The role of transient outward K+ current in electrical remodelling induced by voluntary exercise in female rat hearts

Regular exercise can lead to electrical remodelling of the heart. The cellular mechanisms associated with these changes are not well understood, and are difficult to study in human tissue but are important given that exercise is recommended to the general population. We have investigated the role played by the transient outward K+ current (Ito) in the changes in electrical activity seen in response to voluntary exercise training in rats. Female rats undertook 6 weeks of voluntary wheel running exercise (TRN) or were sedentary controls (SED). Monophasic action potentials (MAPs) were recorded from the surface of whole hearts. Whole cell patch clamp recordings of Ito; mRNA and protein levels of selected targets in sub-epicardial (EPI) and sub-endocardial myocardium of SED and TRN hearts were compared. In TRN rats, heart weight:body weight was significantly increased and epicardial MAPs significantly prolonged. Ito density was reduced in TRN EPI myocytes, such that the transmural gradient of Ito was significantly reduced (P < 0.05). Computer modelling of these changes in Ito predicted the observed changes in action potential profile. However, transmural gradients in mRNA and protein expression for Kv4.2 or mRNA levels of the Kv4.2 regulators; KChIP2 and Irx-5 were not significantly altered by voluntary exercise. We conclude that voluntary exercise electrical remodelling is caused, at least in part, by a decrease in EPI Ito, possibly because of fewer functional channels in the membrane, which results in a fall in the transmural action potential duration gradient

Ensuring young voices are heard in core outcome set development: international workshops with 70 children and young people.

Plain english summaryResearchers test treatments to ensure these work and are safe. They do this by studying the effects that treatments have on patients by measuring outcomes, such as pain and quality of life. Often research teams measure different outcomes even though each team is studying the same condition. This makes it hard to compare the findings from different studies and it can reduce the accuracy of the treatment advice available to patients. Increasingly, researchers are tackling this problem by developing 'core outcome sets'. These are lists of outcomes that all researchers working on a given condition should measure in their studies. It is important that patients have a voice in the development of core outcome sets and children and young people are no exception. But their voices have rarely been heard when core outcome sets are developed. Researchers are trying to address this problem and make sure that core outcome sets are developed in ways that are suitable for children and young people. As a first step, we held two international workshops with children and young people to listen to their views. They emphasised the importance of motivating young people to participate in developing core outcome sets, making them feel valued, and making the development process more interactive, enjoyable and convenient. We hope this commentary will encourage researchers to include children and young people when developing core outcome sets and to adapt their methods so these are suitable for young participants. Future research is important to examine whether these adaptations are effective.AbstractBackground Different research teams looking at treatments for the same condition often select and measure inconsistent treatment outcomes. This makes it difficult to synthesise the results of different studies, leads to selective outcome reporting and impairs the quality of evidence about treatments. 'Core outcome sets' (COS) can help to address these problems. A COS is an agreed, minimum list of outcomes that researchers are encouraged to consistently measure and report in their studies. Including children and young people (CYP) as participants in the development of COS for paediatric conditions ensures that clinically meaningful outcomes are measured and reported. However, few published COS have included CYP as participants. COS developers have described difficulties in recruiting and retaining CYP and there is a lack of guidance on optimising COS methods for them. We aimed to explore CYP's views on the methods used to develop COS and identify ways to optimise these methods.Main body This commentary summarises discussions during two workshops with approximately 70 CYP (aged 10-18 years old) at the International Children's Advisory Network Research and Advocacy Summit, 2018. Delegates described what might motivate them to participate in a COS study, including feeling valued, understanding the need for COS and the importance of input from CYP in their development, and financial and other incentives (e.g. certificates of participation). For Delphi surveys, delegates suggested that lists of outcomes should be as brief as possible, and that scoring and feedback methods should be simplified. For consensus meetings, delegates advised preparing CYP in advance, supporting them during meetings (e.g. via mentors) and favoured arrangements whereby CYP could meet separately from parents and other stakeholders. Overall, they wanted COS methods that were convenient, enjoyable and engaging.Conclusion This commentary points to the limitations of the methods currently used to develop COS with CYP. It also points to ways to motivate CYP to participate in COS studies and to enhancements of methods to make participation more engaging for CYP. Pending much needed research on COS methods for CYP, the perspectives offered in the workshops should help teams developing COS in paediatrics and child health

