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Background Blood eosinophil count has been proposed as a predictor of response to inhaled corticosteroid (ICS) in the prevention of acute exacerbations of COPD. An optimal threshold of blood eosinophil count for prescribing ICS has not been agreed. Doubt has been cast on the role by observational studies. The role of inhaled corticosteroids in this relationship, independent of long-acting bronchodilators, has not been examined. Methods We conducted a systematic review of post-hoc analyses of randomised controlled trials (RCTs) and observational studies examining three blood eosinophil thresholds and the independent role of ICS. Included studies were categorised by the form (relative or absolute count) and cut point of eosinophil threshold used. Thresholds assessed were relative eosinophil count of 2%, and absolute counts of 150 cells/μL and 300 cells/μL. Three meta-analyses of the effect of ICS use in post-hoc analyses of RCTs based on these counts were carried out. Initial analysis included all studies of ICS vs. any non-ICS regimen. Further analysis examined the effect of ICS, independent of the effect of long-acting bronchodilators. Results Sixteen studies examined the association between blood eosinophil count and response of exacerbation risk to ICS, in COPD patients. Eleven studies (25,881 patients) were post-hoc analyses of RCTs. Five studies (109,704 patients) were retrospective observational studies. The independent effect of ICS on the reduction of exacerbation risk was 20% at ≥2% blood eosinophil threshold (RR, 0.80; 95% CI, 0.74–0.85), 35% at ≥150 cells/μL blood eosinophil threshold (RR, 0.65; 0.52–0.79), and 39% at ≥300 cells/μL blood eosinophil threshold (RR, 0.61; 0.44–0.78). No association was found in four out of five observational studies. Conclusion This is the first systematic review to assess, in post-hoc analyses of RCTs, the independent effect of ICS in reducing the risk of COPD exacerbation across a range of blood eosinophil thresholds. Association between ICS prescription and reduced exacerbation risk at these thresholds was confirmed. The lack of association found in the observational studies questions the relevance of these observations to a “real world” COPD population. To clarify the clinical utility of this biomarker, the association should be tested in prospective effectiveness studies.

ObjectivesCognitive impairment poststroke is progressive. We aimed to synthesise the existing evidence evaluating risk factors and the effects of treatments to prevent/improve cognitive function in patients who had a stroke with cognitive impairment.DesignUmbrella review.Data sourceMedline, PsycINFO, EMBASE, Cochrane and PROSPERO were searched from inception until 11 June 2019.Eligibility criteriaPublished systematic review (SR) that incorporated randomised controlled trials to investigate an intervention to improve poststroke cognitive impairment, or SR of longitudinal observational studies that evaluated the risk factors of this condition. No restrictions were applied.Data extraction and synthesisFrom each eligible study, details were recorded by one reviewer in a validated form. Grading of Recommendations, Assessment, Development and Evaluations criteria were used to assess our certainty level of each outcome, and A Measurement Tool to Assess Systematic Reviews 2 to assess quality.ResultsAltogether, 3464 abstracts were retrieved, 135 full texts were evaluated and 22 SRs were included in the final analysis. From four SRs of observational studies, we found 19 significant associations with postulated risk factors, and those which we determined to be confident about were: atrial fibrillation (3 SRs, 25 original studies); relative risk 3.01 (1.96–4.61), ORs 2.4 (1.7–3.5) and 2.0 (1.4–2.8), leukoaraiosis, multiple and recurrent strokes, ORs 2.5 (1.9–3.4), 2.5 (1.9–3.1) and 2.3 (1.5–3.5), respectively. From 18 SRs of interventional trials, we found that interventions including physical activity or cognitive rehabilitation were enhancing cognitive function, while the certainty of the other interventions was rated low, due to limited methodological quality.ConclusionsThis review represents common risk factors related to poststroke cognitive impairment, in particular atrial fibrillation, and points to different interventions that warrant attention in the development of treatment strategies. Physical activity and cognitive rehabilitation interventions showed evidence of enhancing cognitive function; however, we could not recommend a change in practice yet, due to lack of strong evidence.PROSPERO registration numberCRD42018096667.

