Search

Objective: To explore the prevalence and extent of low back pain (LBP) and low back-related disability in working-age adults not seeking care., Methods: A convenience sample of 101 working-age adults not seeking care for LBP completed the Oswestry Disability Index (ODI) and Roland-Morris Disability Questionnaire (RMDQ) as measures of disability and completed questionnaires that collected information on various demographic and health-related variables. Those reporting current LBP also completed a Numeric Pain Rating Scale (NPRS). Prevalence was assessed based on a dichotomization of whether any disability or pain was reported and also as a continuous variable to assess the extent of pain and disability present for each participant., Results: Of the 101 participants, 72.3% reported some level of disability (ODI mean = 7.91%, RMDQ mean = 2.63) and 46.5% reported some level of pain (NRPS mean = 3.68). Previous care-seeking for LBP was associated with increased odds of reporting disability (ODI odds ratio [OR] 7.91, 95% confidence interval [CI], 2.43 to 31.18; RMDQ OR 2.69, 95% CI, 1.05 to 7.24), as was reporting any current LBP (ODI OR 9.45, 95% CI, 3.15 to 33.21; RMDQ OR 7.03, 95% CI, 2.82 to 18.89). No other demographic or health-related variables were associated with the presence or extent of pain or disability., Conclusion: Many non-care-seeking individuals reported some level of LBP and/or disability, suggesting that some level of pain and disability may be considered normal, acceptable, or manageable. One-third of individuals with no pain reported some disability., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Despite inhaled corticosteroid plus long-acting β 2 -agonist (ICS/LABA) therapy, 30-50% of patients with moderate or severe asthma remain inadequately controlled. We investigated the safety and efficacy of single-inhaler fluticasone furoate plus umeclidinium plus vilanterol (FF/UMEC/VI) compared with FF/VI., Methods: In this double-blind, randomised, parallel-group, phase 3A study (Clinical Study in Asthma Patients Receiving Triple Therapy in a Single Inhaler [CAPTAIN]), participants were recruited from 416 hospitals and primary care centres across 15 countries. Participants were eligible if they were aged 18 years or older, with inadequately controlled asthma (Asthma Control Questionnaire [ACQ]-6 score of ≥1·5) despite ICS/LABA, a documented health-care contact or a documented temporary change in asthma therapy for treatment of acute asthma symptoms in the year before screening, pre-bronchodilator FEV 1 between 30% and less than 85% of predicted normal value, and reversibility (defined as an increase in FEV 1 of ≥12% and ≥200 mL in the 20-60 min after four inhalations of albuterol or salbutamol) at screening. Participants were randomly assigned (1:1:1:1:1:1), via central based randomisation stratified by pre-study ICS dose at study entry, to once-daily FF/VI (100/25 μg or 200/25 μg) or FF/UMEC/VI (100/31·25/25 μg, 100/62·5/25 μg, 200/31·25/25 μg, or 200/62·5/25 μg) administered via Ellipta dry powder inhaler (Glaxo Operations UK, Hertfordshire, UK). Patients, investigators, and the funder were masked to treatment allocation. Endpoints assessed in the intention-to-treat population were change from baseline in clinic trough FEV 1 at week 24 (primary) and annualised moderate and/or severe asthma exacerbation rate (key secondary). Other secondary endpoints were change from baseline in clinic FEV 1 at 3 h post-dose, St George's Respiratory Questionnaire (SGRQ) total score, and ACQ-7 total score, all at week 24. Change from baseline in Evaluating Respiratory Symptoms in Asthma total score at weeks 21-24 was also a secondary endpoint but is not reported here. Exploratory analyses of biomarkers of type 2 airway inflammation on treatment response were also done. This study is registered with ClinicalTrials.gov, NCT02924688, and is now complete., Findings: Between Dec 16, 2016, and Aug 31, 2018, 5185 patients were screened and 2439 were recruited and randomly assigned to FF/VI (100/25 μg n=407; 200/25 μg n=406) or FF/UMEC/VI (100/31·25/25 μg n=405; 100/62·5/25 μg n=406; 200/31·25/25 μg n=404; 200/62·5/25 μg n=408), with three patients randomly assigned in error and not included in analyses. In the intention-to-treat population, 922 (38%) patients were men, the mean age was 53·2 years (SD 13·1) and body-mass index was 29·4 (6·6). Baseline demographics were generally similar across all treatment groups. The least squares mean improvement in FEV 1 change from baseline for FF/UMEC/VI 100/62·5/25 μg versus FF/VI 100/25 μg was 110 mL (95% CI 66-153; p<0·0001) and for 