Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti-leukotrienes for chronic asthma

Asthma patients who continue to experience symptoms despite being on regular inhaled corticosteroids (ICS) represent a management challenge. Long-acting beta2-agonists (LABA) or anti-leukotrienes (LTRA) are two treatment options that could be considered as add-on therapy to ICS.ObjectivesWe compared the efficacy and safety profile of adding either daily LABA or LTRA in adults and children with asthma who remain symptomatic on ICS.Search strategyWe searched the Cochrane Airways Group Specialised Register (up to and including March 2010). We consulted reference lists of all included studies and contacted authors and pharmaceutical manufacturers for other published or unpublished studies.Selection criteriaWe included randomised controlled trials (RCTs) conducted in adults or children with recurrent asthma that was treated with ICS and where a fixed dose of a long-acting beta2-agonist or leukotriene agent was added for a minimum of 28 days.Data collection and analysisTwo authors independently assessed the risk of bias of included studies and extracted data. We sought unpublished data and further details of study design, where necessary.Main resultsWe included 17 RCTs (7032 participants), of which 16 recruited adults and adolescents (6850) and one recruited children aged 6 to 17 years (182). Participants demonstrated substantial reversibility to short-acting beta-agonist at baseline. The studies were at a low risk of bias. The risk of exacerbations requiring systemic corticosteroids was lower with the combination of LABA and ICS compared with LTRA and ICS, from 11% to 9% (RR 0.83, 95% CI 0.71 to 0.97; six studies, 5571 adults). The number needed to treat (NNT) with LABA compared to LTRA to prevent one exacerbation over 48 weeks was 38 (95% CI 22 to 244). The choice of LTRA did not significantly affect the results. The effect appeared stronger in the trials using a single device to administer ICS and LABA compared to those using two devices. In the absence of data from the paediatric trial and the clinical homogeneity of studies, we could not perform subgroup analyses. The addition to ICS of LABA compared to LTRA was associated with a statistically greater improvement from baseline in several of the secondary outcomes, including lung function, functional status measures and quality of life. Serious adverse events were more common with LABA than LTRA, although the estimate was imprecise (RR 1.35, 95% CI 1.00 to 1.82), and the NNT to harm for one additional patient to suffer a serious adverse event on LABA over 48 weeks was 78 (95% CI 33 to infinity). The risk of withdrawal for any reason in adults was significantly lower with LABA and ICS compared to LTRA and ICS (RR 0.84, 95% CI 0.74 to 0.96).Authors' conclusionsIn adults with asthma that is inadequately controlled on low doses of inhaled steroids and showing significant reversibility with beta2-agonists, LABA is superior to LTRA in reducing oral steroid treated exacerbations. Differences favouring LABA in lung function, functional status and quality of life scores are generally modest. There is some evidence of increased risk of SAEs with LABA. The findings support the use of a single inhaler for the delivery of LABA and inhaled corticosteroids. We are unable to draw conclusions about which treatment is better as add-on therapy for children.PLAIN LANGUAGE SUMMARYWhat are the effects of long-acting beta2-agonists compared with anti-leukotrienes when added to inhaled steroids?People who continue to experience asthma symptoms despite regularly taking inhaled corticosteroids are a challenge for management. It is not clear whether the addition of a long-acting beta2-agonist (LABA) such as formoterol or salmeterol would provide more benefit in comparison with an oral anti-leukotriene agent (LTRA), for example zafirlukast or montelukast.Seventeen trials (16 in adults and one in children) were included in this review and were of good quality. We found that the addition of a LABA provides significantly greater protection against exacerbations requiring oral steroids when compared with a LTRA for adults. Based on the results of our analyses, approximately 38 adults (with a range of between 22 and 244) would need to be treated with a LABA rather than a LTRA for 48 weeks to prevent one experiencing an exacerbation needing a course of oral steroids. The trial on children did not contribute data on the main outcome and therefore we could not draw any conclusions for children.LABAs also led to a greater improvement in lung function, improvement in symptoms, use of rescue medication, quality of life and symptoms compared to the use of LTRAs. The magnitude of the improvements was modest. Serious adverse events were more frequent with LABA than with LTRAs although this result was imprecise. Based on our analyses, around 78 people would need to be treated for 48 weeks with a LABA rather than a LTRA for one of them to experience a serious adverse event. However, due to the lack of precision around our result, the true number could be between 33 and infinity. There are currently insufficient data to draw any conclusions about the effects of these drugs in children

Skeletal muscle contractile function predicts activity and behaviour in zebrafish