Background Randomised controlled trials (RCTs) are widely regarded as the most powerful research design for evidence-based practice. However, recruiting to RCTs can be challenging resulting in heightened costs and delays in research completion and implementation. Enabling successful recruitment is crucial in mental health research. Despite the increase in the use of remote recruitment strategies and digital health interventions, there is limited evidence on methods to improve recruitment to remotely delivered mental health trials. The paper outlines practical examples and recommendations on how to successfully recruit participants to remotely delivered mental health trials. Methods The Alpha Stim-D Trial was a multi-centre double-blind randomised controlled trial, for people aged 16 years upwards, addressing depressive symptoms in primary care. Despite a 6-month delay in beginning recruitment due to the COVID-19 pandemic, the trial met the recruitment target within the timeframe and achieved high retention rates. Several strategies were implemented to improve recruitment; some of these were adapted in response to the COVID-19 pandemic. This included adapting the original in-person recruitment strategies. Subsequently, systematic recruitment using postal invitations from criteria-specific search of the sites’ electronic health records was added to opportunistic recruitment to increase referrals in response to sub-target recruitment whilst also reducing the burden on referring sites. Throughout the recruitment process, the research team collaborated with key stakeholders, such as primary care clinicians and the project’s Patient and Public Involvement and Engagement (PPI/E) representatives, who gave advice on recruitment strategies. Furthermore, the study researchers played a key role in communicating with participants and building rapport from study introduction to data collection. Conclusions Our findings suggest that trial processes can influence recruitment; therefore, consideration and a regular review of the recruitment figures and strategies is important. Recruitment of participants can be maximised by utilising remote approaches, which reduce the burden and amount of time required by referring sites and allow the research team to reach more participants whilst providing participants and researchers with more flexibility. Effectively communicating and working collaboratively with key stakeholders throughout the trial process, as well as building rapport with participants, may also improve recruitment rates.

Background Acute otitis media (AOM) is a common painful infection in children, with around 2.8 million cases presenting to primary care in England and Wales annually. Nearly all children who present to their general practitioner (GP) with AOM or AOM with discharge (AOMd) are treated with orally administered antibiotics. These can cause side effects; contribute to the growing problem of antimicrobial resistance, and more rarely, allergic reactions. Alternative treatments, such as an antibiotic eardrops, or ‘delayed’ orally administered antibiotics, could be at least as effective and safe as immediate orally administered antibiotics for children with AOMd. Methods/design REST is a pragmatic, three-arm, individually randomised, non-inferiority trial being conducted in 175 GP practices across the United Kingdom (UK). The study aims to recruit 399 children aged (≥ 12 months and < 16 years) presenting to their GP with AOMd. Children will be randomised to one of three arms: immediate ciprofloxacin 0.3% eardrops; delayed orally administered amoxicillin (clarithromycin if penicillin allergic) or immediate orally administered amoxicillin (clarithromycin). Recruitment, including eligibility screening, randomisation and data collection, are conducted using the innovative, TRANSFoRm electronic trial management platform. Integrated within the primary care electronic medical records it provides automatic eligibility checking, part-filling of e-CRFs, study workflow management and routine NHS follow-up data collection. The primary outcome is time to resolution of all significant symptoms and will be collected by the parent using a Symptom Recovery Questionnaire (SRQ). Secondary outcomes, including cost-effectiveness, duration of moderately bad or worse symptoms and repeat AOMd episodes, will be collected at day-14 and at 3 months. Discussion It is unclear whether prescribing orally administered antibiotics to children with AOMd results in a reduction in symptoms or a shorter duration of illness. The REST trial should allow us to compare the non-inferiority of: immediate topically administered ciprofloxacin ear drops, or delayed orally administered amoxicillin (clarithromycin) against immediate orally administered amoxicillin (clarithromycin). We aim to recruit 399 patients from 175 practices in the UK. Using the TRANSFoRm software to randomise participants to the trial will enable recruitment for a relatively uncommon condition. Trial registration Name of Registry: ISCRTN Registration Number: ISRCTN12873692 . This contains all items required to comply with the World Health Organization Trial Registration Data Set Date of Registration: 24 April 2018 Name of Registry: EudraCT Registration Number: 2017-003635-10 Date of Registration: 6 September 2017

