Inhaled corticosteroids versus long-acting beta -agonists for chronic obstructive pulmonary disease (Review).

Long-acting beta(2)-agonists and inhaled corticosteroids can be used as maintenance therapy by patients with moderate to severe chronic obstructive pulmonary disease. These interventions are often taken together in a combination inhaler. However, the relative added value of the two individual components is unclear

Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease.

BACKGROUND: Inhaled corticosteroids (ICS) are anti-inflammatory drugs that have proven benefits for people with worsening symptoms of chronic obstructive pulmonary disease (COPD) and repeated exacerbations. They are commonly used as combination inhalers with long-acting beta2-agonists (LABA) to reduce exacerbation rates and all-cause mortality, and to improve lung function and quality of life. The most common combinations of ICS and LABA used in combination inhalers are fluticasone and salmeterol, budesonide and formoterol and a new formulation of fluticasone in combination with vilanterol, which is now available. ICS have been associated with increased risk of pneumonia, but the magnitude of risk and how this compares with different ICS remain unclear. Recent reviews conducted to address their safety have not compared the relative safety of these two drugs when used alone or in combination with LABA. OBJECTIVES: To assess the risk of pneumonia associated with the use of fluticasone and budesonide for COPD. SEARCH METHODS: We identified trials from the Cochrane Airways Group Specialised Register of trials (CAGR), clinicaltrials.gov, reference lists of existing systematic reviews and manufacturer websites. The most recent searches were conducted in September 2013. SELECTION CRITERIA: We included parallel-group randomised controlled trials (RCTs) of at least 12 weeks' duration. Studies were included if they compared the ICS budesonide or fluticasone versus placebo, or either ICS in combination with a LABA versus the same LABA as monotherapy for people with COPD. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study characteristics, numerical data and risk of bias information for each included study.We looked at direct comparisons of ICS versus placebo separately from comparisons of ICS/LABA versus LABA for all outcomes, and we combined these with subgroups when no important heterogeneity was noted. After assessing for transitivity, we conducted an indirect comparison to compare budesonide versus fluticasone monotherapy, but we could not do the same for the combination therapies because of systematic differences between the budesonide and fluticasone combination data sets.When appropriate, we explored the effects of ICS dose, duration of ICS therapy and baseline severity on the primary outcome. Findings of all outcomes are presented in 'Summary of findings' tables using GRADEPro. MAIN RESULTS: We found 43 studies that met the inclusion criteria, and more evidence was provided for fluticasone (26 studies; n = 21,247) than for budesonide (17 studies; n = 10,150). Evidence from the budesonide studies was more inconsistent and less precise, and the studies were shorter. The populations within studies were more often male with a mean age of around 63, mean pack-years smoked over 40 and mean predicted forced expiratory volume of one second (FEV1) less than 50%.High or uneven dropout was considered a high risk of bias in almost 40% of the trials, but conclusions for the primary outcome did not change when the trials at high risk of bias were removed in a sensitivity analysis.Fluticasone increased non-fatal serious adverse pneumonia events (requiring hospital admission) (odds ratio (OR) 1.78, 95% confidence interval (CI) 1.50 to 2.12; 18 more per 1000 treated over 18 months; high quality), and no evidence suggested that this outcome was reduced by delivering it in combination with salmeterol or vilanterol (subgroup differences: I(2) = 0%, P value 0.51), or that different doses, trial duration or baseline severity significantly affected the estimate. Budesonide also increased non-fatal serious adverse pneumonia events compared with placebo, but the effect was less precise and was based on shorter trials (OR 1.62, 95% CI 1.00 to 2.62; six more per 1000 treated over nine months; moderate quality). Some of the variation in the budesonide data could be explained by a significant difference between the two commonly used doses: 640 mcg was associated with a larger effect than 320 mcg relative to placebo (subgroup differences: I(2) = 74%, P value 0.05).An indirect comparison of budesonide versus fluticasone monotherapy revealed no significant differences with respect to serious adverse events (pneumonia-related or all-cause) or mortality. The risk of any pneumonia event (i.e. less serious cases treated in the community) was higher with fluticasone than with budesonide (OR 1.86, 95% CI 1.04 to 3.34); this was the only significant difference reported between the two drugs. However, this finding should be interpreted with caution because of possible differences in the assignment of pneumonia diagnosis, and because no trials directly compared the two drugs.No significant difference in overall mortality rates was observed between either of the inhaled steroids and the control interventions (both high-quality evidence), and pneumonia-related deaths were too rare to permit conclusions to be drawn. AUTHORS' CONCLUSIONS: Budesonide and fluticasone, delivered alone or in combination with a LABA, are associated with increased risk of serious adverse pneumonia events, but neither significantly affected mortality compared with controls. The safety concerns highlighted in this review should be balanced with recent cohort data and established randomised evidence of efficacy regarding exacerbations and quality of life. Comparison of the two drugs revealed no statistically significant difference in serious pneumonias, mortality or serious adverse events. Fluticasone was associated with higher risk of any pneumonia when compared with budesonide (i.e. less serious cases dealt with in the community), but variation in the definitions used by the respective manufacturers is a potential confounding factor in their comparison.Primary research should accurately measure pneumonia outcomes and should clarify both the definition and the method of diagnosis used, especially for new formulations such as fluticasone furoate, for which little evidence of the associated pneumonia risk is currently available. Similarly, systematic reviews and cohorts should address the reliability of assigning 'pneumonia' as an adverse event or cause of death and should determine how this affects the applicability of findings

