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Abstract Background Patients receiving complementary and alternative medicine (CAM) therapies often report shifts in well-being that go beyond resolution of the original presenting symptoms. We undertook a research program to develop and evaluate a patient-centered outcome measure to assess the multidimensional impacts of CAM therapies, utilizing a novel mixed methods approach that relied upon techniques from the fields of anthropology and psychometrics. This tool would have broad applicability, both for CAM practitioners to measure shifts in patients' states following treatments, and conventional clinical trial researchers needing validated outcome measures. The US Food and Drug Administration has highlighted the importance of valid and reliable measurement of patient-reported outcomes in the evaluation of conventional medical products. Here we describe Phase I of our research program, the iterative process of content identification, item development and refinement, and response format selection. Cognitive interviews and psychometric evaluation are reported separately. Methods From a database of patient interviews (n = 177) from six diverse CAM studies, 150 interviews were identified for secondary analysis in which individuals spontaneously discussed unexpected changes associated with CAM. Using ATLAS.ti, we identified common themes and language to inform questionnaire item content and wording. Respondents' language was often richly textured, but item development required a stripping down of language to extract essential meaning and minimize potential comprehension barriers across populations. Through an evocative card sort interview process, we identified those items most widely applicable and covering standard psychometric domains. We developed, pilot-tested, and refined the format, yielding a questionnaire for cognitive interviews and psychometric evaluation. Results The resulting questionnaire contained 18 items, in visual analog scale format, in which each line was anchored by the positive and negative extremes relevant to the experiential domain. Because of frequent informant allusions to response set shifts from before to after CAM therapies, we chose a retrospective pretest format. Items cover physical, emotional, cognitive, social, spiritual, and whole person domains. Conclusions This paper reports the success of a novel approach to the development of outcome instruments, in which items are extracted from patients' words instead of being distilled from pre-existing theory. The resulting instrument, focused on measuring shifts in patients' perceptions of health and well-being along pre-specified axes, is undergoing continued testing, and is available for use by cooperating investigators.

In 2008, the National Heart, Lung, and Blood Institute announced its intent to support a new asthma network known as AsthmaNet. This clinical trials consortium, now in its fifth year, has been charged with developing and executing clinical trials to address the most important asthma management questions and identify new treatment approaches in pediatric and adult patients. This review will discuss the organization of AsthmaNet and the scientific context in which the network was developed and began its work, report the results of an internal priority-setting exercise designed to guide the network’s scientific strategy, and highlight the portfolio of clinical trials, proof-of-concept studies, and mechanistic studies planned for the 7-year period of the network to update the global asthma community regarding the progress and processes of the network. [Copyright &y& Elsevier]

Background: Improvement in lung function after macrolide antibiotic therapy has been attributed to reduction in bronchial infection by specific bacteria. However, the airway might be populated by a more diverse microbiota, and clinical features of asthma might be associated with characteristics of the airway microbiota present. Objective: We sought to determine whether relationships exist between the composition of the airway bacterial microbiota and clinical features of asthma using culture-independent tools capable of detecting the presence and relative abundance of most known bacteria. Methods: In this pilot study bronchial epithelial brushings were collected from 65 adults with suboptimally controlled asthma participating in a multicenter study of the effects of clarithromycin on asthma control and 10 healthy control subjects. A combination of high-density 16S ribosomal RNA microarray and parallel clone library-sequencing analysis was used to profile the microbiota and examine relationships with clinical measurements. Results: Compared with control subjects, 16S ribosomal RNA amplicon concentrations (a proxy for bacterial burden) and bacterial diversity were significantly higher among asthmatic patients. In multivariate analyses airway microbiota composition and diversity were significantly correlated with bronchial hyperresponsiveness. Specifically, the relative abundance of particular phylotypes, including members of the Comamonadaceae, Sphingomonadaceae, Oxalobacteraceae, and other bacterial families were highly correlated with the degree of bronchial hyperresponsiveness. Conclusion: The composition of bronchial airway microbiota is associated with the degree of bronchial hyperresponsiveness among patients with suboptimally controlled asthma. These findings support the need for further functional studies to examine the potential contribution of members of the airway microbiota in asthma pathogenesis. [ABSTRACT FROM AUTHOR]

The article presents a letter to the editor in response to the article "Management of Chronic Obstructive Pulmonary Disease," by E. R. Sutherland and R. M. Cherniack from the June 24, 2004 issue.

