Nonpharmacological Interventions to Lengthen Sleep Duration in Healthy Children: A Systematic Review and Meta-analysis.

Importance: Adequate sleep duration is necessary for many aspects of child health, development, and well-being, yet sleep durations for children are declining, and effective strategies to increase sleep in healthy children remain to be elucidated. Objective: To determine whether nonpharmaceutical interventions to improve sleep duration in healthy children are effective and to identify the key components of these interventions. Data Sources: CENTRAL, MEDLINE, Embase, PsycINFO, Web of Science Core collection, ClinicalTrials.gov, and WHO trials databases were searched from inception to November 15, 2021. Study Selection: Randomized clinical trials of interventions to improve sleep duration in healthy children were independently screened by 2 researchers. A total of 28 478 studies were identified. Data Extraction and Synthesis: Data were processed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) reporting guideline. Random-effects meta-analytic models were used to estimate pooled effect sizes. Main Outcomes and Measures: Difference in sleep duration, measured in minutes. Results: A total of 13 539 child participants from 45 randomized clinical trials were included. Of these, 6897 (50.9%) were in the intervention group and 6642 (49.1%) in the control group, and the mean age ranged from 18 months to 19 years. Pooled results indicate that sleep interventions were associated with 10.5 minutes (95% CI, 5.6-15.4) longer nocturnal sleep duration. There was substantial variation between trials. Sources of variation that were not associated with the study effect size included age group, whether the population was identified as having a sleep problem or being at a socioeconomic disadvantage (eg, coming from a low-income family or area), method of assessment of sleep duration (objective vs subjective), location of intervention delivery (home vs school), whether interventions were delivered in person or used parental involvement, whether behavioral theory was used, environmental change, or had greater or lower intensity. Interventions that included earlier bedtimes were associated with a 47-minute sleep extension (95% CI, 18.9-75.0; 3 trials) compared with remaining studies (7.4 minutes; 95% CI, 2.9-11.8; 42 trials) (P = .006 for group difference). Trials of shorter duration (6 months or less) had larger effects. Conclusions and Relevance: Interventions focused on earlier bedtimes may offer a simple, pragmatic, effective way to meaningfully increase sleep duration that could have important benefits for child health.

Short-stay crisis units for mental health patients on crisis care pathways: systematic review and meta-analysis.

BACKGROUND: Internationally, an increasing proportion of emergency department visits are mental health related. Concurrently, psychiatric wards are often occupied above capacity. Healthcare providers have introduced short-stay, hospital-based crisis units offering a therapeutic space for stabilisation, assessment and appropriate referral. Research lags behind roll-out, and a review of the evidence is urgently needed to inform policy and further introduction of similar units. AIMS: This systematic review aims to evaluate the effectiveness of short-stay, hospital-based mental health crisis units. METHOD: We searched EMBASE, Medline, CINAHL and PsycINFO up to March 2021. All designs incorporating a control or comparison group were eligible for inclusion, and all effect estimates with a comparison group were extracted and combined meta-analytically where appropriate. We assessed study risk of bias with Risk of Bias in Non-Randomized Studies - of Interventions and Risk of Bias in Randomized Trials. RESULTS: Data from twelve studies across six countries (Australia, Belgium, Canada, The Netherlands, UK and USA) and 67 505 participants were included. Data indicated that units delivered benefits on many outcomes. Units could reduce psychiatric holds (42% after intervention compared with 49.8% before intervention; difference = 7.8%; P < 0.0001) and increase out-patient follow-up care (χ2 = 37.42, d.f. = 1; P < 0.001). Meta-analysis indicated a significant reduction in length of emergency department stay (by 164.24 min; 95% CI -261.24 to -67.23 min; P < 0.001) and number of in-patient admissions (odds ratio 0.55, 95% CI 0.43-0.68; P < 0.001). CONCLUSIONS: Short-stay mental health crisis units are effective for reducing emergency department wait times and in-patient admissions. Further research should investigate the impact of units on patient experience, and clinical and social outcomes.

ERS statement: a core outcome set for clinical trials evaluating the management of COPD exacerbations.

Clinical trials evaluating the management of acute exacerbations of COPD assess heterogeneous outcomes, often omitting those that are clinically relevant or more important to patients. We have developed a core outcome set, a consensus-based minimum set of important outcomes that we recommend are evaluated in all future clinical trials on exacerbations management, to improve their quality and comparability. COPD exacerbations outcomes were identified through methodological systematic reviews and qualitative interviews with 86 patients from 11 countries globally. The most critical outcomes were prioritised for inclusion in the core outcome set through a two-round Delphi survey completed by 1063 participants (256 patients, 488 health professionals and 319 clinical academics) from 88 countries in five continents. Two global, multi-stakeholder, virtual consensus meetings were conducted to 1) finalise the core outcome set and 2) prioritise a single measurement instrument to be used for evaluating each of the prioritised outcomes. Consensus was informed by rigorous methodological systematic reviews. The views of patients with COPD were accounted for at all stages of the project. Survival, treatment success, breathlessness, quality of life, activities of daily living, the need for a higher level of care, arterial blood gases, disease progression, future exacerbations and hospital admissions, treatment safety and adherence were all included in the core outcome set. Focused methodological research was recommended to further validate and optimise some of the selected measurement instruments. The panel did not consider the prioritised set of outcomes and associated measurement instruments to be burdensome for patients and health professionals to use.

