The effect of aclidinium bromide on daily respiratory symptoms of COPD, measured using the Evaluating Respiratory Symptoms in COPD (E-RS: COPD) diary: pooled analysis of two 6-month Phase III studies.

BACKGROUND: Reducing the severity of respiratory symptoms is a key goal in the treatment of chronic obstructive pulmonary disease (COPD). We evaluated the effect of aclidinium bromide 400 μg twice daily (BID) on respiratory symptoms, assessed using the Evaluating Respiratory Symptoms in COPD (E-RS(™): COPD) scale (formerly EXACT-RS). METHODS: Data were pooled from the aclidinium 400 μg BID and placebo arms of two 24-week, double-blind, randomized Phase III studies evaluating aclidinium monotherapy (ATTAIN) or combination therapy (AUGMENT COPD I) in patients with moderate to severe airflow obstruction. Patients were stratified by Global initiative for chronic Obstructive Lung Disease (GOLD) Groups A-D. Change from baseline in E-RS scores, proportion of responders (patients achieving pre-defined improvements in E-RS scores), and net benefit (patients who improved minus patients who worsened) were analyzed. RESULTS: Of 1210 patients, 1167 had data available for GOLD classification. Mean (standard deviation) age was 63.2 (8.6) years, 60.7 % were male, and mean post-bronchodilator forced expiratory volume in 1 s was 54.4 % predicted. Compared with placebo, aclidinium 400 μg BID significantly improved RS-Total (2.38 units vs 0.79 units, p < 0.001) and domain scores (all p < 0.001) at Week 24, and doubled the likelihood of being an RS-Total score responder (p < 0.05), irrespective of GOLD group. The net benefit for RS-Total (Overall: 56.9 % vs 19.4 %; A + C: 65.7 % vs 6.3 %; B + D: 56.0 % vs 20.8 %, for aclidinium 400 μg BID and placebo respectively; all p < 0.05) and domain scores (all p < 0.05) was significantly greater with aclidinium compared with placebo, in both GOLD Groups A + C and B + D. CONCLUSIONS: Aclidinium 400 μg BID significantly improved respiratory symptoms regardless of the patients' level of symptoms at baseline. Net treatment benefit was similar in patients with low or high levels of symptoms. TRIAL REGISTRATION: ATTAIN (ClinicalTrials.gov identifier: NCT01001494 ) and AUGMENT COPD I (ClinicalTrials.gov identifier: NCT01437397 )

The vegetation history of an Amazonian domed peatland

The peatland pole forests of the Pastaza-Marañón Foreland Basin (PMFB), Peru, are the most carbon-dense ecosystems known in Amazonia once below ground carbon stores are taken into account. Here we present the first multiproxy palaeoenvironmental record including pollen data from one of these peatlands, San Jorge in northern Peru, supported by an age model based on radiocarbon and 210Pb dating. The pollen data indicate that vegetation changes during the early phases of peat initiation resulted from autogenic succession in combination with fluvial influence. The overall pattern of vegetation change is not straightforward: the record does not reflect a process of unidirectional, progressive terrestrialization, but includes a reversal in the succession and vegetation transitions, which omit predicted successional phases. This complexity is similar to that seen in the only other existing pollen record from a PMFB peatland, at Quistococha, but contrasts with peat records from Panama and Southeast Asia where successional patterning appears more predictable. Our dating results provide the first evidence from a PMFB peatland that peat accumulation may have been discontinuous, with evidence for reduced rates of peat accumulation, or a possible hiatus, around 1300–400 cal yr BP. An ecological shift from open lake to palm swamp occurs at this time, possibly driven by climatic change. The pollen data indicate that the present pole forest vegetation at San Jorge began to assemble c. 200–150 cal yr BP. Given this young age, it is likely that the pole forest at this site remains in a state of transition

Stage 1 Development of a Patient Reported Experience Measure (PREM) for Chronic Obstructive Pulmonary Disease (COPD)