Long-acting beta2-agonists for chronic obstructive pulmonary disease.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a respiratory disease that causes progressive symptoms of breathlessness, cough and mucus build-up. It is the fourth or fifth most common cause of death worldwide and is associated with significant healthcare costs.Inhaled long-acting beta2-agonists (LABAs) are widely prescribed to manage the symptoms of COPD when short-acting agents alone are no longer sufficient. Twice-daily treatment with an inhaled LABA is aimed at relieving symptoms, improving exercise tolerance and quality of life, slowing decline and even improving lung function and preventing and treating exacerbations. OBJECTIVES: To assess the effects of twice-daily long-acting beta2-agonists compared with placebo for patients with COPD on the basis of clinically important endpoints, primarily quality of life and COPD exacerbations. SEARCH METHODS: We searched the Cochrane Airways Group trials register, ClinicalTrials.gov and manufacturers' websites in June 2013. SELECTION CRITERIA: Parallel, randomised controlled trials (RCTs) recruiting populations of patients with chronic obstructive pulmonary disease. Studies were required to be at least 12 weeks in duration and designed to assess the safety and efficacy of a long-acting beta2-agonist against placebo. DATA COLLECTION AND ANALYSIS: Data and characteristics were extracted independently by two review authors, and each study was assessed for potential sources of bias. Data for all outcomes were pooled and subgrouped by LABA agent (formoterol 12 μg, formoterol 24 μg and salmeterol 50 μg) and then were separately analysed by LABA agent and subgrouped by trial duration. Sensitivity analyses were conducted for the proportion of participants taking inhaled corticosteroids and for studies with high or uneven rates of attrition. MAIN RESULTS: Twenty-six RCTs met the inclusion criteria, randomly assigning 14,939 people with COPD to receive twice-daily LABA or placebo. Study duration ranged from three months to three years; the median duration was six months. Participants were more often male with moderate to severe symptoms at randomisation; mean forced expiratory volume in 1 second (FEV1) was between 33% and 55% predicted normal in the studies, and mean St George's Respiratory Questionnaire score (SGRQ) ranged from 44 to 55 when reported.Moderate-quality evidence showed that LABA treatment improved quality of life on the SGRQ (mean difference (MD) -2.32, 95% confidence interval (CI) -3.09 to -1.54; I(2) = 50%; 17 trials including 11,397 people) and reduced the number of exacerbations requiring hospitalisation (odds ratio (OR) 0.73, 95% CI 0.56 to 0.95; I(2) = 10%; seven trials including 3804 people). In absolute terms, 18 fewer people per 1000 were hospitalised as the result of an exacerbation while receiving LABA therapy over a weighted mean of 7 months (95% CI 3 to 31 fewer). Scores were also improved on the Chronic Respiratory Disease Questionnaire (CRQ), and more people receiving LABA treatment showed clinically important improvement of at least four points on the SGRQ.The number of people who had exacerbations requiring a course of oral steroids or antibiotics was also lower among those taking LABA (52 fewer per 1000 treated over 8 months; 95% CI 24 to 78 fewer, moderate quality evidence).Mortality was low, and combined findings of all studies showed that LABA therapy did not significantly affect mortality (OR 0.90, 95% CI 0.75 to 1.08; I(2) = 21%; 23 trials including 14,079 people, moderate quality evidence). LABA therapy did not affect the rate of serious adverse events (OR 0.97, 95% CI 0.83 to 1.14; I(2) = 34%, moderate quality evidence), although there was significant unexplained heterogeneity, especially between the two formoterol doses.LABA therapy improved predose FEV1 by 73 mL more than placebo (95% CI 48 to 98; I(2) = 71%, low quality evidence), and people were more likely to withdraw from placebo than from LABA therapy (OR 0.74, 95% CI 0.69 to 0.80; I(2) = 0%). Higher rates of withdrawal in the placebo arm may reduce our confidence in some results, but the disparity is more likely to reduce the magnitude of difference between LABA and placebo than inflate the true effect; removing studies at highest risk of bias on the basis of high and unbalanced attrition did not change conclusions for the primary outcomes. AUTHORS' CONCLUSIONS: Moderate-quality evidence from 26 studies showed that inhaled long-acting beta2-agonists are effective over the medium and long term for patients with moderate to severe COPD. Their use is associated with improved quality of life and reduced exacerbations, including those requiring hospitalisation. Overall, findings showed that inhaled LABAs did not significantly reduce mortality or serious adverse events