A survey and stakeholder group prioritised key systematic review questions in airways disease.

Objective: Priority setting is important for healthcare research. The Cochrane Airways Group wanted to prioritise topics for systematic reviews across all chronic respiratory diseases with limited resources and according to latest Cochrane policy.The objective was to prioritise 10 reviews of importance to the public (patients, carers, healthcare professionals and researchers) from a patient survey. Study design and setting: We convened a stakeholder group of patients, carers, healthcare professionals and representatives from charities. We conducted an online survey to collect uncertainties about the treatment and management of respiratory disease from the public. Uncertainties were ranked by the stakeholder group, and scoping searches refined the uncertainties into systematic review questions. Results: We received 147 survey responses. We removed duplicates and blank responses and asked the stakeholder group to rank 100 uncertainties. The first round of voting produced a list of 29 topics and the second round resulted in 12 uncertainties. These uncertainties were scoped with literature searches and teased out further into systematic review topics. We identified 3 Cochrane reviews to update, 8 new review topics, and 3 evidence gaps. Conclusion: We successfully convened a stakeholder group and prioritised a list of uncertainties in the treatment and management of airways diseases that had been identified by patients and the public.

Assessing Treatment Success or Failure as an Outcome in Randomised Clinical Trials of COPD Exacerbations. A Meta-Epidemiological Study.

A recently published ERS core outcome set recommends that all trials of COPD exacerbation management should assess the treatment success (or "cure" of the exacerbation), defined as a dichotomous measure of the overall outcome of an exacerbation. This methodological systematic review describes and compares the instruments that were used to assess treatment success or failure in 54 such RCTs, published between 2006-2020. Twenty-three RCTs used composite measures consisting of several undesirable outcomes of an exacerbation, together defining an overall unfavourable outcome, to define treatment failure. Thirty-four RCTs used descriptive instruments that used qualitative or semi-quantitative descriptions to define cure, marked improvement, improvement of the exacerbation, or treatment failure. Treatment success and failure rates among patients receiving guidelines-directed treatments at different settings and timepoints are described and could be used to inform power calculations in future trials. Descriptive instruments appeared more sensitive to treatment effects compared to composite instruments. Further methodological studies are needed to optimise the evaluation of treatment success/failure. In the meantime, based on the findings of this systematic review, the ERS core outcome set recommends that cure should be defined as sufficient improvement of the signs and symptoms of the exacerbation such that no additional systemic treatments are required.

Individual-level interventions to reduce personal exposure to outdoor air pollution and their effects on people with long-term respiratory conditions.

