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.

1-(1-Acetyl-piperidin-4-yl)-3-adamantan-1-yl-urea 14a (AR9281), a potent and selective soluble epoxide hydrolase inhibitor, was recently tested in a phase 2a clinical setting for its effectiveness in reducing blood pressure and improving insulin-resistance in pre-diabetic patients. In a mouse model of diet induced obesity, AR9281 attenuated the enhanced glucose excursion following an intraperitoneal glucose tolerance test. AR9281 also attenuated the increase in blood pressure in angiotensin-II-induced hypertension in rats. These effects were dose-dependent and well correlated with inhibition of the sEH activity in whole blood, consistent with a role of sEH in the observed pharmacology in rodents.

Background

Endurance exercise capacity diminishes under hot environmental conditions. Time to exhaustion can be increased by lowering body temperature prior to exercise (pre-cooling). This systematic literature review synthesizes the current findings of the effects of pre-cooling on endurance exercise performance, providing guidance for clinical practice and further research.

Methods

The MEDLINE, EMBASE, CINAHL, Web of Science and SPORTDiscus databases were searched in May 2012 for studies evaluating the effectiveness of pre-cooling to enhance endurance exercise performance in hot environmental conditions (≥ 28°C). Studies involving participants with increased susceptibility to heat strain, cooling during or between bouts of exercise, and protocols where aerobic endurance was not the principle performance outcome were excluded. Potential publications were assessed by two independent reviewers for inclusion and quality. Means and standard deviations of exercise performance variables were extracted or sought from original authors to enable effect size calculations.

Results

In all, 13 studies were identified. The majority of studies contained low participant numbers and/or absence of sample size calculations. Six studies used cold water immersion, four crushed ice ingestion and three cooling garments. The remaining study utilized mixed methods. Large heterogeneity in methodological design and exercise protocols was identified. Effect size calculations indicated moderate evidence that cold water immersion effectively improved endurance performance, and limited evidence that ice slurry ingestion improved performance. Cooling garments were ineffective. Most studies failed to document or report adverse events. Low participant numbers in each study limited the statistical power of certain reported trends and lack of blinding could potentially have introduced either participant or researcher bias in some studies.

Conclusions

Current evidence indicates cold water immersion may be the most effective method of pre-cooling to improve endurance performance in hot conditions, although practicality must be considered. Ice slurry ingestion appears to be the most promising practical alternative. Interestingly, cooling garments appear of limited efficacy, despite their frequent use. Mechanisms behind effective pre-cooling remain uncertain, and optimal protocols have yet to be established. Future research should focus on standardizing exercise performance protocols, recruiting larger participant numbers to enable direct comparisons of effectiveness and practicality for each method, and ensuring potential adverse events are evaluated.

Advances in genome technology have facilitated a new understanding of the historical and genetic processes crucial to rapid phenotypic evolution under domestication1,2. To understand the process of dog diversification better, we conducted an extensive genome-wide survey of more than 48,000 single nucleotide polymorphisms in dogs and their wild progenitor, the grey wolf. Here we show that dog breeds share a higher proportion of multi-locus haplotypes unique to grey wolves from the Middle East, indicating that they are a dominant source of genetic diversity for dogs rather than wolves from east Asia, as suggested by mitochondrial DNA sequence data3. Furthermore, we find a surprising correspondence between genetic and phenotypic/functional breed groupings but there are exceptions that suggest phenotypic diversification depended in part on the repeated crossing of individuals with novel phenotypes. Our results show that Middle Eastern wolves were a critical source of genome diversity, although interbreeding with local wolf populations clearly occurred elsewhere in the early history of specific lineages. More recently, the evolution of modern dog breeds seems to have been an iterative process that drew on a limited genetic toolkit to create remarkable phenotypic diversity.

Background

The authors previously introduced a highly abstract generic insulin infusion pump (GIIP) model that identified common features and hazards shared by most insulin pumps on the market.

