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Effect of tiotropium/olodaterol on sedentary and active time in patients with COPD: post hoc analysis of the VESUTO® study.
Minakata, Y, Motegi, T, Ueki, J, Gon, Y, Nakamura, S, Anzai, T, Hirata, K, Ichinose, M
International journal of chronic obstructive pulmonary disease. 2019;:1789-1801
Abstract
BACKGROUND Patients with COPD are less physically active. This post hoc analysis of a randomized, double-blind, active-controlled, crossover trial assessed the efficacy of once-daily tiotropium/olodaterol combination therapy versus tiotropium monotherapy in Japanese patients with COPD. PATIENTS AND METHODS Patients were provided with a three-axis accelerometer to measure sedentary and active behavior defined as 1.0-1.5 metabolic equivalents (METs), ≥2.0 METs, and ≥3.0 METs, respectively. Of the 182 patients enrolled, 131 satisfied the conditions for the present analysis and were randomized to tiotropium monotherapy (n=62) or tiotropium/olodaterol combination therapy (n=69). RESULTS Tiotropium/olodaterol combination therapy significantly reduced the duration of 1.0-1.5 MET activity by 8.64 mins (p=0.040) and significantly increased the duration of ≥2.0 MET and ≥3.0 MET activity by 6.51 mins (p=0.017) and 2.60 mins (p=0.008), respectively, compared with tiotropium alone. Subgroup analyses showed that better lung function, milder dyspnea, and higher levels of physical activity at baseline were associated with reduced sedentary time and increased duration of physical activity. CONCLUSION Tiotropium/olodaterol combination therapy significantly reduced sedentary time and improved physical activity compared with tiotropium monotherapy. This trial was registered in ClinicalTrials.gov (NCT02629965).
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Choline Supplementation in Cystic Fibrosis-The Metabolic and Clinical Impact.
Bernhard, W, Lange, R, Graepler-Mainka, U, Engel, C, Machann, J, Hund, V, Shunova, A, Hector, A, Riethmüller, J
Nutrients. 2019;(3)
Abstract
BACKGROUND Choline is essential for the synthesis of liver phosphatidylcholine (PC), parenchymal maintenance, bile formation, and lipoprotein assembly to secrete triglycerides. In choline deficiency, the liver accretes choline/PC at the expense of lung tissue, thereby impairing pulmonary PC homoeostasis. In cystic fibrosis (CF), exocrine pancreas insufficiency results in impaired cleavage of bile PC and subsequent fecal choline loss. In these patients, the plasma choline concentration is low and correlates with lung function. We therefore investigated the effect of choline supplementation on plasma choline/PC concentration and metabolism, lung function, and liver fat. METHODS 10 adult male CF patients were recruited (11/2014⁻1/2016), and orally supplemented with 3 × 1 g choline chloride for 84 (84⁻91) days. Pre-/post-supplementation, patients were spiked with 3.6 mg/kg [methyl-D₉]choline chloride to assess choline/PC metabolism. Mass spectrometry, spirometry, and hepatic nuclear resonance spectrometry served for analysis. RESULTS Supplementation increased plasma choline from 4.8 (4.1⁻6.2) µmol/L to 10.5 (8.5⁻15.5) µmol/L at d84 (p < 0.01). Whereas plasma PC concentration remained unchanged, D₉-labeled PC was decreased (12.2 [10.5⁻18.3] µmol/L vs. 17.7 [15.5⁻22.4] µmol/L, p < 0.01), indicating D₉-tracer dilution due to higher choline pools. Supplementation increased Forced Expiratory Volume in 1 second percent of predicted (ppFEV1) from 70.0 (50.9⁻74.8)% to 78.3 (60.1⁻83.9)% (p < 0.05), and decreased liver fat from 1.58 (0.37⁻8.82)% to 0.84 (0.56⁻1.17)% (p < 0.01). Plasma choline returned to baseline concentration within 60 h. CONCLUSIONS Choline supplementation normalized plasma choline concentration and increased choline-containing PC precursor pools in adult CF patients. Improved lung function and decreased liver fat suggest that in CF correcting choline deficiency is clinically important. Choline supplementation of CF patients should be further investigated in randomized, placebo-controlled trials.
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Analysis of a large cohort of cystic fibrosis patients with severe liver disease indicates lung function decline does not significantly differ from that of the general cystic fibrosis population.
