and to a lesser extent, hypoxia. In hypoxia, NO3 (-) supplementation enhances V̇o2 kinetics during moderate-intensity exercise and improves severe-intensity exercise tolerance. These findings may have important implications for individuals exercising at altitude

Motor vehicle accidents in patients with an implantable cardioverter-defibrillator

Objectives.This study was designed to examine driving safety in patients at risk for sudden death after implantation of a cardioverter-defibrillator.Background.Cardioverter-defibrillators are frequently implanted in patients at high risk for sudden death. Despite concern about the safety of driving in these patients, little is known about their actual motor vehicle accident rates.Methods.Surveys were sent to all 742 physicians in the United States involved in cardioverter-defibrillator implantation and follow-up. Physicians were questioned about numbers of patients followed up, numbers of fatal and nonfatal accidents, physician recommendations to patients about driving and knowledge of state driving laws.Results.Surveys were returned by 452 physicians (61%). A total of 30 motor vehicle accidents related to shocks from implantable defibrillators were reported by 25 physicians over a 12-year period from 1980 to 1992. Of these, nine were fatal accidents involving eight patients with a defibrillator and one passenger in a car driven by a patient. No bystanders were fatally injured. There were 21 nonfatal accidents involving 15 patients, 3 passengers and 3 bystanders. The estimated fatality rate for patients with a defibrillator, 7.5/100,000 patient-years, is significantly lower than that for the general population (18.4/100,000 patient-years, p < 0.05). The estimated injury rate, 17.6/100,000 patient-years, is also significantly lower than that for the general public (2,224/100,000 patient-years, p < 0.05). Only 10.5% (30 of 286) of all defibrillator discharges during driving resulted in accidents. Regarding physician recommendations, most physicians (58.1%) ask their patients to wait a mean (± SD) of 7.3 ± 3.4 months after implantation or a shock before driving again.Conclusions.The motor vehicle accident rate caused by discharge from an implantable cardioverter-defibrillator is low. Although restricting driving for a short period of time after implantation may be appropriate, excessive restrictions or a total ban on driving appears to be unwarranted

Developing an international concept-based curriculum for pharmacology education: The promise of core concepts and concept inventories

\ua9 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley &amp; Sons Ltd on behalf of British Pharmacological Society.Over recent years, studies have shown that science and health profession graduates demonstrate gaps in their fundamental pharmacology knowledge and ability to apply pharmacology concepts in practice. This article reviews the current challenges faced by pharmacology educators, including the exponential growth in discipline knowledge and competition for curricular time. We then argue that pharmacology education should focus on essential concepts that enable students to develop beyond ‘know’ towards ‘know how to’. A concept-based approach will help educators prioritize and benchmark their pharmacology curriculum, facilitate integration of pharmacology with other disciplines in the curriculum, create alignment between universities and improve application of pharmacology knowledge to professional contexts such as safe prescribing practices. To achieve this, core concepts first need to be identified and unpacked, and methods for teaching and assessment using concept inventories developed. The International Society for Basic and Clinical Pharmacology Education Section (IUPHAR-Ed) Core Concepts of Pharmacology (CCP) initiative involves over 300 educators from the global pharmacology community. CCP has identified and defined the core concepts of pharmacology, together with key underpinning sub-concepts. To realize these benefits, pharmacology educators must develop methods to teach and assess core concepts. Work to develop concept inventories is ongoing, including identifying student misconceptions of the core concepts and creating a bank of multiple-choice questions to assess student understanding. Future work aims to develop and validate materials and methods to help educators embed core concepts within curricula. Potential strategies that educators can use to overcome factors that inhibit adoption of core concepts are presented

How should we discuss genetic testing with women newly diagnosed with breast cancer? Design and implementation of a randomized controlled trial of two models of delivering education about treatment-focused genetic testing to younger women newly diagnosed with breast cancer