200/62·5/25 μg versus 200/25 μg was 92 mL (49-135; p<0·0001). Adding UMEC 31·25 μg to FF/VI produced similar improvements (FF/UMEC/VI 100/31·25/25 μg vs FF/VI 100/25 μg: 96 mL [52-139; p<0·0001]; and 200/31·25/25 μg vs 200/25 μg: 82 mL [39-125; p=0·0002]). These results were supported by the analysis of clinic FEV 1 at 3 h post-dose. Non-significant reductions in moderate and/or severe exacerbation rates were observed for FF/UMEC 62·5 μg/VI versus FF/VI (pooled analysis), with rates lower in FF 200 μg-containing versus FF 100 μg-containing treatment groups. All pooled treatment groups demonstrated mean improvements (decreases) in SGRQ total score at week 24 compared with baseline in excess of the minimal clinically important difference of 4 points; however, there were no differences between treatment groups. For mean change from baseline to week 24 in asthma control questionnaire-7 score, improvements (decreases) exceeding the minimal clinically important difference of 0·5 points were observed in all pooled treatment groups. Adding UMEC to FF/VI resulted in small, dose-related improvements compared with FF/VI (pooled analysis: FF/UMEC 31·25 μg/VI versus FF/VI, -0·06 (95% CI -0·12 to 0·01; p=0·094) FF/UMEC 62·5 μg/VI versus FF/VI, -0·09 (-0·16 to -0·02, p=0·0084). By contrast with adding UMEC, the effects of higher dose FF on clinic trough FEV 1 and annualised moderate and/or severe exacerbation rate were increased in patients with higher baseline blood eosinophil count and exhaled nitric oxide. Occurrence of adverse events was similar across treatment groups (patients with at least one event ranged from 210 [52%] to 258 [63%]), with the most commonly reported adverse events being nasopharyngitis (51 [13%]-63 [15%]), headache (19 [5%]-36 [9%]), and upper respiratory tract infection (13 [3%]-24 [6%]). The incidence of serious adverse events was similar across all groups (range 18 [4%]-25 [6%)). Three deaths occurred, of which one was considered to be related to study drug (pulmonary embolism in a patient in the FF/UMEC/VI 100/31·25/25 μg group)., Interpretation: In patients with uncontrolled moderate or severe asthma on ICS/LABA, adding UMEC improved lung function but did not lead to a significant reduction in moderate and/or severe exacerbations. For such patients, single-inhaler FF/UMEC/VI is an effective treatment option with a favourable risk-benefit profile. Higher dose FF primarily reduced the rate of exacerbations, particularly in patients with raised biomarkers of type 2 airway inflammation. Further confirmatory studies into the differentiating effect of type 2 inflammatory biomarkers on treatment outcomes in asthma are required to build on these exploratory findings and further guide clinical practice., Funding: GSK., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Previous studies have highlighted a relationship between reduction in rate of exacerbations with therapies containing inhaled corticosteroids (ICS) and baseline blood eosinophil count in patients with chronic obstructive pulmonary disease (COPD). The IMPACT trial showed that once-daily single-inhaler triple therapy significantly reduced exacerbations versus dual therapies. Blood eosinophil counts and smoking status could be important modifiers of treatment response to ICS. We aimed to model these relationships and their interactions, including outcomes other than exacerbations., Methods: IMPACT was a phase 3, randomised, double-blind, parallel-group, 52-week global study comparing once-daily single-inhaler triple therapy (fluticasone furoate-umeclidinium-vilanterol) with dual inhaled therapy (fluticasone furoate-vilanterol or umeclidinium-vilanterol). Eligible patients had moderate-to-very-severe COPD and at least one moderate or severe exacerbation in the previous year. We used fractional polynomials to model continuous blood eosinophil counts. We used negative binomial regression for numbers of moderate and severe exacerbations, severe exacerbations, and pneumonia. We modelled differences at week 52 in trough FEV 1 , St George's Respiratory Questionnaire (SGRQ) total score, and Transition Dyspnoea Index using repeated measurements mixed effect models. IMPACT was registered with ClinicalTrials.gov, number NCT02164513., Findings: The magnitude of benefit of regimens containing ICS (fluticasone furoate-umeclidinium-vilanterol n=4151 and fluticasone furoate-vilanterol n=4134) in reducing rates of moderate and severe exacerbations increased in proportion with blood eosinophil count, compared with a non-ICS dual long-acting bronchodilator (umeclidinium-vilanterol n=2070). The moderate and severe exacerbation rate