The aim of this article is to extend our previous work on the GIIP model by articulating safety requirements that address the identified GIIP hazards. These safety requirements can be validated by manufacturers, and may ultimately serve as a safety reference for insulin pump software. Together, these two publications can serve as a basis for discussing insulin pump safety in the diabetes community.

Methods

In our previous work, we established a generic insulin pump architecture that abstracts functions common to many insulin pumps currently on the market and near-future pump designs. We then carried out a preliminary hazard analysis based on this architecture that included consultations with many domain experts. Further consultation with domain experts resulted in the safety requirements used in the modeling work presented in this article.

Results

Generic safety requirements for the GIIP model are presented, as appropriate, in parameterized format to accommodate clinical practices or specific insulin pump criteria important to safe device performance.

Conclusions

We believe that there is considerable value in having the diabetes, academic, and manufacturing communities consider and discuss these generic safety requirements. We hope that the communities will extend and revise them, make them more representative and comprehensive, experiment with them, and use them as a means for assessing the safety of insulin pump software designs. One potential use of these requirements is to integrate them into model-based engineering (MBE) software development methods. We believe, based on our experiences, that implementing safety requirements using MBE methods holds promise in reducing design/implementation flaws in insulin pump development and evolutionary processes, therefore improving overall safety of insulin pump software.

The OECD’s Brain and Learning project (2002) emphasized that many misconceptions about the brain exist among professionals in the field of education. Though these so-called “neuromyths” are loosely based on scientific facts, they may have adverse effects on educational practice. The present study investigated the prevalence and predictors of neuromyths among teachers in selected regions in the United Kingdom and the Netherlands. A large observational survey design was used to assess general knowledge of the brain and neuromyths. The sample comprised 242 primary and secondary school teachers who were interested in the neuroscience of learning. It would be of concern if neuromyths were found in this sample, as these teachers may want to use these incorrect interpretations of neuroscience findings in their teaching practice. Participants completed an online survey containing 32 statements about the brain and its influence on learning, of which 15 were neuromyths. Additional data was collected regarding background variables (e.g., age, sex, school type). Results showed that on average, teachers believed 49% of the neuromyths, particularly myths related to commercialized educational programs. Around 70% of the general knowledge statements were answered correctly. Teachers who read popular science magazines achieved higher scores on general knowledge questions. More general knowledge also predicted an increased belief in neuromyths. These findings suggest that teachers who are enthusiastic about the possible application of neuroscience findings in the classroom find it difficult to distinguish pseudoscience from scientific facts. Possessing greater general knowledge about the brain does not appear to protect teachers from believing in neuromyths. This demonstrates the need for enhanced interdisciplinary communication to reduce such misunderstandings in the future and establish a successful collaboration between neuroscience and education.

Patients with chronic obstructive pulmonary disease (COPD) present with a variety of symptoms and pathological consequences. Although primarily viewed as a respiratory disease, COPD has both pulmonary and extrapulmonary effects, which have an impact on many aspects of physical, emotional, and mental well-being. Traditional assessment of COPD relies heavily on measuring lung function, specifically forced expiratory volume in 1 second (FEV1). However, the evidence suggests that FEV1 is a relatively poor correlate of symptoms such as breathlessness and the impact of COPD on daily life. Furthermore, many consequences of the disease, including anxiety and depression and the ability to perform daily activities, can only be described and reported reliably by the patient. Thus, in order to provide a comprehensive view of the effects of interventions in clinical trials, it is essential that spirometry is accompanied by assessments using patient-reported outcome (PRO) instruments. We provide an overview of patient-reported outcome concepts in COPD, such as breathlessness, physical functioning, and health status, and evaluate the tools used for measuring these concepts. Particular attention is given to the newly developed instruments emerging in response to recent regulatory guidelines for the development and use of PROs in clinical trials. We conclude that although data from the development and validation of these new PRO instruments are emerging, to build the body of evidence that supports the use of a new instrument takes many years. Furthermore, new instruments do not necessarily have better discriminative or evaluative properties than older instruments. The development of new PRO tools, however, is crucial, not only to ensure that key COPD concepts are being reliably measured but also that the relevant treatment effects are being captured in clinical trials. In turn, this will help us to understand better the patient’s experience of the disease.