BACKGROUND: Germline BRCA1 and BRCA2 mutation testing offered shortly after a breast cancer diagnosis to inform women's treatment choices - treatment-focused genetic testing 'TFGT' - has entered clinical practice in specialist centers and is likely to be soon commonplace in acute breast cancer management, especially for younger women. Yet the optimal way to deliver information about TFGT to younger women newly diagnosed with breast cancer is not known, particularly for those who were not suspected of having a hereditary breast cancer syndrome prior to their cancer diagnosis. Also, little is known about the behavioral and psychosocial impact or cost effectiveness of educating patients about TFGT. This trial aims to examine the impact and efficiency of two models of educating younger women newly diagnosed with breast cancer about genetic testing in order to provide evidence for a safe and effective future clinical pathway for this service. DESIGN/METHODS: In this non-inferiority randomized controlled trial, 140 women newly diagnosed with breast cancer (aged less than 50 years) are being recruited from nine cancer centers in Australia. Eligible women with either a significant family history of breast and/or ovarian cancer or with other high risk features suggestive of a mutation detection rate of > 10% are invited by their surgeon prior to mastectomy or radiotherapy. After completing the first questionnaire, participants are randomized to receive either: (a) an educational pamphlet about genetic testing (intervention) or (b) a genetic counseling appointment at a family cancer center (standard care). Each participant is offered genetic testing for germline BRCA mutations. Decision-related and psychosocial outcomes are assessed over 12 months and include decisional conflict (primary outcome);uptake of bilateral mastectomy and/or risk-reducing salpingo-oophorectomy; cancer-specific- and general distress; family involvement in decision making; and decision regret. A process-oriented retrospective online survey will examine health professionals' attitudes toward TFGT; a health economic analysis will determine the cost effectiveness of the intervention. DISCUSSION: This trial will provide crucial information about the impact, efficiency and cost effectiveness of an educational pamphlet designed to inform younger women newly diagnosed with breast cancer about genetic testing. Issues regarding implementation of the trial are discussed

The Extracellular Vesicle Citrullinome and Signature in a Piglet Model of Neonatal Seizures

Neonatal seizures are commonly associated with acute perinatal brain injury, while understanding regarding the downstream molecular pathways related to seizures remains unclear. Furthermore, effective treatment and reliable biomarkers are still lacking. Post-translational modifications can contribute to changes in protein function, and post-translational citrullination, which is caused by modification of arginine to citrulline via the calcium-mediated activation of the peptidylarginine deiminase (PAD) enzyme family, is being increasingly linked to neurological injury. Extracellular vesicles (EVs) are lipid-bilayer structures released from cells; they can be isolated from most body fluids and act as potential liquid biomarkers for disease conditions and response to treatment. As EVs carry a range of genetic and protein cargo that can be characteristic of pathological processes, the current study assessed modified citrullinated protein cargo in EVs isolated from plasma and CSF in a piglet neonatal seizure model, also following phenobarbitone treatment. Our findings provide novel insights into roles for PAD-mediated changes on EV signatures in neonatal seizures and highlight the potential of plasma- and CSF-EVs to monitor responses to treatment

The dynamics of transcript abundance during cellularization of developing barley endosperm

Within the cereal grain, the endosperm and its nutrient reserves are critical for successful germination and in the context of grain utilization. The identification of molecular determinants of early endosperm development, particularly regulators of cell division and cell wall deposition, would help predict end-use properties such as yield, quality, and nutritional value. Custom microarray data have been generated using RNA isolated from developing barley grain endosperm 3 d to 8 d after pollination (DAP). Comparisons of transcript abundance over time revealed 47 gene expression modules that can be clustered into 10 broad groups. Superimposing these modules upon cytological data allowed patterns of transcript abundance to be linked with key stages of early grain development. Here, attention was focused on how the datasets could be mined to explore and define the processes of cell wall biosynthesis, remodeling, and degradation. Using a combination of spatial molecular network and gene ontology enrichment analyses, it is shown that genes involved in cell wall metabolism are found in multiple modules, but cluster into two main groups that exhibit peak expression at 3 DAP to 4 DAP and 5 DAP to 8 DAP. The presence of transcription factor genes in these modules allowed candidate genes for the control of wall metabolism during early barley grain development to be identified. The data are publicly available through a dedicated web interface (https://ics.hutton.ac.uk/barseed/), where they can be used to interrogate co- and differential expression for any other genes, groups of genes, or transcription factors expressed during early endosperm development.Runxuan Zhang, Matthew R. Tucker, Rachel A Burton, Neil J. Shirley, Alan Little, Jenny Morris, Linda Milne, Kelly Houston, Pete E. Hedley, Robbie Waugh, and Geoffrey B. Finche