ratio for triple therapy versus umeclidinium-vilanterol was 0·88 (95% CI 0·74 to 1·04) at blood eosinophil count less than 90 cells per μL and 0·56 (0·47 to 0·66) at counts of 310 cells per μL or more; the corresponding rate ratio for fluticasone furoate-vilanterol versus umeclidinium-vilanterol was 1·09 (0·91 to 1·29) and 0·56 (0·47 to 0·66), respectively. Similar results were observed for FEV 1 , Transition Dyspnoea Index, and SGRQ total score; however, the relationship with FEV 1 was less marked. At blood eosinophil counts less than 90 cells per μL and at counts of 310 cells per μL or more, the triple therapy versus umeclidinium-vilanterol treatment difference was 40 mL (95% CI 10 to 70) and 60 mL (20 to 100) for trough FEV 1 , -0·01 (-0·68 to 0·66) and 0·30 (-0·37 to 0·97) for Transition Dyspnoea Index score, and -0·01 (-1·81 to 1·78) and -2·78 (-4·64 to -0·92) for SGRQ total score, respectively. Smoking status modified the relationship between observed efficacy and blood eosinophil count for moderate or severe exacerbations, Transition Dyspnoea Index, and FEV 1 , with former smokers being more corticosteroid responsive at any eosinophil count than current smokers., Interpretation: This analysis of the IMPACT trial shows that assessment of blood eosinophil count and smoking status has the potential to optimise ICS use in clinical practice in patients with COPD and a history of exacerbations., Funding: GlaxoSmithKline., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Chronic obstructive pulmonary disease (COPD) is a heterogeneous disorder and patients respond differently to treatment. Blood eosinophils are a potential biomarker to stratify patient subsets for COPD therapy. We reviewed the value of blood eosinophils in predicting exacerbation risk and response to corticosteroid treatment in the available literature (PubMed articles in English; keywords: "COPD" and "eosinophil"; published prior to May 2017). Overall, clinical data suggest that in patients with a history of COPD exacerbations, a higher blood eosinophil count predicts an increased risk of future exacerbations and is associated with improved response to treatment with inhaled corticosteroids (in combination with long-acting bronchodilator[s]). Blood eosinophils are therefore a promising biomarker for phenotyping patients with COPD, although prospective studies are needed to assess blood eosinophils as a biomarker of corticosteroid response for this., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The role of temozolomide chemotherapy in newly diagnosed 1p/19q non-co-deleted anaplastic gliomas, which are associated with lower sensitivity to chemotherapy and worse prognosis than 1p/19q co-deleted tumours, is unclear. We assessed the use of radiotherapy with concurrent and adjuvant temozolomide in adults with non-co-deleted anaplastic gliomas., Methods: This was a phase 3, randomised, open-label study with a 2 × 2 factorial design. Eligible patients were aged 18 years or older and had newly diagnosed non-co-deleted anaplastic glioma with WHO performance status scores of 0-2. The randomisation schedule was generated with the electronic EORTC web-based ORTA system. Patients were assigned in equal numbers (1:1:1:1), using the minimisation technique, to receive radiotherapy (59·4 Gy in 33 fractions of 1·8 Gy) alone or with adjuvant temozolomide (12 4-week cycles of 150-200 mg/m 2 temozolomide given on days 1-5); or to receive radiotherapy with concurrent temozolomide 75 mg/m 2 per day, with or without adjuvant temozolomide. The primary endpoint was overall survival adjusted for performance status score, age, 1p loss of heterozygosity, presence of oligodendroglial elements, and MGMT promoter methylation status, analysed by intention to treat. We did a planned interim analysis after 219 (41%) deaths had occurred to test the null hypothesis of no efficacy (threshold for rejection p<0·0084). This trial is registered with ClinicalTrials.gov, number NCT00626990., Findings: At the time of the interim analysis, 745 (99%) of the planned 748 patients had been enrolled. The hazard ratio for overall survival with use of adjuvant temozolomide was 0·65 (99·145% CI 0·45-0·93). Overall survival at 5 years was 55·9% (95% CI 47·2-63·8) with and 44·1% (36·3-51·6) without adjuvant temozolomide. Grade 3-4 adverse events were seen in 8-12% of 549 patients assigned temozolomide, and were mainly haematological and reversible., Interpretation: Adjuvant temozolomide chemotherapy was associated with a significant survival benefit in patients with newly diagnosed non-co-deleted anaplastic glioma. Further analysis of the role of concurrent