Making research central to good paediatric practice

There is evidence abroad of a cautious if not protective approach to research involving children and young people (CYP). We are sensitive to these views but believe they are based on a misconception that we must address together. In this introductory article we look at the complexities and risks of this research, how we must involving CYP and their families in the all aspects of research, how to seek valid consent and assent and how research findings should be reported. Considering how we should conduct this ongoing debate, we outline seven principles that we believe should underpin the necessary dialogue between all with legitimate interest. Our debate should be: (1) evidence informed: arguments should be supported by appropriate and reasonably accurate factual claims; (2) transparent about the grounds for decisions; (3) balanced: arguments should be met by contrary arguments; (4) conscientious: we must be willing to talk and listen, with civility and respect; (5) substantive: arguments should be considered sincerely on their merits, not on how they are made or by who is making them; (6) comprehensive: all points of view held by significant portions of the population should receive attention; and (7) with procedures for revising decisions in light of challenges, and it should be our responsibility to ensure we have met all of these

Voluntary exercise-induced changes in β2-adrenoceptor signalling in rat ventricular myocytes

Regular exercise is beneficial to cardiovascular health. We tested whether mild voluntary exercise training modifies key myocardial parameters [ventricular mass, intracellular calcium ([Ca2+]i) handling and the response to β-adrenoceptor (β-AR) stimulation] in a manner distinct from that reported for beneficial, intensive training and pathological hypertrophic stimuli. Female rats performed voluntary wheel-running exercise for 6–7 weeks. The mRNA expression of target proteins was measured in left ventricular tissue using real-time reverse transcriptase-polymerase chain reaction. Simultaneous measurement of cell shortening and [Ca2+]i transients were made in single left ventricular myocytes and the inotropic response to β1- and β2-AR stimulation was measured. Voluntary exercise training resulted in cardiac hypertrophy, the heart weight to body weight ratio being significantly greater in trained compared with sedentary animals. However, voluntary exercise caused no significant alteration in the size or time course of myocyte shortening and [Ca2+]i transients or in the mRNA levels of key proteins that regulate Ca2+ handling. The positive inotropic response to β1-AR stimulation and the level of β1-AR mRNA were unaltered by voluntary exercise but both mRNA levels and inotropic response to β2-AR stimulation were significantly reduced in trained animals. The β2-AR inotropic response was restored by exposure to pertussis toxin. We propose that in contrast to pathological stimuli and to beneficial, intense exercise training, modulation of Ca2+ handling is not a major adaptive mechanism in the response to mild voluntary exercise. In addition, and in a reversal of the situation seen in heart failure, voluntary exercise training maintains the β1-AR response but reduces the β2-AR response. Therefore, although voluntary exercise induces cardiac hypertrophy, there are distinct differences between its effects on key myocardial regulatory mechanisms and those of hypertrophic stimuli that eventually cause cardiac decompensation

EULAR points to consider for the development, evaluation and implementation of mobile health applications aiding self-management in people living with rheumatic and musculoskeletal diseases

Background: Mobile health applications (apps) are available to enable people with rheumatic and musculoskeletal diseases (RMDs) to better self-manage their health. However, guidance on the development and evaluation of such apps is lacking. Objectives: The objective of this EULAR task force was to establish points to consider (PtC) for the development, evaluation and implementation of apps for self-management of RMDs. Methods: A systematic literature review of app content and development strategies was conducted, followed by patient focus group and an online survey. Based on this information and along with expert opinion, PtC were formulated in a face-to-face meeting by a multidisciplinary task force panel of experts, including two patient research partners. The level of agreement among the panel in regard to each PtC was established by anonymous online voting. Results: Three overarching principles and 10 PtC were formulated. Three PtC are related to patient safety, considered as a critical issue by the panel. Three were related to relevance of the content and functionalities. The requirement for transparency around app development and funding sources, along with involvement of relevant health professionals were also raised. Ease of app access across ages and abilities was highlighted, in addition to considering the cost-benefit of apps from the outset. The level of agreement was from 8.8 to 9.9 out of 10. Conclusion: These EULAR PtC provide guidance on important aspects that should be considered for the development, evaluation and implementation of existing and new apps

Highly selective and solvent-dependent reduction of Nitrobenzene to N-phenylhydroxylamine, azoxybenzene, and aniline catalyzed by phosphino-modified polymer immobilized ionic liquid-stabilized AuNPs

