Inspiratory flow profile and usability of the NEXThaler, a multidose dry powder inhaler, in asthma and COPD.

BACKGROUND: Inhaler selection is important when managing respiratory conditions; a patient's inhalation technique should be appropriate for the selected device, and patients should ideally be able to use a device successfully regardless of disease severity. The NEXThaler is a multidose dry-powder inhaler with a breath-actuated mechanism (BAM) and dose counter that activates only following inhalation, so effectively an 'inhalation counter'. We assessed inspiratory flow through the NEXThaler in two studies and examined whether inhalation triggered the BAM. METHODS: The two studies were open-label, single-arm, and single visit. One study recruited patients with asthma aged ≥ 18 years; the other recruited patients with chronic obstructive pulmonary disease (COPD) aged ≥ 40 years. All patients inhaled twice through a placebo NEXThaler. The inspiratory profile through the device was assessed for each inhalation using acoustic monitoring, with flow at and time to BAM firing, peak inspiratory flow (PIF), and total inhalation time assessed. RESULTS: A total of 40 patients were enrolled in the asthma study: 20 with controlled asthma and 20 with partly controlled/uncontrolled asthma. All patients were able to trigger the BAM, as evidenced by the inhalation counter activating on closing the device. Mean flow at BAM firing following first inhalation was 35.0 (range 16.3-52.3) L/min; mean PIF was 64.6 (35.0-123.9) L/min. A total of 72 patients were enrolled in the COPD study, with data analysed for 69 (mean forced expiratory volume in 1 s 48.7% predicted [17-92%]). As with the asthma study, all patients, regardless of airflow limitation, were able to trigger the BAM. Mean flow at BAM firing following first inhalation was 41.9 (26.6-57.1) L/min; mean PIF was 68.0 (31.5-125.4) L/min. Device usability was rated highly in both studies, with 5 min sufficient to train the patients, and a click heard shortly after inhalation in all cases (providing feedback on BAM firing). CONCLUSIONS: Inhalation flows triggering the BAM in the NEXThaler were similar between patients with controlled and partly controlled/uncontrolled asthma, and were similar across COPD airflow limitation. All enrolled patients were able to activate the device.

Daily Impact of COPD in Younger and Older Adults: Global Online Survey Results from over 1,300 Patients.

The daily impact of chronic obstructive pulmonary disease (COPD) on younger patients is often underappreciated. To assess this, we investigated the disease burden experienced by younger and older patients. A panel of questions was developed in conjunction with the European Federation of Allergy and Airways Diseases Patients' Associations and Boehringer Ingelheim. The online survey was conducted by Instar Research. Data were collected from eight countries in Europe, plus China, Japan and the United States. All patients were receiving COPD maintenance therapy. Patients were stratified by age (45-54, 55-64, ≥65 years). Data were analyzed from 1,375 patients from Europe (925), China (150), Japan (100) and the US (200); 365 were aged 45-54, 440 aged 55-64, and 570 aged ≥65 years. Mean age was 61.8 years; 771 (56%) were male. A significantly higher proportion of patients aged 45-54 years reported "poor" or "very poor" wellbeing (35% vs. 28%; p < 0.05) and "high impact" on 8 of the 11 daily activities and requirements for adjusting activities assessed (all p < 0.05), compared with patients aged ≥65 years. Significantly more patients aged 45-54 versus ≥65 years associated their COPD with feeling "anxious", "stressed", "sad", or "overwhelmed" (all p < 0.05). Younger patients with COPD reported a higher impact on their daily activities, wellbeing and requirement for adjusting their activities due to their symptoms than older patients. Our findings highlight the importance of optimizing treatment for younger patients with COPD and suggest that clinicians should not overlook the burden of disease in these patients.

Inhaler technique mastery and maintenance in healthcare professionals trained on different devices.