BACKGROUND: More than 90% of the global population lives in areas exceeding World Health Organization air quality limits. More than four million people each year are thought to die early due to air pollution, and poor air quality is thought to reduce an average European's life expectancy by one year. Individuals may be able to reduce health risks through interventions such as masks, behavioural changes and use of air quality alerts. To date, evidence is lacking about the efficacy and safety of such interventions for the general population and people with long-term respiratory conditions. This topic, and the review question relating to supporting evidence to avoid or lessen the effects of air pollution, emerged directly from a group of people with chronic obstructive pulmonary disease (COPD) in South London, UK. OBJECTIVES: 1. To assess the efficacy, safety and acceptability of individual-level interventions that aim to help people with or without chronic respiratory conditions to reduce their exposure to outdoor air pollution. 2. To assess the efficacy, safety and acceptability of individual-level interventions that aim to help people with chronic respiratory conditions reduce the personal impact of outdoor air pollution and improve health outcomes. SEARCH METHODS: We identified studies from the Cochrane Airways Trials Register, Cochrane Central Register of Controlled Trials, and other major databases. We did not restrict our searches by date, language or publication type and included a search of the grey literature (e.g. unpublished information). We conducted the most recent search on 16 October 2020. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and non-randomised studies (NRS) that included a comparison treatment arm, in adults and children that investigated the effectiveness of an individual-level intervention to reduce risks of outdoor air pollution. We included studies in healthy individuals and those in people with long-term respiratory conditions. We excluded studies which focused on non-respiratory long-term conditions, such as cardiovascular disease. We did not restrict eligibility of studies based on outcomes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Two review authors independently selected trials for inclusion, extracted study characteristics and outcome data, and assessed risk of bias using the Cochrane Risk of Bias tool for RCTs and the Risk Of Bias In Non-randomised Studies - of Interventions (ROBINS-I) as appropriate. One review author entered data into the review; this was spot-checked by a second author. We planned to meta-analyse results from RCTs and NRS separately, using a random-effects model. This was not possible, so we presented evidence narratively. We assessed certainty of the evidence using the GRADE approach. Primary outcomes were: measures of air pollution exposure; exacerbation of respiratory conditions; hospital admissions; quality of life; and serious adverse events. MAIN RESULTS: We identified 11 studies (3372 participants) meeting our inclusion criteria (10 RCTs and one NRS). Participants' ages ranged from 18 to 74 years, and the duration of studies ranged from 24 hours to 104 weeks. Six cross-over studies recruited healthy adults and five parallel studies included either people with pre-existing conditions (three studies) or only pregnant women (two studies). Interventions included masks (e.g. an N95 mask designed to filter out airborne particles) (five studies), an alternative cycle route (one study), air quality alerts and education (five studies). Studies were set in Australia, China, Iran, the UK, and the USA. Due to the diversity of study designs, populations, interventions and outcomes, we did not perform any meta-analyses and instead summarised results narratively. We judged both RCTs and the NRS to be at risk of bias from lack of blinding and lack of clarity regarding selection methods. Many studies did not provide a prepublished protocol or trial registration. From five studies (184 participants), we found that masks or altered cycle routes may have little or no impact on physiological markers of air pollution exposure (e.g. blood pressure and heart rate variability), but we are very uncertain about this estimate using the GRADE approach. We found conflicting evidence regarding health care usage from three studies of air pollution alerts, with one non-randomised cross-over trial (35 participants) reporting an increase in emergency hospital attendances and admissions, but the other two randomised parallel trials (1553 participants) reporting little to no difference. We also gave the evidence for this outcome a very uncertain GRADE rating. None of our included trials reported respiratory exacerbations, quality of life or serious adverse events. Secondary outcomes were not well reported, but indicated inconsistent impacts of air quality alerts and education interventions on adherence, with some trials reporting improvements in the intervention groups and others reporting little or no difference. Symptoms were reported by three trials, with one randomised cross-over trial (15 participants) reporting a small increase in breathing difficulties associated with the mask intervention, one non-randomised cross-over trial (35 participants) reporting reduced throat and nasal irritation in the lower-pollution cycle route group (but no clear difference in other respiratory symptoms), and another randomised parallel trial (519 participants) reporting no clear difference in symptoms between those who received a smog warning and those who did not. AUTHORS' CONCLUSIONS: The lack of evidence and study diversity has limited the conclusions of this review. Using a mask or a lower-pollution cycle route may mitigate some of the physiological impacts from air pollution, but evidence was very uncertain. We found conflicting results for other outcomes, including health care usage, symptoms and adherence/behaviour change. We did not find evidence for adverse events. Funders should consider commissioning larger, longer studies, using high-quality and well-described methods, recruiting participants with pre-existing respiratory conditions. Studies should report outcomes of importance to people with respiratory conditions, such as exacerbations, hospital admissions, quality of life and adverse events.

Pre-operative prognostic factors for walking capacity after surgery for lumbar spinal stenosis: a systematic review.

BACKGROUND: Lumbar spinal stenosis (LSS) reduces walking and quality of life. It is the main indication for spinal surgery in older people yet 40% report walking disability post-operatively. Identifying the prognostic factors of post-operative walking capacity could aid clinical decision-making, guide rehabilitation and optimise health outcomes. OBJECTIVE: To synthesise the evidence for pre-operative mutable and immutable prognostic factors for post-operative walking in adults with LSS. DESIGN: Systematic review with narrative synthesis. METHODS: Electronic databases (CENTRAL, MEDLINE, EMBASE, CINAHL, PsycINFO, Web of Science, OpenGrey) were searched for observational studies, evaluating factors associated with walking after surgery in adults receiving surgery for LSS from database inception to January 2020. Two reviewers independently evaluated studies for eligibility, extracted data and assessed risk of bias (Quality in Prognosis Studies). The Grading of Recommendations Assessment, Development and Evaluation method was used to determine level of evidence for each factor. RESULTS: 5526 studies were screened for eligibility. Thirty-four studies (20 cohorts, 9,973 participants, 26 high, 2 moderate, 6 low risk of bias) were included. Forty variables (12 mutable) were identified. There was moderate quality of evidence that pre-operative walking capacity was positively associated with post-operative walking capacity. The presence of spondylolisthesis and the severity of stenosis were not associated with post-operative walking capacity. All other factors investigated had low/very low level of evidence. CONCLUSION: Greater pre-operative walking is associated with greater post-operative walking capacity but not spondylolisthesis or severity of stenosis. Few studies have investigated mutable prognostic factors that could be potentially targeted to optimise surgical outcomes.