temozolomide treatment and molecular factors is needed., Funding: Schering Plough and MSD., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Introduction: The long-acting muscarinic antagonist, umeclidinium (UMEC), combined with the inhaled corticosteroid, fluticasone furoate (FF), improves lung function in symptomatic patients with asthma. We assessed FF/UMEC in patients with a primary diagnosis of asthma or chronic obstructive pulmonary disease (COPD), but physiological characteristics of both (fixed airflow obstruction and reversibility to salbutamol)., Methods: This double-blind, parallel-arm, 3-phase study randomised 338 patients (1:1:1:1:2:2) to FF 100 mcg alone or combined with UMEC (15.6, 62.5, 125, or 250 mcg) or vilanterol 25 mcg (Phase A, 4 weeks). Primary endpoint: change from baseline in clinic trough forced expiratory volume in 1 s (FEV 1 ) (end of Phase A). Secondary endpoints: morning peak expiratory flow (PEF), rescue medication use and Evaluating Respiratory Symptoms in COPD (E-RS™: COPD) scores. Safety was assessed., Results: In the intent-to-treat population, the increase in trough FEV 1 over FF was significant for FF/UMEC 62.5 (0.140 L [p = 0.019]) and 125 mcg (0.120 L [p = 0.039]), with similar changes for patients with a primary diagnosis of asthma or COPD. Changes from baseline in morning PEF and E-RS total score were greater for all FF/UMEC doses vs FF (p ≤ 0.05). Change from baseline in rescue medication use was statistically or clinically significant for all FF/UMEC doses vs FF. The incidence of on-treatment adverse events was 15%-32% (Phase A), with no dose-related effects., Conclusions: FF/UMEC 62.5 mcg produced clinically meaningful improvements in FEV 1 , morning PEF, E-RS total score and rescue medication use. FF/UMEC may benefit patients with features of both asthma and COPD. CLINICALTRIALS.GOV: NCT02164539; GSK: 200699., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rationale: p38 mitogen-activated protein kinase (MAPK) expression is increased in chronic inflammatory disease. Losmapimod, a p38 MAPK inhibitor, has been developed as a potential anti-inflammatory therapy in COPD., Objectives: To evaluate the effect of losmapimod in reducing exacerbations in subjects with moderate-to-severe COPD., Methods: In this double-blind, parallel-group study, subjects at risk of COPD exacerbations and ?2% blood eosinophils at screening, were randomized 1:1 to losmapimod 15 mg or placebo (variable treatment duration: 26-52 weeks). The primary endpoint was the annualized rate of moderate/severe exacerbations. Using a Bayesian framework, treatment success was defined as >90% posterior probability that the true ratio of the losmapimod/placebo exacerbation rate was <1. Lung function and health status (St George's Respiratory Questionnaire (SGRQ)) were also assessed., Results: A planned interim analysis resulted in early study termination due to the low probability of a successful study outcome; a total of 94 subjects were randomized to placebo and 90 to losmapimod 15 mg, and 14 and 10 subjects respectively completed the study. Losmapimod treatment was not associated with an improvement in the adjusted posterior median annualized exacerbation rate (losmapimod/placebo ratio: 1.04 (95% Cr I: 0.63, 1.73)). The posterior probability for the losmapimod/placebo annualized rate ratio being <1 was 0.44 (success criterion: >0.90). A statistically significant improvement in post-bronchodilator forced expiratory volume in 1 s was seen at Week 26, at the 5% significance level, with losmapimod treatment versus placebo (p = 0.007). Changes from baseline in SGRQ total score were similar in both groups. No new risks or safety signals were identified with losmapimod treatment., Conclusions: Losmapimod treatment did not reduce the rate of exacerbations in, subjects with COPD at high risk of exacerbation and ?2% blood eosinophils. These data do not support its use as a therapy in COPD in addition to standard of care., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Domestic violence (DV) has significant health impacts for victims and their families. Despite evidence that routine screening increases the identification of DV and opportunities for support; routine screening is uncommon in Australian emergency departments (EDs). This study explored ED clinicians' level of support for DV screening; current screening practices; and perceived barriers and readiness to screen prior to a pilot intervention., Methods: Census survey of 76 ED clinicians. A number of questionnaire items were generated through a review of the literature, with readiness to screen for DV assessed through