ABSTRACT
BACKGROUND: Stroke prevention guidance for patients with atrial fibrillation (AF) uses evidence generated from randomised controlled trials (RCTs). However, applicability to patient groups excluded from trials remains unknown. Real-world patient data provide an opportunity to evaluate outcomes in a trial analogous population of direct oral anticoagulants (DOACs) users and in patients otherwise excluded from RCTs; however, there remains uncertainty on the validity of methods and suitability of the data. Successful reference trial emulation can support the generation of evidence around treatment effects in groups excluded or underrepresented in trials. We used linked United Kingdom primary care data to investigate whether we could emulate the pivotal ARISTOTLE trial (apixaban versus warfarin) and extend the analysis to investigate the impact of warfarin time in therapeutic range (TTR) on results. METHODS AND FINDINGS: Patients with AF in the UK Clinical Practice Research Datalink (CPRD Aurum) prescribed apixaban or warfarin from 1 January 2013 to 31 July 2019 were selected. ARISTOTLE eligibility criteria were applied to this population and matched to the RCT apixaban arm on baseline characteristics creating a trial-analogous apixaban cohort; this was propensity-score matched to warfarin users in the CPRD Aurum. ARISTOTLE outcomes were assessed using Cox proportional hazards regression stratified by prior warfarin exposure status during 2.5 years of patient follow-up and results benchmarked against the trial results before treatment effectiveness was further evaluated based on (warfarin) TTR. The dataset comprised 8,734 apixaban users and propensity-score matched 8,734 warfarin users. Results [hazard ratio (95% confidence interval)] confirmed apixaban noninferiority for stroke or systemic embolism (SE) [CPRD 0.98 (0.82,1.19) versus trial 0.79 (0.66,0.95)] and death from any cause [CPRD 1.03 (0.93,1.14) versus trial 0.89 (0.80,0.998)] but did not indicate apixaban superiority. Absolute event rates for stroke/SE were similar for apixaban in CPRD Aurum and ARISTOTLE (1.27%/year), whereas a lower event rate was observed for warfarin (CPRD Aurum 1.29%/year, ARISTOTLE 1.60%/year). Analysis by TTR suggested similar effectiveness of apixaban compared with poorly controlled warfarin (TTR < 0.75) for stroke/SE [0.91 (0.73, 1.14)], all-cause death [0.94 (0.84, 1.06)], and superiority for major bleeding [0.74 (0.63, 0.86)]. However, when compared with well-controlled warfarin (TTR ≥ 0.75), apixaban was associated with an increased hazard for all-cause death [1.20 (1.04, 1.37)], and there was no significant benefit for major bleeding [1.08 (0.90, 1.30)]. The main limitation of the study's methodology are the risk of residual confounding, channelling bias and attrition bias in the warfarin arm, and selection bias and misclassification in the analysis by TTR. CONCLUSIONS: Analysis of noninterventional data generated results demonstrating noninferiority of apixaban versus warfarin consistent with prespecified benchmarking criteria. Unlike in ARISTOTLE, superiority of apixaban versus warfarin was not seen, possible due to the lower proportion of Asian patients and higher proportion of patients with well-controlled warfarin compared to ARISTOTLE. This methodological template can be used to investigate treatment effects of oral anticoagulants in patient groups excluded from or underrepresented in trials and provides a framework that can be adapted to investigate treatment effects for other conditions.