Polineni, D, Piccorelli, AV, Hannah, WB, Dalrymple, SN, Pace, RG, Durie, PR, Ling, SC, Knowles, MR, Stonebraker, JR
PloS one. 2018;(10):e0205257
Abstract
Previous reports of lung function in cystic fibrosis (CF) patients with liver disease have shown worse, similar, or even better forced expiratory volume in 1 second (FEV1), compared to CF patients without liver disease. Varying definitions of CF liver disease likely contribute to these inconsistent relationships reported between CF lung function and liver disease. We retrospectively evaluated spirometric data in 179 subjects (62% male; 58% Phe508del homozygous) with severe CF liver disease (CFLD; defined by presence of portal hypertension due to cirrhosis). FEV1 values were referenced to both a normal population (FEV1% predicted) and CF population (CF-specific FEV1 percentile). We utilized a linear mixed model with repeated measures to assess changes in lung function (before and after diagnosis of CFLD), relative to both the normal and CF populations. At diagnosis of CFLD, the mean FEV1 was 81% predicted, or at the 53rd percentile referenced to CF patients without CFLD. There was a significant difference in post-CFLD slope compared to pre-CFLD slope (post-pre) using FEV1% predicted (-1.94, p-value < 0.0001). However, there was insignificant evidence of this difference using the CF-specific FEV1 percentile measure (-0.99, p-value = 0.1268). Although FEV1% predicted values declined in patients following CFLD diagnosis, there was not significant evidence of lung function decline in CF-specific FEV1 percentiles. Thus, the observed study cohort indicates diagnosis of severe CFLD was not associated with worsened CF lung disease when compared to a large CF reference population.
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Evidence for large-scale gene-by-smoking interaction effects on pulmonary function.
Aschard, H, Tobin, MD, Hancock, DB, Skurnik, D, Sood, A, James, A, Vernon Smith, A, Manichaikul, AW, Campbell, A, Prins, BP, et al
International journal of epidemiology. 2017;(3):894-904
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Abstract
BACKGROUND Smoking is the strongest environmental risk factor for reduced pulmonary function. The genetic component of various pulmonary traits has also been demonstrated, and at least 26 loci have been reproducibly associated with either FEV 1 (forced expiratory volume in 1 second) or FEV 1 /FVC (FEV 1 /forced vital capacity). Although the main effects of smoking and genetic loci are well established, the question of potential gene-by-smoking interaction effect remains unanswered. The aim of the present study was to assess, using a genetic risk score approach, whether the effect of these 26 loci on pulmonary function is influenced by smoking. METHODS We evaluated the interaction between smoking exposure, considered as either ever vs never or pack-years, and a 26-single nucleotide polymorphisms (SNPs) genetic risk score in relation to FEV 1 or FEV 1 /FVC in 50 047 participants of European ancestry from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) and SpiroMeta consortia. RESULTS We identified an interaction ( βint = -0.036, 95% confidence interval, -0.040 to -0.032, P = 0.00057) between an unweighted 26 SNP genetic risk score and smoking status (ever/never) on the FEV 1 /FVC ratio. In interpreting this interaction, we showed that the genetic risk of falling below the FEV /FVC threshold used to diagnose chronic obstructive pulmonary disease is higher among ever smokers than among never smokers. A replication analysis in two independent datasets, although not statistically significant, showed a similar trend in the interaction effect. CONCLUSIONS This study highlights the benefit of using genetic risk scores for identifying interactions missed when studying individual SNPs and shows, for the first time, that persons with the highest genetic risk for low FEV 1 /FVC may be more susceptible to the deleterious effects of smoking.
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Calcium channel blockers for lung function improvement in asthma: A systematic review and meta-analysis.
