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1.  Differentiation of escherichia coli serotypes using dc gradient insulator dielectrophoresis 
Bacteria play a significant role in both human health and disease. An estimated 9.4 million cases of foodborne illness occur in the United States each year. As a result, rapid identification and characterization of microorganisms remains an important research objective. Despite limitations, selective culturing retains a central role amongst a cadre of identification strategies. For the past decade, separations-based approaches to rapid bacterial identification have been under investigation. Gradient insulator dielectrophoresis (g-iDEP) promises benefits in the form of rapid and specific separation of very similar bacteria, including serotypes of a single species. Furthermore, this approach allows simultaneous concentration of analyte, facilitating detection and downstream analysis. Differentiation of three serotypes or strains of Escherichia coli bacteria is demonstrated within a single g-iDEP microchannel, based on their characteristic electrokinetic properties. Whole cells were captured and concentrated using a range of applied potentials, which generated average electric fields between 160 and 470 V/cm. Bacteria remained viable after exposure to these fields, as determined by cellular motility. These results indicate the potential g-iDEP holds in terms of both separatory power and the possibility for diagnostic applications.
PMCID: PMC3935418  PMID: 24202194
dielectrophoresis; Escherichia coli; bioanalytical methods; electrokinetic separations; microfluidics
2.  Short-Term Variability and Predictors of Urinary Pentachlorophenol Levels in Ohio Preschool Children 
Pentachlorophenol (PCP) is a persistent and ubiquitous environmental contaminant. No published data exist on the temporal variability or important predictors of urinary PCP concentrations in young children. In this further analysis of study data, we have examined the associations between selected sociodemographic or lifestyle factors and urinary PCP concentrations in 115 preschool children over a 48-h period and assessed the 48-hour variability of urinary PCP levels in a subset of 15 children. Monitoring was performed at 115 homes and 16 daycares in Ohio (USA) in 2001. Questionnaires/diaries and spot urine samples were collected from each child. The median urinary PCP level was 0.8 ng/mL (range < 0.2–23.8 ng/mL). The intraclass correlation coefficient for urinary PCP was 0.42, which indicates fairly low reliability for a single sample over a 48-h period. In a multiple regression model, age of home and ln(creatinine levels) were significant predictors and sampling season, time spent outside, and pet ownership were marginally significant predictors of ln(urinary PCP levels), collectively explaining 29% of the variability of PCP in urine. To adequately assess short-term exposures of children to PCP, several spot urine measurements are likely needed as well as information regarding residence age, seasonality, time spent outdoors, and pet ownership.
PMCID: PMC4306893  PMID: 25594782
biomarkers; urine; children; determinants; phenol; home; daycare center
3.  The relationship between the COPD Assessment Test score and airflow limitation in Japan in patients aged over 40 years with a smoking history 
A large number of chronic obstructive pulmonary disease (COPD) patients in Japan remain undiagnosed, primarily due to the underuse of spirometry. Two studies were conducted to see whether the COPD Assessment Test (CAT) in primary care has the potential to identify those patients who need spirometry for a diagnosis of COPD and to determine whether patients with cardiovascular disease had airflow limitation, which could be detected by CAT.
Materials and methods
Two multicenter, noninterventional, prospective studies (studies 1 and 2) were conducted across Japan. Patients in both studies were ≥40 years old with a smoking history. Those in study 1 were seen in primary care and had experienced repeated respiratory tract infections, but had no diagnosis of COPD. Patients in study 2 were identified in cardiovascular disease clinics when routinely visiting for their cardiovascular disease. All patients completed the CAT prior to lung-function testing by hand-held spirometry. The presence of airflow limitation was defined as a forced expiratory volume in 1 second (FEV1)/FEV6 ratio <0.73.
A total of 3,062 subjects completed the CAT (2,067 in study 1, 995 in study 2); 88.8% were male, and the mean age (± standard deviation) was 61.5±11.6 years. Airflow limitation was found in 400 (19.4%) patients in study 1, and 269 (27.0%) in study 2. The CAT score in patients with airflow limitation was significantly higher than in patients without airflow limitation in both studies: 8.6 (95% confidence interval [CI] 7.9–9.2) versus 7.4 (95% CI 7.1–7.6) in study 1, and 8.3 (95% CI 7.5–9.2) versus 6.4 (95% CI 6.0–6.8) in study 2 (both P<0.001).
These findings suggest that the CAT has the potential to identify patients with cardiovascular disease or a history of frequent chest infections who need spirometry to diagnose COPD.
PMCID: PMC4266247  PMID: 25525353
COPD; CAT; spirometry; airflow limitation
4.  Efficacy and safety of aclidinium bromide/formoterol fumarate fixed-dose combinations compared with individual components and placebo in patients with COPD (ACLIFORM-COPD): a multicentre, randomised study 
BMC Pulmonary Medicine  2014;14(1):178.
Aclidinium/formoterol is a twice-daily (BID) fixed-dose combination (FDC) in development for chronic obstructive pulmonary disease (COPD). The efficacy and safety of aclidinium/formoterol versus monotherapy and placebo in patients with COPD was assessed.