Gold nanoparticles stabilized by phosphine-decorated polymer immobilized ionic liquids (AuNP@PPh2-PIILP) is an extremely efficient multiproduct selective catalyst for the sodium borohydride-mediated reduction of nitrobenzene giving N-phenylhydroxylamine, azoxybenzene, or aniline as the sole product under mild conditions and a very low catalyst loading. The use of a single nanoparticle-based catalyst for the partial and complete reduction of nitroarenes to afford three different products with exceptionally high selectivities is unprecedented. Under optimum conditions, thermodynamically unfavorable N-phenylhydroxylamine can be obtained as the sole product in near quantitative yield in water, whereas a change in reaction solvent to ethanol results in a dramatic switch in selectivity to afford azoxybenzene. The key to obtaining such a high selectivity for N-phenylhydroxylamine is the use of a nitrogen atmosphere at room temperature as reactions conducted under an inert atmosphere occur via the direct pathway and are essentially irreversible, while reactions in air afford significant amounts of azoxy-based products by virtue of competing condensation due to reversible formation of N-phenylhydroxylamine. Ultimately, aniline can also be obtained quantitatively and selectively by adjusting the reaction temperature and time accordingly. Introduction of PEG onto the polyionic liquid resulted in a dramatic improvement in catalyst efficiency such that N-phenylhydroxylamine could be obtained with a turnover number (TON) of 100 000 (turnover frequency (TOF) of 73 000 h–1, with >99% selectivity), azoxybenzene with a TON of 55 000 (TOF of 37 000 h–1 with 100% selectivity), and aniline with a TON of 500 000 (TOF of 62 500 h–1, with 100% selectivity). As the combination of ionic liquid and phosphine is required to achieve high activity and selectivity, further studies are currently underway to explore whether interfacial electronic effects influence adsorption and thereby selectivity and whether channeling of the substrate by the electrostatic potential around the AuNPs is responsible for the high activity. This is the first report of a AuNP-based system that can selectively reduce nitroarenes to either of two synthetically important intermediates as well as aniline and, in this regard, is an exciting discovery that will form the basis to develop a continuous flow process enabling facile scale-up

Autism is associated with interindividual variations of gray and white matter morphology

Background: Although many studies have explored atypicalities in gray matter (GM) and white matter (WM) morphology of autism, most of them relied on unimodal analyses that did not benefit from the likelihood that different imaging modalities may reflect common neurobiology. We aimed to establish brain patterns of modalities that differentiate between individuals with and without autism and explore associations between these brain patterns and clinical measures in the autism group. Methods: We studied 183 individuals with autism and 157 nonautistic individuals (age range, 6-30 years) in a large, deeply phenotyped autism dataset (EU-AIMS LEAP [European Autism Interventions-A Multicentre Study for Developing New Medications Longitudinal European Autism Project]). Linked independent component analysis was used to link all participants' GM volume and WM diffusion tensor images, and group comparisons of modality shared variances were examined. Subsequently, we performed univariate and multivariate brain-behavior correlation analyses to separately explore the relationships between brain patterns and clinical profiles. Results: One multimodal pattern was significantly related to autism. This pattern was primarily associated with GM volume in bilateral insula and frontal, precentral and postcentral, cingulate, and caudate areas and co-occurred with altered WM features in the superior longitudinal fasciculus. The brain-behavior correlation analyses showed a significant multivariate association primarily between brain patterns that involved variation of WM and symptoms of restricted and repetitive behavior in the autism group. Conclusions: Our findings demonstrate the assets of integrated analyses of GM and WM alterations to study the brain mechanisms that underpin autism and show that the complex clinical autism phenotype can be interpreted by brain covariation patterns that are spread across the brain involving both cortical and subcortical areas

Patient and public involvement in a study of multimedia clinical trial information for children, young people and families

© 2020 Sheridan, Preston, Stones, Ainsworth, Taylor, Challinor, Ainsworth, Martin-Kerry, Brady and Knapp. This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (CC BY) 4.0. https://creativecommons.org/licenses/by/4.0/.There is increasing recognition of the need to involve the public in health research, but accounts of how best to achieve this are scarce. This article describes public involvement in the TRials Engagement in Children and Adolescents (TRECA) study, which is developing and evaluating multimedia information resources to inform children, young people and their familes about clinical trials. A dedicated group of young people with long-term health conditions and their parents met regularly throughout the study; further involvement was sought when specific input was required. Review of formal impact records and informal discussions highlighted how public involvement can positively influence research practice and the people involved. By detailing the methods of involvement used, this work also provides guidance for successfully implementing public involvement in research, and highlights challenges that should be considered in future research projects.Peer reviewe

Place recognition using batlike sonar

Echolocating bats have excellent spatial memory and are able to navigate to salient locations using bio-sonar. Navigating and route-following require animals to recognize places. Currently, it is mostly unknown how bats recognize places using echolocation. In this paper, we propose template based place recognition might underlie sonar-based navigation in bats. Under this hypothesis, bats recognize places by remembering their echo signature - rather than their 3D layout. Using a large body of ensonification data collected in three different habitats, we test the viability of this hypothesis assessing two critical properties of the proposed echo signatures: (1) they can be uniquely classified and (2) they vary continuously across space. Based on the results presented, we conclude that the proposed echo signatures satisfy both criteria. We discuss how these two properties of the echo signatures can support navigation and building a cognitive map. DOI: http://dx.doi.org/10.7554/eLife.14188.00

Different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis: the SIRJIA mixed-methods feasibility study.

BACKGROUND:In the UK, juvenile idiopathic arthritis is the most common inflammatory disorder in childhood, affecting 10 : 100,000 children and young people aged < 16 years each year, with a population prevalence of around 1 : 1000. Corticosteroids are commonly used to treat juvenile idiopathic arthritis; however, there is currently a lack of consensus as to which corticosteroid induction regimen should be used with various disease subtypes and severities of juvenile idiopathic arthritis. OBJECTIVE:The main study objective was to determine the feasibility of conducting a randomised controlled trial to compare the different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis. DESIGN:This was a mixed-methods study. Work packages included a literature review; qualitative interviews with children and young people with juvenile idiopathic arthritis and their families; a questionnaire survey and screening log to establish current UK practice; a consensus meeting with health-care professionals, children and young people with juvenile idiopathic arthritis, and their families to establish the primary outcome; a feasibility study to pilot data capture and to collect data for future sample size calculations; and a final consensus meeting to establish the final protocol. SETTING:The setting was rheumatology clinics across the UK. PARTICIPANTS:Children, young people and their families who attended clinics and health-care professionals took part in this mixed-methods study. INTERVENTIONS:This study observed methods of prescribing corticosteroids across the UK. MAIN OUTCOME MEASURES:The main study outcomes were the acceptability of a future trial for children, young people, their families and health-care professionals, and the feasibility of delivering such a trial. RESULTS:Qualitative interviews identified differences in the views of children, young people and their families on a randomised controlled trial and potential barriers to recruitment. A total of 297 participants were screened from 13 centres in just less than 6 months. In practice, all routes of corticosteroid administration were used, and in all subtypes of juvenile idiopathic arthritis. Intra-articular corticosteroid injection was the most common treatment. The questionnaire surveys showed the varying clinical practice across the UK, but established intra-articular corticosteroids as the treatment control for a future trial. The primary outcome of choice for children, young people, their families and health-care professionals was the Juvenile Arthritis Disease Activity Score, 71-joint count. However, results from the feasibility study showed that, owing to missing blood test data, the clinical Juvenile Arthritis Disease Activity Score should be used. The Juvenile Arthritis Disease Activity Score, 71-joint count, and the clinical Juvenile Arthritis Disease Activity Score are composite disease activity scoring systems for juvenile arthritis. Two final trial protocols were established for a future randomised controlled trial. LIMITATIONS:Fewer clinics were included in this feasibility study than originally planned, limiting the ability to draw strong conclusions about these units to take part in future research. CONCLUSIONS:A definitive randomised controlled trial is likely to be feasible based on the findings from this study; however, important recommendations should be taken into account when planning such a trial. FUTURE WORK:This mixed-methods study has laid down the foundations to develop the evidence base in this area and conducting a randomised control trial to compare different corticosteroid induction regimens in children and young people with juvenile idiopathic arthritis is likely to be feasible. STUDY REGISTRATION:Current Controlled Trials ISRCTN16649996. FUNDING:This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 36. See the NIHR Journals Library website for further project information