Tailored or adapted interventions for adults with chronic obstructive pulmonary disease and at least one other long-term condition: a mixed methods review.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition characterised by shortness of breath, cough and recurrent exacerbations. People with COPD often live with one or more co-existing long-term health conditions (comorbidities). People with more severe COPD often have a higher number of comorbidities, putting them at greater risk of morbidity and mortality. OBJECTIVES: To assess the effectiveness of any single intervention for COPD adapted or tailored to their comorbidity(s) compared to any other intervention for people with COPD and one or more common comorbidities (quantitative data, RCTs) in terms of the following outcomes: Quality of life, exacerbations, functional status, all-cause and respiratory-related hospital admissions, mortality, pain, and depression and anxiety. To assess the effectiveness of an adapted or tailored single COPD intervention (simple or complex) that is aimed at changing the management of people with COPD and one or more common comorbidities (quantitative data, RCTs) compared to usual care in terms of the following outcomes: Quality of life, exacerbations, functional status, all-cause and respiratory-related hospital admissions, mortality, pain, and depression and anxiety. To identify emerging themes that describe the views and experiences of patients, carers and healthcare professionals when receiving or providing care to manage multimorbidities (qualitative data). SEARCH METHODS: We searched multiple databases including the Cochrane Airways Trials Register, CENTRAL, MEDLINE, Embase, and CINAHL, to identify relevant randomised and qualitative studies. We also searched trial registries and conducted citation searches. The latest search was conducted in January 2021. SELECTION CRITERIA: Eligible randomised controlled trials (RCTs) compared a) any single intervention for COPD adapted or tailored to their comorbidity(s) compared to any other intervention, or b) any adapted or tailored single COPD intervention (simple or complex) that is aimed at changing the management of people with COPD and one or more comorbidities, compared to usual care. We included qualitative studies or mixed-methods studies to identify themes. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods for analysis of the RCTs. We used Cochrane's risk of bias tool for the RCTs and the CASP checklist for the qualitative studies. We planned to use the Mixed Methods Appraisal tool (MMAT) to assess the risk of bias in mixed-methods studies, but we found none. We used GRADE and CERQual to assess the quality of the quantitative and qualitative evidence respectively. The primary outcome measures for this review were quality of life and exacerbations. MAIN RESULTS: Quantitative studies We included seven studies (1197 participants) in the quantitative analyses, with interventions including telemonitoring, pulmonary rehabilitation, treatment optimisation, water-based exercise training and case management. Interventions were either compared with usual care or with an active comparator (such as land-based exercise training). Duration of trials ranged from 4 to 52 weeks. Mean age of participants ranged from 64 to 72 years and COPD severity ranged from mild to very severe. Trials included either people with COPD and a specific comorbidity (including cardiovascular disease, metabolic syndrome, lung cancer, head or neck cancer, and musculoskeletal conditions), or with one or more comorbidities of any type. Overall, we judged the evidence presented to be of moderate to very low certainty (GRADE), mainly due to the methodological quality of included trials and imprecision of effect estimates. Intervention versus usual care Quality of life as measured by the St George's Respiratory Questionnaire (SGRQ) total score may improve with tailored pulmonary rehabilitation compared to usual care at 52 weeks (mean difference (MD) -10.85, 95% confidence interval (CI) -12.66 to -9.04; 1 study, 70 participants; low-certainty evidence). Tailored pulmonary rehabilitation is likely to improve COPD assessment test (CAT) scores compared with usual care at 52 weeks (MD -8.02, 95% CI -9.44 to -6.60; 1 study, 70 participants, moderate-certainty evidence) and with a multicomponent telehealth intervention at 52 weeks (MD -6.90, 95% CI -9.56 to -4.24; moderate-certainty evidence). Evidence is uncertain about effects of pharmacotherapy optimisation or telemonitoring interventions on CAT improvement compared with usual care. There may be little to no difference in the number of people experiencing exacerbations, or mean exacerbations with case management compared with usual care (OR 1.09, 95% CI 0.75 to 1.57; 1 study, 470 participants; very low-certainty evidence). For secondary outcomes, six-minute walk distance (6MWD) may improve with pulmonary rehabilitation, water-based exercise or multicomponent interventions at 38 to 52 weeks (low-certainty evidence). A multicomponent intervention may result in fewer people being admitted to hospital at 17 weeks, although there may be little to no difference in a telemonitoring intervention. There may be little to no difference between intervention and usual care for mortality. Intervention versus active comparator We included one study comparing water-based and land-based exercise (30 participants). We found no evidence for quality of life or exacerbations. There may be little to no difference between water- and land-based exercise for 6MWD (MD 5 metres, 95% CI -22 to 32; 38 participants; very low-certainty evidence). Qualitative studies One nested qualitative study (21 participants) explored perceptions and experiences of people with COPD and long-term conditions, and of researchers and health professionals who were involved in an RCT of telemonitoring equipment. Several themes were identified, including health status, beliefs and concerns, reliability of equipment, self-efficacy, perceived ease of use, factors affecting usefulness and perceived usefulness, attitudes and intention, self-management and changes in healthcare use. We judged the qualitative evidence presented as of very low certainty overall. AUTHORS' CONCLUSIONS: Owing to a paucity of eligible trials, as well as diversity in the intervention type, comorbidities and the outcome measures reported, we were unable to provide a robust synthesis of data. Pulmonary rehabilitation or multicomponent interventions may improve quality of life and functional status (6MWD), but the evidence is too limited to draw a robust conclusion. The key take-home message from this review is the lack of data from RCTs on treatments for people living with COPD and comorbidities. Given the variation in number and type of comorbidity(s) an individual may have, and severity of COPD, larger studies reporting individual patient data are required to determine these effects.

Regular treatment with formoterol and an inhaled corticosteroid versus regular treatment with salmeterol and an inhaled corticosteroid for chronic asthma: serious adverse events.