In this 24-week double-blind, parallel-group, active- and placebo-controlled, multicentre Phase III study, patients (≥40 years, post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity <70% and FEV1 ≥30% but <80% predicted normal) were randomised 2:2:2:2:1 to aclidinium/formoterol 400/12 μg (n = 385) or 400/6 μg (n = 381), aclidinium 400 μg (n = 385), formoterol 12 μg (n = 384) or placebo (n = 194) BID via Genuair®/Pressair®a.
At Week 24, aclidinium/formoterol 400/12 μg and 400/6 μg lead to significant improvements from baseline in 1-hour post-dose FEV1 versus aclidinium (125 mL [95% CI: 90, 160; p < 0 · 001] and 69 mL [95% CI: 34, 105; p < 0.001], respectively) and trough FEV1 versus formoterol (85 mL [95% CI: 51, 119; p < 0.001] and 53 mL [95% CI: 19, 87; p < 0.01], respectively; co-primary endpoints). Additionally, aclidinium/formoterol 400/12 μg and 400/6 μg provided significant improvements in Transition Dyspnoea Index (TDI) focal score versus placebo (1.29 units [95% CI: 0.73, 1.86; p < 0.001] and 1.16 units [95% CI: 0.59, 1.73; p < 0.001], respectively; secondary endpoint). All treatments were well tolerated, with safety profiles of the FDCs similar to those of placebo and monotherapy.
Both aclidinium/formoterol BID doses significantly improved bronchodilation versus monotherapy, and dyspnoea versus placebo, with no increase in safety risk. Aclidinium/formoterol may be an effective treatment for patients with COPD.
Trial registration NCT01462942.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2466-14-178) contains supplementary material, which is available to authorized users.
PMCID: PMC4273456  PMID: 25404569
Aclidinium bromide/formoterol fumarate; Chronic obstructive pulmonary disease; Fixed-dose combination
5.  Measuring respiratory symptoms of COPD: performance of the EXACT- Respiratory Symptoms Tool (E-RS) in three clinical trials 
Respiratory Research  2014;15(1):124.
Symptomatic relief is an important treatment goal for patients with COPD. To date, no diary for evaluating respiratory symptoms in clinical trials has been developed and scientifically-validated according to FDA and EMA guidelines. The EXACT – Respiratory Symptoms (E-RS) scale is a patient-reported outcome (PRO) measure designed to address this need. The E-RS utilizes 11 respiratory symptom items from the existing and validated 14-item EXACT, which measures symptoms of exacerbation. The E-RS total score quantifies respiratory symptom severity, and 3 domains assess breathlessness, cough and sputum, and chest symptoms.
This study examined the performance of the E-RS in each of 3 controlled trials with common and unique validation variables: one 6-month (N = 235, US) and two 3-month (N = 749; N = 597; international). Subjects completed the E-RS as part of a daily eDiary. Tests of reliability, validity, and responsiveness were conducted in each dataset.
In each study, RS-Total score was internally consistent (Cronbach α) (0.88, 0.92, 0.92) and reproducible (intra-class correlation) in stable patients (2 days apart: 0.91; 7 days apart: 0.71, 0.74). RS-Total scores correlated significantly with the following criterion variables (Spearman’s rho; p < 0.01, all comparisons listed here): FEV1% predicted (−0.19, −0.14, −0.15); St. George’s Respiratory Questionnaire (SGRQ) (0.65, 0.52, 0.51); Breathlessness, Cough, and Sputum Scale (BCSS) (0.89, 0.89); modified Medical Research Council dyspnoea scale (mMRC) (0.40); rescue medication use (0.43, 0.42); Functional Performance Inventory Short-Form (FPI-SF) (0.43); 6-minute walk distance (6-MWT) (−0.30, −0.14) and incremental shuttle walk (ISWT) (−0.18) tests. Correlations between these variables and RS-Breathlessness, RS-Cough and Sputum, RS-Chest Symptoms scores supported subscale validity. RS-Total, RS-Breathlessness, and RS-Chest Symptoms differentiated mMRC levels of breathlessness severity (p < 0.0001). RS-Total and domain scores differentiated subjects with no rescue medication use and 3 or more puffs (p < 0.0001). Sensitivity to changes in health status (SGRQ), symptoms (BCSS), and exercise capacity (6MWT, ISWT) were also shown and responder definitions using criterion- and distribution-based methods are proposed.
Results suggest the E-RS is a reliable, valid, and responsive measure of respiratory symptoms of COPD suitable for use in natural history studies and clinical trials.