Introduction

Two studies examined whether stereotype threat impairs women's math performance and whether concurrent threat reduction strategies can be used to offset this effect.

Method

In Study 1, collegiate men and women (N = 100) watched a video purporting that males and females performed equally well (gender-fair) or males outperformed females (gender differences) on an imminent math test. In Study 2, (N = 44) women viewed the gender differences video, followed by misattribution (cue present, absent) and self-affirmation (present, absent) manipulations, before taking the aforesaid test.

Results

In the initial study, women underperformed men on the test after receiving the gender differences video, whereas no gender differences emerged in the gender-fair condition. In Study 2, affirming the self led to better performance than not doing so. Planned contrasts indicated, however, that only women receiving a misattribution cue and self-affirmation opportunity outperformed their counterparts not given these reduction strategies.

Discussion

These findings are discussed relative to Stereotype Threat Theory and educational implications are provided.

Background

Dyspnea is a prominent symptom in asthma. The Dyspnea-12 (D-12), an instrument that quantifies breathlessness using 12 descriptors that tap the physical and affective aspects, has shown promise for the measurement of dyspnea in cardiorespiratory disease.

Objective

We report the results of a study designed to test the validity and reliability of the D-12 in a population of patients with asthma.

Methods

This cross-sectional study included 102 patients with asthma. Subjects completed the D-12, Hospital Anxiety and Depression Scale (HAD), St George’s Respiratory Questionnaire (SGRQ), MRC scale. Confirmatory factor analysis confirmed the two-component structure of the D-12 (i.e. 7 items that tap the Physical aspects of breathlessness and 5 items that tap the Affective aspects).

Results

The D-12 subscales had excellent internal reliability (Cronbach’s alpha for the ‘Physical’ score was 0.94 and the Affective score was 0.95). The D-12 Physical component was more strongly correlated with SGRQ Symptoms (r = 0.648), SGRQ Activities (r = 0.635) and MRC grade (r = 0.636), while the Affective component was more strongly correlated with SGRQ Impacts (r = 0.765) and HAD scores (anxiety r = 0.641 and depression r = 0.602).

Conclusion

This study supports validity of the D-12 for use in the assessment of dyspnea of patients with asthma. It assesses one of the most pertinent symptoms of asthma from two viewpoints -physical and affective.

Summary

Objective

To establish a predictive method using whole genome genotyping for early intervention in canine hip dysplasia (CHD) risk management, for the prevention of the progression of secondary osteoarthritis (OA), and for selective breeding.

Design

Two sets of dogs (6 breeds) were genotyped with dense SNPs covering the entire canine genome. The first set contained 359 dogs upon which a predictive formula for genomic breeding value (GBV) was derived by using their estimated breeding value (EBV) of the Norberg angle (a measure of CHD) and their genotypes. To investigate how well the formula would work for an individual dog with genotype only (without using EBV or phenotype), a cross validation was performed by masking the EBV of one dog at a time. The genomic data and the EBV of the remaining dogs were used to predict the GBV for the single dog that was left out. The second set of dogs included 38 new Labrador retriever dogs, which had no pedigree relationship to the dogs in the first set.

Results

The cross validation showed a strong correlation (r>0.7) between the EBV and the GBV. The independent validation showed a strong correlation (r=0.5) between GBV for the Norberg angle and the observed Norberg angle (no EBV was available for the new 38 dogs). Sensitivity, specificity, positive, and negative predictive value of the genomic data were all above 70%.

Conclusions

Prediction of CHD from genomic data is feasible, and can be applied for risk management of CHD and early selection for genetic improvement to reduce the prevalence of CHD in breeding programs. The prediction can be implemented before maturity, at which age current radiographic screening programs are traditionally applied, and as soon as DNA is available.