BACKGROUND: Asthma is characterised by chronic inflammation of the airways and recurrent exacerbations with wheezing, chest tightness, and cough. Treatment with inhaled steroids and bronchodilators can result in good control of symptoms, prevention of further morbidity, and improved quality of life. However, an increase in serious adverse events with the use of both regular formoterol and regular salmeterol (long-acting beta2-agonists) compared with placebo for chronic asthma has been demonstrated in previous Cochrane Reviews. This increase was statistically significant in trials that did not randomise participants to an inhaled corticosteroid, but not when formoterol or salmeterol was combined with an inhaled corticosteroid. The confidence intervals were found to be too wide to ensure that the addition of an inhaled corticosteroid renders regular long-acting beta2-agonists completely safe; few participants and insufficient serious adverse events in these trials precluded a definitive decision about the safety of combination treatments. OBJECTIVES: To assess risks of mortality and non-fatal serious adverse events in trials that have randomised patients with chronic asthma to regular formoterol and an inhaled corticosteroid versus regular salmeterol and an inhaled corticosteroid. SEARCH METHODS: We searched the Cochrane Airways Register of Trials, CENTRAL, MEDLINE, Embase, and two trial registries to identify reports of randomised trials for inclusion. We checked manufacturers' websites and clinical trial registers for unpublished trial data, as well as Food and Drug Administration (FDA) submissions in relation to formoterol and salmeterol. The date of the most recent search was  24 February 2021. SELECTION CRITERIA: We included controlled clinical trials with a parallel design, recruiting patients of any age and severity of asthma, if they randomised patients to treatment with regular formoterol versus regular salmeterol (each with a randomised inhaled corticosteroid) and were of at least 12 weeks' duration. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion in the review, extracted outcome data from published papers and trial registries, and applied GRADE rating for the results. We sought unpublished data on mortality and serious adverse events from study sponsors and authors. The primary outcomes were all cause mortality and non-fatal serious adverse events. We chose not to calculate an average result from all the formulations of formoterol and inhaled steroid, as the doses and delivery devices are too diverse to assume a single class effect. MAIN RESULTS: Twenty-one studies in 11,572 adults and adolescents and two studies in 723 children met the eligibility criteria of the review. No data were available for two studies; therefore these were not included in the analysis. Among adult and adolescent studies, seven compared formoterol and budesonide to salmeterol and fluticasone (N = 7764), six compared formoterol and beclomethasone to salmeterol and fluticasone (N = 1923), two compared formoterol and mometasone to salmeterol and fluticasone (N = 1126), two compared formoterol and fluticasone to salmeterol and fluticasone (N = 790), and one compared formoterol and budesonide to salmeterol and budesonide (N = 229). In total, five deaths were reported among adults, none of which was thought to be related to asthma. The certainty of evidence for all-cause mortality was low, as there were not enough deaths to permit any precise conclusions regarding the risk of mortality on combination formoterol versus combination salmeterol. In all, 201 adults reported non-fatal serious adverse events. In studies comparing formoterol and budesonide to salmeterol and fluticasone, there were 77 in the formoterol arm and 68 in the salmeterol arm (Peto odds ratio (OR) 1.14, 95% confidence interval (CI) 0.82 to 1.59; 5935 participants, 7 studies; moderate-certainty evidence). In the formoterol and beclomethasone studies, there were 12 adults in the formoterol arm and 13 in the salmeterol arm with events (Peto OR 0.94, 95% CI 0.43 to 2.08; 1941 participants, 6 studies; moderate-certainty evidence). In the formoterol and mometasone studies, there were 18 in the formoterol arm and 11 in the salmeterol arm (Peto OR 1.02, 95% CI 0.47 to 2.20; 1126 participants, 2 studies; moderate-certainty evidence). One adult in the formoterol and fluticasone studies in the salmeterol arm experienced an event (Peto OR 0.05, 95% CI 0.00 to 3.10; 293 participants, 2 studies; low-certainty evidence). Another adult in the formoterol and budesonide compared to salmeterol and budesonide study in the formoterol arm had an event (Peto OR 7.45, 95% CI 0.15 to 375.68; 229 participants, 1 study; low-certainty evidence). Only 46 adults were reported to have experienced asthma-related serious adverse events. The certainty of the evidence was low to very low due to the small number of events and the absence of independent assessment of causation. The two studies in children compared formoterol and fluticasone to salmeterol and fluticasone. No deaths and no asthma-related serious adverse events were reported in these studies. Four all-cause serious adverse events were reported: three in the formoterol arm, and one in the salmeterol arm (Peto OR 2.72, 95% CI 0.38 to 19.46; 548 participants, 2 studies; low-certainty evidence). AUTHORS' CONCLUSIONS: Overall, for both adults and children, evidence is insufficient to show whether regular formoterol in combination with budesonide, beclomethasone, fluticasone, or mometasone has a different safety profile from salmeterol in combination with fluticasone or budesonide. Five deaths of any cause were reported across all studies and no deaths from asthma; this information is insufficient to permit any firm conclusions about the relative risks of mortality on combination formoterol in comparison to combination salmeterol inhalers. Evidence on all-cause non-fatal serious adverse events indicates that there is probably little to no difference between formoterol/budesonide and salmeterol/fluticasone inhalers. However events for the other formoterol combination inhalers were too few to allow conclusions. Only 46 non-fatal serious adverse events were thought to be asthma related; this small number in addition to the absence of independent outcome assessment means that we have very low confidence for this outcome. We found no evidence of safety issues that would affect the choice between salmeterol and formoterol combination inhalers used for regular maintenance therapy by adults and children with asthma.