Trial registration
MPEX: NCT00739648; AZ1: NCT00949975; AZ 2: NCT01023516
Electronic supplementary material
The online version of this article (doi:10.1186/s12931-014-0124-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4203869  PMID: 25287629
COPD; Respiratory symptoms; Clinical trials; Dyspnoea; Cough; Sputum; Chest symptoms
6.  Implications of the GOLD 2011 Disease Severity Classification in the COPDGene Cohort 
The 2011 Global Strategy for the Diagnosis, Management, and Prevention of COPD (GOLD) consensus report uses symptoms, exacerbation history and FEV1% to define four categories: A, low symptoms/low risk; B, high symptoms/low risk; C, low symptoms/high risk; and D, high symptoms/high risk where risk refers to exacerbations, hospitalization and death. Our objective was to determine (1) the influence of symptom instrument on category membership and (2) prospective exacerbation risk by category.
4,484 COPD subjects from COPDGene were analyzed. All subjects had smoking history ≥ 10 pack-years and FEV1/FVC<0·7. Categories were defined using the modified Medical Research Council Dyspnea [mMRC] (0–1 versus ≥ 2) and the Saint George’s Respiratory Questionnaire [SGRQ] (≥25 versus <25 as a surrogate for the COPD Assessment Test ≥ 10 versus <10) in addition to COPD exacerbations in the prior year (<2 versus ≥ 2), and FEV1% predicted (≥50 versus <50).
Category assignment using mMRC versus SGRQ were similar but not identical. Using the mMRC, category assignments were 34% A, 21% B, 8% C and 38% D and for SGRQ were 29% A, 25% B, 5% C and 41% D (kappa=0·77). Significant heterogeneity in exacerbation rates (exacerbations/person-year) were seen particularly within the D group, depending on the risk factor that determined category assignment (lung function (0·89), prior exacerbation history (1·34) or both (1·86), p<0·001.
The GOLD classification emphasizes the importance of symptoms and exacerbation risk in assessing COPD severity. The choice of symptom measure influences category assignment. The relative number of subjects with low symptoms and high risk for exacerbations (category C) is low. Differences in exacerbation rates for subjects in the highest risk category D were seen depending on whether risk was based on lung function, exacerbation history or both.
PMCID: PMC4105297  PMID: 24321803
7.  Deep Illumina-Based Shotgun Sequencing Reveals Dietary Effects on the Structure and Function of the Fecal Microbiome of Growing Kittens 
PLoS ONE  2014;9(7):e101021.
Previously, we demonstrated that dietary protein:carbohydrate ratio dramatically affects the fecal microbial taxonomic structure of kittens using targeted 16S gene sequencing. The present study, using the same fecal samples, applied deep Illumina shotgun sequencing to identify the diet-associated functional potential and analyze taxonomic changes of the feline fecal microbiome.
Methodology & Principal Findings
Fecal samples from kittens fed one of two diets differing in protein and carbohydrate content (high–protein, low–carbohydrate, HPLC; and moderate-protein, moderate-carbohydrate, MPMC) were collected at 8, 12 and 16 weeks of age (n = 6 per group). A total of 345.3 gigabases of sequence were generated from 36 samples, with 99.75% of annotated sequences identified as bacterial. At the genus level, 26% and 39% of reads were annotated for HPLC- and MPMC-fed kittens, with HPLC-fed cats showing greater species richness and microbial diversity. Two phyla, ten families and fifteen genera were responsible for more than 80% of the sequences at each taxonomic level for both diet groups, consistent with the previous taxonomic study. Significantly different abundances between diet groups were observed for 324 genera (56% of all genera identified) demonstrating widespread diet-induced changes in microbial taxonomic structure. Diversity was not affected over time. Functional analysis identified 2,013 putative enzyme function groups were different (p<0.000007) between the two dietary groups and were associated to 194 pathways, which formed five discrete clusters based on average relative abundance. Of those, ten contained more (p<0.022) enzyme functions with significant diet effects than expected by chance. Six pathways were related to amino acid biosynthesis and metabolism linking changes in dietary protein with functional differences of the gut microbiome.
These data indicate that feline feces-derived microbiomes have large structural and functional differences relating to the dietary protein:carbohydrate ratio and highlight the impact of diet early in life.
PMCID: PMC4091873  PMID: 25010839
8.  Derivation of normative data for the COPD assessment test (CAT) 
Respiratory Research  2014;15(1):68.
The tradition classification of the severity of COPD, based on spirometry, fails to encompass the heterogeneity of the disease. The COPD assessment test (CAT), a multi-dimensional, patient-filled questionnaire, assesses the overall health status of patients, and is recommended as part of the assessment of individuals with COPD. However, information regarding the range of values for the test in a non-COPD population (normative values) is limited, and consequently, knowledge regarding the optimal cut-off, and the minimum clinically important difference (MCID) for the test remain largely empirical.
CanCOLD is a population-based multi-center cohort study conducted across Canada, the methodology of which is based on the international BOLD initiative. The study includes subjects with COPD, at-risk individuals who smoke, and healthy control subjects. CAT questionnaires were administered at baseline to all subjects. Among non-COPD subjects, normative values for the CAT questionnaire, and psychometric properties of the test were characterized. Predictors of high CAT scores were identified using multivariable logistic regression.