Epoxyeicosatrienoic acids that have anti-hypertensive and anti-inflammatory properties are mainly metabolized by soluble epoxide hydrolase (sEH, EC 3.3.2.3). Therefore, sEH has emerged as a therapeutic target for treating various cardiovascular diseases and inflammatory pain. N,N’-Disubstituted ureas are potent sEH inhibitors in vitro. However, in vivo usage of early sEH inhibitors has been limited by their low bioavailability and poor physiochemical properties. Therefore, a group of highly potent compounds with more drug-like physiochemical properties were evaluated by monitoring their plasma profiles in dogs treated orally with sEH inhibitors. Urea compounds with an adamantyl or a 4-trifluoromethoxyphenyl group on one side and a piperidyl or a cyclohexyl ether group on the other side of the urea function showed pharmacokinetic profiles with high plasma concentrations and long half lives. In particular, the inhibitor trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid (t-AUCB) not only is very potent with good physiochemical properties, but also shows high oral bioavailability for doses ranging from 0.01 to 1 mg/kg. This compound is also very potent against the sEH of several mammals, suggesting that t-AUCB will be an excellent tool to evaluate the biology of sEH in multiple animal models. Such compounds may also be a valuable lead for the development of veterinary therapeutics.

A series of 1,3-disubstituted ureas possessing a piperidyl moiety has been synthesized to investigate their structure-activity relationships as inhibitors of the human and murine soluble epoxide hydrolase (sEH). Oral administration of thirteen 1-aryl-3-(1-acylpiperidin-4-yl)urea inhibitors in mice revealed substantial improvements in pharmacokinetic parameters over previously reported 1-adamantyl-urea based inhibitors. For example, 1-(1-(cyclopropanecarbonyl)piperidin-4-yl)-3-(4-(trifluoromethoxy)phenyl)urea (52) showed a 7-fold increase in potency, a 65-fold increase in Cmax† and a 3300 fold increase in AUC over its adamantane analogue 1-(1-adamantyl)-3-(1-propionylpiperidin-4-yl)urea (2). This novel sEH inhibitor showed a 1000 fold increase in potency when compared to morphine by reducing hyperalgesia as measured by mechanical withdrawl threshold using the in vivo carrageenan induced inflammatory pain model.

Background

Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV1) are correlated with changes in patient-reported outcomes.

Methods

Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George's Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of ΔFEV1. Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use.

Results

With increasing positive ΔFEV1, TDI and ΔSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort-level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV1 was associated with improved TDI (0.46 units), ΔSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between ΔFEV1 and outcomes.

Conclusions

These results suggest that larger improvements in FEV1 are likely to be associated with larger patient-reported benefits across a range of clinical outcomes.

Trial Registration

ClinicalTrials.gov NCT00393458, NCT00463567, and NCT00624286

Background

The COPD Assessment Test (CAT™) is a new short health status measure for routine use. New questionnaires require reference points so that users can understand the scores; descriptive scenarios are one way of doing this. A novel method of creating scenarios is described.

Methods

A Bland and Altman plot showed a consistent relationship between CAT scores and scores obtained with the St George's Respiratory Questionnaire for COPD (SGRQ-C) permitting a direct mapping process between CAT and SGRQ items. The severity associated with each CAT item was calculated using a probabilistic model and expressed in logits (log odds of a patient of given severity affirming that item 50% of the time). Severity estimates for SGRQ-C items in logits were also available, allowing direct comparisons with CAT items. CAT scores were categorised into Low, Medium, High and Very High Impact. SGRQ items of corresponding severity were used to create scenarios associated with each category.

Results

Each CAT category was associated with a scenario comprising 12 to 16 SGRQ-C items. A severity 'ladder' associating CAT scores with exemplar health status effects was also created. Items associated with 'Low' and 'Medium' Impact appeared to be subjectively quite severe in terms of their effect on daily life.

Conclusions

These scenarios provide users of the CAT with a good sense of the health impact associated with different scores. More generally they provide a surprising insight into the severity of the effects of COPD, even in patients with apparently mild-moderate health status impact.

Background

Approximately 210 million people are estimated to have chronic obstructive pulmonary disease [COPD] worldwide. The burden of disease is known to be high, though less is known about those of a younger age. The aim of this study was to investigate the wider personal, economic and societal burden of COPD on a cross country working-age cohort.