Subject(s)
Anticoagulants , Atrial Fibrillation , Pyrazoles , Pyridones , Stroke , Warfarin , Humans , Atrial Fibrillation/drug therapy , Atrial Fibrillation/complications , Warfarin/therapeutic use , Warfarin/adverse effects , Warfarin/administration & dosage , Anticoagulants/therapeutic use , Anticoagulants/adverse effects , Anticoagulants/administration & dosage , Stroke/prevention & control , Stroke/etiology , United Kingdom/epidemiology , Female , Aged , Male , Pyridones/therapeutic use , Pyridones/administration & dosage , Pyridones/adverse effects , Pyrazoles/therapeutic use , Pyrazoles/administration & dosage , Administration, Oral , Aged, 80 and over , Middle Aged , Treatment Outcome , Hemorrhage/chemically induced , Factor Xa Inhibitors/therapeutic use , Factor Xa Inhibitors/adverse effects , Factor Xa Inhibitors/administration & dosageABSTRACT
Cardiovascular disease (CVD) is a leading cause of death globally. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB), compared in the ONTARGET trial, each prevent CVD. However, trial results may not be generalisable and their effectiveness in underrepresented groups is unclear. Using trial emulation methods within routine-care data to validate findings, we explored generalisability of ONTARGET results. For people prescribed an ACEi/ARB in the UK Clinical Practice Research Datalink GOLD from 1/1/2001-31/7/2019, we applied trial criteria and propensity-score methods to create an ONTARGET trial-eligible cohort. Comparing ARB to ACEi, we estimated hazard ratios for the primary composite trial outcome (cardiovascular death, myocardial infarction, stroke, or hospitalisation for heart failure), and secondary outcomes. As the pre-specified criteria were met confirming trial emulation, we then explored treatment heterogeneity among three trial-underrepresented subgroups: females, those aged ≥75 years and those with chronic kidney disease (CKD). In the trial-eligible population (n=137,155), results for the primary outcome demonstrated similar effects of ARB and ACEi, (HR 0.97 [95% CI: 0.93, 1.01]), meeting the pre-specified validation criteria. When extending this outcome to trial-underrepresented groups, similar treatment effects were observed by sex, age and CKD. This suggests that ONTARGET trial findings are generalisable to trial-underrepresented subgroups.
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Background: Although exposure to potentially traumatic events (PTEs) for Black and Latinx may be comparable or lower than their White counterparts, type of trauma experiences differ such as more interpersonal trauma and violence reported by Black people, who also experience higher rates of PTSD. In this retrospective study, we examined the association between use of particular substances and various PTEs and the race/ethnicity-group differences for this association. Methods: One-hundred seventy-nine participants recruited from an outpatient substance use disorder program from February 2018 to October 2020 completed measures on lifetime trauma history and current/past cocaine, cannabis, and alcohol misuse. Bayesian generalized linear modeling with horseshoe prior was used to predict substance misuse using 17 PTEs, then PTEs were ranked and examined by racial/ethnic group. Results: No PTEs were associated with substance misuse across all four r/e groups. Transportation accident, natural disaster, war exposure, and other stressful events were associated with substance misuse across two or three r/e groups. Notably, the three PTEs involving interpersonal violence in our study (weapon assault, physical assault, and sexual assault) were only associated with substance misuse (posterior probability ≥70%) for Latinx participants. Conclusion: The relational nature of interpersonal/violent traumas may make them particularly salient for Latinx people where interpersonal relationships are prioritized. These types of traumas may also be viewed as an extension of discrimination and exclusion, two longstanding, intractable issues for people of color in the US, making them even more damaging. Furthermore, lack of resources may limit options for coping, resulting in substance use problems.
Subject(s)
Cannabis , Stress Disorders, Post-Traumatic , Substance-Related Disorders , Humans , Retrospective Studies , Bayes Theorem , Violence , Substance-Related Disorders/epidemiologyABSTRACT
Over the last hundred years, idiopathic hypertrophic pyloric stenosis has undergone an evolution in treatment, with subsequent improvements in outcome. Initially, it was treated by physicians with antispasmodics and various alternative feeding and resuscitation modalities. The evolution of surgical approaches led to a revolution in outcome, from almost certain death to complete cure. The progression of surgical and medical treatments is reviewed in this article until, ultimately, Ramstedt's pyloromyotomy is reached. This distilled operation has remained the gold-standard procedure for over a century.