Chiu, KY, Li, JG, Lin, Y
Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology. 2017;(6):518-523.e3
Abstract
BACKGROUND For decades, calcium channel blockers (CCBs) have been believed to play a role in asthma treatment. However, the clinical efficacy of CCBs for lung function improvement in patients with asthma has not been qualitatively evaluated. OBJECTIVE To assess the effect of CCBs vs placebo on lung function test results in adults with asthma. METHODS Various databases were systematically searched to identify all randomized clinical trials with adults with asthma. We aimed to assess the influence of CCBs on forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), peak expiratory flow rate (PEFR), and provocative concentration of bronchoconstrictive agents causing a 20% decrease in FEV1 (PC20) compared with a placebo. All effect estimates were pooled by the generic inverse variance method with random-effects meta-analysis. Subgroup analysis, sensitivity analysis, and heterogeneity investigation were performed. RESULTS Thirty eligible articles with 301 patients were included in this meta-analysis. Our results revealed that in a standard exercise test CCBs could produce a mean maximal percentage decrease in FEV1 of 11.56% (95% confidence interval, 8.97%-14.16%; P < .001) and an increase in postdose FEV1 by 80 mL (95% confidence interval, 0.02-0.15 mL; P = .01). However, there was no statistical significance for CCBs in postdose FVC, PEFR, or PC20 of histamine and methacholine. CONCLUSION CCBs may be beneficial for lung function improvement in asthma, especially in exercise-induced asthma. However, there is a lack of evidence for CCBs protecting asthma patients from chemical irritation.
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Effect of inhaled MgSO4 on FEV1 and PEF in children with asthma induced by acetylcholine: a randomized controlled clinical trail of 330 cases.
Sun, YX, Gong, CH, Liu, S, Yuan, XP, Yin, LJ, Yan, L, Shi, TT, Dai, JH
Journal of tropical pediatrics. 2014;(2):141-7
Abstract
OBJECTIVES To determine the response of nebulized magnesium sulfate on the lung function of acetylcholine-induced asthma children. METHODS Three hundred and thirty children of asthma with positive bronchial provocation test were randomly divided into three groups: magnesium sulfate, albuterol, and a combination of magnesium sulfate and albuterol. Lung function was compared between the three groups. RESULTS Forced expiratory volume in one second (FEV1) and peak expiratory flow (PEF) as percentage over predicted at 10 min and 20 min in albuterol and combination group were significantly improved when compared to magnesium group. The changes in FEV1 and PEF expressed as absolute and percentage over predicted was not statistically significant from baseline to 20 min in magnesium, albuterol, and combination of magnesium sulfate and albuterol. There was no significant adverse effect observed during the present study. CONCLUSION Nebulized magnesium sulfate alone has a bronchodilatory effect in Ach-induced asthmatic children. The combination of MgSO4 and albuterol did not has a synergistic effect.
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Monosodium glutamate avoidance for chronic asthma in adults and children.
Zhou, Y, Yang, M, Dong, BR
The Cochrane database of systematic reviews. 2012;(6):CD004357
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BACKGROUND Monosodium glutamate (MSG) is the sodium salt of the non-essential amino acid, glutamic acid, and is used as a flavour enhancer. It has been implicated in causing adverse reactions, which have been referred to as "Chinese restaurant syndrome". Over the last two decades there have been a number of studies investigating whether MSG ingestion induces an asthmatic response, and several reviews have been published (ILSI 1991; Stevenson 2000; Woods 2001), but no meta-analysis or Cochrane systematic review has been performed. OBJECTIVES The objectives of this review are to: 1) identify randomised controlled trials (RCTs) of MSG ingestion and asthma response in adults and children older than two years of age with asthma; 2) assess the methodological quality of these trials; and 3) determine the effect of MSG ingestion on asthma outcomes. SEARCH METHODS We searched the Cochrane Airways group's Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), and bibliographies of existing trials. Searches were current up to May 2012. SELECTION CRITERIA We included RCTs that investigated the effect of MSG on chronic asthma in adults and children. DATA COLLECTION AND ANALYSIS Two authors independently extracted, entered and analysed data from included studies. We contacted study authors for additional information. MAIN RESULTS Only two cross-over studies involving 24 adults met the eligibility criteria; the challenge dosages of MSG were 1 g, 5 g and 25 mg/kg. They reported the number of subjects who had a maximum fall in forced expiratory volume in the first second (FEV(1)) greater than 15% or 200 mL after MSG or the control challenge. The pooled data found no statistically significant difference between MSG and placebo. One trial reported the mean change at four hours and maximum fall in FEV(1) over four hours after MSG or the placebo challenge, but found no statistically significant difference between interventions. There were no differences in symptom scores, non-specific bronchial hyper-responsiveness (BHR), eosinophil cationic protein (ECP) or tryptase levels in peripheral blood between MSG and control, although we were unable to perform meta-analyses. AUTHORS' CONCLUSIONS The limited evidence available (n = 24) found no significant difference between MSG or the control challenge for the number of subjects who had a maximum fall in FEV(1) greater than 15% or 200 mL. There is no evidence to support the avoidance of MSG in adults with chronic asthma, but as data were limited, this review cannot provide a reliable evidence base for determining whether MSG avoidance is a worthwhile strategy. We could not find any studies conducted on the effect of MSG in children with chronic asthma. There is therefore, a need for further RCTs to investigate any relationship between MSG and asthma, especially in children.
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Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.
Hancock, DB, Soler Artigas, M, Gharib, SA, Henry, A, Manichaikul, A, Ramasamy, A, Loth, DW, Imboden, M, Koch, B, McArdle, WL, et al
PLoS genetics. 2012;(12):e1003098
Abstract
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.
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Sodium cromoglycate and eformoterol attenuate sensitivity and reactivity to inhaled mannitol in subjects with bronchiectasis.
Briffa, PJ, Anderson, SD, Burton, DL, Young, IH
Respirology (Carlton, Vic.). 2011;(1):161-6
Abstract
BACKGROUND AND OBJECTIVE Dry powder mannitol has the potential to be used to enhance clearance of mucus in subjects with bronchiectasis. A reduction in FEV1 has been recorded in some subjects with bronchiectasis after inhaling mannitol. The aim of this study was to investigate if pre-medicating with either sodium cromoglycate (SCG) or eformoterol could inhibit this reduction in FEV1. METHODS A double-blind, placebo-controlled, randomized cross-over study was conducted. Lung function and airway response to mannitol was assessed on a control day and then re-assessed after pre-medication with placebo, SCG and eformoterol in nine subjects. Sensitivity to mannitol, expressed as the dose required to induce a 15% fall in FEV1 (PD15), and reactivity to mannitol, expressed as the % fall in FEV1 per mg of mannitol (response-dose ratio, RDR), are reported. RESULTS Subjects had an FEV1 of 68 ± 14% predicted, FVC of 97 ± 15% predicted and FEV1 /FVC of 71 ± 8%. They were mildly hypoxemic and the SpO2 was 95 ± 2%.They had a PD15 to mannitol of 235 mg (95% CI: 150-368 mg) and a RDR of 0.057% fall in FEV1 per mg (95% CI: 0.038-0.085). After pre-medication with SCG, PD15 increased (773 mg, P < 0.05) and RDR was reduced (0.013, P < 0.05). Pre-medication with eformoterol also resulted in an increased PD15 (1141 mg, P < 0.01) and a reduced RDR (0.009, P < 0.01). A small but significant decrease in SpO2 from baseline was noted after mannitol in the presence of SCG (P < 0.05). CONCLUSIONS Pre-medication with either SCG or eformoterol protects patients with bronchiectasis from developing a significant reduction in FEV1 after inhaling mannitol.
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Clinical use of dornase alpha is associated with a slower rate of FEV1 decline in cystic fibrosis.
Konstan, MW, Wagener, JS, Pasta, DJ, Millar, SJ, Jacobs, JR, Yegin, A, Morgan, WJ, ,
Pediatric pulmonology. 2011;(6):545-53
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OBJECTIVES Randomized controlled trials of dornase alpha have shown forced expiratory volume in 1 sec (FEV(1) ) to improve in patients with cystic fibrosis (CF) but have not assessed change in the rate of lung function decline. We assessed the relationship of dornase alpha use and FEV(1) decline using the Epidemiologic Study of Cystic Fibrosis (ESCF). METHODOLOGY Patients aged 8-38 years who had been enrolled in ESCF for 2 years when initially treated with dornase alpha were selected if they remained on treatment during the following 2 years. A comparator group included patients aged 8-38 who were not yet reported to have received dornase alpha. For each patient we estimated the annual rate of decline in FEV(1) % predicted before and after the index using a mixed-effects model adjusted for age, gender, pulmonary exacerbations, respiratory therapies, and nutritional supplements. RESULTS The dornase alpha group (n = 2,230) had a lower FEV(1) % predicted at index and a more rapid decline during the pre-index period. The mean rate of FEV(1) decline improved for the dornase alpha group; the improvement was similar in adults and children 8-17 years old but was not statistically significant in adults. The comparator group (n = 5,970) showed no change among adults and an increased rate of decline among children 8-17 years old. CONCLUSIONS The use of dornase alpha for a 2-year period is associated with a reduction in the rate of FEV(1) decline. These results also demonstrate the value of using an observational study to assess the association of instituting new therapies in the clinical setting with changes in the rate of FEV(1) decline in patients with CF.