Core outcome set for the management of acute exacerbations of chronic obstructive pulmonary disease: the COS-AECOPD ERS Task Force study protocol.

Randomised controlled trials (RCTs) on the management of COPD exacerbations evaluate heterogeneous outcomes, often omitting those that are clinically important and patient relevant. This limits their usability and comparability. A core outcome set (COS) is a consensus-based minimum set of clinically important outcomes that should be evaluated in all RCTs in specific areas of health care. We present the study protocol of the COS-AECOPD ERS Task Force, aiming to develop a COS for COPD exacerbation management, that could remedy these limitations. For the development of this COS we follow standard methodology recommended by the COMET initiative. A comprehensive list of outcomes is assembled through a methodological systematic review of the outcomes reported in relevant RCTs. Qualitative research with patients with COPD will also be conducted, aiming to identify additional outcomes that may be important to patients, but are not currently addressed in clinical research studies. Prioritisation of the core outcomes will be facilitated through an extensive, multi-stakeholder Delphi survey with a global reach. Selection will be finalised in an international, multi-stakeholder meeting. For every core outcome, we will recommend a specific measurement instrument and standardised time points for evaluation. Selection of instruments will be based on evidence-informed consensus. Our work will improve the quality, usability and comparability of future RCTs on the management of COPD exacerbations and, ultimately, the care of patients with COPD. Multi-stakeholder engagement and societal support by the European Respiratory Society will raise awareness and promote implementation of the COS.

Comparison of outpatient and home-based exercise training programmes for COPD: A systematic review and meta-analysis.

Chronic obstructive pulmonary disease is a common, preventable and treatable disease. Exercise training programmes (ETPs) improve symptoms, health-related quality of life (HRQoL) and exercise capacity, but the optimal setting is unknown. In this review, we compared the effects of ETPs in different settings on HRQoL and exercise capacity. We searched (5 July 2016) the Cochrane Airways Group Specialised Register, ClinicalTrials.gov and World Health Organization trials portal. We selected studies, extracted data and assessed risk of bias with two independent reviewers. We calculated mean differences (MD) with 95% CI. We assessed the quality of evidence using Grades of Recommendation, Assessment, Development and Evaluation. Ten trials (934 participants) were included. Hospital (outpatient) and home-based ETPs (seven trials) were equally effective at improving HRQoL on the Chronic Respiratory Questionnaire (CRQ) (dyspnoea: MD -0.09, 95% CI: -0.28 to 0.10; fatigue: MD -0.00, 95% CI: -0.18 to 0.17; emotional: MD 0.10, 95% CI: -0.24 to 0.45; and mastery: MD -0.02, 95% CI: -0.28 to 0.25; moderate quality) and on the St George's Respiratory Questionnaire (SGRQ) (MD -0.82, 95% CI: -7.47 to 5.83, low quality). Hospital (outpatient) and community-based ETPs (three trials) were equally effective at improving HRQoL (CRQ dyspnoea: MD 0.29, 95% CI: -0.05 to 0.62, moderate quality; fatigue: MD -0.02, 95% CI: -1.09 to 1.05, low quality; emotional: MD 0.10, 95% CI: -0.40 to 0.59, moderate quality; and mastery: MD -0.08, 95% CI: -0.45 to 0.28, moderate quality). There was no difference in exercise capacity. There was low to moderate evidence that outpatient and home-based ETPs are equally effective. See related Editorial.

Interventions to improve adherence to inhaled steroids for asthma.