Subject(s)
Pyloric Stenosis/history , Pyloromyotomy/history , Pylorus/surgery , Fluid Therapy/history , History, 20th Century , Humans , Infant , Pyloric Stenosis/surgery , Pyloric Stenosis/therapy , Pyloromyotomy/methodsABSTRACT
INTRODUCTION: The process of transitioning young people from children's or adolescents' health services into adults' services is a crucial time in the lives and health of young people and has been reported to be disjointed rather than a process of preparation in which they are involved. Such transitions not only fail to meet the needs of young people and families at this time of significant change, but they may also result in a deterioration in health, or disengagement with services, which can have deleterious long-term consequences. Despite the wealth of literature on this topic, there has yet to be a focus on what works for whom, in what circumstances, how and why, in relation to all young people transitioning from children's into adults' services, which this realist synthesis aims to address. METHODS AND ANALYSIS: This realist synthesis will be undertaken in six stages: (1) the scope of the review will be defined; (2) initial programme theories (IPTs) developed; (3) evidence searched; (4) selection and appraisal; (5) data extraction and synthesis; and (6) finally, refine/confirm programme theory. A theory-driven, iterative approach using the 'On Your Own Feet Ahead' theoretical framework, will be combined with an evidence search including a review of national transition policy documents, supplemented by citation tracking, snowballing and stakeholder feedback to develop IPTs. Searches of EMBASE, EMCARE, Medline, CINAHL, Cochrane Library, Web of Science, Scopus, APA PsycINFO and AMED will be conducted from 2014 to present, supplemented with grey literature, free-text searching (title, abstract and keywords) and citation tracking. Data selection will be based on relevance and rigour and extracted and synthesised iteratively with the aim of identifying and exploring causal links between contexts, mechanisms and outcomes. Results will be reported according to the Realist And Meta-narrative Evidence Syntheses: Evolving Standards Quality and Publication Standards. ETHICS AND DISSEMINATION: This realist synthesis forms part of the National Transition Evaluation Study, which has received ethical and regulatory approval (IRAS ID: 313576). Results will be disseminated through peer-review publication, conference presentations and working with healthcare organisations, stakeholder groups and charities. TRIAL REGISTRATION NUMBER: NCT05867745. PROSPERO REGISTRATION NUMBER: CRD42023388985.
Subject(s)
Delivery of Health Care , Health Facilities , Adolescent , Adult , Child , Humans , Policy , Systematic Reviews as Topic/methodsABSTRACT
BACKGROUND: Estimations of Lyme disease incidence rates in the United Kingdom vary. There is evidence that this disease is associated with fatigue in its early stage but reports are contradictory as far as long-term fatigue is concerned. METHODS AND FINDINGS: A population-based historical cohort study was conducted on patients treated in general practices contributing to IQVIA Medical Research Data: 2,130 patients with a first diagnosis of Lyme disease between 2000 and 2018 and 8,510 randomly-sampled patients matched by age, sex, and general practice, followed-up for a median time of 3 years and 8 months. Main outcome measure was time to consultation for (1) any fatigue-related symptoms or diagnosis; or (2) myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Adjusted hazard ratios (HRs) were estimated from Cox models. Average incidence rate for Lyme disease across the UK was 5.18 per 100,000 person-years, increasing from 2.55 in 2000 to 9.33 in 2018. In total, 929 events of any types of fatigue were observed, leading to an incidence rate of 307.90 per 10,000 person-years in the Lyme cohort (282 events) and 165.60 in the comparator cohort (647 events). Effect of Lyme disease on any subsequent fatigue varied by index season: adjusted HRs were the highest in autumn and winter with 3.14 (95%CI: 1.92-5.13) and 2.23 (1.21-4.11), respectively. For ME/CFS, 17 events were observed in total. Incidence rates were 11.76 per 10,000 person-years in Lyme patients (12 events) and 1.20 in comparators (5 events), corresponding to an adjusted HR of 16.95 (5.17-55.60). Effects were attenuated 6 months after diagnosis but still clearly visible. CONCLUSIONS: UK primary care records provided strong evidence that Lyme disease was associated with subsequent fatigue and ME/CFS. Albeit weaker on the long-term, these effects persisted beyond 6 months, suggesting patients and healthcare providers should remain alert to fatigue symptoms months to years following Lyme disease diagnosis.
Subject(s)
Fatigue Syndrome, Chronic , Lyme Disease , Child, Preschool , Cohort Studies , Fatigue Syndrome, Chronic/diagnosis , Humans , Incidence , Lyme Disease/complications , Lyme Disease/diagnosis , Lyme Disease/epidemiology , United Kingdom/epidemiologyABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0265765.].