Locomotion facilitates behaviour and its underlying physiological mechanisms may therefore impact behavioural phenotypes. Metabolism is often thought to modulate locomotion and behaviour, but empirical support for this suggestion is equivocal. Muscle contractile function is directly associated with locomotion. Here, we test the hypotheses that muscle mechanics determine locomotor performance and activity in zebrafish (Danio rerio) and thereby also affect risk-taking behaviour. We show that there is a mechanistic link between muscle performance and behaviour by manipulating muscle contractile properties, which caused proportional changes in critical sustained swimming performance and, in an open arena, voluntary swimming speed, the proportion of time fish were active, and the latency to move. We modelled the relationships between muscle contractile properties, swimming performance, activity and behaviour with a partial least-squares path model. The latent variable ‘muscle’, formed by isolated muscle force production, stress, fatigue resistance and activation and relaxation rates, had a significant positive effect on swimming performance (‘swim’ reflected in sustained and sprint speeds). Together, muscle and swim had a significant positive effect on activity, and explained 71.8% of variation in the distance moved, time active and maximum voluntary speed in an open field. Activity had a significant positive effect on boldness, explaining 76.0% of variation in latencies to move and to approach a novel object. Muscle contractile function determines voluntary movement and we suggest that exploration and dispersal are functions of physiological and mechanical optimisation. Boldness therefore may be partly explained by the greater likelihood of faster fish to move further and encounter novel objects and conspecifics more quickly as a result

Inhaled steroids with and without regular salmeterol for asthma: serious adverse events.

BACKGROUND: Epidemiological evidence has suggested a link between use of beta₂-agonists and increased asthma mortality. Much debate has surrounded possible causal links for this association, and whether regular (daily) long-acting beta₂-agonists (LABAs) are safe, particularly when used in combination with inhaled corticosteroids (ICSs). This is an update of a Cochrane Review that now includes data from two large trials including 11,679 adults and 6208 children; both were mandated by the US Food and Drug Administration (FDA).  OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events (SAEs) in trials that randomised participants with chronic asthma to regular salmeterol and ICS versus the same dose of ICS. SEARCH METHODS: We identified randomised trials using the Cochrane Airways Group Specialised Register of trials. We checked websites of clinical trials registers for unpublished trial data. We also checked FDA submissions in relation to salmeterol. The date of the most recent search was 10 October 2018. SELECTION CRITERIA: We included parallel-design randomised trials involving adults, children, or both with asthma of any severity who were randomised to treatment with regular salmeterol and ICS (in separate or combined inhalers) versus the same dose of ICS of at least 12 weeks in duration. DATA COLLECTION AND ANALYSIS: We conducted the review according to standard procedures expected by Cochrane. We obtained unpublished data on mortality and SAEs from the sponsors, from ClinicalTrials.gov, and from FDA submissions. We assessed our confidence in the evidence according to current GRADE recommendations. MAIN RESULTS: We have included in this review 41 studies (27,951 participants) in adults and adolescents, along with eight studies (8453 participants) in children. We judged that the overall risk of bias was low for all-cause events, and we obtained data on SAEs from all study authors. All except 542 adults (and none of the children) were given salmeterol and fluticasone in the same (combination) inhaler.DeathsEleven of a total of 14,233 adults taking regular salmeterol and ICS died, as did 13 of 13,718 taking regular ICS at the same dose. The pooled Peto odds ratio (OR) was 0.80 (95% confidence interval (CI) 0.36 to 1.78; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). In other words, for every 1000 adults treated for 25 weeks, one death occurred among those on ICS alone, and the corresponding risk among those taking salmeterol and ICS was also one death (95% CI 0 to 2 deaths).No children died, and no adults or children died of asthma, so we remain uncertain about mortality in children and about asthma mortality in any age group.Non-fatal serious adverse eventsA total of 332 adults receiving regular salmeterol with ICS experienced a non-fatal SAE of any cause, compared to 282 adults receiving regular ICS. The pooled Peto OR was 1.14 (95% CI 0.97 to 1.33; participants = 27,951; studies = 41; I² = 0%; moderate-certainty evidence). For every 1000 adults treated for 25 weeks, 21 adults on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 23 adults (95% CI 20 to 27).Sixty-five of 4229 children given regular salmeterol with ICS suffered an SAE of any cause, compared to 62 of 4224 children given regular ICS. The pooled Peto OR was 1.04 (95% CI 0.73 to 1.48; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, 15 children on ICS alone had an SAE, and the corresponding risk for those on salmeterol and ICS was 15 children (95% CI 11 to 22).Asthma-related serious adverse eventsEighty and 67 adults in each group, respectively, experienced an asthma-related non-fatal SAE. The pooled Peto OR was 1.15 (95% CI 0.83 to 1.59; participants = 27,951; studies = 41; I² = 0%; low-certainty evidence). For every 1000 adults treated for 25 weeks, five receiving ICS alone had an asthma-related SAE, and the corresponding risk among those on salmeterol and ICS was six adults (95% CI 4 to 8).Twenty-nine children taking salmeterol and ICS and 23 children taking ICS alone reported asthma-related events. The pooled Peto OR was 1.25 (95% CI 0.72 to 2.16; participants = 8453; studies = 8; I² = 0%; moderate-certainty evidence). For every 1000 children treated for 23 weeks, five receiving an ICS alone had an asthma-related SAE, and the corresponding risk among those receiving salmeterol and ICS was seven children (95% CI 4 to 12). AUTHORS' CONCLUSIONS: We did not find a difference in the risk of death or serious adverse events in either adults or children. However, trial authors reported no asthma deaths among 27,951 adults or 8453 children randomised to regular salmeterol and ICS or ICS alone over an average of six months. Therefore, the risk of dying from asthma on either treatment was very low, but we remain uncertain about whether the risk of dying from asthma is altered by adding salmeterol to ICS.Inclusion of new trials has increased the precision of the estimates for non-fatal SAEs of any cause. We can now say that the worst-case estimate is that at least 152 adults and 139 children must be treated with combination salmeterol and ICS for six months for one additional person to be admitted to the hospital (compared to treatment with ICS alone). These possible risks still have to be weighed against the benefits experienced by people who take combination treatment.However more than 90% of prescribed treatment was taken in the new trials, so the effects observed may be different from those seen with salmeterol in combination with ICS in daily practice