BACKGROUND: Despite its proven efficacy in improving symptoms and reducing exacerbations, many patients with asthma are not fully adherent to their steroid inhaler. Suboptimal adherence leads to poorer clinical outcomes and increased health service utilisation, and has been identified as a contributing factor to a third of asthma deaths in the UK. Reasons for non-adherence vary, and a variety of interventions have been proposed to help people improve treatment adherence. OBJECTIVES: To assess the efficacy and safety of interventions intended to improve adherence to inhaled corticosteroids among people with asthma. SEARCH METHODS: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted the most recent searches on 18 November 2016. SELECTION CRITERIA: We included parallel and cluster randomised controlled trials of any duration conducted in any setting. We included studies reported as full-text articles, those published as abstracts only and unpublished data. We included trials of adults and children with asthma and a current prescription for an inhaled corticosteroid (ICS) (as monotherapy or in combination with a long-acting beta2-agonist (LABA)). Eligible trials compared an intervention primarily aimed at improving adherence to ICS versus usual care or an alternative intervention. DATA COLLECTION AND ANALYSIS: Two review authors screened the searches, extracted study characteristics and outcome data from included studies and assessed risk of bias. Primary outcomes were adherence to ICS, exacerbations requiring at least oral corticosteroids and asthma control. We graded results and presented evidence in 'Summary of findings' tables for each comparison.We analysed dichotomous data as odds ratios, and continuous data as mean differences or standardised mean differences, all using a random-effects model. We described skewed data narratively. We made no a priori assumptions about how trials would be categorised but conducted meta-analyses only if treatments, participants and the underlying clinical question were similar enough for pooling to make sense. MAIN RESULTS: We included 39 parallel randomised controlled trials (RCTs) involving adults and children with asthma, 28 of which (n = 16,303) contributed data to at least one meta-analysis. Follow-up ranged from two months to two years (median six months), and trials were conducted mainly in high-income countries. Most studies reported some measure of adherence to ICS and a variety of other outcomes such as quality of life and asthma control. Studies generally were at low or unclear risk of selection bias and at high risk of biases associated with blinding. We considered around half the studies to be at high risk for attrition bias and selective outcome reporting.We classified studies into four comparisons: adherence education versus control (20 studies); electronic trackers or reminders versus control (11 studies); simplified drug regimens versus usual drug regimens (four studies); and school-based directly observed therapy (three studies). Two studies are described separately.All pooled results for adherence education, electronic trackers or reminders and simplified regimens showed better adherence than controls. Analyses limited to studies using objective measures revealed that adherence education showed a benefit of 20 percentage points over control (95% confidence interval (CI) 7.52 to 32.74; five studies; low-quality evidence); electronic trackers or reminders led to better adherence of 19 percentage points (95% CI 14.47 to 25.26; six studies; moderate-quality evidence); and simplified regimens led to better adherence of 4 percentage points (95% CI 1.88 to 6.16; three studies; moderate-quality evidence). Our confidence in the evidence was reduced by risk of bias and inconsistency.Improvements in adherence were not consistently translated into observable benefit for clinical outcomes in our pooled analyses. None of the intervention types showed clear benefit for our primary clinical outcomes - exacerbations requiring an oral corticosteroid (OCS) (evidence of very low to low quality) and asthma control (evidence of low to moderate quality); nor for our secondary outcomes - unscheduled visits (evidence of very low to moderate quality) and quality of life (evidence of low to moderate quality). However, some individual studies reported observed benefits for OCS and use of healthcare services. Most school or work absence data were skewed and were difficult to interpret (evidence of low quality, when graded), and most studies did not specifically measure or report adverse events.Studies investigating the possible benefit of administering ICS at school did not measure adherence, exacerbations requiring OCS, asthma control or adverse events. One study showed fewer unscheduled visits, and another found no differences; data could not be combined. AUTHORS' CONCLUSIONS: Pooled results suggest that a variety of interventions can improve adherence. The clinical relevance of this improvement, highlighted by uncertain and inconsistent impact on clinical outcomes such as quality of life and asthma control, is less clear. We have low to moderate confidence in these findings owing to concerns about risk of bias and inconsistency. Future studies would benefit from predefining an evidence-based 'cut-off' for acceptable adherence and using objective adherence measures and validated tools and questionnaires. When possible, covert monitoring and some form of blinding or active control may help disentangle effects of the intervention from effects of inclusion in an adherence trial.

Study flow diagrams in Cochrane systematic review updates: an adapted PRISMA flow diagram.

Cochrane systematic reviews are conducted and reported according to rigorous standards. A study flow diagram must be included in a new review, and there is clear guidance from the PRISMA statement on how to do this. However, for a review update, there is currently no guidance on how study flow diagrams should be presented. To address this, a working group was formed to find a solution and produce guidance on how to use these diagrams in review updates.A number of different options were devised for how these flow diagrams could be used in review updates, and also in cases where multiple searches for a review or review update have been conducted. These options were circulated to the Cochrane information specialist community for consultation and feedback. Following the consultation period, the working group refined the guidance and made the recommendation that for review updates an adapted PRISMA flow diagram should be used, which includes an additional box with the number of previously included studies feeding into the total. Where multiple searches have been conducted, the results should be added together and treated as one set of results.There is no existing guidance for using study flow diagrams in review updates. Our adapted diagram is a simple and pragmatic solution for showing the flow of studies in review updates.

Inhaled antibiotics for stable non-cystic fibrosis bronchiectasis: a systematic review.

We conducted a meta-analysis of randomised trials to evaluate the efficacy and safety of inhaled antibiotics in patients with stable non-cystic fibrosis (CF) bronchiectasis. We searched the Cochrane Airways Group Register of Trials from inception until March 2014. 12 trials with 1264 adult patients were included, of which five were unpublished studies. Eight trials on 590 patients contributed data to the meta-analysis. Amikacin, aztreonam, ciprofloxacin, gentamicin, colistin or tobramycin were used for 4 weeks to 12 months. Inhaled antibiotics were more effective than placebo or symptomatic treatment in reducing sputum bacterial load (five trials; weighted mean difference -2.65 log10 CFU · g(-1), 95% CI -4.38- -0.92 log10 CFU · g(-1)), eradicating the bacteria from sputum (six trials; risk ratio 4.2, 95% CI 1.66-10.64) and reducing the risk of acute exacerbations (five trials; risk ratio 0.72, 95% CI 0.55-0.94). Bronchospasm occurred in 10% of patients treated with inhaled antibiotics compared with 2.3% in the control group (seven trials; risk ratio 2.96, 95% CI 1.30-6.73), but the two groups had the same withdrawal rate due to adverse events (12.2%). Inhaled antibiotics may provide an effective suppressive antibiotic therapy with an acceptable safety profile in adult patients with stable non-CF bronchiectasis and chronic bronchial infection.