ABSTRACT
BACKGROUND: Early evidence has shown that anticoagulant reduces the risk of thrombotic events in those infected with COVID-19. However, evidence of the role of routinely prescribed oral anticoagulants (OACs) in COVID-19 outcomes is limited. AIM: To investigate the association between OACs and COVID-19 outcomes in those with atrial fibrillation and a CHA2DS2-VASc score of 2. DESIGN AND SETTING: On behalf of NHS England, a population-based cohort study was conducted. METHOD: The study used primary care data and pseudonymously-linked SARS-CoV-2 antigen testing data, hospital admissions, and death records from England. Cox regression was used to estimate hazard ratios (HRs) for COVID-19 outcomes comparing people with current OAC use versus non-use, accounting for age, sex, comorbidities, other medications, deprivation, and general practice. RESULTS: Of 71 103 people with atrial fibrillation and a CHA2DS2-VASc score of 2, there were 52 832 current OAC users and 18 271 non-users. No difference in risk of being tested for SARS-CoV-2 was associated with current use (adjusted HR [aHR] 0.99, 95% confidence interval [CI] = 0.95 to 1.04) versus non-use. A lower risk of testing positive for SARS-CoV-2 (aHR 0.77, 95% CI = 0.63 to 0.95) and a marginally lower risk of COVID-19-related death (aHR, 0.74, 95% CI = 0.53 to 1.04) were associated with current use versus non-use. CONCLUSION: Among those at low baseline stroke risk, people receiving OACs had a lower risk of testing positive for SARS-CoV-2 and severe COVID-19 outcomes than non-users; this might be explained by a causal effect of OACs in preventing severe COVID-19 outcomes or unmeasured confounding, including more cautious behaviours leading to reduced infection risk.
Subject(s)
Atrial Fibrillation , COVID-19 , Stroke , Administration, Oral , Anticoagulants/therapeutic use , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Atrial Fibrillation/epidemiology , COVID-19/epidemiology , Cohort Studies , Humans , SARS-CoV-2 , Stroke/drug therapy , Stroke/epidemiology , Stroke/prevention & controlABSTRACT
Background: Patients surviving hospitalisation for COVID-19 are thought to be at high risk of cardiometabolic and pulmonary complications, but quantification of that risk is limited. We aimed to describe the overall burden of these complications in people after discharge from hospital with COVID-19. Methods: Working on behalf of NHS England, we used linked primary care records, death certificate and hospital data from the OpenSAFELY platform. We constructed three cohorts: patients discharged following hospitalisation with COVID-19, patients discharged following pre-pandemic hospitalisation with pneumonia, and a frequency-matched cohort from the general population in 2019. We studied seven outcomes: deep vein thrombosis (DVT), pulmonary embolism (PE), ischaemic stroke, myocardial infarction (MI), heart failure, AKI and new type 2 diabetes mellitus (T2DM) diagnosis. Absolute rates were measured in each cohort and Fine and Gray models were used to estimate age/sex adjusted subdistribution hazard ratios comparing outcome risk between discharged COVID-19 patients and the two comparator cohorts. Results: Amongst the population of 77,347 patients discharged following hospitalisation with COVID-19, rates for the majority of outcomes peaked in the first month post-discharge, then declined over the following four months. Patients in the COVID-19 population had markedly higher risk of all outcomes compared to matched controls from the 2019 general population. Across the whole study period, the risk of outcomes was more similar when comparing patients discharged with COVID-19 to those discharged with pneumonia in 2019, although COVID-19 patients had higher risk of T2DM (15.2 versus 37.2 [rate per 1,000-person-years for COVID-19 versus pneumonia, respectively]; SHR, 1.46 [95% CI: 1.31 - 1.63]). Conclusions: Risk of cardiometabolic and pulmonary adverse outcomes is markedly raised following discharge from hospitalisation with COVID-19 compared to the general population. However, excess risks were similar to those seen following discharge post-pneumonia. Overall, this suggests a large additional burden on healthcare resources.
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INTRODUCTION: Patients with atrial fibrillation experience an irregular heart rate and have an increased risk of stroke; prophylactic treatment with anticoagulation medication reduces this risk. Direct-acting oral anticoagulants (DOACs) have been approved providing an alternative to vitamin K antagonists such as warfarin. There is interest from regulatory bodies on the effectiveness of medications in routine clinical practice; however, uncertainty remains regarding the suitability of non-interventional data for answering questions on drug effectiveness and on the most suitable methods to be used. In this study, we will use data from Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE)-the pivotal trial for the DOAC apixaban-to validate non-interventional methods for assessing treatment effectiveness of anticoagulants. These methods could then be applied to analyse treatment effectiveness in people excluded from or under-represented in ARISTOTLE. METHODS AND ANALYSIS: Patient characteristics from ARISTOTLE will be used to select a cohort of patients with similar baseline characteristics from two UK electronic health record (EHR) databases, Clinical Practice Research Datalink Gold and Aurum (between 1 January 2013 and 31 July 2019). Methods such as propensity score matching and coarsened exact matching will be explored in matching between EHR treatment groups to determine the optimal method of obtaining a balanced cohort.Absolute and relative risk of outcomes in the EHR trial-analogous cohort will be calculated and compared with the ARISTOTLE results; if results are deemed compatible the methods used for matching EHR treatment groups can then be used to examine drug effectiveness over a longer duration of exposure and in special patient groups of interest not studied in the trial. ETHICS AND DISSEMINATION: The study has been approved by the Independent Scientific Advisory Committee of the UK Medicines and Healthcare Products Regulatory Agency. Results will be disseminated in scientific publications and at relevant conferences.