OBJECTIVE: Healthcare professionals (HCPs) are required to assess and train patients in the correct use of inhalers but are often unable to demonstrate correct technique themselves. We sought to assess the level of training required for HCPs to master and maintain device mastery when using two different dry powder inhalers (DPIs). METHODS: We conducted a randomized, un-blinded, crossover study in undergraduate HCPs who undertook a six-step training procedure (intuitive use, patient information leaflet, instructional video, individual tuition from expert, then two repeats of individual tuition) for the use of Turbuhaler® (an established device) and Spiromax® (a newer device, reportedly easier to use). Device mastery (absence of errors) was evaluated by expert assessors at each training step. Maintenance of mastery was assessed 4 ± 1 week (visit 2) and 8 ± 2 weeks (visit 3) after initial training (visit 1). RESULTS: Of 516 eligible participants, 113 (22%) demonstrated device mastery prior to training on Spiromax® compared with 20 (4%) on Turbuhaler® (p < 0.001). The median number of training steps required to achieve mastery was 2 (interquartile range [IQR] 2-4) for Spiromax® and 3 (IQR 2-4) for Turbuhaler® (p < 0.001). A higher number of participants maintained mastery with Spiromax® compared with Turbuhaler®, at visits 2 and 3 (64% vs 41% and 79% vs 65%, respectively; p < 0.001). CONCLUSIONS: There are significant differences in the nature and extent of training required to achieve and maintain mastery for Spiromax® and Turbuhaler® devices. The implications on clinical practice, device education delivery, and patient outcomes require further evaluation.

Distress in suspected lung cancer patients following rapid and standard diagnostic programs: a prospective observational study.

OBJECTIVE: Timeliness may influence emotional distress during the diagnostic phase of suspected lung cancer patients. We performed a prospective observational study to compare distress and quality of life (QoL) in two medical centres with a Rapid Outpatient Diagnostic Program (RODP) and two using conventional Stepwise Diagnostic Approach (SDA) on the basis of trained nurse-led care. METHODS: Outpatients with radiological suspicion of lung cancer completed the Hospital Anxiety and Depression Scale (HADS), European Organization for Research and Treatment of Cancer 30-item Quality of Life Questionnaire (QLQ-C30) and its 13-item Lung Cancer specific module (QLQ-LC13) upon first visit, 2 days later, thereafter weekly for 5 weeks and after 3 months. RESULTS: The 72 SDA patients and 121 RODP patients had a mean pre-diagnostic HADS-total score of 13.5 (SD 7.6); 63.4% had a score ≥10. Baseline QLQ-C30 global QoL was 61.6 (SD 22.7) exceeding reference values for lung cancer patients. Generalized least square models showed a significant centre by time interaction effect: during the first 6 weeks, HADS-total scores decreased in RODP patients (13.8-11.9) but sustained in SDA patients (13.1-13.6), whereas QoL showed no relevant changes. Times to diagnosis and discussion of therapy plan for RODP patients were 7 and 11 days shorter, respectively. CONCLUSIONS: Suspected lung cancer patients had high baseline distress levels. A decrease over time was found in RODP compared with SDA patients. QoL did not change relevantly. Albeit observational, these data indicate that patients experience less distress in rapid diagnostic programs than in stepwise diagnostic evaluation.

Levosimendan affects oxidative and inflammatory pathways in the diaphragm of ventilated endotoxemic mice.

INTRODUCTION: Controlled mechanical ventilation and endotoxemia are associated with diaphragm muscle atrophy and dysfunction. Oxidative stress and activation of inflammatory pathways are involved in the pathogenesis of diaphragmatic dysfunction. Levosimendan, a cardiac inotrope, has been reported to possess anti-oxidative and anti-inflammatory properties. The aim of the present study was to investigate the effects of levosimendan on markers for diaphragm nitrosative and oxidative stress, inflammation and proteolysis in a mouse model of endotoxemia and mechanical ventilation. METHODS: Three groups were studied: (1) unventilated mice (CON, n =8), (2) mechanically ventilated endotoxemic mice (MV LPS, n =17) and (3) mechanically ventilated endotoxemic mice treated with levosimendan (MV LPS + L, n =17). Immediately after anesthesia (CON) or after 8 hours of mechanical ventilation, blood and diaphragm muscle were harvested for biochemical analysis. RESULTS: Mechanical ventilation and endotoxemia increased expression of inducible nitric oxide synthase (iNOS) mRNA and cytokine levels of interleukin (IL)-1ß, IL-6 and keratinocyte-derived chemokine, and decreased IL-10, in the diaphragm; however, they had no effect on protein nitrosylation and 4-hydroxy-2-nonenal protein concentrations. Levosimendan decreased nitrosylated proteins by 10% (P <0.05) and 4-hydroxy-2-nonenal protein concentrations by 13% (P <0.05), but it augmented the rise of iNOS mRNA by 47% (P <0.05). Levosimendan did not affect the inflammatory response in the diaphragm induced by mechanical ventilation and endotoxemia. CONCLUSIONS: Mechanical ventilation in combination with endotoxemia results in systemic and diaphragmatic inflammation. Levosimendan partly decreased markers of nitrosative and oxidative stress, but did not affect the inflammatory response.