Methods

A cross-country [Brazil, China, Germany, Turkey, US, UK] cross-sectional survey methodology was utilised to answer the research questions. 2426 participants aged 45-67 recruited via a number of recruitment methods specific to each country completed the full survey. Inclusion criteria were a recalled physician diagnosis of COPD, a smoking history of > 10 pack years and the use of COPD medications in the previous 3 months prior to questioning. The survey included items from the validated Work Productivity and Activity Impairment [WPAI] scale and the EuroQoL 5 Dimension [EQ-5D] scale. Disease severity was measured using the 5-point MRC [Medical Research Council] dyspnoea scale as a surrogate measure.

Results

64% had either moderate [n = 1012] or severe [n = 521] COPD, although this varied by country. 75% of the cohort reported at least one comorbid condition. Quality of life declined with severity of illness [mild, mean EQ-5D score = 0.84; moderate 0.58; severe 0.41]. The annual cost of healthcare utilisation [excluding treatment costs and diagnostic tests] per individual was estimated to be $2,364 [£1,500]. For those remaining in active employment [n: 677]: lost time from work cost the individual an average of $880 [£556] per annum and lifetime losses of $7,365 [£4,661] amounting to $596,000 [£377,000] for the cohort. 447 [~40%] of the working population had retired prematurely because of COPD incurring individual estimated lifetime income losses of $316,000 [£200,000] or a combined total of $141 m [£89.6 m]. As the mean age of retirees was 58.3 and average time since retirement was 4 years, this suggests the average age of retirement is around 54. This would mean a high societal and economic impact in all study countries, particularly where typical state retirement ages are higher, for example in Brazil, Germany and the UK [65] and the US [65,66,67], compared to Turkey [58 for women, 60 for men] and China [60].

Conclusions

Although generalisation across a broader COPD population is limited due to the varied participant recruitment methods, these data nevertheless suggest that COPD has significant personal, economic and societal burden on working age people. Further efforts to improve COPD diagnosis and management are required.

Background

Hyperglycaemia is associated with poor outcomes from exacerbations of chronic obstructive pulmonary disease (COPD). Glycaemic control could improve outcomes by reducing infection, inflammation and myopathy. Most patients with COPD are managed on the acute medical unit (AMU) outside intensive care (ICU).

Objective

To determine the feasibility, safety and efficacy of tight glycaemic control in patients on an AMU.

Design

Prospective, non-randomised, phase II, single-arm study of tight glycaemic control in COPD patients with acute exacerbations and hyperglycaemia admitted to the AMU. Participants received intravenous, then subcutaneous, insulin to control blood glucose to 4.4–6.5 mmol/l. Tight glycaemic control was evaluated: feasibility, protocol adherence; acceptability, patient questionnaire; safety, frequency of hypoglycaemia (capillary blood glucose (CBG) <2.2 mmol/l and 2.2–3.3 mmol/l); efficacy, median CBG, fasting CBG, proportion of measurements/time in target range, glycaemic variability. Results were compared with 25 published ICU studies.

Results

20 patients (10 females, age 71±9 years; forced expiratory volume in 1 s: 41±16% predicted) were recruited. Tight glycaemic control was feasible (78% CBG measurements and 89% of insulin-dose adjustments were adherent to protocol) and acceptable to patients. 0.2% CBG measurements were <2.2 mmol/l and 4.1% measurements 2.2–3.3 mmol/l. The study CBG and proportion of measurements/time in target range were similar to that of ICU studies, whereas the fasting CBG was lower, and the glycaemic variability was greater.

Conclusions

Tight glycaemic control is feasible and has similar safety and efficacy on AMU to ICU. However, as more recent ICU studies have shown no benefit and possible harm from tight glycaemic control, alternative strategies for blood glucose control in COPD exacerbations should now be explored.

Trial registration number

ISRCTN: 42412334. http://Clinical.Trials.gov NCT00764556.

Article summary

Article focus

Hyperglycaemia is associated with poor outcomes from acute chronic obstructive pulmonary disease (COPD) exacerbations requiring hospital admission.