Safety of regular formoterol or salmeterol in children with asthma: an overview of Cochrane reviews.

BACKGROUND: Two large surveillance studies in adults with asthma have found an increased risk of asthma-related mortality in those who took regular salmeterol as monotherapy in comparison to placebo or regular salbutamol. No similar sized surveillance studies have been carried out in children with asthma, and we remain uncertain about the comparative safety of regular combination therapy with either formoterol or salmeterol in children with asthma. OBJECTIVES: We have used the paediatric trial results from Cochrane systematic reviews to assess the safety of regular formoterol or salmeterol, either as monotherapy or as combination therapy, in children with asthma. METHODS: We included Cochrane reviews relating to the safety of regular formoterol and salmeterol from a search of the Cochrane Database of Systematic Reviews conducted in May 2012, and ran updated searches for each of the reviews. These were independently assessed. All the reviews were assessed for quality using the AMSTAR tool. We extracted the data relating to children from each review and from new trials found in the updated searches (including risks of bias, study characteristics, serious adverse event outcomes, and control arm event rates).The safety of regular formoterol and salmeterol were assessed directly from the paediatric trials in the Cochrane reviews of monotherapy and combination therapy with each product. Then monotherapy was indirectly compared to combination therapy by looking at the differences between the pooled trial results for monotherapy and the pooled results for combination therapy. The comparative safety of formoterol and salmeterol was assessed using direct evidence from trials that randomised children to each treatment; this was combined with the result of an indirect comparison of the combination therapy trials, which represents the difference between the pooled results of each product when randomised against inhaled corticosteroids alone. MAIN RESULTS: We identified six high quality, up to date Cochrane reviews. Four of these related to the safety of regular formoterol or salmeterol (as monotherapy or combination therapy) and these included 19 studies in children. We added data from two recent studies on salmeterol combination therapy in 689 children which were published after the relevant Cochrane review had been completed, making a total of 21 trials on 7474 children (from four to 17 years of age). The two remaining reviews compared the safety of formoterol with salmeterol from trials randomising participants to one or other treatment, but the reviews only included a single trial in children in which there were 156 participants.Only one child died across all the trials, so impact on mortality could not be assessed.We found a statistically significant increase in the odds of suffering a non-fatal serious adverse event of any cause in children on formoterol monotherapy (Peto odds ratio (OR) 2.48; 95% confidence interval (CI) 1.27 to 4.83, I(2) = 0%, 5 trials, N = 1335, high quality) and smaller increases in odds which were not statistically significant for salmeterol monotherapy (Peto OR 1.30; 95% CI 0.82 to 2.05, I(2) = 17%, 5 trials, N = 1333, moderate quality), formoterol combination therapy (Peto OR 1.60; 95% CI 0.80 to 3.28, I(2) = 32%, 7 trials, N = 2788, moderate quality) and salmeterol combination therapy (Peto OR 1.20; 95% CI 0.37 to 2.91, I(2) = 0%, 5 trials, N = 1862, moderate quality).We compared the pooled results of the monotherapy and combination therapy trials. There was no significant difference between the pooled ORs of children with a serious adverse event (SAE) from long-acting beta(2)-agonist beta agonist (LABA) monotherapy (Peto OR 1.60; 95% CI 1.10 to 2.33, 10 trials, N = 2668) and combination trials (Peto OR 1.50; 95% CI 0.82 to 2.75, 12 trials, N = 4,650). However, there were fewer children with an SAE in the regular inhaled corticosteroid (ICS) control group (0.7%) than in the placebo control group (3.6%). As a result, there was an absolute increase of an additional 21 children (95% CI 4 to 45) suffering such an SAE of any cause for every 1000 children treated over six months with either regular formoterol or salmeterol monotherapy, whilst for combination therapy the increased risk was an additional three children (95% CI 1 fewer to 12 more) per 1000 over three months.We only found a single trial in 156 children comparing the safety of regular salmeterol to regular formoterol monotherapy, and even with the additional evidence from indirect comparisons between the combination formoterol and salmeterol trials, the CI around the effect on SAEs is too wide to tell whether there is a difference in the comparative safety of formoterol and salmeterol (OR 1.26; 95% CI 0.37 to 4.32). AUTHORS' CONCLUSIONS: We do not know if regular combination therapy with formoterol or salmeterol in children alters the risk of dying from asthma.Regular combination therapy is likely to be less risky than monotherapy in children with asthma, but we cannot say that combination therapy is risk free. There are probably an additional three children per 1000 who suffer a non-fatal serious adverse event on combination therapy in comparison to ICS over three months. This is currently our best estimate of the risk of using LABA combination therapy in children and has to be balanced against the symptomatic benefit obtained for each child. We await the results of large on-going surveillance studies to further clarify the risks of combination therapy in children and adolescents with asthma.The relative safety of formoterol in comparison to salmeterol remains unclear, even when all currently available direct and indirect trial evidence is combined.