Subject(s)
Atrial Fibrillation , Stroke , Administration, Oral , Anticoagulants/therapeutic use , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Cohort Studies , Humans , Pyridones/therapeutic use , Randomized Controlled Trials as Topic , Stroke/drug therapy , Stroke/etiology , Stroke/prevention & control , United Kingdom , Warfarin/therapeutic useABSTRACT
OBJECTIVE: The aim of this study was to investigate the association between oral anticoagulant type (direct oral anticoagulants (DOACs) vs vitamin K antagonists (VKAs)) and incident dementia or mild cognitive impairment (MCI) among patients with newly diagnosed atrial fibrillation (AF). METHODS: Using linked electronic health record (EHR) data from the Clinical Practice Research Datalink in the UK, we conducted a historical cohort study among first-time oral anticoagulant users with incident non-valvular AF diagnosed from 2012 to 2018. We compared the incidence of (1) clinically coded dementia and (2) MCI between patients prescribed VKAs and DOACs using Cox proportional hazards regression models, with age as the underlying timescale, accounting for calendar time and time on treatment, sociodemographic and lifestyle factors, clinical comorbidities and medications. RESULTS: Of 39 200 first-time oral anticoagulant users (44.6% female, median age 76 years, IQR 68-83), 20 687 (53%) were prescribed a VKA and 18 513 (47%) a DOAC at baseline. Overall, 1258 patients (3.2%) had GP-recorded incident dementia, incidence rate 16.5 per 1000 person-years. DOAC treatment for AF was associated with a 16% reduction in dementia diagnosis compared with VKA treatment in the whole cohort (adjusted HR 0.84, 95% CI: 0.73 to 0.98) and with a 26% reduction in incident MCI (adjusted HR 0.74, 95% CI: 0.65 to 0.84). Findings were similar across various sensitivity analyses. CONCLUSIONS: Incident EHR-recorded dementia and MCI were less common among patients prescribed DOACs for new AF compared with those prescribed VKAs.
Subject(s)
Anticoagulants/administration & dosage , Atrial Fibrillation/epidemiology , Cognition/drug effects , Dementia/epidemiology , Drug Prescriptions/statistics & numerical data , Risk Assessment/methods , Stroke/prevention & control , Administration, Oral , Adult , Aged , Aged, 80 and over , Atrial Fibrillation/complications , Atrial Fibrillation/drug therapy , Comorbidity , Dementia/physiopathology , Female , Follow-Up Studies , Humans , Incidence , Male , Middle Aged , Retrospective Studies , Risk Factors , Stroke/etiology , United Kingdom/epidemiologyABSTRACT
BACKGROUND: Thromboembolism has been reported as a consequence of severe COVID-19. Although warfarin is a commonly used anticoagulant, it acts by antagonising vitamin K, which is low in patients with severe COVID-19. To date, the clinical evidence on the impact of regular use of warfarin on COVID-19-related thromboembolism is lacking. METHODS: On behalf of NHS England, we conducted a population-based cohort study investigating the association between warfarin and COVID-19 outcomes compared with direct oral anticoagulants (DOACs). We used the OpenSAFELY platform to analyse primary care data and pseudonymously linked SARS-CoV-2 antigen testing data, hospital admissions and death records from England. We used Cox regression to estimate hazard ratios (HRs) for COVID-19-related outcomes comparing warfarin with DOACs in people with non-valvular atrial fibrillation. We also conducted negative control outcome analyses (being tested for SARS-CoV-2 and non-COVID-19 death) to assess the potential impact of confounding. RESULTS: A total of 92,339 warfarin users and 280,407 DOAC users were included. We observed a lower risk of all outcomes associated with warfarin versus DOACs [testing positive for SARS-CoV-2, HR 0.73 (95% CI 0.68-0.79); COVID-19-related hospital admission, HR 0.75 (95% CI 0.68-0.83); COVID-19-related deaths, HR 0.74 (95% CI 0.66-0.83)]. A lower risk of negative control outcomes associated with warfarin versus DOACs was also observed [being tested for SARS-CoV-2, HR 0.80 (95% CI 0.79-0.81); non-COVID-19 deaths, HR 0.79 (95% CI 0.76-0.83)]. CONCLUSIONS: Overall, this study shows no evidence of harmful effects of warfarin on severe COVID-19 disease.