Of the 525 non-COPD subjects enrolled, 500 were included in the analysis. Mean FEV1/FVC ratio among the 500 included subjects was 0.77 (SD 0.49); the mean predicted FEV1 was 99.38% (SD 16.88%). The overall mean CAT score was 6 (SD 5.09); scores were higher among females (6.43, SD 5.59), and subjects over 80 years of age (mean 7.58, SD 6.82). Cronbach alpha for the CAT was 0.79, suggesting a high internal consistency for the test. A score of 16 was the 95th percentile for the population, and 27 subjects (5.4%) were found to have a CAT score > =16. Current smoking (aOR 3.41, 95% CI 1.05, 11.02), subject-reported physician-diagnosed asthma (aOR 7.59, 95% CI 2.71, 21.25) and musculoskeletal disease (aOR 4.09, 95% CI 1.72, 9.71) were found to be significantly associated with a score ≥16.
The characterization of CAT scores in the general population will be useful for norm-based comparisons. Longitudinal follow-up of these subjects will help in the optimization of cut-offs for the test.
PMCID: PMC4100027  PMID: 24957783
COPD assessment test; Health-related quality of life; Normative data; Questionnaire
9.  Health-Related Stereotype Threat Predicts Health Services Delays Among Blacks 
Race and social problems  2013;5(2):121-136.
To our knowledge, no published research has developed an individual difference measure of health-related stereotype threat (HRST). We adapted existing measures of academic stereotype threat to the health domain on a sample of black college students (N = 280). The resulting health-related stereotype threat scale-24 (HRST-24) was assessed for internal consistency, construct and incremental validity, and whether it explains variance in self-reported delays among four preventive health behaviors—blood pressure and cholesterol assays, physical exams, and routine checkups. After adjusting for several control variables, the HRST-24’s (full scale α = 0.96) perceived black health inferiority (18 items; α = 0.96) and perceived physician racial bias (6 items; α = 0.85) sub-scales explained unique variance in delays among two of the four behaviors including a blood cholesterol check (p < .01) and routine checkup—albeit at marginal levels (p = .063) in the case of the latter. Overall, these data provide preliminary evidence of construct and incremental validity for the HRST-24 among blacks. Recommendations for administering the scale are provided and future directions for HRST research are discussed.
PMCID: PMC3806300  PMID: 24163710
Stereotype threat; Health services; African-Americans; Blacks; Health-related stereotype threat scale; Health disparities
10.  Prevalence of airflow limitation in outpatients with cardiovascular diseases in Japan 
Background and objectives
Cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD) commonly coexist and share common risk factors. The prevalence of COPD in outpatients with a smoking history and CVD in Japan is unknown. The aim of this study was to determine the proportion of Japanese patients with a smoking history being treated for CVD who have concurrent airflow limitation compatible with COPD. A secondary objective was to test whether the usage of lung function tests performed in the clinic influenced the diagnosis rate of COPD in the patients identified with airflow limitation.
In a multicenter observational prospective study conducted at 17 centers across Japan, the prevalence of airflow limitation compatible with COPD (defined as forced expiratory volume (FEV)1/FEV6 <0.73, by handheld spirometry) was investigated in cardiac outpatients ≥40 years old with a smoking history who routinely visited the clinic for their CVD. Each patient completed the COPD Assessment Test prior to spirometry testing.
Data were available for 995 patients with a mean age of 66.6±10.0 years, of whom 95.5% were male. The prevalence of airflow limitation compatible with COPD was 27.0% (n=269), and 87.7% of those patients (n=236) did not have a prior diagnosis of COPD. The prevalence of previously diagnosed airflow limitation was higher in sites with higher usage of lung function testing (14.0%, 15.2% respectively) compared against sites where it is performed seldom (11.1%), but was still low.
The prevalence of airflow limitation in this study indicates that a quarter of outpatients with CVD have COPD, almost all of whom are undiagnosed. This suggests that it is important to look routinely for COPD in CVD outpatients.
PMCID: PMC4044996  PMID: 24920894
COPD; CVD; handheld spirometer; lung function; diagnosis
12.  Analysis of comorbid factors that increase the COPD assessment test scores 
Respiratory Research  2014;15(1):13.
The chronic obstructive pulmonary disease (COPD) Assessment Test (CAT) is a concise health status measure for COPD. COPD patients have a variety of comorbidities, but little is known about their impact on quality of life. This study was designed to investigate comorbid factors that may contribute to high CAT scores.
An observational study at Keio University and affiliated hospitals enrolled 336 COPD patients and 67 non-COPD subjects. Health status was assessed by the CAT, the St. Georges Respiratory Questionnaire (SGRQ), and all components of the Medical Outcomes Study Short-Form 36-Item (SF-36) version 2, which is a generic measure of health. Comorbidities were identified based on patients’ reports, physicians’ records, and questionnaires, including the Frequency Scale for the Symptoms of Gastro-esophageal reflux disease (GERD) and the Hospital Anxiety and Depression Scale. Dual X-ray absorptiometry measurements of bone mineral density were performed.
The CAT showed moderate-good correlations with the SGRQ and all components of the SF-36. The presence of GERD, depression, arrhythmia, and anxiety was significantly associated with a high CAT score in the COPD patients.
Symptomatic COPD patients have a high prevalence of comorbidities. A high CAT score should alert the clinician to a higher likelihood of certain comorbidities such as GERD and depression, because these diseases may co-exist unrecognized.
Trial registration
Clinical trial registered with UMIN (UMIN000003470).
PMCID: PMC3922022  PMID: 24502760
Chronic obstructive pulmonary disease; Health status; Depression; Gastro-esophageal reflux; Comorbidity; Osteoporosis
13.  Changes in plasma levels of B-type natriuretic peptide with acute exacerbations of chronic obstructive pulmonary disease 
Elevated plasma B-type natriuretic peptide (BNP) levels and their association with heart failure have been reported in subjects with acute exacerbations of chronic obstructive pulmonary disease (AECOPD).
To examine and compare plasma BNP levels and diastolic and systolic dysfunction in subjects with AECOPD and stable chronic obstructive pulmonary disease (COPD).
In all, 87 unselected consecutive hospitalizations due to AECOPD in 61 subjects and a total of 190 consecutive subjects with stable COPD were recruited. Plasma BNP levels were compared cross-sectionally and longitudinally. Transthoracic echocardiographic examinations were also performed in the hospitalized subjects.
In the hospitalized subjects, the median plasma BNP level (interquartile range) was 55.4 (26.9–129.3) pg/mL and was higher than that of patients with stable COPD: 18.3 (10.0–45.3) for Global Initiative for Chronic Obstructive Lung Disease grade I; 25.8 (11.0–53.7) for grade II; 22.1 (9.1–52.6) for grade III; and 17.2 (9.6–22.9) pg/mL for grade I V, all P<0.001. In 15 subjects studied prospectively, the median plasma BNP level was 19.4 (9.8–32.2) pg/mL before AECOPD, 72.7 (27.7–146.3) pg/mL during AECOPD, and 14.6 (12.9–39.0) pg/mL after AECOPD (P<0.0033 and P<0.0013, respectively). Median plasma BNP levels during AECOPD were significantly higher in ten unsuccessfully discharged subjects 260.5 (59.4–555.0) than in 48 successfully discharged subjects 48.5 (24.2–104.0) pg/mL (P=0.0066). Only 5.6% of AECOPD subjects were associated with systolic dysfunction defined as a left ventricular ejection fraction (LVEF) <50%; a further 7.4% were considered to have impaired relaxation defined as an E/A wave velocity ratio <0.8 and a deceleration time of E >240 ms. BNP levels were weakly correlated with the E/peak early diastolic velocity of the mitral annulus (Ea) ratio (Spearman’s rank correlation coefficient =0.353, P=0.018), but they were not correlated with the LVEF (Spearman’s rank correlation coefficient =−0.221, P=0.108).
A modest elevation of plasma BNP is observed during AECOPD. It appears that AECOPD may have an impact on plasma BNP levels that is not attributable to heart failure.
PMCID: PMC3921082  PMID: 24523584
chronic obstructive pulmonary disease; acute exacerbations of chronic obstructive pulmonary disease; B-type natriuretic peptide; heart failure
14.  Comparative efficacy of 3 soluble epoxide hydrolase inhibitors in rat neuropathic and inflammatory pain models 
European journal of pharmacology  2012;700(1-3):93-101.
Epoxy-fatty acids have been recognized as important cell signaling molecules with multiple biological effects including anti-nociception. The main degradation pathway of these signaling molecules is via the soluble epoxide hydrolase (sEH) enzyme. Inhibitors of sEH extend the anti-nociceptive effects of fatty acid epoxides. In this study two models of pain with different etiology, streptozocin induced type I diabetic neuropathic pain and lipopolysaccharide induced inflammatory pain were employed to test sEH inhibitors. A dose range of three sEH inhibitors with the same central pharmacophore but varying substituent moieties was used to investigate maximal anti-allodynic effects in these two models of pain. Inhibiting the sEH enzyme in these models successfully blocked pain related behavior in both models. The sEH inhibitors were more potent and more efficacious than celecoxib in reducing both diabetic neuropathic pain and lipopolysaccharide induced inflammatory pain. Because of their ability to block diabetic neuropathic pain sEH inhibition is a promising new approach to treat chronic pain conditions.
PMCID: PMC3578047  PMID: 23276668
15.  Can Mindfulness-Based Interventions Help Adolescents with Cancer? 
Psycho-oncology  2013;22(9):10.1002/pon.3251.
During the past 30 years, there has been an increase in the incidence of cancer in adolescents. While recent studies have illustrated remarkable resilience in youth living with cancer, they can also face daunting acute and chronic adjustment struggles, cognitive and school problems, family and peer relational difficulties, depression, post-traumatic stress symptoms, and other anxiety disorders. Mindfulness-based interventions (MBIs), increasingly shown to be effective in a variety of medical and mental health settings, may be particularly beneficial for adolescents with cancer. This paper reviews evidence from clinical trials of MBIs showing a variety of benefits for adult cancer patients, adolescents with anxiety disorders and chronic pain, and clinically healthy teenagers, which collectively point to likely benefits of MBIs for teen cancer patients. The authors also explore ways that the particular psychological problems often faced by teen cancer patients, including anxiety about the future, may be especially well suited to mindfulness approaches such as learning to observe physical sensations, thoughts, and emotions, as well as cultivating compassion towards themselves and others. The paper concludes with an exploration of unanswered and potential research questions regarding the future use of MBIs with adolescents with cancer, and potentially with teenagers with other chronic diseases.
PMCID: PMC3836438  PMID: 23417883
Mindfulness; adolescents; cancer; mind-body interventions
16.  The Lesser of Two Weevils: Molecular-Genetics of Pest Palm Weevil Populations Confirm Rhynchophorus vulneratus (Panzer 1798) as a Valid Species Distinct from R. ferrugineus (Olivier 1790), and Reveal the Global Extent of Both 
PLoS ONE  2013;8(10):e78379.
The red palm weevil (RPW) is a major pest of palms. It is native to southeast Asia and Melanesia, but in recent decades has vastly expanded its range as the result of multiple accidental anthropogenic introductions into the Middle East, Mediterranean Basin, Caribbean, and U.S.A. Currently regarded as a single species, Rhynchophorus ferrugineus (Olivier), RPW displays remarkable color variation across its range, and consequently has a taxonomic history littered with new species descriptions and synonymization. We compared DNA sequences of the mitochondrial cytochrome oxidase subunit I (COI) gene from RPW populations throughout the native and invaded ranges, to investigate the specific status and invasion history of this serious economic pest, and to identify possible common routes of entry. Analyses of COI haplotype data provide conclusive support, corroborated by sequences of additional nuclear gene regions, for the existence of at least two predominantly allopatric species. The true R. ferrugineus is native only to the northern and western parts of continental southeast Asia, Sri Lanka and the Philippines, and is responsible for almost all invasive populations worldwide. In contrast, the second species, which is currently synonymized under R. ferrugineus and should be resurrected under the name R. vulneratus (Panzer), has a more southern distribution across Indonesia, and is responsible for only one invasive population; that in California, U.S.A. The distribution of COI haplotypes is used to discuss the possible existence of further cryptic species, sources and routes of entry of different invasive populations, and the implications of our findings for current control methods.
PMCID: PMC3797061  PMID: 24143263
17.  Comparative efficacy of long-acting bronchodilators for COPD - a network meta-analysis 
Respiratory Research  2013;14(1):100.
Clinicians are faced with an increasingly difficult choice regarding the optimal bronchodilator for patients with chronic obstructive pulmonary disease (COPD) given the number of new treatments. The objective of this study is to evaluate the comparative efficacy of indacaterol 75/150/300 μg once daily (OD), glycopyrronium bromide 50 μg OD, tiotropium bromide 18 μg/5 μg OD, salmeterol 50 μg twice daily (BID), formoterol 12 μg BID, and placebo for moderate to severe COPD.
Forty randomized controlled trials were combined in a Bayesian network meta-analysis. Outcomes of interest were trough and post-dose forced expiratory volume in 1 second (FEV1), St. George’s Respiratory Questionnaire (SGRQ) score and responders (≥4 points), and Transition Dyspnea Index (TDI) score and responders (≥1 point) at 6 months.
Indacaterol was associated with a higher trough FEV1 than other active treatments (difference for indacaterol 150 μg and 300 μg versus placebo: 152 mL (95% credible interval (CrI): 126, 179); 160 mL (95% CrI: 133, 187)) and the greatest improvement in SGRQ score (difference for indacaterol 150 μg and 300 μg versus placebo: -3.9 (95% CrI -5.2, -2.6); -3.6 (95% CrI -4.8, -2.3)). Glycopyrronium and tiotropium 18 μg resulted in the next best estimates for both outcomes with minor differences (difference for glycopyrronium versus tiotropium for trough FEV1 and SGRQ: 18 mL (95% CrI: -16, 51); -0.55 (95% CrI: -2.04, 0.92).
In terms of trough FEV1 and SGRQ score indacaterol, glycopyrronium, and tiotropium are expected to be the most effective bronchodilators.
PMCID: PMC4014806  PMID: 24093477
COPD; Bronchodilator; Systematic review; Meta-analysis; Mixed treatment comparison
18.  A study to assess COPD Symptom-based Management and to Optimise treatment Strategy in Japan (COSMOS-J) based on GOLD 2011 
Background and objective
The Global initiative for chronic Obstructive Lung Disease (GOLD) Committee has proposed a chronic obstructive pulmonary disease (COPD) assessment framework focused on symptoms and on exacerbation risk. This study will evaluate a symptom and exacerbation risk-based treatment strategy based on GOLD in a real-world setting in Japan. Optimal management of COPD will be determined by assessing symptoms using the COPD Assessment Test (CAT) and by assessing the frequency of exacerbations.