It is not known whether glycaemic control can improve COPD exacerbation outcomes.

The aim of this phase II study was to determine the feasibility, safety and efficacy of tight glycaemic control with insulin in COPD patients with exacerbations on acute medical wards, towards testing this intervention in a randomised controlled trial.

Key messages

Tight glycaemic control with insulin was feasible and acceptable to patients in a general ward setting.

The efficacy and safety of tight glycaemic control were similar in COPD patients on acute medical wards to that achieved in intensive care settings, with improved glycaemic control but increased hypoglycaemia and glycaemic variability.

Strengths and limitations of this study

This study was conducted when tight glycaemic control was standard practice in intensive care units (ICUs), following the publication of two single-centre studies demonstrating reduced morbidity and mortality compared with conventional glycaemic control.

More recent ICU studies have shown no benefit and possible harm from tight glycaemic control.

In this context, our finding that tight glycaemic control in the acute medical unit has a similar safety and efficacy to ICU protocols indicates that we should explore alternative strategies for blood glucose control in COPD exacerbations.

Background

Little is known about factors that determine health status decline in clinical trials of COPD.

Objectives

To examine health status changes over 3 years in the TORCH study of salmeterol+fluticasone propionate (SFC) vs. salmeterol alone, fluticasone propionate alone or placebo.

Methods

St George's Respiratory Questionnaire (SGRQ) was administered at baseline then every 6 months.

Measurements and Main Results

Data from 4951 patients in 28 countries were available. SFC produced significant improvements over placebo in all three SGRQ domains during the study: (Symptoms -3.6 [95% CI -4.8, -2.4], Activity -2.8 [95% CI -3.9, -1.6], Impacts -3.2 [95% CI -4.3, -2.1]) but the pattern of change over time differed between domains. SGRQ deteriorated faster in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages III & IV relative to GOLD stage II (p < 0.001). There was no difference in the relationship between deterioration in SGRQ Total score and forced expiratory volume in one second (FEV1) decline (as % predicted) in men and women. Significantly faster deterioration in Total score relative to FEV1 % predicted was seen in older patients (≥ 65 years) and there was an age-related change in Total score that was independent of change in FEV1. The relationship between deterioration in FEV1 and SGRQ did not differ in different world regions, but patients in Asia-Pacific showed a large improvement in score that was unrelated to FEV1 change.

Conclusions

In addition to treatment effects, health status changes in clinical trials may be influenced by demographic and disease-related factors. Deterioration in health status appears to be fastest in older persons and those with severe airflow limitation.

Trial Registration

ClinicalTrials.gov: NCT00268216

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability in all its stages, and death in patients with moderate or severe obstruction. At present, COPD is suboptimally managed; current health is often not measured properly and hardly taken into account in management plans, and the future risk for patients with regard to health status and quality of life is not being evaluated. This review addresses the effect of COPD on the lives of patients and examines ways in which existing assessment tools meet physicians’ needs for a standardized, simple method to measure consistently the full impact of COPD on patients in routine clinical practice. Current assessment of COPD severity tends to focus on airflow limitation, but this does not capture the full impact of the disease and is not well correlated with patient perception of symptoms and health-related quality of life. Qualitative studies have demonstrated that patients usually consider COPD impact in terms of frequency and severity of symptoms, and physical and emotional wellbeing. However, patients often have difficulty expressing their disease burden and physicians generally have insufficient time to collect this information. Therefore, it is important that methods are implemented to help generate a more complete understanding of the impact of COPD. This can be achieved most efficiently using a quick, reliable, and standardized measure of disease impact, such as a short questionnaire that can be applied in daily clinical practice. Questionnaires are precision instruments that contribute sensitive and specific information, and can potentially help physicians provide optimal care for patients with COPD. Two short, easy-to-use, specific measures, ie, the COPD Assessment Test and the Clinical COPD Questionnaire, enable physicians to assess patients’ health status accurately and improve disease management. Such questionnaires provide important measurements that can assist primary care physicians to capture the impact of COPD on patients’ daily lives and wellbeing, and improve long-term COPD management.