Cost of Sustainable Development

To be included at a later dat

Under the influence : identifying determinants of young adults' involvement in alcohol-influenced aquatic activity to improve drowning prevention efforts

BACKGROUND: Young adults are an at-risk group for experiencing an alcohol-related drowning incident. Investigations and drowning prevention efforts have aimed to address young adults’ prevalence in alcohol-related drownings and contribute to understanding their level of risk. Some explanations have concluded young adults’ need for autonomy and independence coincides with their exposure to alcohol and social norm pressures. However, gaps in knowledge remain, specifically young adults’: behaviours, knowledge and attitudes towards alcohol-influenced aquatic activity and the associated risks; and, their awareness and perceptions of alcohol-themed drowning prevention campaigns. METHODS: This PhD, completed with publications, aimed to address these gaps through four interlinked projects: (i) a systematic review of alcohol education programs to determine evidence-based quality criteria necessary for inclusion in programs to successfully change young adults’ alcohol-related behaviours, knowledge and attitudes; (ii) a program audit of alcohol-themed drowning prevention campaigns to establish current prevention efforts in high-income countries and areas for improvement; (iii) a survey among young adults from Australia and the United Kingdom to establish their knowledge, attitudes and predictors of intentions and involvement in alcohol-influenced aquatic activities; and, (iv) interviews to deepen understanding of young adults’ knowledge, attitudes and behaviours relating to alcohol-influenced aquatic activity, their awareness of alcohol-themed drowning prevention campaigns and their suggestions for improvement. Six publications resulted from this research. RESULTS: Friends influenced frequency of young adults’ involvement in alcohol-influenced aquatic activity, but involvement was dependent on the characteristics of the peer group, self-confidence and risk disassociation. Attitudes were neutral towards alcohol-influenced aquatic activity, but when participants perceived personal control over the risks it was deemed more acceptable. Alcohol-related safety strategies from other contexts (e.g., driving) were applied to aquatic settings, but specific water safety knowledge/education was low. Stronger swimmers, Australian young adults and those who had received alcohol-specific water safety education displayed more knowledge of alcohol and its effects in aquatic contexts. Participants lacked awareness of alcohol-themed drowning prevention campaigns, and used campaign logos and names to interpret key messages. Little information was available on the alcohol-themed drowning prevention campaigns identified in the program audit and only two had evidence of evaluation, limiting progress of future prevention efforts. Ten quality criteria identified from evidence-based literature were considered to be necessary for inclusion in alcohol education programs. Programs included in the systematic review which incorporated these criteria were more likely to report success in influencing behaviour changes among the participants. CONCLUSIONS: To decrease the incidence of alcohol-related drowning among young adults, the findings of the projects included within this thesis result in the following recommendations. For enhanced likelihood of successful outcomes, alcohol-themed drowning prevention campaigns should align campaign design, implementation and evaluation with best-practice literature. The identified influencers on young adults’ involvement in alcohol-influenced aquatic activity, such as their peers, should be incorporated into prevention efforts and appropriate information provided to encourage informed decision making. Alcohol education programs (e.g., drink driving education) should include information about alcohol use in aquatic settings to clarify the risks associated with transferring safety strategies between drinking contexts, and appropriate information should be provided about alcohol consumption in aquatic settings.Doctor of Philosoph