The study aimed to explore patients’ experience of living with COPD and their perspective of their community health care for COPD to extract affective responses in order to develop potential items for a patient reported experience measure (PREM) for Chronic Obstructive Pulmonary Disease (COPD). Qualitative face-face interviews were conducted, in the community, with 64 patients with COPD recruited from General Practices and Breath-Easy community groups in the Outer North East, East and City, London and Essex, UK. A two phase analysis of the qualitative data was conducted to identify themes arising from patients’ description of living with COPD and their perceptions of their community health care and subsequently the affective responses underlying the themes raised by patients, which gave emotional colour to the themes, bringing the thematic analysis closer to the subjective patient experience. Five themes were identified from the interview data: ‘Journey to diagnosis’; ‘Smoking’; ‘Usual care’; ‘My everyday life’; and ‘Exacerbations’. Twenty affective responses were identified and categorised as either ‘negative’, ‘positive’ or ‘bivalent’. ‘Frustration’, a negative affective response was prevalent in four themes. ‘Gratitude’, ‘hope’ and ‘happiness/enjoyment’ were among the more positive responses more prevalent across several themes. By conducting a novel two-way analysis (thematic and affective) it was possible to identify themes and affective responses that were aligned to those themes. This enabled the development of 38 COPD specific experience items to take forward for further testing including item reduction and validity and reliability in the next stage of the PREM development

A mindfulness-based intervention to increase resilience to stress in university students (the Mindful Student Study): a pragmatic randomised controlled trial

Background More young people are going to university, but there is concern about an increasing demand for student mental health services. We designed a pragmatic randomised controlled trial to test the hypothesis that providing mindfulness courses to university students would promote their resilience to stress. Methods University of Cambridge students without severe mental illness or crisis (self-assessed) were remotely randomised to join an 8-week mindfulness course adapted for university students (MSS), or to mental health support as usual (SAU). The primary outcome was self-reported psychological distress during the examination period measured using the Clinical Outcomes in Routine Evaluation Outcome Measure. Main outcome intention-to-treat analysis was masked to allocation. Trial registration: ACTRN12615001160527 (complete). Findings In total, 616 students were randomised (circa 3% of all students; 309 to MSS, 307 to SAU); 74% completed the primary outcome measure; 65% of the MSS arm participants completed at least half of the MSS course. MSS reduced distress scores during the exam period compared with SAU (β=-0.44, 95%CI -0.60 to -0.29; p < 0.0001); 57% of SAU participants had distress scores above an accepted clinical threshold level compared with 37% of MSS participants. On average, six students needed to be offered the MSS course to prevent one from experiencing clinical levels of distress (number needed to treat 6, 95%CI 4 to 10). SAU distress worsened over the year whereas MSS scores improved after the course and were maintained during exams. Active monitoring revealed no adverse reactions related to self-harm, suicidality or harm to others. Interpretation The main limitation of this trial is the lack of control for non-specific effects. However, the provision of mindfulness training appears an effective component of a wider student mental health strategy. Funding University of Cambridge and NIHR Collaboration for Leadership in Applied Health Research and Care East of England.University of Cambridge and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care East of England

Potassium deficiency decreases the capacity for urea synthesis and markedly increases ammonia in rats

Our study provides novel findings of experimental hypokalemia reducing urea cycle functionality and thereby severely increasing plasma ammonia. This is pathophysiologically interesting because plasma ammonia increases during hypokalemia by a hitherto unknown mechanism, which may be particular important in relation to the unexplained link between hypokalemia and hepatic encephalopathy. Potassium deficiency decreases gene expression, protein synthesis, and growth. The urea cycle maintains body nitrogen homeostasis including removal of toxic ammonia. Hyperammonemia is an obligatory trait of liver failure, increasing the risk for hepatic encephalopathy, and hypokalemia is reported to increase ammonia. We aimed to clarify the effects of experimental hypokalemia on the in vivo capacity of the urea cycle, on the genes of the enzymes involved, and on ammonia concentrations. Female Wistar rats were fed a potassium-free diet for 13 days. Half of the rats were then potassium repleted. Both groups were compared with pair- and free-fed controls. The following were measured: in vivo capacity of urea-nitrogen synthesis (CUNS); gene expression (mRNA) of urea cycle enzymes; plasma potassium, sodium, and ammonia; intracellular potassium, sodium, and magnesium in liver, kidney, and muscle tissues; and liver sodium/potassium pumps. Liver histology was assessed. The diet induced hypokalemia of 1.9 ± 0.4 mmol/L. Compared with pair-fed controls, the in vivo CUNS was reduced by 34% (P < 0.01), gene expression of argininosuccinate synthetase 1 (ASS1) was decreased by 33% (P < 0.05), and plasma ammonia concentrations were eightfold elevated (P < 0.001). Kidney and muscle tissue potassium contents were markedly decreased but unchanged in liver tissue. Protein expressions of liver sodium/potassium pumps were unchanged. Repletion of potassium reverted all the changes. Hypokalemia decreased the capacity for urea synthesis via gene effects. The intervention led to marked hyperammonemia, quantitatively explainable by the compromised urea cycle. Our findings motivate clinical studies of patients with liver disease

Development of the chronic obstructive pulmonary disease morning symptom diary (COPD-MSD).