The article studies the reduction in progression of airflow limitation in patients with chronic obtrusive pulmonary disease (COPD) after inhalation of corticosteroids. This disease is basically found in smokers in whom normal age related decline in lung function is accelerated. Unlike asthma, the airflow obstruction and airway inflammation of COPD respond poorly to corticosteroids. COPD is now the fourth most common cause of death and only oxygen is helpful in its cure. Smoking prevention and cessation sessions can be helpful for prevention.

Lung function in a healthy individual varies in a circadian rhythm, with peak lung function occurring near 4:00 PM (1600 hours) and minimal lung function occurring near 4:00 AM (0400 hours). An episode of nocturnal asthma is characterized by an exaggeration in this normal variation in lung function from daytime to nighttime, with diurnal changes in pulmonary function generally of > 15%. The occurrence of nocturnal asthma is associated with increased morbidity and inadequate asthma control, and has an important negative impact on quality of life (QOL). Newer data have shed light on physiologic and immunologic mechanisms that underlie the nocturnal development of airway obstruction. It remains controversial whether nocturnal asthma is a distinct entity or is a manifestation of more severe asthma. The current data do not resolve these two alternatives, as well-controlled studies have reached opposite conclusions. However, the clinical associations of gastroesophageal reflux disease and obesity appear to be strong. The treatment of asthma with effective controller agents can reduce nighttime symptoms, improve psychometric outcomes, and improve QOL. [ABSTRACT FROM AUTHOR]

Discusses the importance of alterations in hypothalamic-pituitary-adrenal axis function in the pathogenesis of nocturnal asthma. Increase in adrenocorticotropic hormone (ACTH) and cortisol levels during sleep; Adrenal response to ACTH; Airway inflammation.

Examines the role of interleukin-4 (IL), IL-13 and dexamethasone (DX) in enhancing the proliferation of distal lung fibroblasts. Incubation of freshly trypsinized cells with IL-4, IL-13 and DX; Thymidine incorporation; Production of procollagen I.

A response by E. M. Sutherland and his colleagues to a letter to the editor about their article "EEG, memory and confusion in dominant, non-dominant and bi-temporal ECT" in the September 1969 issue is presented.

Background: Family factors may alter the risk of developing posttraumatic stress disorder (PTSD) or depression in young people after a traumatic event, but it is not clear which modifiable family variables can be addressed in psychological therapies. This study examined the relationships between family factors (Expressed Emotion [EE] and family accommodation) and psychopathology (posttraumatic stress symptoms; PTSS) in young people following a single incident trauma. Potential mediators of these relationships were also investigated.Method: Sixty-six parent-child dyads (aged 8-17 years) were assessed within one month of attending an Emergency Department. Self-reported PTSS and perceived EE were assessed in young people. Parents' own PTSS, mood symptoms, EE, and accommodating behaviours were also assessed.Results: Cross-sectional analyses revealed that young person-perceived EE, parent-reported emotional over involvement (EOI) and accommodation behaviours significantly predicted higher PTSS in young people. The stress experienced as a consequence of EE mediated the relationship between young person-perceived EOI and PTSS in young people. Parental PTSS and anxiety were positively correlated with EOI and accommodation. Parental PTSS was not significantly associated with symptoms in young people.Conclusions: The results support the hypothesis that EE and accommodation are positively associated with PTSS in young people in the month following a potentially traumatic event. Understanding the child in the context of their family environment and relationships offers an important framework for making sense of and facilitating adaptive adjustment following a traumatic event. [ABSTRACT FROM AUTHOR]

Background: Dupilumab, a fully human anti-interleukin-4 receptor α monoclonal antibody, inhibits interleukin-4 and interleukin-13 signalling, key drivers of type-2-mediated inflammation. Adults with uncontrolled persistent asthma who are receiving medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist require additional treatment options as add-on therapy. We aimed to assess the efficacy and safety of dupilumab as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist, irrespective of baseline eosinophil count.Methods: We did this randomised, double-blind, placebo-controlled, parallel-group, pivotal phase 2b clinical trial at 174 study sites across 16 countries or regions. Adults (aged ≥18 years) with an asthma diagnosis for 12 months or more based on the Global Initiative for Asthma 2009 Guidelines receiving treatment with medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist were eligible for participation. Patients were randomly assigned (1:1:1:1:1) to receive subcutaneous dupilumab 200 mg or 300 mg every 2 weeks or every 4 weeks, or placebo, over a 24-week period. The primary endpoint was change from baseline at week 12 in forced expiratory volume in 1 s (FEV1 in L) in patients with baseline blood eosinophil counts of at least 300 eosinophils per μL assessed in the intention-to-treat population. Safety outcomes were assessed in all patients that received at least one dose or part of a dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT01854047, and with the EU Clinical Trials Register, EudraCT number 2013-000856-16.Findings: 769 patients (158 in the placebo group and 611 in the dupilumab groups) received at least one dose of study drug. In the subgroup with at least 300 eosinophils per μL, the greatest increases (200 mg every 2 weeks, p=0·0008; 300 mg every 2 weeks, p=0·0063) in FEV1 compared with placebo were observed at week 12 with doses every 2 weeks in the 300 mg group (mean change 0·39 L [SE 0·05]; mean difference 0·21 [95% CI 0·06-0·36; p=0·0063]) and in the 200 mg group (mean change 0·43 L [SE 0·05]; mean difference 0·26 [0·11-0·40; p=0·0008]) compared with placebo (0·18 L [SE 0·05]). Similar significant increases were observed in the overall population and in the fewer than 300 eosinophils per μL subgroup (overall population: 200 mg every 2 weeks, p<0·0001; 300 mg every 2 weeks, p<0·0001; <300 eosinophils per μL: 200 mg every 2 weeks, p=0·0034; 300 mg every 2 weeks, p=0·0086), and were maintained to week 24. Likewise, dupilumab every 2 weeks produced the greatest reductions in annualised rates of exacerbation in the overall population (70-70·5%), the subgroup with at least 300 eosinophils per μL (71·2-80·7%), and the subgroup with fewer than 300 eosinophils per μL (59·9-67·6%). The most common adverse events with dupilumab compared with placebo were upper respiratory tract infections (33-41% vs 35%) and injection-site reactions (13-26% vs 13%).Interpretation: Dupilumab increased lung function and reduced severe exacerbations in patients with uncontrolled persistent asthma irrespective of baseline eosinophil count and had a favourable safety profile, and hence in addition to inhaled corticosteroids plus long-acting β2-agonist therapy could improve the lives of patients with uncontrolled persistent asthma compared with standard therapy alone.Funding: Sanofi-Genzyme and Regeneron Pharmaceuticals. [ABSTRACT FROM AUTHOR]

Importance: Dupilumab has demonstrated efficacy in patients with asthma and atopic dermatitis, which are both type 2 helper T-cell-mediated diseases.Objective: To assess inhibition of interleukins 4 and 13 with dupilumab in patients with chronic sinusitis and nasal polyposis.Design, Setting, and Participants: A randomized, double-blind, placebo-controlled parallel-group study conducted at 13 sites in the United States and Europe between August 2013 and August 2014 in 60 adults with chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids with 16 weeks of follow-up.Interventions: Subcutaneous dupilumab (a 600 mg loading dose followed by 300 mg weekly; n = 30) or placebo (n = 30) plus mometasone furoate nasal spray for 16 weeks.Main Outcomes and Measures: Change in endoscopic nasal polyp score (range, 0-8; higher scores indicate worse status) at 16 weeks (primary end point). Secondary end points included Lund-Mackay computed tomography (CT) score (range, 0-24; higher scores indicate worse status), 22-item SinoNasal Outcome Test score (range, 0-110; higher scores indicating worse quality of life; minimal clinically important difference ≥8.90), sense of smell assessed using the University of Pennsylvania Smell Identification Test (UPSIT) score (range, 0-40; higher scores indicate better status), symptoms, and safety.Results: Among the 60 patients who were randomized (mean [SD] age, 48.4 years [9.4 years]; 34 men [56.7%]; 35 with comorbid asthma), 51 completed the study. The least squares (LS) mean change in nasal polyp score was -0.3 (95% CI, -1.0 to 0.4) with placebo and -1.9 (95% CI, -2.5 to -1.2) with dupilumab (LS mean difference, -1.6 [95% CI, -2.4 to -0.7]; P < .001). The LS mean difference between the 2 groups for the Lund-Mackay CT total score was -8.8 (95% CI, -11.1 to -6.6; P < .001). Significant improvements with dupilumab were also observed for the 22-item SinoNasal Outcome Test (LS mean difference between groups, -18.1 [95% CI, -25.6 to -10.6]; P < .001) and sense of smell assessed by UPSIT (LS mean difference, 14.8 [95% CI, 10.9 to 18.7]; P < .001). The most common adverse events were nasopharyngitis (33% in the placebo group vs 47% in the dupilumab group), injection site reactions (7% vs 40%, respectively), and headache (17% vs 20%).Conclusions and Relevance: Among adults with symptomatic chronic sinusitis and nasal polyposis refractory to intranasal corticosteroids, the addition of subcutaneous dupilumab to mometasone furoate nasal spray compared with mometasone alone reduced endoscopic nasal polyp burden after 16 weeks. Further studies are needed to assess longer treatment duration, larger samples, and direct comparison with other medications.Trial Registration: clinicaltrials.gov Identifier: NCT01920893. [ABSTRACT FROM AUTHOR]