An official American Thoracic Society/European Respiratory Society statement: update on limb muscle dysfunction in chronic obstructive pulmonary disease.

BACKGROUND: Limb muscle dysfunction is prevalent in chronic obstructive pulmonary disease (COPD) and it has important clinical implications, such as reduced exercise tolerance, quality of life, and even survival. Since the previous American Thoracic Society/European Respiratory Society (ATS/ERS) statement on limb muscle dysfunction, important progress has been made on the characterization of this problem and on our understanding of its pathophysiology and clinical implications. PURPOSE: The purpose of this document is to update the 1999 ATS/ERS statement on limb muscle dysfunction in COPD. METHODS: An interdisciplinary committee of experts from the ATS and ERS Pulmonary Rehabilitation and Clinical Problems assemblies determined that the scope of this document should be limited to limb muscles. Committee members conducted focused reviews of the literature on several topics. A librarian also performed a literature search. An ATS methodologist provided advice to the committee, ensuring that the methodological approach was consistent with ATS standards. RESULTS: We identified important advances in our understanding of the extent and nature of the structural alterations in limb muscles in patients with COPD. Since the last update, landmark studies were published on the mechanisms of development of limb muscle dysfunction in COPD and on the treatment of this condition. We now have a better understanding of the clinical implications of limb muscle dysfunction. Although exercise training is the most potent intervention to address this condition, other therapies, such as neuromuscular electrical stimulation, are emerging. Assessment of limb muscle function can identify patients who are at increased risk of poor clinical outcomes, such as exercise intolerance and premature mortality. CONCLUSIONS: Limb muscle dysfunction is a key systemic consequence of COPD. However, there are still important gaps in our knowledge about the mechanisms of development of this problem. Strategies for early detection and specific treatments for this condition are also needed.

Burden of Exacerbations in Patients with Moderate to Very Severe COPD in the Netherlands: A Real-life Study.

OBJECTIVE: The objective of this study was to compare rates of different types of acute exacerbations of COPD (AECOPDs) and healthcare utilization among patients with different severities of COPD. METHODS: Data for this study was obtained from the PHARMO Database Network, which includes drug dispensing records from pharmacies, hospitalization records and information from general practitioners. Patients with moderate to very severe COPD (GOLD II-III-IV) and a moderate or severe AECOPD between 2000 and 2010 were included in the study. Moderate and severe AECOPDs were defined by drug use and hospitalizations respectively. Study patients were followed from the first AECOPD to end of registration in PHARMO, death or end of study period, whichever occurred first. During follow-up, all recurrent AECOPDs were characterized and healthcare utilization was assessed. RESULTS: Of 886 patients in the study, 52% had GOLD-II, 34% GOLD-III and 14% had GOLD-IV. The overall AECOPD recurrence rate per person year (PY) increased from 0.63 for patients with GOLD-II to 1.09 for patients with GOLD-III and 1.33 for patients with GOLD-IV. The rate of severe AECOPD was 0.06, 0.14 and 0.17 per PY, respectively. CONCLUSION: AECOPD recurrence rates and healthcare utilization are significantly higher among patients with more severe COPD.

Hypercapnia attenuates ventilator-induced diaphragm atrophy and modulates dysfunction.

INTRODUCTION: Diaphragm weakness induced by prolonged mechanical ventilation may contribute to difficult weaning from the ventilator. Hypercapnia is an accepted side effect of low tidal volume mechanical ventilation, but the effects of hypercapnia on respiratory muscle function are largely unknown. The present study investigated the effect of hypercapnia on ventilator-induced diaphragm inflammation, atrophy and function. METHODS: Male Wistar rats (n = 10 per group) were unventilated (CON), mechanically ventilated for 18 hours without (MV) or with hypercapnia (MV + H, Fico2 = 0.05). Diaphragm muscle was excised for structural, biochemical and functional analyses. RESULTS: Myosin concentration in the diaphragm was decreased in MV versus CON, but not in MV + H versus CON. MV reduced diaphragm force by approximately 22% compared with CON. The force-generating capacity of diaphragm fibers from MV + H rats was approximately 14% lower compared with CON. Inflammatory cytokines were elevated in the diaphragm of MV rats, but not in the MV + H group. Diaphragm proteasome activity did not significantly differ between MV and CON. However, proteasome activity in the diaphragm of MV + H was significantly lower compared with CON. LC3B-II a marker of lysosomal autophagy was increased in both MV and MV + H. Incubation of MV + H diaphragm muscle fibers with the antioxidant dithiothreitol restored force generation of diaphragm fibers. CONCLUSIONS: Hypercapnia partly protects the diaphragm against adverse effects of mechanical ventilation.

High performance of F-fluorodeoxyglucose positron emission tomography and contrast-enhanced CT in a rapid outpatient diagnostic program for patients with suspected lung cancer.

BACKGROUND: The diagnostic evaluation of patients presenting with possible lung cancer is often complex and time consuming. A rapid outpatient diagnostic program (RODP) including (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) and contrast-enhanced computed tomography (CT) as a routine diagnostic tool may improve timeliness, however the diagnostic performance of such a combined approach of RODP remains unclear. OBJECTIVES: We evaluated timeliness of care and diagnostic performance of FDG-PET and contrast-enhanced CT (FDG-PET/CT) in an RODP for all patients referred with a chest X-ray suspicious of lung cancer. METHODS: Charts of patients referred to the 2-day RODP of our tertiary care university clinic after an abnormal chest X-ray between 1999 and 2009 were reviewed. Between 1999 and 2005 co-registered FDG-PET and CT imaging took place; from September 2005 onwards, a hybrid system was used. We analyzed timeliness of care and diagnostic performance of FDG-PET/CT to differentiate malignant from benign lesions. RESULTS: In 386 patients available for analysis, 260 were diagnosed with lung cancer and 23 had another type of malignancy; in 78 patients benign disease was confirmed, and in another 45 the diagnosis was not pathologically confirmed but a median 24.5-month follow-up confirmed a benign outcome. Sensitivity, specificity, negative and positive predictive values and accuracy of FDG-PET/CT to differentiate lung cancer from benign disease were 97.7, 60.2, 92.5, 84.0 and 85.8%, respectively. Lung cancer patients had a median referral, diagnostic and therapeutic delay of 7, 2 and 19 days, respectively. CONCLUSIONS: FDG-PET/CT in an RODP setting for suspected lung cancer has high performance in detecting cancer and facilitates timely care.

The geographic diversity of nontuberculous mycobacteria isolated from pulmonary samples: an NTM-NET collaborative study.

A significant knowledge gap exists concerning the geographical distribution of nontuberculous mycobacteria (NTM) isolation worldwide. To provide a snapshot of NTM species distribution, global partners in the NTM-Network European Trials Group (NET) framework (www.ntm-net.org), a branch of the Tuberculosis Network European Trials Group (TB-NET), provided identification results of the total number of patients in 2008 in whom NTM were isolated from pulmonary samples. From these data, we visualised the relative distribution of the different NTM found per continent and per country. We received species identification data for 20 182 patients, from 62 laboratories in 30 countries across six continents. 91 different NTM species were isolated. Mycobacterium avium complex (MAC) bacteria predominated in most countries, followed by M. gordonae and M. xenopi. Important differences in geographical distribution of MAC species as well as M. xenopi, M. kansasii and rapid-growing mycobacteria were observed. This snapshot demonstrates that the species distribution among NTM isolates from pulmonary specimens in the year 2008 differed by continent and differed by country within these continents. These differences in species distribution may partly determine the frequency and manifestations of pulmonary NTM disease in each geographical location.

Manual vs. automated analysis of polysomnographic recordings in patients with chronic obstructive pulmonary disease.

PURPOSE: The sleep quality, as assessed by polysomnography (PSG), of patients with chronic obstructive pulmonary disease (COPD) can be severely disturbed. The manual analysis of PSGs is time-consuming, and computer systems have been developed to automatically analyze PSGs. Studies on the reliability of automated analyses in healthy subjects show varying results, and the purpose of this study was to assess whether automated analysis of PSG by one certain automatic system in patients with COPD provide accurate outcomes when compared to manual analysis. METHODS: In a retrospective study, the full-night polysomnographic recordings of patients with and without COPD were analyzed automatically by Matrix Sleep Analysis software and manually. The outcomes of manual and automated analyses in both groups were compared using Bland-Altman plots and Students' paired t tests. RESULTS: Fifty PSGs from patients with COPD and 57 PSGs from patients without COPD were included. In both study groups, agreement between manual and automated analysis was poor in nearly all sleep and respiratory parameters, like total sleep time, sleep efficiency, sleep latency, amount of rapid eye movement sleep and other sleep stages, number of arousals, apnea-hypopnea index, and desaturation index. CONCLUSION: Automated analysis of PSGs by the studied automated system in patients with COPD has poor agreement with manual analysis when looking at sleep and respiratory parameters and should, therefore, not replace the manual analysis of PSG recordings in patients with COPD.

Does mixing inhaler devices lead to unchecked inhaler technique errors in patients with COPD? Findings from the cross-sectional observational MISMATCH study.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) may be prescribed multiple inhalers that require different techniques for optimal performance. Mixing devices has been associated with poorer COPD outcomes suggesting that it leads to inappropriate inhaler technique. However, empirical evidence is lacking. AIMS: Compare the nature and frequency of dry powder inhaler (DPI) technique errors in patients with COPD using (1) a single DPI or (2) mixed-devices (a DPI and pressurised metered dose inhaler (pMDI)). METHODS: Data from the PIFotal study-a cross-sectional study on Peak Inspiratory Flow in patients with COPD using a DPI as maintenance therapy, capturing data from 1434 patients on demographic characteristics, COPD health status and inhaler technique-were used to select 291 patients using mixed-devices. Frequency matching based on country of residence and DPI device type was used to select 291 patients using a DPI-only for comparison. Predetermined checklists were used for the evaluation of DPI video recordings and complemented with additional errors that were observed in ≥10%. Error proportions were calculated for the (1) individual and total number of errors, (2) number of critical errors and (3) number of pMDI-related errors. RESULTS: The study sample contained 582 patients (mean (SD) age 69.6 (9.4) years, 47.1% female). DPI technique errors were common, but not significantly different between the groups. The majority of patients made at least one critical error (DPI-only: 90.7% vs mixed-devices: 92.8%). Proportions of total, 'pMDI-related' and critical errors did not significantly differ between the groups. CONCLUSION: The nature and frequency of inhaler technique errors did not substantially differ between patients prescribed with a single DPI and mixed-devices. Currently, 'pMDI-related errors' in DPI use are not accounted for in existing checklists. TRIAL REGISTRATION NUMBER: ENCEPP/EUPAS48776.

Validation of pncA gene sequencing in combination with the mycobacterial growth indicator tube method to test susceptibility of Mycobacterium tuberculosis to pyrazinamide.