This study ( identifier: NCT01762800) is a 24-week, multicenter, randomized, double-blind, double-dummy, parallel-group study. It aims to recruit 400 patients with moderate-to-severe COPD. Patients will be randomized to receive treatment with either salmeterol/fluticasone propionate (SFC) 50/250 μg twice daily or with tiotropium bromide 18 μg once daily. Optimal management of patients will be assessed at four-weekly intervals and, if patients remain symptomatic, as measured using the CAT, or experience an exacerbation, they have the option to step up to treatment with both drugs, ie, SFC twice daily and tiotropium once daily (TRIPLE therapy). The primary endpoint of the study will be the proportion of patients who are able to remain on the randomized therapy.
No data are available. This paper summarizes the methodology of the study in advance of the study starting.
The results of this study will help physicians to understand whether TRIPLE therapy is more effective than either treatment strategy alone in controlling symptoms and exacerbations in patients with moderate-to-severe COPD. It will also help physicians to understand the GOLD recommendation work in Japan.
PMCID: PMC3795054  PMID: 24124358
COPD; GOLD; symptom; exacerbation risk; TRIPLE therapy
19.  Bacterial Communities Associated with Culex Mosquito Larvae and Two Emergent Aquatic Plants of Bioremediation Importance 
PLoS ONE  2013;8(8):e72522.
Microbes are important for mosquito nutrition, growth, reproduction and control. In this study, we examined bacterial communities associated with larval mosquitoes and their habitats. Specifically, we characterized bacterial communities associated with late larval instars of the western encephalitis mosquito (Culextarsalis), the submerged portions of two emergent macrophytes (California bulrush, Schoenoplectuscalifornicus and alkali bulrush, Schoenoplectusmaritimus), and the associated water columns to investigate potential differential use of resources by mosquitoes in different wetland habitats. Using next-generation sequence data from 16S rRNA gene hypervariable regions, the alpha diversity of mosquito gut microbial communities did not differ between pond mesocosms containing distinct monotypic plants. Proteobacteria, dominated by the genus Thorsellia (Enterobacteriaceae), was the most abundant phylum recovered from C. tarsalis larvae. Approximately 49% of bacterial OTUs found in larval mosquitoes were identical to OTUs recovered from the water column and submerged portions of the two bulrushes. Plant and water samples were similar to one another, both being dominated by Actinobacteria, Bacteroidetes, Cyanobacteria, Proteobacteria and Verrucomicrobia phyla. Overall, the bacterial communities within C. tarsalis larvae were conserved and did not change across sampling dates and between two distinct plant habitats. Although Thorsellia spp. dominated mosquito gut communities, overlap of mosquito gut, plant and water-column OTUs likely reveal the effects of larval feeding. Future research will investigate the role of the key indicator groups of bacteria across the different developmental stages of this mosquito species.
PMCID: PMC3744470  PMID: 23967314
20.  Development and validity testing of an IPF-specific version of the St George's Respiratory Questionnaire 
Thorax  2010;65(10):921-926.
The St George's Respiratory Questionnaire (SGRQ) is often applied to assess health-related quality of life in patients with idiopathic pulmonary fibrosis (IPF). Some SGRQ items will inevitably have weaker measurement properties than others when applied to this population. This study was conducted to develop an IPF-specific version of the SGRQ.
Data from a recently completed trial that enrolled subjects with IPF (n=158) who completed the SGRQ and other measures were analysed at baseline and 6 months. There were four phases to the study: (1) removing items with missing responses and using Rasch analysis on retained items to identify fit and refine item response categories; (2) development of a new scoring scheme; (3) testing agreement between original and revised versions and testing construct validity of the revised SGRQ; and (4) rewording to finalise the IPF-specific version (SGRQ-I).
Items were removed due to missing responses (6 items) and misfit to the Rasch model (10 items); 34 items from the original 50 were retained. For certain items, disordered response thresholds were identified and corrected by collapsing response categories. A scoring algorithm was developed to place SGRQ-I scores on a scale with SGRQ scores. For any given outcome measure (eg, forced vital capacity (% predicted) and lung carbon monoxide transfer factor (% predicted), 6-min walk distance and patient-reported questionnaires), Pearson correlations were similar between pairs that included original SGRQ scores and corresponding pairs that included SGRQ-I scores. Internal reliability (Cronbach α) for each SGRQ-I component was comparable to the original SGRQ (Symptoms 0.62; Activities 0.80; Impacts 0.85).
The SGRQ-I contains items from the original SGRQ that are the most reliable for measuring health-related quality of life in patients with IPF.
PMCID: PMC3697105  PMID: 20861296
21.  COPD and disease-specific health status in a working population 
Respiratory Research  2013;14(1):61.
It has been debated whether treatment should be started early in subjects with mild to moderate COPD. An impaired health status score was associated with a higher probability of being diagnosed with COPD as compared with undiagnosed COPD.
To investigate the health status in a healthy working population, to determine reference scores for healthy non-smoking subjects, and to investigate the relationship between their health status and airflow limitation.