Comparison of Students' Views across Police Entry Routes: Report for Lancashire Constabulary

Police Education is undergoing a revolution. Beginning with the recognition in the 1980s and 1990s that traditional policing methods had little or no impact on crime rates, there has been increasing pressure over the last few decades for a shift towards evidence based policing. In Britain a key moment in this shift was the launch of the Initial Police Learning and Development Programme (IPLDP) in 2006. However, though this programme was intended to educate police officers in the ways of evidence based policing, its inheritance of a predominantly training culture and alongside its limitations as a Level 3 qualification, meant that IPLDP effectively marked the opening of a process of change rather than its realisation. The next step on this process was the launch of Police Education Qualifications Framework (PEQF) as a series of connected degree level programmes (Level 6 qualifications) in collaboration with several Higher Education Institutions (HEI’s) including UCLan. Alongside the launch of a standard undergraduate degree in Professional Policing, two on-the-job programmes of learning were created: a three year Police Constable Degree Apprenticeship (PCDA) culminating in a Level 6 qualification for non-degree holding applicants to the police service alongside a two year Degree Holder Entry Programme (DHEP) for those officers who already held a Level 6 qualification. The present study is intended to measure the response of trainee police officers undergoing the new education routes. Lancashire Constabulary conducted surveys at three time points – after one week, twenty-four weeks and thirty four weeks of the courses – to allow for a comparative assessment of attitudes towards the IPLDP, PCDA and DHEP courses. This data analysis was carried out by colleagues from UCLan. There were two standout features of the data: First, IPLDP, PCDA and DHEP students all had very similar experiences, both positive and negative, across the three courses. This is particularly interesting given that the launch of PEQF provision at UCLan was quickly followed by the Covid Lockdown, with its attended and previously unforeseen shift to online learning. This is contrasted to the IPLDP cohort which began in 2018 and was not adversely affected by national lockdowns, meaning students underwent a ‘normal’ period of training. Positively, all three cohorts enjoyed their learning experience, especially roleplay and scenario based learning, and praised their tutors. Negatively, all recognised problems of work-life balance. This problem was more pronounced amongst PEQF Officers who had more academic demands on their time, and suggested the need for more time and resource given over to their education both by UCLan and Lancashire. Second, while all three cohorts expressed a commitment to evidence based policing, the IPLDP students expressed concern that they had insufficient opportunity to critically reflect on what they had learnt. This concern suggests that PEQF marks not only a step in the right direction, but it is one that fits with the hopes and expectations of the new police recruits. Overall, the study illuminates real strengths of PEQF provision as an evolutionary development of IPLDP from which officers should develop a critical understanding of evidence based policing. PEQF seems to be working despite lockdown, though this study does point to obvious areas for improvement including more protected time for student officers to learn, more scenario based teaching, better lecturing, less online provision and more time for critical reflections on that which is being taught and learned. Whilst increasing numbers of students undergoing PEQF will mean meeting these needs will be difficult, the current report provides an evidence-base from which such improvements can be made to benefit PEQF students in future