the short version of the Domestic Violence Healthcare Provider Scale [1]. The confidential and anonymous online survey was hosted on the Qualtrics platform. Descriptive and comparative statistical analysis was performed using IBM SPSS version 22., Results: Most clinicians supported screening for DV in the ED. In the absence of protocols, 72.3% (n=55) of clinicians reported currently engaging in case-based screening, which preferenced women with physical injury. The majority did not always feel comfortable screening for DV (79.7% n=59) and reported they had received insufficient training for this role (88.7% n=55). Lower perceived self-efficacy and fear of offending were statistically associated with discomfort or negative beliefs about DV enquiry (p=<0.05)., Conclusion: Emergency department clinicians reported feeling ill-equipped and under-prepared to inquire about and respond to DV. These findings provide valuable insight about the training and support needs of ED clinicians prior to the commencement of routine screening in EDs., (Copyright © 2017. Published by Elsevier Ltd.)

Asthma-chronic obstructive pulmonary disease overlap syndrome (ACOS) is a loosely-defined clinical entity referring to patients who exhibit characteristics of both asthma and chronic obstructive pulmonary disease (COPD). Clinical definitions and classifications for ACOS vary widely, which impacts our understanding of prevalence, diagnosis and treatment of the condition. This literature review was therefore conducted to characterize the prevalence of ACOS and the effect of different disease definitions on these estimates, as this has not previously been explored. From an analysis of English language literature published from 2000 to 2014, the estimated prevalence of ACOS ranges from 12.1% to 55.2% among patients with COPD and 13.3%-61.0% among patients with asthma alone. This variability is linked to differences in COPD and asthma diagnostic criteria, disease ascertainment methods (spirometry-based versus clinical or symptom-based diagnoses and claims data), and population characteristics including age, gender and smoking. Understanding the reasons for differences in prevalence estimates of ACOS across the literature may help guide decision making on the most appropriate criteria for defining ACOS and aid investigators in designing future ACOS clinical studies aimed at effective treatment., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: A six month study of the p38 MAPK inhibitor, losmapimod, suggested a trend in reducing COPD exacerbations with the 15 mg twice daily dose., Objective and Methods: Using data from this study which evaluated the efficacy of twice daily losmapimod, 2.5 mg, 7.5 mg, and 15 mg, versus placebo in patients with moderate-to-severe COPD, we analysed the effect of losmapimod in reducing the rate of moderate/severe exacerbations in patient subgroups with ≤2% and >2% blood eosinophils at baseline. Lung function, fibrinogen and hsCRP were also evaluated., Results: In the ≤2% eosinophil subgroup, there was an exposure-related reduction in the rate of moderate/severe exacerbations with losmapimod relative to placebo (losmapimod 15 mg: 55% reduction; losmapimod 7.5 mg: 29%; losmapimod 2.5 mg: 10%); with the 15 mg dose reaching statistical significance (15 mg/placebo mean rate ratio [95% CI]: 0.45 [0.22; 0.90]). There was also an improvement in lung function with 15 mg losmapimod over Weeks 1-12. No improvement in the rate of moderate/severe exacerbations or post-bronchodilator FEV1 was observed for subjects treated with Losmapimod compared to placebo in the patient subgroup with blood eosinophils >2% at baseline. Transient reductions in fibrinogen and hsCRP were observed with losmapimod 7.5 mg and 15 mg in both eosinophil subgroups., Conclusions: These findings indicate eosinophil-related heterogeneity within COPD and suggest that losmapimod could be a potential therapy to reduce exacerbations in COPD patients with eosinophil levels ≤2%. This needs to be explored further in a prospectively designed study with pre-specified criteria for blood eosinophil subgroups in COPD patients., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: The short-term benefits of inhaled corticosteroids for patients with chronic obstructive pulmonary disease (COPD) are greater in patients with evidence of eosinophilic airway inflammation. We investigated whether blood eosinophil count is a useful biomarker of the long-term effect of the inhaled corticosteroid fluticasone furoate on exacerbation frequency., Methods: We did a post-hoc analysis of data from two replicate, randomised, double-blind trials of 