BACKGROUND: The morning tends to be the most difficult time of day for many patients with chronic obstructive pulmonary disease (COPD) when symptoms can limit one's ability to perform even simple activities. Morning symptoms have been linked to higher levels of work absenteeism, thereby increasing the already substantial economic burden associated with COPD. A validated patient-reported outcome (PRO) instrument designed to capture morning symptoms will allow for a more comprehensive approach to the evaluation of treatment benefit in COPD clinical trials. METHODS: A qualitative interview study was conducted among a sample of symptomatic adults with COPD. Concept elicitation interviews (n = 35) were conducted to identify COPD morning symptoms, followed by cognitive interviews (n = 21) to ensure patient comprehension of the items, instructions and response options of the draft COPD Morning Symptom Diary (COPD-MSD). All interview transcript data were coded using ATLAS.ti software for content analysis. RESULTS: Mean age of the concept elicitation and cognitive interview sample was 65.0 years (±7.5) and 62.3 years (±8.3), respectively. The study sample represented the full range of COPD severity (Global Initiative for Chronic Lung Disease [GOLD] classifications I-IV) and included a mix of racial backgrounds, employment status and educational achievement. During the concept elicitation interviews, the three most frequently reported morning symptoms were shortness of breath (n = 35/35; 100 %), phlegm/mucus (n = 31/35; 88.6 %), and cough (n = 30/35; 85.7 %). A group of clinical and instrument development experts convened to review the concept elicitation data and develop the initial 32-item draft COPD-MSD. Cognitive interviews indicated subjects found the draft COPD-MSD to be comprehensive, clear, and easy to understand. The COPD-MSD underwent minor editorial revisions and streamlining based on cognitive interviews and input from the experts to yield the final 19-item daily diary. CONCLUSIONS: This study supports the content validity of the new COPD-MSD and positions the diary for quantitative psychometric testing

What is macroecology?

The symposium 'What is Macroecology?' was held in London on 20 June 2012. The event was the inaugural meeting of the Macroecology Special Interest Group of the British Ecological Society and was attended by nearly 100 scientists from 11 countries. The meeting reviewed the recent development of the macroecological agenda. The key themes that emerged were a shift towards more explicit modelling of ecological processes, a growing synthesis across systems and scales, and new opportunities to apply macroecological concepts in other research fields

Performance of Glass Woven Fabric Composites with Admicellar-Coated Thin Elastomeric Interphase

Adequate stress transfer between the inorganic reinforcement and surrounding polymeric matrix is essential for achieving enhanced structural integrity and extended lifetime performance of fiber-reinforced composites. The insertion of an elastomeric interlayer helps increase the stress-transfer capabilities across the fiber/matrix interface and considerably reduces crack initiation phenomena at the fiber ends. In this study, admicellar polymerization is used to modify the fiber/matrix interface in glass woven fabric composites by forming thickness-controlled poly(styrene-co-isoprene) coatings. These admicellar interphases have distinct characteristics (e.g., topology and surface coverage) depending on the surfactant/monomer (S/M) ratios used during the polymerization reaction. Overall, the admicellar coatings have a positive effect on the mechanical response of resin transfer molded (RTM), E-glass/epoxy parts. For instance, ultimate tensile strength (UTS) of composites with admicellar sizings improved 50 to 55% over the control desized samples. Interlaminar shear strength (ILSS) also showed increases ranging from 18 to 38% over the same control group. Interestingly, the flexural properties of these composites proved sensitive to the type of interphase formed for various admicellar polymerization conditions. Higher surface coverage and film connectedness in admicellar polymeric sizings are observed to enhance stress transfer at the interfacial region.Ye

Design of Experiments for Screening

The aim of this paper is to review methods of designing screening experiments, ranging from designs originally developed for physical experiments to those especially tailored to experiments on numerical models. The strengths and weaknesses of the various designs for screening variables in numerical models are discussed. First, classes of factorial designs for experiments to estimate main effects and interactions through a linear statistical model are described, specifically regular and nonregular fractional factorial designs, supersaturated designs and systematic fractional replicate designs. Generic issues of aliasing, bias and cancellation of factorial effects are discussed. Second, group screening experiments are considered including factorial group screening and sequential bifurcation. Third, random sampling plans are discussed including Latin hypercube sampling and sampling plans to estimate elementary effects. Fourth, a variety of modelling methods commonly employed with screening designs are briefly described. Finally, a novel study demonstrates six screening methods on two frequently-used exemplars, and their performances are compared