On the variability of quasars: a link between Eddington ratio and optical variability?

Repeat scans by the Sloan Digital Sky Survey (SDSS) of a 278 square degree stripe along the Celestial equator have yielded an average of over 10 observations each for nearly 8,000 spectroscopically confirmed quasars. Over 2500 of these quasars are in the redshift range such that the CIV emission line is visible in the SDSS spectrum. Utilising the width of these CIV lines and the luminosity of the nearby continuum, we estimate black hole masses for these objects. In an effort to isolate the effects of black hole mass and luminosity on the photometric variability of our dataset, we create several subsamples by binning in these two physical parameters. By comparing the ensemble structure functions of the quasars in these bins, we are able to reproduce the well-known anticorrelation between luminosity and variability, now showing that this anticorrelation is independent of the black hole mass. In addition, we find a correlation between variability and the mass of the central black hole. By combining these two relations, we identify the Eddington ratio as a possible driver of quasar variability, most likely due to differences in accretion efficiency.Comment: 13 pages, 5 figures, Accepted for publication in MNRA

Electrical stimulation devices for the prevention of venous thromboembolism: Preliminary studies of physiological efficacy and user satisfaction.

Introduction: Electrical stimulation could provide an alternative method for preventing venous thromboembolism in stroke patients. The purpose of this preliminary study was to explore the effects of electrical stimulation and intermittent pneumatic compression on enhancing lower limb venous return in healthy and chronic stroke patients and also to evaluate patient and nurse satisfaction. Methods: We investigated the effectiveness of two electrical stimulation devices: Geko (Firstkind Ltd, High Wycombe, UK) and Orthopaedic Microstim 2V2 (Odstock Medical Ltd, Salisbury, UK); and one intermittent pneumatic compression device: Huntleigh Flowstron Universal (Huntleigh Healthcare Ltd, Cardiff, UK). We recruited 12 healthy and 5 chronic stroke participants. The devices were fitted sequentially, and Doppler ultrasound measurements were taken. Eight patients and nurses were also recruited for a separate usability evaluation. Results: The electrical stimulation devices emulated the blood flow characteristics of intermittent pneumatic compression in both healthy and stroke participants provided that the intensity of electrical stimulation was sufficient. Patients and nurses also felt that the electrical stimulation devices were acceptable. Conclusions: Electrical stimulation may offer benefit as an alternative method for venous thromboembolism prevention in stroke patients. The apparent benefit is sufficient to warrant further investigation in a full powered randomised controlled trial

Simulating the influences of groundwater on regional geomorphology using a distributed, dynamic, landscape evolution modelling platform

A dynamic landscape evolution modelling platform (CLiDE) is presented that allows a variety of Earth system interactions to be explored under differing environmental forcing factors. Representation of distributed surface and subsurface hydrology within CLiDE is suited to simulation at sub-annual to centennial time-scales. In this study the hydrological components of CLiDE are evaluated against analytical solutions and recorded datasets. The impact of differing groundwater regimes on sediment discharge is examined for a simple, idealised catchment, Sediment discharge is found to be a function of the evolving catchment morphology. Application of CLiDE to the upper Eden Valley catchment, UK, suggests the addition of baseflow-return from groundwater into the fluvial system modifies the total catchment sediment discharge and the spatio-temporal distribution of sediment fluxes during storm events. The occurrence of a storm following a period of appreciable antecedent rainfall is found to increase simulated sediment fluxes