Subject(s)
Anticoagulants/therapeutic use , COVID-19/epidemiology , Thromboembolism/drug therapy , Thromboembolism/virology , Warfarin/therapeutic use , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Anticoagulants/pharmacology , COVID-19/blood , COVID-19/virology , Cohort Studies , England/epidemiology , Humans , Middle Aged , SARS-CoV-2/isolation & purification , Thromboembolism/blood , Thromboembolism/epidemiology , Treatment Outcome , Young Adult , COVID-19 Drug TreatmentABSTRACT
Visualization of single neurons and glia, as well as neural lineages within their complex environment is a pivotal step towards uncovering the mechanisms that control neural circuit development and function. This chapter provides detailed technical information on how to use Drosophila variants of the mouse Brainbow-2 system, called Flybow, for stochastic labeling of individual cells or lineages with different fluorescent proteins in one sample. We describe the genetic strategies and the heat shock regime required for induction of recombination events. Furthermore, we explain how Flybow and the mosaic analysis with a repressible cell marker (MARCM) approach can be combined to generate wild-type or homozygous mutant clones that are positively labeled in multiple colors. This is followed by a detailed protocol as to how to prepare samples for imaging. Finally, we provide specifications to facilitate multichannel image acquisition using confocal microscopy.
Subject(s)
Drosophila Proteins/genetics , Drosophila melanogaster/cytology , Luminescent Proteins/metabolism , Animals , Animals, Genetically Modified , Brain/cytology , Brain/metabolism , Cell Lineage , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Luminescent Proteins/genetics , Microscopy, Confocal , MutationABSTRACT
To assess the wider application of the SHARP (Stretching whilst moving, High repetition of skills, Accessibility, Reducing sitting and standing, and Promotion of physical activity) Principles intervention on children's moderate to vigorous physical activity (MVPA) in physical education (PE), when applied by teachers and coaches. A quasi-experimental intervention was employed in nine primary schools (experimental, n = 6: control, n = 3) including teachers (n = 10), coaches (n = 4), and children (aged 5 to 11 years, n = 84) in the West Midlands, UK. Practitioners applied the SHARP Principles to PE lessons, guided by an innovative behaviour change model. The System for Observing Fitness and Instruction Time (SOFIT) was used to measure children's MVPA in 111 lessons at pre- (n = 60) and post-intervention (n = 51). Seven interviews were conducted post-intervention to explore practitioners' perceptions. Two-way ANOVA (Analysis of Variance) revealed that teachers increased children's MVPA by 27.7%. No statistically significant change in children's MVPA was observed when taught by the coaches. The qualitative results for teachers were 'children's engagement', a 'pedagogical paradigm shift', and 'relatedness'; and for coaches 'organisational culture' and 'insufficient support and motivation'. The SHARP Principles intervention is the most effective teaching strategy at increasing MVPA in primary PE when taught by school based staff (rather than outsourced coaches), evidencing increases almost double that of any previously published study internationally and demonstrating the capacity to influence educational policy and practice internationally.
ABSTRACT
Autophagy is the degradation of cytoplasmic material through the lysosomal pathway. One of the most studied autophagy-related proteins is LC3. Despite growing evidence that LC3 is enriched in the nucleus, its nuclear role is poorly understood. Here, we show that Drosophila Atg8a protein, homologous to mammalian LC3, interacts with the transcription factor Sequoia in a LIR motif-dependent manner. We show that Sequoia depletion induces autophagy in nutrient-rich conditions through the enhanced expression of autophagy genes. We show that Atg8a interacts with YL-1, a component of a nuclear acetyltransferase complex, and that it is acetylated in nutrient-rich conditions. We also show that Atg8a interacts with the deacetylase Sir2, which deacetylates Atg8a during starvation to activate autophagy. Our results suggest a mechanism of regulation of the expression of autophagy genes by Atg8a, which is linked to its acetylation status and its interaction with Sequoia, YL-1, and Sir2.
Subject(s)
Autophagy-Related Protein 8 Family/genetics , Drosophila Proteins/metabolism , Drosophila/metabolism , Histone Chaperones/metabolism , Histone Deacetylases/metabolism , Sequoia/metabolism , Sirtuins/metabolism , AnimalsABSTRACT
Despite the known benefits of engaging in daily moderate to vigorous physical activity (MVPA), only 22% of children in England are meeting the recommended guidelines. School break times have been advocated as a key part of children's daily routines in which their MVPA can be increased. The main aim of this study was to evaluate the effect of installing a walking-track on children's MVPA during school break times. A mixed method design was employed which allowed for the quantitative measurement of children's PA at three time points (baseline, mid-intervention (1â»5 weeks) and follow-up (6â»9 weeks)), using pedometers (n = 81, 5â»9 years) and systematic observation (n = 23, 7â»9 years). A semi-structured interview (n = 1) was also conducted at 10 weeks' follow-up. The installation of the walking-track was grounded in a unique set of theoretical constructs to aid the behaviour change of the teachers. Short term positive increases in girls' and boys' MVPA and longer term increases in boys' vigorous PA (VPA) were found. Qualitative data highlighted that boys dominated the walking-track and the inconsistent behaviour of school staff negatively impacted upon children's MVPA. A set of principles to guide the installment of walking-tracks in school playgrounds are recommended.
ABSTRACT
OBJECTIVES: To evaluate the effectiveness of a one-year teaching intervention to increase moderate to vigorous physical activity (MVPA) during primary school physical education (PE). METHODS: A quasi-experimental, non-equivalent group design involving four classes from two primary schools in the West Midlands, UK. In March 2014 schools were selected through purposive sampling to match schools in terms of size and demographics (baseline, n = 111: post-intervention, n = 95); data were collected from children in school years 3 and 4 (aged 7 to 9 years). The intervention involved developing teacher effectiveness through the SHARP Principles Model which was grounded in the Self Determination Theory (SDT), the Social Ecological Model (SEM) and three key ingredients from the Behaviour Change Taxonomy (BCT). MVPA was assessed at baseline and four weeks post-intervention using the System for Observing Fitness and Instruction Time (SOFIT). Four individual teacher interviews were conducted with the intervention school, to explore teachers' perceptions of the intervention. RESULTS: A two-way ANOVA (Analysis of Variance) indicated large interaction effect sizes for time spent in MVPA (F(1, 27) = 11.07, p = 0.003, ηp (2) = .316) and vigorous activity (VPA) (F = (1,27) = 8.557, p = .007, ηp (2) = .263). PA in the intervention school increased significantly whereas in the control school MVPA remained relatively constant and VPA decreased. The qualitative findings revealed two main emergent themes: a paradigm shift and teacher's developing pedagogy. CONCLUSIONS: The intervention was effective in increasing MVPA in PE. Recommendations based on this evaluation would be for the SHARP Principles Model to be replicated and evaluated on a wider scale across a variety of contexts.
ABSTRACT
PURPOSE: The aim of this study was to examine the performance of adolescents with acquired brain injury (ABI) during a spoken persuasive discourse task. Persuasive discourse is frequently used in social and academic settings and is of importance in the study of adolescent language. METHOD: Participants included 8 adolescents with ABI and 8 peers without ABI who were matched for age, gender, and education. A spoken persuasive discourse task requiring participants to express their opinion on a topic was administered, and the 2 groups were compared on measures of language productivity, syntactic complexity, and language content. In addition, the relationship between working memory and discourse production was explored. RESULTS: There were no statistically significant group differences on measures of language productivity or syntactic complexity, with the exception of the use of mazes, which was more prevalent in the discourse of the group with ABI. However, there were significant differences in language content, with age-matched peers producing more than twice as many supporting reasons and far fewer tangentially related utterances than the adolescents with ABI. CONCLUSIONS: Persuasive discourse production was affected following ABI. Given the importance of persuasive discourse in social and academic situations, further investigations into factors that influence discourse production in adolescents with ABI are warranted.