Probing the Intergalactic Medium with high-redshift quasars

Clues about the timing of reionization and the nature of the ionizing sources responsible are imprinted in the ionization and thermal state of the IGM. In this thesis, I use high-resolution quasar spectra in conjunction with state-of-the-art hydrodynamical simulations to probe the IGM at high redshift, focusing on the ionization and thermal state of the gas. After reionization, the ionization state of the IGM is set by the intensity of the ultraviolet background (UVB), quantified by the hydrogen photoionization rate, Γ_bkg. At high redshifts this has been estimated by measuring the mean flux in the Lyα forest, and scaling Γ_bkg in simulations such that the simulated mean flux matches the observed value. In Chapter 3 I investigate whether the precision of these estimates can be improved by using the entire flux probability distribution function (PDF) instead of only the mean flux. Although I find it cannot improve the precision directly, the flux PDF can potentially be used to constrain other sources of error in observational estimates of Γ_bkg, and so may increase the precision indirectly. The ionizing output of a quasar will locally dominate over the UVB, and this leads to enhanced transmission bluewards of the quasar Lyα line, known as the proximity effect. In Chapter 4 I present the first measurements of Γ_bkg at z > 5 from the proximity effect. The UVB intensity declines smoothly with redshift over 4.6 6.4. There is a drop in Γ_bkg by roughly a factor of five, which corresponds to a drop in the ionizing emissivity by about a factor of two. Such a redshift evolution in the emissivity cannot continue to much higher redshift without reionization failing to complete, which suggests that reionization cannot have ended much higher than z = 6.4. Estimates of Γ_bkg from the proximity effect and the mean flux are generally discrepant at z ∼ 2−4, with those from the proximity effect systematically higher. This is generally attributed to effects of the quasar environment. I investigate the significance of several environmental biases on proximity effect measurements at z ∼ 5−6 in Chapter 5. The biases are found to be small, and so the proximity effect is expected to give relatively unbiased estimates of Γ_bkg at z > 5, in contrast to lower redshifts. Photoionization heats the gas in the IGM, and so the thermal history of the IGM provides important constraints on reionization. The thermal state of the IGM is reflected in the level of small-scale structure in the Lyα forest. In Chapter 6 I quantify the small-scale structure using two independent statistics, the curvature and the peakiness, and convert these into a temperature by comparing with simulations. These are the first measurements of the temperature in the general IGM at z > 5. Both statistics show an increase in the temperature by a factor of roughly two from z = 4.4 to 5.6. This rise is sensitive, however, to any smoothing of the gas density distribution due to the thermal history spanning reionization. I find that this should only be a small effect, as otherwise the corrected temperatures at z ∼ 4−5 are implausibly low. The temperature evolution therefore suggests a late reionization. The temperatures at z ≥ 4.8 are well fit by an adiabatic cooling curve, for which reasonable peak temperatures at the end of reionization are reached at 6 ≤ z ≤ 7. The temperatures at z ∼ 4−5 are consistent with reionization being carried out by Pop II stars. In conclusion, the ionization and thermal state of the IGM at z ∼ 5−6 suggest a late hydrogen reionization, driven by star-forming galaxies and ending around 6.5 ≤ z ≤ 7. This is consistent with other recent lines of observational evidence, and supports theoretical models that infer a late reionization from the observed star formation rate history