Pyrazinamide is important in the treatment of tuberculosis. Unfortunately, the diagnosis of pyrazinamide resistance is hampered by technical difficulties. We hypothesized that mutation analysis combined with the mycobacterial growth indicator tube (MGIT) phenotypic method would be a good predictor of pyrazinamide resistance. We prospectively analyzed 1,650 M. tuberculosis isolates referred to our tuberculosis reference laboratory in 2008 and 2009. In our laboratory, the MGIT 960 system was used for pyrazinamide resistance screening. If a pyrazinamide-resistant strain was detected, we performed a pncA gene mutation analysis. A second MGIT 960 susceptibility assay was performed afterwards to evaluate the accuracy of the pncA mutation analysis to detect true- or false-positive MGIT results. We observed pyrazinamide resistance in 69 samples using the first MGIT 960 analysis. In a second MGIT 960 analysis, 47 of the 69 samples proved susceptible (68% false positivity). Sensitivity of nonsynonymous pncA mutations for detecting resistant isolates was 73% (95% confidence interval [CI], 61% to 73%), and specificity was 100% (95% CI, 95% to 100%). A diagnostic algorithm incorporating phenotypic and molecular methods would have a 100% positive predictive value for detecting pyrazinamide-resistant isolates, indicating that such an algorithm, based on both methods, is a good predictor for pyrazinamide resistance in routine diagnostics.

Toll-like receptor 4 signaling in ventilator-induced diaphragm atrophy.

BACKGROUND: Mechanical ventilation induces diaphragm muscle atrophy, which plays a key role in difficult weaning from mechanical ventilation. The signaling pathways involved in ventilator-induced diaphragm atrophy are poorly understood. The current study investigated the role of Toll-like receptor 4 signaling in the development of ventilator-induced diaphragm atrophy. METHODS: Unventilated animals were selected for control: wild-type (n = 6) and Toll-like receptor 4 deficient mice (n = 6). Mechanical ventilation (8 h): wild-type (n = 8) and Toll-like receptor 4 deficient (n = 7) mice.Myosin heavy chain content, proinflammatory cytokines, proteolytic activity of the ubiquitin-proteasome pathway, caspase-3 activity, and autophagy were measured in the diaphragm. RESULTS: Mechanical ventilation reduced myosin content by approximately 50% in diaphragms of wild-type mice (P less than 0.05). In contrast, ventilation of Toll-like receptor 4 deficient mice did not significantly affect diaphragm myosin content. Likewise, mechanical ventilation significantly increased interleukin-6 and keratinocyte-derived chemokine in the diaphragm of wild-type mice, but not in ventilated Toll-like receptor 4 deficient mice. Mechanical ventilation increased diaphragmatic muscle atrophy factor box transcription in both wild-type and Toll-like receptor 4 deficient mice. Other components of the ubiquitin-proteasome pathway and caspase-3 activity were not affected by ventilation of either wild-type mice or Toll-like receptor 4 deficient mice. Mechanical ventilation induced autophagy in diaphragms of ventilated wild-type mice, but not Toll-like receptor 4 deficient mice. CONCLUSION: Toll-like receptor 4 signaling plays an important role in the development of ventilator-induced diaphragm atrophy, most likely through increased expression of cytokines and activation of lysosomal autophagy.

The faster the better?­A systematic review on distress in the diagnostic phase of suspected cancer, and the influence of rapid diagnostic pathways.

OBJECTIVE: To perform a systematic review of articles published in the last 25 years on prevalence and course of distress and quality of life surrounding the diagnostic process of suspected cancer, and the influence of rapid diagnostic programs. METHODS: Twenty-three articles were identified via Pubmed, PsycINFO, and reference lists of articles. Except for three randomized clinical trials and one case control study all studies were uncontrolled cohort studies. RESULTS: Most studies involved patients with suspected breast cancer and therefore had a sex selection bias. Four studies on the effect of rapid outpatient diagnostic programs were found.Studies showed very high prevalence of anxiety, decreasing in case of a benign diagnosis but increasing or sustaining in patients waiting for results or after cancer diagnosis though not significantly more in rapid programs. Quality of life was low and showed varying patterns. CONCLUSIONS: Distress in the diagnostic phase of cancer is a major problem and the rapid decrease of anxiety in patients eventually not diagnosed with cancer suggests a benefit of rapid diagnostic programs. The available evidence however is limited and shows some inconsistencies. Studies differ in subjects, objective and are limited by quality and quantity. Conflicting results prohibit a conclusion on patients ultimately diagnosed with cancer.

Is Inhaler Technique Adequately Assessed and Reported in Clinical Trials of Asthma and Chronic Obstructive Pulmonary Disease Therapy? A Systematic Review and Suggested Best Practice Checklist.

BACKGROUND: Inhaled medications are central to treating asthma and chronic obstructive pulmonary disease (COPD), yet critical inhaler technique errors are made by up to 90% of patients. In the clinical research setting, recruitment of subjects with poor inhaler technique may give a false impression of both the benefits and the necessity of add-on treatments such as biologic therapies. OBJECTIVE: To assess the frequency with which inhaler technique is assessed and reliably optimized before and during patient enrollment into randomized controlled trials (RCTs) addressing the efficacy of topical therapy, and the escalation of therapy for asthma and COPD. METHODS: Systematic searches were conducted of PubMed and Embase for RCTs published in the past 10 years involving patients with a diagnosis of asthma or COPD undergoing escalation of baseline inhaled therapy (stepping up, changing, adding, switching, increasing, etc) or the introduction of biologic agents. RESULTS: Searches highlighted 1,014 studies, 118 of which were eligible after the removal of duplicates as well as screening and full text review. Of these, only 14 (11.9%) included accessible information in the methods section or referred to such information in online supplements or protocols concerning assessment of participants' inhaler technique. We therefore developed the proposed Best Practice Inhaler Technique Assessment and Reporting Checklist. CONCLUSIONS: Our study identifies a concerning lack of checking and correcting inhaler technique, or at least reporting that this was undertaken, before enrollment in asthma and COPD RCTs, which may affect the conclusions drawn. Mandating the use of a standardized checklist in RCT protocols and ensuring all published RCTs report checking and correcting inhaler technique before enrollment are important next steps.

The heparan sulfate motif (GlcNS6S-IdoA2S)3, common in heparin, has a strict topography and is involved in cell behavior and disease.

Heparan sulfate (HS) is a structurally complex polysaccharide that interacts with a broad spectrum of extracellular effector ligands and thereby is thought to regulate a diverse array of biologic processes. The specificity of HS-ligand interactions is determined by the arrangement of sulfate groups on HS, which creates distinct binding motifs. Biologically important HS motifs are expected to exhibit regulated expression, yet there is a profound lack of tools to identify such motifs; consequently, little is known of their structures and functions. We have identified a novel phage display-derived antibody (NS4F5) that recognizes a highly regulated HS motif (HS(NS4F5)), which we have rigorously identified as (GlcNS6S-IdoA2S)(3). HS(NS4F5) exhibits a restricted expression in healthy adult tissues. Blocking HS(NS4F5) on cells in culture resulted in reduced proliferation and enhanced sensitivity to apoptosis. HS(NS4F5) is up-regulated in tumor endothelial cells, consistent with a role in endothelial cell activation. Indeed, TNF-α stimulated endothelial expression of HS(NS4F5), which contributed to leukocyte adhesion. In a mouse model of severe systemic amyloid protein A amyloidosis, HS(NS4F5) was expressed within amyloid deposits, which were successfully detected by microSPECT imaging using NS4F5 as a molecularly targeted probe. Combined, our results demonstrate that NS4F5 is a powerful tool for elucidating the biological function of HS(NS4F5) and can be exploited as a probe to detect novel polysaccharide biomarkers of disease processes.

Nontuberculous mycobacteria in respiratory tract infections, eastern Asia.

To characterize the distribution of nontuberculous mycobacteria (NTM) species isolated from pulmonary samples from persons in Asia and their association with pulmonary infections, we reviewed the literature. Mycobacterium avium complex bacteria were most frequently isolated (13%-81%) and were the most common cause of pulmonary NTM disease (43%-81%). Also pathogenic were rapidly growing mycobacteria (M. chelonae, M. fortuitum, M. abscessus). Among all NTM isolated from pulmonary samples, 31% (582/1,744) were considered clinically relevant according to American Thoracic Society diagnostic criteria. Most patients were male (79%) and had a history of tuberculosis (37%). In Asia, high prevalence of rapidly growing mycobacteria and a history of tuberculosis are distinct characteristics of pulmonary NTM disease. This geographic variation is not well reflected in the American Thoracic Society criteria for NTM infections and could be incorporated in future guidelines.