Background Early intervention gives young people the best chance to recover from eating disorders (EDs). An important focus of early intervention is shortening the time between a person first developing symptoms and starting treatment (duration of untreated eating disorder; DUED). Patient-related factors (e.g. poor mental health literacy and help-seeking difficulties) are strongly associated with DUED. The aims of our study are to co-design and test the feasibility of FREED-Mobile (FREED-M), an online intervention tool for young people with early-stage EDs. This tool aims to improve knowledge about EDs, increase motivation to seek treatment and teach early steps towards change or recovery, thus reducing DUED. Methods We will carry out a randomised controlled feasibility trial comparing the FREED-M tool with a control intervention where individuals are sign-posted to an ED charity website. The objectives of the proposed trial are to establish/estimate: (a) attrition rates at follow-up (primary feasibility outcome); (b) participant recruitment; (c) intervention uptake, completion rates and acceptability; (d) intervention effect sizes and standard deviations for outcomes to inform the sample size calculation for a large-scale randomised controlled trial (RCT); (e) stakeholder views on the intervention. We aim to recruit 116 participants (young people, aged 16–25, with first episode ED) from primary care, schools and universities, ED services and social media. Online assessments will be carried out at baseline, end of intervention and follow-up (weeks 0, 4 and 12 post-randomisation, respectively). Outcomes will include motivation and readiness to change, attitudes and intentions towards help-seeking, ED symptoms, mood and social functioning, and health-related quality of life. Additionally, we will carry out a qualitative evaluation of participants’ views of the intervention and study design. Discussion The results of this feasibility trial will inform adaptations to the intervention as needed, as well as the study design (e.g. sample size, primary outcomes) of a future large-scale RCT to assess the effectiveness of the FREED-M intervention. If effective, this novel, online intervention has the potential for wide dissemination and for substantially reducing DUED to improve long-term patient outcomes. Trial registration ISRCTN, ISRCTN15662055. Registered 27 July 2022, https://www.isrctn.com/ISRCTN15662055 .

BackgroundIn England, there is a discrepancy between the prevalence of attention-deficit/hyperactivity disorder (ADHD) ascertained from medical records and community surveys. There is also a lack of data on variation in recorded prevalence by deprivation and geographical region; information that is important for service development and commissioning.MethodsCohort study using data from the Clinical Practice Research Datalink comprising 5196 children and young people aged 3–17 years with ADHD and 490 016 without, in 2012.ResultsIn 2012, the recorded prevalence of ADHD was 1.06% (95% CI 1.03 to 1.09). Prevalence in the most deprived areas was double that of the least deprived areas (prevalence rate ratio 2.58 (95% CI 2.36 to 2.83)), with a linear trend from least to most deprived areas across all regions in England.ConclusionsThe low prevalence of ADHD in medical records may indicate considerable underdiagnosis. Higher rates in more disadvantaged areas indicate greater need for services in those areas.

ObjectiveTo compare use of healthcare services and reasons for attendance by children and young people (CYP) with attention-deficit/hyperactivity disorder (ADHD) versus non-ADHD controls.DesignPopulation-based matched case-control study.SettingEnglish primary care electronic health records with linked hospital records from the Clinical Practice Research Datalink, 1998–2015.Participants8127 CYP with an ADHD diagnosis aged 4–17 years at the time of diagnosis and 40 136 non-ADHD controls matched by age, sex and general practitioner (GP) practice.Main outcome measuresMedical diagnoses, prescriptions, hospital admissions and hospital procedures in the 2 years before diagnosis (or the index date for controls).ResultsCYP with ADHD attended healthcare services twice as often as controls (rate ratios: GP: 2.0, 95% CI=2.0, 2.1; hospital 1.8, 95% CI=1.8, 1.9). CYP with ADHD attended their GP, received prescriptions and were admitted to hospital for a wide range of reasons. The strongest association for GP attendances, comparing CYP with versus without ADHD, was for ‘mental and behavioural disorders’ (OR=25.2, 95% CI=23.3, 27.2). Common reasons for GP attendance included eye, ear, nose, throat, oral (OR=1.5, 95% CI=1.4, 1.5) and conditions such as asthma (OR=1.3, 95% CI=1.3, 1.4) or eczema (OR=1.2, 95% CI=1.0, 1.3).ConclusionsTwo years before diagnosis, CYP with ADHD attended healthcare services twice as often as CYP without. CYP with ADHD had increased rates of physical conditions, such as asthma and eczema. These contacts may be an opportunity for earlier recognition and diagnosis of ADHD.

BackgroundChildren and young people (CYP) with attention-deficit/hyperactivity disorder (ADHD) face delays in diagnosis and barriers to accessing appropriate interventions. Evidence is limited on how these barriers are perceived by their parents and carers.MethodsFocus group in South London with parents/carers of CYP with ADHD. Data were thematically analysed using an inductive/deductive hybrid approach.ResultsParticipants (n=8) described the challenge of accessing services within a disjointed, multiagency system for their CYP’s ADHD and broader health needs. They described feeling judged and overlooked by healthcare professionals, which could negatively impact the health, relationships and educational progress of their children. Pragmatic solutions were proposed, including providing parents with information on navigating services at an early stage of ADHD symptom recognition.ConclusionsParents/carers sought improved continuity of care within and between services. They are a key group for consultation on the development of interventions to improve access for CYP with ADHD.

Children and young people with Autism Spectrum Disorder (ASD) have an increased risk of comorbidities, such as epilepsy and Attention-Deficit/Hyperactivity Disorder (ADHD). However, little is known about the relationship between early childhood epilepsy (below age 7) and later ADHD diagnosis (at age 7 or above) in ASD. In this historical cohort study, we examined this relationship using an innovative data source, which included linked data from routinely collected acute hospital paediatric records and childhood community and inpatient psychiatric records. In a large sample of children and young people with ASD (N = 3237), we conducted a longitudinal analysis to examine early childhood epilepsy as a risk factor for ADHD diagnosis while adjusting for potential confounders, including socio-demographic characteristics, intellectual disability, family history of epilepsy and associated physical conditions. We found that ASD children and young people diagnosed with early childhood epilepsy had nearly a twofold increase in risk of developing ADHD later in life, an association which persisted after adjusting for potential confounders (adjusted OR = 1.72, CI95% = 1.13–2.62). This study suggests that sensitive monitoring of ADHD symptoms in children with ASD who have a history of childhood epilepsy may be important to promote early detection and treatment. It also highlights how linked electronic health records can be used to examine potential risk factors over time for multimorbidity in neurodevelopmental conditions.

Attention-deficit hyperactivity disorder (ADHD) has a significant impact on children’s classroom behaviour, daily functioning and experience of school life. However, the effects of drug treatment for ADHD on learning and academic achievement are not fully understood. This review was undertaken to describe the effects of methylphenidate, dexamfetamine, mixed amfetamine salts and atomoxetine on children’s on-task behaviour and their academic performance, and to perform a meta-analysis to quantify these effects. Nine electronic databases were systematically searched for randomized controlled trials comparing drug treatment for ADHD against (i) no drug treatment, (ii) baseline (in crossover trials), or (iii) placebo; reporting outcomes encompassing measures of educational achievement within the classroom environment. Forty-three studies involving a pooled total of 2,110 participants were identified for inclusion. Drug treatment benefited children in the amount of school work that they completed, by up to 15 %, and less consistently improved children’s accuracy in specific types of academic assignments, such as arithmetic. Similar improvements were seen in classroom behaviour, with up to 14 % more of children’s time spent “on task”. Methylphenidate, dexamfetamine and mixed amfetamine formulations all showed beneficial effects on children’s on-task behaviour and academic work completion. Atomoxetine was examined in two studies, and was found to have no significant effect. These review findings suggest that medication for ADHD has the potential to improve children’s learning and academic achievement.