Background: Data from early-stage studies suggested that interleukin (IL)-4 and IL-13 are requisite drivers of atopic dermatitis, evidenced by marked improvement after treatment with dupilumab, a fully-human monoclonal antibody that blocks both pathways. We aimed to assess the efficacy and safety of several dose regimens of dupilumab in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical treatments.Methods: In this randomised, placebo-controlled, double-blind study, we enrolled patients aged 18 years or older who had an Eczema Area and Severity Index (EASI) score of 12 or higher at screening (≥16 at baseline) and inadequate response to topical treatments from 91 study centres, including hospitals, clinics, and academic institutions, in Canada, Czech Republic, Germany, Hungary, Japan, Poland, and the USA. Patients were randomly assigned (1:1:1:1:1:1), stratified by severity (moderate or severe, as assessed by Investigator's Global Assessment) and region (Japan vs rest of world) to receive subcutaneous dupilumab: 300 mg once a week, 300 mg every 2 weeks, 200 mg every 2 weeks, 300 mg every 4 weeks, 100 mg every 4 weeks, or placebo once a week for 16 weeks. We used a central randomisation scheme, provided by an interactive voice response system. Drug kits were coded, providing masking to treatment assignment, and allocation was concealed. Patients on treatment every 2 weeks and every 4 weeks received volume-matched placebo every week when dupilumab was not given to ensure double blinding. The primary outcome was efficacy of dupilumab dose regimens based on EASI score least-squares mean percentage change (SE) from baseline to week 16. Analyses included all randomly assigned patients who received one or more doses of study drug. This trial is registered with ClinicalTrials.gov, number NCT01859988.Findings: Between May 15, 2013, and Jan 27, 2014, 452 patients were assessed for eligibility, and 380 patients were randomly assigned. 379 patients received one or more doses of study drug (300 mg once a week [n=63], 300 mg every 2 weeks [n=64], 200 mg every 2 weeks [n=61], 300 mg every 4 weeks [n=65], 100 mg every 4 weeks [n=65]; placebo [n=61]). EASI score improvements favoured all dupilumab regimens versus placebo (p<0·0001): 300 mg once a week (-74% [SE 5·16]), 300 mg every 2 weeks (-68% [5·12]), 200 mg every 2 weeks (-65% [5·19]), 300 mg every 4 weeks (-64% [4·94]), 100 mg every 4 weeks (-45% [4·99]); placebo (-18% [5·20]). 258 (81%) of 318 patients given dupilumab and 49 (80%) of 61 patients given placebo reported treatment-emergent adverse events; nasopharyngitis was the most frequent (28% and 26%, respectively).Interpretation: Dupilumab improved clinical responses in adults with moderate-to-severe atopic dermatitis in a dose-dependent manner, without significant safety concerns. Our findings show that IL-4 and IL-13 are key drivers of atopic dermatitis.Funding: Sanofi and Regeneron Pharmaceuticals. INSET: Panel: Research in context.. [ABSTRACT FROM AUTHOR]

The prostaglandin D 2 (PGD 2 ) receptor, CRTH2, plays a role in allergic airway inflammation. The efficacy of BI 671800, a CRTH2 antagonist, was assessed in 2 separate trials in patients with asthma, in either the absence or the presence of inhaled corticosteroid (ICS) therapy. In this study, BI 671800 (50, 200 or 400 mg) and fluticasone propionate (220 μg) all given twice daily (bid) were compared with bid placebo in symptomatic controller-naïve adults with asthma (Trial 1), and BI 671800 400 mg bid compared with montelukast 10 mg once daily (qd), and matching placebo bid, in patients with asthma receiving inhaled fluticasone (88 μg bid) (Trial 2). The primary endpoint in both trials was change from baseline in trough forced expiratory volume in 1 s (FEV 1 ) percent predicted. After 6 weeks' treatment, adjusted mean treatment differences (SE) for the primary endpoint compared with placebo in Trial 1 were 3.08% (1.65%), 3.59% (1.60%) and 3.98% (1.64%) for BI 671800 50, 200 and 400 mg bid, respectively, and 8.62% (1.68%) for fluticasone 220 μg bid ( p = 0.0311, p = 0.0126, p = 0.0078 and p < 0.0001, respectively). In Trial 2, adjusted mean FEV 1 (SE) treatment differences compared with placebo were 3.87% (1.49%) for BI 671800 400 mg bid and 2.37% (1.57%) for montelukast ( p = 0.0050 and p = 0.0657, respectively). These findings suggest that BI 671800 is associated with a small improvement in FEV 1 in symptomatic controller-naïve asthma patients, and in patients on ICS. [ABSTRACT FROM AUTHOR]

Background The role of CD8 T lymphocytes in the pathogenesis of asthma is not well understood. We investigated whether a subset of IL-13-producing BLT1-positive CD8 T lymphocytes are present in asthmatic airways and are associated with impaired lung function. Methods Bronchoalveolar lavage ( BAL) cells were obtained from asthmatic ( n = 39) and healthy control ( n = 28) subjects. Cells were stimulated with phorbol ester and ionomycin in the presence of brefeldin A and stained for CD8, BLT1, and intracellular IL-13. The frequency of IL-13-producing BLT1-positive CD8 T lymphocytes was compared between the two groups and related to lung function, serum Ig E levels, and reticular basement membrane ( RBM) thickness. Results A subset of CD8 T lymphocytes expressing BLT1 and producing IL-13 were detected in the airways of all asthmatic subjects. The frequency of this subset among recovered lymphocytes was significantly higher in the airways of asthmatic subjects compared with controls (mean ± SEM: 16.2 ± 1.4 vs 5.3 ± 0.5, respectively, P < 0.001) and correlated positively with serum IgE levels and RBM thickness. More importantly, the frequency of CD8 T lymphocytes co-expressing BLT1 and IL-13 was inversely related to FEV1 and FEF[25-75] percent predicted values ( P < 0.001). Conclusions A subset of CD8 T lymphocytes expressing BLT1 and producing IL-13 is present in the airways of asthmatics. The accumulation of these cells is associated with airway obstruction, suggesting that they may play a significant pathogenic role in bronchial asthma. [ABSTRACT FROM AUTHOR]

The literature is divided into two sections, one on assessment and one on observation, with only one study that tries to make any connection between them. This study, conducted in both acute and forensic areas, attempts to show that there are some direct relationships between assessment criteria and observation levels in both these areas. An instrument was designed and implemented prospectively to collect data about both assessment criteria and the resulting decisions about observation level. Logistic Regression Analysis, descriptive, and inferential statistics, such as Chi-square and cross-tabulations, were used to analyse the data. The results showed that there is a relationship between the risk assessment and the enhanced observation level that patients are placed on at the time of admission. The nature of the relationship was limited to seven variables from the 12 in the risk assessment used. This implies that the variables may be different in risk assessment content and extent in each clinical area and we can speculate that there may be individual profiles of the assessment-observation level relationship in each clinical area. [ABSTRACT FROM AUTHOR]

Tandem mass spectrometry (MS/MS) is the gold standard for intact glycopeptide identification, enabling peptide sequence elucidation and site-specific localization of glycan compositions. Beam-type collisional activation is generally sufficient for N- glycopeptides, while electron-driven dissociation is crucial for site localization in O- glycopeptides. Modern glycoproteomic methods often employ multiple dissociation techniques within a single LC-MS/MS analysis, but this approach frequently sacrifices sensitivity when analyzing multiple glycopeptide classes simultaneously. Here we explore the utility of intelligent data acquisition for glycoproteomics through real-time library searching (RTLS) to match oxonium ion patterns for on-the-fly selection of the appropriate dissociation method. By matching dissociation method with glycopeptide class, this autonomous dissociation-type selection (ADS) generates equivalent numbers of N- glycopeptide identifications relative to traditional beam-type collisional activation methods while also yielding comparable numbers of site-localized O- glycopeptide identifications relative to conventional electron transfer dissociation-based methods. The ADS approach represents a step forward in glycoproteomics throughput by enabling site-specific characterization of both N- and O- glycopeptides within the same LC-MS/MS acquisition.