12 months' duration (Sept 25, 2009 to Oct 21, 2011 and Oct 17, 2011) in which once a day vilanterol 25 μg was compared with 25 μg vilanterol plus 50 μg, 100 μg, or 200 μg fluticasone furoate in patients with moderate-to-severe COPD and a history of one or more exacerbation in the previous year. We compared exacerbation rates according to two baseline eosinophil cell count strata (<2% and ≥2%), and according to four baseline percentage groupings. We also assessed lung function and incidence of pneumonia per strata in treatment groups., Findings: We included 3177 patients in the analyses, with 2083 patients (66%) having an eosinophil count of 2% or higher at study entry. Across all doses of inhaled corticosteroids, fluticasone furoate and vilanterol reduced exacerbations by 29% compared with vilanterol alone (mean 0·91 vs 1·28 exacerbations per patient per year; p<0·0001) in patients with eosinophil counts of 2% or higher, and by 10% (0·79 vs 0·89; p=0·2827) in patients with eosinophil counts lower than 2%. Reductions in exacerbations with fluticasone furoate and vilanterol, compared with vilanterol alone, were 24% in patients with baseline eosinophil counts of ≥2-<4%, 32% for those with counts of 4-<6%, and 42% for those with eosinophil counts of ≥6%. In patients treated with vilanterol alone, exacerbation rates increased progressively with increasing eosinophil count percentage category. Improvement in trough forced expiratory volume in 1 s (FEV1) and the increased risk of pneumonia with fluticasone furoate and vilanterol compared with vilanterol alone were not associated with eosinophil count., Interpretation: Blood eosinophil count is a promising biomarker of response to inhaled corticosteroids in patients with COPD. Blood eosinophil count could potentially be used to stratify patients for different exacerbation rate reduction strategies., Funding: GlaxoSmithKline (study ID 201595)., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: To our knowledge, no studies in patients with asthma have assessed a long-acting muscarinic antagonist in the absence of inhaled corticosteroids (ICS)., Objective: Evaluate the dose-response, efficacy, and safety of umeclidinium (UMEC) in patients with asthma not receiving ICS., Methods: In this double-blind, three-period crossover study, 350 subjects were randomized to a sequence of three of eight inhaled treatments: UMEC 15.6, 31.25, 62.5, 125, or 250 mcg once daily (OD), UMEC 15.6 or 31.25 mcg twice daily (BID), or placebo, administered for 14 days (12-14-day washout). Trough forced expiratory volume in one second (FEV1), 0-24-h weighted mean (WM) FEV1, and safety were assessed. Serial spirometry and pharmacokinetic assessments were performed in a subgroup., Results: Subjects had a mean baseline pre- and post-bronchodilator FEV1 of 71% and 88% predicted, respectively. Significant improvements in change from baseline trough FEV1 were observed for UMEC 15.6 OD (0.066 L; p = 0.036) and UMEC 125 OD (0.088 L; p = 0.005) versus placebo, but not other OD or BID doses. UMEC increased 0-24-h WM FEV1 versus placebo (0.068-0.121 L [p ≤ 0.017] with no clear dose-response). Treatment differences were similar for corresponding OD and BID doses in serial assessments. UMEC was rapidly absorbed, with evidence of some accumulation. The incidence of on-treatment adverse events was 9-21% for UMEC and 12% for placebo. There were no treatment-related effects on laboratory parameters., Conclusion: The modest trough FEV1 improvements did not conclusively support a therapeutic benefit of UMEC in non-ICS treated patients with asthma., Clinicaltrialsgov: NCT01641692., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: We evaluated the dose-response of umeclidinium (UMEC; a long-acting muscarinic antagonist) combined with fluticasone furoate (FF; an inhaled corticosteroid [ICS]) in patients with asthma., Methods: In a double-blind, three-period crossover study, 421 subjects (symptomatic on ICS), were randomized to a sequence of three of seven treatments: FF 100 mcg alone, FF 100 mcg combined with UMEC (15.6, 31.25, 62.5, 125, or 250 mcg), or vilanterol 25 mcg (a long-acting β-agonist), inhaled once-daily for 14 days (12-14-day washout). Trough forced expiratory volume in one second (FEV1), peak expiratory flow (PEF), and safety were assessed., Results: Period baseline was a significant covariate, indicating a potential carryover effect between treatment periods. Across all treatment periods, trough FEV1 improved with FF/UMEC 125 and 250 versus FF (treatment difference 0.055 L [both doses]; p = 0.018). FF/UMEC increased morning (15.9-22.9 L/min) and evening (16.2-28.8 L/min) PEF versus FF. As intended assessments were confounded, post hoc Period 1 data analyses were performed, demonstrating significant increases in trough FEV1 with FF/UMEC 31.25, 62.5, and 250 versus FF. Trough FEV1 improvements with FF/UMEC were greater in subjects with fixed (0.095-0.304 L) versus non-fixed (-0.084 to 0.041 L) obstruction. The incidence of on-treatment adverse events was 13-25% across groups. No treatment-related effects on laboratory parameters were reported., Conclusion: FF/UMEC may be a viable treatment for patients with asthma symptomatic on ICS; benefit may be most prominent in those with fixed obstruction. The carryover effect suggests future UMEC studies should use an alternative design. ClinicalTrials.gov: NCT01573624., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Dual contraceptive method use is advocated for adolescent women to prevent pregnancy, sexually transmitted diseases and HIV., Methods: We examined data from a nationally representative sample of South African women aged 15-24 years to establish factors associated with dual method use., Results: Only 7% of current contraceptive users reported using dual methods, although this percentage increased to 28.1% when women reporting hormonal contraception and condom use at last sex were included. In multivariate analyses, having talked about condoms with a partner was most strongly associated with dual method use (adjusted odds ratio (AOR), 12.3; 95% confidence interval (CI), 6.1-25.1) and suggests that communication skills might be the most effective way of increasing dual method use. Difficulty in accessing condoms was associated with lower odds of dual method use (AOR, 0.5; 95% CI, 0.2-1.0)., Conclusion: We conclude with recommendations to increase male involvement and encourage communication between partners for the integration of HIV prevention and other reproductive health care services.

Whole mount in situ hybridization studies were performed to investigate the expression pattern of the homeobox gene Hex (also known as Prh) during early stages of chick embryogenesis. At the time of laying, cHex transcripts are detected in Koller's sickle and the forming hypoblast. During gastrulation (HH stage 4), cHex is expressed in anteriorly-displaced hypoblast cells. At stage 6, cHex transcripts are observed within endoderm in an anterior are that overlaps the cardiogenic region. Later cHex expression is observed within pharyngeal endoderm immediately adjacent to the forming myocardium, in the endocardium and in the liver and thyroid gland primordia. cHex transcripts are also detected within blood islands beginning at stage 4, and in extraembryonic and intraembryonic vascular endothelial cells as vessels form.

In the pharmaceutical industry, the majority of drug-safety evaluation studies are carried out preferentially in the rat. Consequently, drug absorption, distribution, metabolism and excretion profiles are available for this species. Such data usually have to be generated independently in the mouse, to allow validation of any micronucleus tests carried out in this species. Unfortunately, at the present time, the rat is not ideal for use in the micronucleus test due to the presence of large numbers of contaminating mast cell granules. Such granules are stained blue by the most commonly accepted staining procedure (May-Grunwald-Giemsa), and can be erroneously scored as micronuclei when they overlay erythrocytes. A simple haematoxylin and eosin staining procedure was evaluated in the micronucleus test using rats and mice. With this procedure, micronuclei stained blue-black and were readily distinguishable from cell inclusions resembling micronuclei such as mast cell granules, which remained unstained. Essentially similar quantitative data for micronucleus incidence and erythrocyte distribution were obtained in mice using this staining technique when compared to the use of the more established May-Grunwald-Giemsa staining procedure. However, unlike the use of the May-Grunwald-Giemsa procedure, the use of the haematoxylin and eosin stains allowed the accurate estimation of micronucleus incidence within the marrows of treated rats in the presence of contaminating mast-cell granules. Furthermore, unlike alternative procedures using fluorescent stains, the haematoxylin and eosin stained preparations are stable, constitute a permanent record of the experiment, and can be analysed at the convenience of the investigator. Therefore, this staining procedure may offer a useful alternative, for example, when evaluating rat bone-marrow smears within which considerable mast cell contamination can occur.