The accuracy of the exposure assessment is a critical factor in epidemiological investigations of pesticide exposures and health in agricultural populations. However, few studies have been conducted to evaluate questionnaire-based exposure metrics. The Agricultural Health Study (AHS) is a prospective cohort study of pesticide applicators who provided detailed questionnaire information on their use of specific pesticides. A field study was performed for a subset of the applicators enrolled in the AHS to assess a pesticide exposure algorithm through comparison of algorithm intensity scores with measured exposures. Pre- and post-application urinary biomarker measurements were made for 2,4-D (n = 69) and chlorpyrifos (n = 17) applicators. Dermal patch, hand wipe, and personal air samples were also collected. Intensity scores were calculated using information from technician observations and an interviewer-administered questionnaire. Correlations between observer and questionnaire intensity scores were high (Spearman r = 0.92 and 0.84 for 2,4-D and chlorpyrifos, respectively). Intensity scores from questionnaires for individual applications were significantly correlated with post-application urinary concentrations for both 2,4-D (r = 0.42, p < 0.001) and chlorpyrifos (r = 0.53, p = 0.035) applicators. Significant correlations were also found between intensity scores and estimated hand loading, estimated body loading, and air concentrations for 2,4-D applicators (r-values 0.28–0.50, p-values<0.025). Across all chlorpyrifos applicators, body loading measurements were significantly correlated with intensity scores from questionnaires (r=0.50, p=0.039) but not from observations (r=0.18, p=0.482). Dermal measures for in-furrow granular applications of chlorpyrifos (n = 12) were very low and not correlated with intensity scores. A linear regression model indicated that the algorithm factors for individual applications explained 24% of the variability in post-application urinary 2,4-D concentration, which increased to 60% when the pre-application urine concentration was included. The results of the measurements support the use of the algorithm for estimating questionnaire-based exposure intensities in the AHS for liquid pesticide products. Refinement of the algorithm may be possible using the results from this and other measurement studies.

Background

The long-term efficacy and safety of aclidinium bromide, a novel, long-acting muscarinic antagonist, were investigated in patients with moderate to severe chronic obstructive pulmonary disease (COPD).

Methods

In two double-blind, 52-week studies, ACCLAIM/COPD I (n = 843) and II (n = 804), patients were randomised to inhaled aclidinium 200 μg or placebo once-daily. Patients were required to have a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity ratio of ≤70% and FEV1 <80% of the predicted value. The primary endpoint was trough FEV1 at 12 and 28 weeks. Secondary endpoints were health status measured by St George's Respiratory Questionnaire (SGRQ) and time to first moderate or severe COPD exacerbation.

Results

At 12 and 28 weeks, aclidinium improved trough FEV1 versus placebo in ACCLAIM/COPD I (by 61 and 67 mL; both p < 0.001) and ACCLAIM/COPD II (by 63 and 59 mL; both p < 0.001). More patients had a SGRQ improvement ≥4 units at 52 weeks with aclidinium versus placebo in ACCLAIM/COPD I (48.1% versus 39.5%; p = 0.025) and ACCLAIM/COPD II (39.0% versus 32.8%; p = 0.074). The time to first exacerbation was significantly delayed by aclidinium in ACCLAIM/COPD II (hazard ratio [HR] 0.7; 95% confidence interval [CI] 0.55 to 0.92; p = 0.01), but not ACCLAIM/COPD I (HR 1.0; 95% CI 0.72 to 1.33; p = 0.9). Adverse events were minor in both studies.

Conclusion

Aclidinium is effective and well tolerated in patients with moderate to severe COPD.

Trial registration

ClinicalTrials.gov: NCT00363896 (ACCLAIM/COPD I) and NCT00358436 (ACCLAIM/COPD II).

Background

Interactions between spirometry and patient-reported outcomes in COPD are not well understood. This systematic review and study-level analysis investigated the relationship between changes in FEV1 and changes in health status with bronchodilator therapy.