A total of 1333 healthy industrial workers aged ≥40 years performed spirometry and completed the St. George’s Respiratory Questionnaire (SGRQ) and the COPD Assessment Test (CAT).
The prevalence of COPD defined by the fixed ratio of the forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) was 10.9%, and the prevalence defined by the Lower Limit of Normal was 5.0%. All SGRQ and CAT scores were skewed to the milder end. In 512 non-smoking subjects with normal spirometry, the mean SGRQ score was 5.7, and the mean CAT score was 5.8. In 145 people with COPD defined by the fixed ratio, the mean SGRQ score was 7.9, with a zero score in 6.9% of the subjects. Using the CAT, the mean score was 7.3, with 7.6% of the scores being zero. The scores in patients identified using the Lower Limit of Normal approach were: SGRQ 8.4 (13.4% had a score of zero) and CAT 7.4 (13.4% had a score of zero). Although the 95th percentiles of the Total, Symptoms, Activity, and Impact scores of the SGRQ and CAT sores were 13.8, 34.0, 23.4, 7.2 and 13.6 in the 512 healthy non-smoking subjects, respectively, they were also distributed under their upper limits in over 80% of the COPD subjects.
The COPD-specific health status scores in a working population were good, even in those with spirometrically diagnosed COPD. All scores were widely distributed in both healthy non-smoking subjects and in subjects with COPD, and the score distribution overlapped remarkably between these two groups. This suggests that symptom-based methods are not suitable screening tools in a healthy general population.
PMCID: PMC3679860  PMID: 23725096
Chronic obstructive pulmonary disease; St. George’s Respiratory Questionnaire; Symptoms and COPD; Smoking and health; Health related quality of life
22.  Novel study design to assess the utility of the copd assessment test in a primary care setting 
The quality of a consultation provided by a physician can have a profound impact on the quality of care and patient engagement in treatment decisions. When the COPD Assessment Test (CAT) was developed, one of its aims was to aid the communication between physician and patient about the impact of COPD. We developed a novel study design to assess this in a primary care consultation.
Primary care physicians across five countries in Europe conducted videoed consultations with six standardised COPD patients (played by trained actors) which had patient-specific issues that the physician needed to identify through questioning. Half the physicians saw the patients with the completed CAT, and half without. Independent assessors scored the physicians on their ability to identify and address the patient-specific issues, review standard COPD aspects, their understanding of the case and their overall performance. This novel study design presented many challenges which needed to be addressed to achieve an acceptable level of robustness to assess the utility of the CAT. This paper discusses these challenges and the measures adopted to eliminate or minimise their impact on the study results.
PMCID: PMC3667066  PMID: 23663700
COPD; CAT; Primary care consultation; Videoed assessment
23.  The Bernese peri-acetabular osteotomy through a modified approach. A technical note 
A modification of the technique for performing the Bernese periacetabular osteotomy is described.
Materials and methods
A medial approach to the Ischium and a subtle re-orientation of the pubic osteotomy are detailed.
Surgical morbidity is likely decreased with a concurrent cosmetic advantage without compromise to surgical correction or patient safety.
PMCID: PMC3593015  PMID: 24432067
Peri-acetabular osteotomy; Hip; Approach
24.  Dielectrophoretic mobility determination in DC insulator-based dielectrophoresis 
Electrophoresis  2011;32(17):2292-2297.
Insulator based dielectrophoresis is powerful tool for separating and charactering particles, yet it is limited by a lack of quantitative characterizations. Here this limitation is addressed by employing a method capable of quantifying the dielectrophoretic mobility of particles. Using streak-based velocimetry the particle properties are deduced from their motion in a microfluidic channel with a constant electric field gradient. From this approach the dielectrophoretic mobility of 1 μm polystyrene particles was found to be −2 ± 0.4 × 10−8 cm4/(V2·s). In the future, such quantitative treatment will allow for the elucidation of unique insights and rational design of devices.
PMCID: PMC3517931  PMID: 21823129
Dielectrophoresis; Dielectrophoretic Mobility; Velocimetry
25.  Modeling High-Grade Serous Carcinoma: How Converging Insights into Pathogenesis and Genetics are Driving Better Experimental Platforms 
Frontiers in Oncology  2013;3:217.
Recent developments in the study of epithelial ovarian cancer have called into question the traditional views regarding the site of tumor initiation. Histopathologic studies and genomic analyses suggest that extra-ovarian sites, like the fallopian tube, may harbor the coveted cell of origin and could therefore contribute significantly to the development of high-grade serous ovarian carcinoma (HG-SOC). Our ability to validate these emerging genomic and pathologic observations and characterize the early transformation events of HG-SOC hinges on the development of novel model systems. Currently, there are only a handful of new model systems that are addressing these concerns. This review will chronicle the convergent evolution of these ovarian cancer model systems in the context of the changing pathologic and genomic understanding of HG-SOC.
PMCID: PMC3752910  PMID: 23986883
ovarian cancer; genetics; pathogenesis; model systems; OSE; fallopian tube

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