The Espresso Sequencing Network: HotShot Consensus, Tiramisu Data-Availability, and Builder-Exchange

Building a Consensus platform for shared sequencing can power an ecosystem of layer-2 solutions such as rollups which are crucial for scaling blockchains (e.g.,Ethereum). However, it drastically differs from conventional Consensus for blockchains in two key considerations: • (No) Execution: A shared sequencing platform is not responsible for pre-validating blocks nor for processing state updates. Therefore, agreement is formed on a sequence of certificates of block data-availability (DA) without persisting them or obtaining blocks in full. At the same time, the platform must stream block data with very high efficiency to layer-2 entities for execution, or (in the case of rollups) for proof generation. • Builder-Exchange: A shared sequencing platform delegates to external entities to build blocks and separates it from the role of a consensus proposer. This allows an ecosystem of specialized builders to pre-validate transactions for diversified rollups, languages, and MEV exploits. However, separating the task of block-building from proposing brings a new challenge. Builders want assurances that their blocks would commit in exchange for revealing their contents, whereas validators/proposers want assurance that the data in committed blocks will be available and fees paid. Neither one trusts the other, hence the shared sequencing platform should facilitate a “fair-exchange” between builders and the sequencing network. The Espresso Sequencing Network is purpose-built to address these unique considerations. Among the main novelties of the design are (i) a three-layered DA system called Tiramisu, coupled with (ii) a costless integration of the DA with the platform’s consensus core, and (iii) a Builder-Exchange mechanism between builders and the consensus core. Note that this paper relies substantially on and can be seen as an extension of The Espresso Sequencer: HotShot Consensus and Tiramisu Data Availability [84]

Molecular systematics of flyingfishes (Teleostei: Exocoetidae): evolution in the epipelagic zone

The flyingfish family Exocoetidae is a diverse group of marine fishes that are widespread and abundant in tropical and subtropical seas. Flyingfishes are epipelagic specialists that are easily distinguished by their enlarged fins, which are used for gliding leaps over the surface of the water. Although phylogenetic hypotheses have been proposed for flyingfish genera based on morphology, no comprehensive molecular studies have been performed. In the present study, we describe a species-level molecular phylogeny for the family Exocoetidae, based on data from the mitochondrial cytochrome b gene (1137 bp) and the nuclear RAG2 gene (882 bp). We find strong support for previous morphology-based phylogenetic hypotheses, as well as the monophyly of most currently accepted flyingfish genera. However, the most diverse genus Cheilopogon is not monophyletic. Using our novel flyingfish topology, we examine previously proposed hypotheses for the origin and evolution of gliding. The results support the progressive transition from two-wing to four-wing gliding. We also use phylogenetic approaches to test the macroecological effects of two life history characters (e.g. egg buoyancy and habitat) on species range size in flyingfishes. © 2010 The Linnean Society of London, Biological Journal of the Linnean Society , 2011, 102, 161–174.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/79173/1/BIJ_1550_sm_Appendix_S1.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/79173/2/j.1095-8312.2010.01550.x.pd

The private life of echidnas: Using accelerometry and GPS to examine field biomechanics and assess the ecological impact of a widespread, semi-fossorial monotreme

The short-beaked echidna (Tachyglossus aculeatus) is a monotreme and therefore provides a unique combination of phylogenetic history, morphological differentiation and ecological specialisation for a mammal. The echidna has a unique appendicular skeleton, a highly specialised myrmecophagous lifestyle and a mode of locomotion that is neither typically mammalian nor reptilian, but has aspects of both lineages. We therefore were interested in the interactions of locomotor biomechanics, ecology and movements for wild, free-living short-beaked echidnas. To assess locomotion in its complex natural environment, we attached both GPS and accelerometer loggers to the back of echidnas in both spring and summer. We found that the locomotor biomechanics of echidnas is unique, with lower stride length and stride frequency than reported for similar-sized mammals. Speed modulation is primarily accomplished through changes in stride frequency, with a mean of 1.39 Hz and a maximum of 2.31 Hz. Daily activity period was linked to ambient air temperature, which restricted daytime activity during the hotter summer months. Echidnas had longer activity periods and longer digging bouts in spring compared with summer. In summer, echidnas had higher walking speeds than in spring, perhaps because of the shorter time suitable for activity. Echidnas spent, on average, 12% of their time digging, which indicates their potential to excavate up to 204 m3 of soil a year. This information highlights the important contribution towards ecosystem health, via bioturbation, of this widespread Australian monotreme