Methods

Six databases (to October 2009) were searched to identify studies with long-acting bronchodilator therapy reporting FEV1 and health status, dyspnoea or exacerbations. Mean and standard deviations of treatment effects were extracted for each arm of each study. Relationships between changes in trough FEV1 and outcomes were assessed using correlations and random-effects regression modelling. The primary outcome was St George's Respiratory Questionnaire (SGRQ) total score.

Results

Thirty-six studies (≥3 months) were included. Twenty-two studies (23,654 patients) with 49 treatment arms each contributing one data point provided SGRQ data. Change in trough FEV1 and change in SGRQ total score were negatively correlated (r = -0.46, p < 0.001); greater increases in FEV1 were associated with greater reductions (improvements) in SGRQ. The correlation strengthened with increasing study duration from 3 to 12 months. Regression modelling indicated that 100 mL increase in FEV1 (change at which patients are more likely to report improvement) was associated with a statistically significant reduction in SGRQ of 2.5 (95% CI 1.9, 3.1), while a clinically relevant SGRQ change (4.0) was associated with 160.6 (95% CI 129.0, 211.6) mL increase in FEV1. The association between change in FEV1 and other patient-reported outcomes was generally weak.

Conclusions

Our analyses indicate, at a study level, that improvement in mean trough FEV1 is associated with proportional improvements in health status.

Background

Researchers at the Food and Drug Administration (FDA)/Center for Device and Radiological Health/Office of Science and Engineering Laboratories have been exploring the concept of model-based engineering as a means for improving the quality of medical device software. Insulin pumps were chosen as a research subject because their design provides the desired degree of research complexity and these types of devices present an ongoing regulatory challenge.

Methods

Insulin pump hazards and their contributing factors are considered in the context of a highly abstract generic insulin infusion pump (GIIP) model. Hazards were identified by consulting with manufacturers, pump users, and clinicians; by reviewing national and international standards and adverse event reports collected by the FDA; and from workshops sponsored by Diabetes Technology Society. This information has been consolidated in tabular form to facilitate further community analysis and discussion.

Results

A generic insulin infusion pump model architecture has been established. A fairly comprehensive hazard analysis document, corresponding to the GIIP model, is presented in this article.

Conclusions

We believe that this work represents the genesis of an insulin pump safety reference standard upon which future insulin pump designs can be based to help ensure a basic level of safety. More interaction with the diabetes community is needed to assure the quality of this safety modeling process.

Diabetes Technology Society facilitated a second meeting of insulin pump experts at Mills-Peninsula Health Services, San Mateo, California on November 4, 2009, at the request of the Food and Drug Administration, Center for Devices and Radiological Health, Office of Science and Engineering Laboratories. The first such meeting was held in Bethesda, Maryland, on November 12, 2008. The group of physicians, nurses, diabetes educators, and engineers from across the United States discussed safety issues in insulin pump therapy and recommended adjustments to current insulin pump design and use to enhance overall safety. The meeting discussed safety issues in the context of pump operation; software; hardware; physical structure; electrical, biological, and chemical considerations; use; and environment from engineering, medical, nursing, and pump/user perspectives. There was consensus among meeting participants that insulin pump designs have made great progress in improving the quality of life of people with diabetes, but much more remains to be done.

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide. Developments in the understanding of COPD have led to standard guidelines for diagnosis, treatment, and spirometry assessments, which have in turn influenced trial designs and inclusion criteria. Substantial clinical evidence has been gained from clinical trials and supports a positive approach to COPD management. However, there appear to be changing trends in recent trials. Large bronchodilator studies have reported lower improvements in trough forced expiratory volume in 1 second (FEV1) values versus placebo than were observed in earlier studies, while the rate of FEV1 decline seems to be lower in more recent trials. In addition, recent evidence has called into question the usefulness of bronchodilator reversibility testing as a trial inclusion criterion. Baseline patient populations and use of concomitant medications have also changed over recent years due to increased treatment options. The impact of these many variables on clinical trial results is explored, with a particular focus on changes in inclusion criteria and patient baseline demographics.

Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis.